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Baylor College of Medicine , located in the Texas Medical Center in Houston, Texas, US, is a health science university. It includes a medical school, Baylor College of Medicine; the Graduate School of Biomedical science; the School of Allied Health science; and the National School of Tropical Medicine. The school, located in the middle of the world's largest medical center, is part owner of Baylor St. Luke's Medical Center, part of the CHI St. Luke's Health system, and has hospital affiliations with: Harris Health System, Texas Children's Hospital, The University of Texas MD Anderson Cancer Center, Memorial Hermann - The Institute for Rehabilitation and Research, Menninger Clinic, the Michael E. DeBakey Veterans Affairs Medical Center and Children's Hospital of San Antonio.The medical school has been consistently considered in the top-tier of programs in the country, and is particularly noted for having the lowest tuition among all private medical schools in the US. Its Graduate School of Biomedical science is among the top 30 graduate schools in the United States. Within the School of Allied Health science, the nurse anesthesia ranks 5th and the physician assistant program ranks 6th. A program in Orthotics and Prosthetics began in 2013, with 18 students in the first class. The National School of Tropical Medicine is the only school in the nation dedicated exclusively to patient care, research, education and policy related to neglected tropical diseases.On June 21, 2010, Dr. Paul Klotman was named as the new President and CEO of the Baylor College of Medicine. In January 2014, the College and CHI St. Luke's became joint owners of Baylor St. Luke's Medical Center. Wikipedia.


Doukas D.J.,University of Louisville | McCullough L.B.,Baylor College of Medicine | Wear S.,State University of New York at Buffalo
Academic Medicine | Year: 2012

Medical education accreditation organizations require medical ethics and humanities education to develop professionalism in medical learners, yet there has never been a comprehensive critical appraisal of medical education in ethics and humanities. The Project to Rebalance and Integrate Medical Education (PRIME) I Workshop, convened in May 2010, undertook the first critical appraisal of the definitions, goals, and objectives of medical ethics and humanities teaching. The authors describe assembling a national expert panel of educators representing the disciplines of ethics, history, literature, and the visual arts. This panel was tasked with describing the major pedagogical goals of art, ethics, history, and literature in medical education, how these disciplines should be integrated with one another in medical education, and how they could be best integrated into undergraduate and graduate medical education. The authors present the recommendations resulting from the PRIME I discussion, centered on three main themes. The major goal of medical education in ethics and humanities is to promote humanistic skills and professional conduct in physicians. Patient-centered skills enable learners to become medical professionals, whereas critical thinking skills assist learners to critically appraise the concept and implementation of medical professionalism. Implementation of a comprehensive medical ethics and humanities curriculum in medical school and residency requires clear direction and academic support and should be based on clear goals and objectives that can be reliably assessed. The PRIME expert panel concurred that medical ethics and humanities education is essential for professional development in medicine. © 2012 Association American Medical Colleges. Unauthorized reproduction of the artical is prohibited. Source


Clayton E.W.,Vanderbilt University | McGuire A.L.,Baylor College of Medicine
Genetics in Medicine | Year: 2012

Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing "consensus," which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue. ©American College of Medical Genetics and Genomics. Source


Magoulas P.L.,Baylor College of Medicine | El-Hattab A.W.,University of Missouri
Orphanet Journal of Rare Diseases | Year: 2012

Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals. Disease name and synonyms. Chromosome 15q24 deletion syndrome. 15q24 deletion syndrome. 15q24 microdeletion syndrome. © 2012 Magoulas and El-Hattab. Source


Marsh L.,Baylor College of Medicine
Current Neurology and Neuroscience Reports | Year: 2013

Depressive disturbances are common in patients with Parkinson's disease (PD) and influence many other clinical aspects of the disease. In addition to causing inherent emotional distress, depressive disorders negatively impact quality of life, motor and cognitive deficits, functional disability, and other psychiatric comorbidities in patients with PD. Knowledge of the pathophysiology of PD depression remains limited. However, clinical studies demonstrate the efficacy of medications and psychotherapies for PD depression, underscoring the importance of their timely detection and concerted management. © 2013 Springer Science+Business Media New York (outside the USA). Source


Garber A.J.,Baylor College of Medicine
Heart Failure Clinics | Year: 2012

Epidemiologic evidence indicates that abnormal elevations in glycemia and lipidemia after a meal, termed postprandial dysmetabolism, are linked with increased risk of morbidity and mortality due to cardiovascular disease in individuals with or without type 2 diabetes. Both postprandial hyperglycemia and postprandial hyperlipidemia are independently associated with deteriorating endothelial function and vascular damage, which are likely mediated by increased oxidative stress and are more pronounced when both derangements coexist. Pharmacotherapies that target postprandial hyperglycemia and/or postprandial dyslipidemia are likely to improve endothelial function, which may have positive implications for cardiovascular outcomes. © 2012 Elsevier Inc. Source


Abraham N.S.,Baylor College of Medicine
Current Opinion in Gastroenterology | Year: 2012

PURPOSE OF REVIEW: This review summarizes adverse effects of potential proton pump inhibitors (PPIs), including nutritional deficiencies (B12 and magnesium), rebound acid hypersecretion, acute interstitial nephritis, gastric carcinoid tumor, cardiovascular risk with clopidogrel and PPI coprescription, bone fractures, enteric infections and pneumonia. An epidemiologic framework is applied to assess clinical relevance and reinforce best practice recommendations. RECENT FINDINGS: The evidence for PPI adverse events is limited by the absence of Level 1 (randomized controlled trial) studies. The best evidence supports Clostridium difficile and bone fractures in susceptible populations. A substantial reduction in gastrointestinal bleeding risk without increase in cardiovascular events was observed in the COGENT trial when clopidogrel was coprescribed with omeprazole. The risk of pneumonia is inconsistent, and although acute interstitial nephritis, nutritional deficiencies (including B12 and hypomagnesemia), gastric carcinoid and rebound hyperacidity are biologically plausible, studies have failed to demonstrate supportive clinical relevance. SUMMARY: Prescribe PPI for robust indications only. Strong data supporting risk of adverse events are lacking; however, exercise caution in the elderly and in patients with other risk factors for bone fractures or C. difficile infection. © 2012 Wolters Kluwer Health Lippincott Williams & Wilkins. Source


Kyle W.B.,Baylor College of Medicine
Congenital Heart Disease | Year: 2012

Pulmonary hypertension (PH) is a complex condition with a broad range of etiologies that result in a common outcome-elevated pulmonary arterial pressure. For the pediatric cardiologist, this entity provides a manifest demonstration of the interrelationship of cardiac and pulmonary physiology. A thoughtful approach must be applied to each patient with PH in order to achieve a thorough understanding of the nature of disease and to proceed with individualized therapy in an appropriate and timely manner. This article aims to provide a clinically relevant, practical review of current literature related to PH in patients with congenital heart disease, including the causes, diagnostic considerations, and an overview of management. © 2012 Wiley Periodicals, Inc. Source


Wefel J.S.,University of Houston | Noll K.R.,University of Houston | Scheurer M.E.,Baylor College of Medicine
The Lancet Oncology | Year: 2016

Impairment of neurocognitive functioning is a common result of cerebral neoplasms and treatment, although there is substantial heterogeneity in the pattern and severity of neurocognitive dysfunction across individuals and tumour types. The effects of many clinical and patient characteristics on neurocognitive functioning have been documented, but little research has been devoted to understanding the effect of genetic variation on neurocognitive outcomes in patients with brain tumours. This Review highlights preliminary evidence that suggests an association between various genes and risk of adverse neurocognitive outcomes in patients with brain tumours. Studies include genes specific to neuronal function, and those associated with more systemic cellular regulation. Related scientific literature in other disease populations is briefly discussed to indicate additional candidate genes. We consider methodological issues central to the study of neurocognitive functioning and genetic associations for patients with brain tumours, and emphasise the need for future research integrating novel investigative techniques. © 2016 Elsevier Ltd. Source


Eijsvogels T.M.H.,Liverpool John Moores University | Eijsvogels T.M.H.,Radboud University Nijmegen | Molossi S.,Baylor College of Medicine | Lee D.-C.,Iowa State University | And 2 more authors.
Journal of the American College of Cardiology | Year: 2016

Habitual physical activity and regular exercise training improve cardiovascular health and longevity. A physically active lifestyle is, therefore, a key aspect of primary and secondary prevention strategies. An appropriate volume and intensity are essential to maximally benefit from exercise interventions. This document summarizes available evidence on the relationship between the exercise volume and risk reductions in cardiovascular morbidity and mortality. Furthermore, the risks and benefits of moderate- versus high-intensity exercise interventions are compared. Findings are presented for the general population and cardiac patients eligible for cardiac rehabilitation. Finally, the controversy of excessive volumes of exercise in the athletic population is discussed. © 2016 American College of Cardiology Foundation. Source


Rosen T.,Baylor College of Medicine
Journal of Drugs in Dermatology | Year: 2012

Botanical products, including and especially green tea leaves, have a wide range of both reputed and demonstrated health benefits and have been used medicinally for thousands of years. This paper focuses on green tea catechins, principally reviewing their known biologic properties and potential mechanisms of action (MOAs). The primary objective is to discuss the proposed antiviral, antiproliferative, and immunostimulatory activity of catechins based on strong evidence from in vitro and in vivo studies conducted to date, including two preclinical in vitro studies with sinecatechins, a proprietary mixture of catechins. This review also discusses the clinical implications of catechins for the treatment of external genital and perianal warts (EGWs) and other conditions caused by human papillomavirus (HPV). While the MOA of catechins in the treatment of EGWs and other HPV-related conditions may be related to or associated with postulated or proven antiviral and immunostimulatory activity, the precise clinical significance of the various in vitro findings remains largely unknown. Copyright © 2012 Journal of Drugs in Dermatology. Source


Zheng Z.Y.,Baylor College of Medicine
Small GTPases | Year: 2012

Ras proteins are best known to function on the plasma membrane to mediate growth factor signaling. Controlling the length of time that Ras proteins stay on the plasma membrane is an effective way to properly modulate the intensity and duration of growth factor signaling. It has been shown previously that H- and N-Ras proteins in the GTP-bound state can be ubiquitylated via a K-63 linkage, which leads to endosome internalization and results in a negative-feedback loop for efficient signal attenuation. In a more recent study, two new Ras effectors have been isolated, CHMP6 and VPS4A, which are components of the ESCRT-III complex, best known for mediating protein sorting in the endosomes. Surprisingly, these molecules are required for efficient Ras-induced transformation. They apparently do so by controlling recycling of components of the Ras pathway back to the plasma membrane, thus creating a positive-feedback loop to enhance growth factor signaling. These results suggest the fates of endosomal Ras proteins are complex and dynamic - they can be either stored and/or destroyed or recycled. Further work is needed to decipher how the fate of these endosomal Ras proteins is determined. Source


Rice A.P.,Baylor College of Medicine
Wiley Interdisciplinary Reviews: RNA | Year: 2015

MicroRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are involved in many biological processes, including viral replication. In this review, the role of miRNAs and lncRNAs in human immunodeficiency virus (HIV) replication will be discussed. The review focuses on miRNAs that target cellular proteins involved in HIV replication-proteins that mediate steps in the viral life cycle, as well as proteins of the innate immune system that inhibit HIV replication. Given the large number of miRNAs encoded in the human genome, as well as the large number of cellular proteins involved in HIV replication, the number of miRNAs identified to date that affect viral replication are certainly only the 'tip of the iceberg'. The review also discusses two lncRNAs that are involved in HIV gene regulation-7SK RNA and NEAT1 RNA. 7SK RNA is involved in HIV Tat protein stimulation of RNA polymerase II elongation of the integrated provirus, while NEAT1 RNA is involved in HIV Rev protein export of incompletely spliced viral transcripts. © 2015 John Wiley & Sons, Ltd. Source


Guse K.,Baylor College of Medicine
Human gene therapy | Year: 2012

Skeletal muscle represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders and as a production platform for systemic expression of therapeutic proteins. However, adenovirus serotype 5 vectors do not efficiently transduce adult muscle tissue. Here we evaluated whether capsid modifications on adenoviral vectors could improve transduction in mature murine muscle tissue. First-generation and helper-dependent serotype 5 adenoviral vectors featuring the serotype 3 knob (5/3) showed significantly increased transduction of skeletal muscle after intramuscular injection in adult mice. Furthermore, we showed that full-length dystrophin could be more efficiently transferred to muscles of mdx mice using a 5/3-modified helper-dependent adenoviral vector. In contrast to first-generation vectors, helper-dependent adenoviral vectors mediated stable marker gene expression for at least 1 year after intramuscular injection. In conclusion, 5/3 capsid-modified helper-dependent adenoviral vectors show enhanced transduction in adult murine muscle tissue and mediate long-term gene expression, suggesting the suitability of these vectors for muscle-directed gene therapy. Source


Uncini A.,University of Chieti Pescara | Susuki K.,Baylor College of Medicine | Yuki N.,National University of Singapore
Clinical Neurophysiology | Year: 2013

In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain-Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region. © 2013 International Federation of Clinical Neurophysiology. Source


Susuki K.,Baylor College of Medicine
ASN neuro | Year: 2013

Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na+ channels) that are required for the rapid and efficient saltatory conduction of action potentials. Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon-glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease. Source


Wang S.,University of Houston | Larin K.V.,University of Houston | Larin K.V.,Baylor College of Medicine
Optics Letters | Year: 2014

We report on a noncontact low-coherence optical phase-based imaging method, termed shear wave imaging optical coherence tomography (SWI-OCT), which enables 2D depth-resolved visualization of the low-amplitude elastic wave propagation in tissue with ultrahigh frame rate. SWI-OCT is based on 1D transverse scanning of the M-mode OCT imaging that is precisely synchronized with a low-pressure short-duration air-puff loading system. This approach of scanning and data recording allows visualization of the induced tissue deformation at high frame rate. The applied phase-resolved interferometric technique, with sensitivity on the nanometer scale, makes the low-amplitude tissue displacement detectable. For the demonstration of this method, and to study its application for tissue biomechanics, we performed pilot experiments on agar phantoms and ex vivo rabbit corneas. Samples with different elastic properties can be differentiated based on the velocity of the elastic wave propagation that is directly visualized with a 25 kHz frame rate. Our results indicate that SWI-OCT has the potential to be further developed as a major technique for depthresolved high-resolution tissue elastography in vivo. © 2013 Optical Society of America. Source


Hotez P.J.,Baylor College of Medicine | Hotez P.J.,The Texas Institute | Savioli L.,World Health Organization | Fenwick A.,Imperial College London
PLoS Neglected Tropical Diseases | Year: 2012

The neglected tropical diseases (NTDs) are highly endemic but patchily distributed among the 20 countries and almost 400 million people of the Middle East and North Africa (MENA) region, and disproportionately affect an estimated 65 million people living on less than US$2 per day. Egypt has the largest number of people living in poverty of any MENA nation, while Yemen has the highest prevalence of people living in poverty. These two nations stand out for having suffered the highest rates of many NTDs, including the soil-transmitted nematode infections, filarial infections, schistosomiasis, fascioliasis, leprosy, and trachoma, although they should be recognized for recent measures aimed at NTD control. Leishmaniasis, especially cutaneous leishmaniasis, is endemic in Syria, Iran, Iraq, Libya, Morocco, and elsewhere in the region. Both zoonotic (Leishmania major) and anthroponotic (Leishmania tropica) forms are endemic in MENA in rural arid regions and urban regions, respectively. Other endemic zoonotic NTDs include cystic echinococcosis, fascioliasis, and brucellosis. Dengue is endemic in Saudi Arabia, where Rift Valley fever and Alkhurma hemorrhagic fever have also emerged. Great strides have been made towards elimination of several endemic NTDs, including lymphatic filariasis in Egypt and Yemen; schistosomiasis in Iran, Morocco, and Oman; and trachoma in Morocco, Algeria, Iran, Libya, Oman, Saudi Arabia, Tunisia, and the United Arab Emirates. A particularly noteworthy achievement is the long battle waged against schistosomiasis in Egypt, where prevalence has been brought down by regular praziquantel treatment. Conflict and human and animal migrations are key social determinants in preventing the control or elimination of NTDs in the MENA, while local political will, strengthened international and intersectoral cooperative efforts for surveillance, mass drug administration, and vaccination are essential for elimination. © 2012 Hotez et al. Source


Schaaf C.P.,Baylor College of Medicine | Schaaf C.P.,The Texas Institute
Genetics in Medicine | Year: 2014

Nicotinic acetylcholine receptors represent a family of ligand-gated ion channels that are widely expressed in the central and peripheral nervous systems. To date, 16 genes encoding subunits of mammalian nicotinic acetylcholine receptors have been identified. The various subunits form homomeric or heteromeric receptor proteins, allowing for a complex and adaptable system of nicotinic neurotransmission. Mutations of nicotinic receptor genes can cause Mendelian disorders, most importantly congenital myasthenic syndromes, multiple pterygium syndromes, and nocturnal frontal lobe epilepsies. Haploinsufficiency of CHRNA7 predisposes to neuropsychiatric phenotypes in 15q13.3 deletion syndrome. The role of various nicotinic receptor genes is also discussed for complex disorders such as addiction, schizophrenia, Alzheimer disease, and Parkinson disease.Genet Med 16 9, 649-656. © American College of Medical Genetics and Genomics. Source


Richards S.,Baylor College of Medicine
Trends in Genetics | Year: 2015

The availability of reference genome sequences, especially the human reference, has revolutionized the study of biology. However, while the genomes of some species have been fully sequenced, a wide range of biological problems still cannot be effectively studied for lack of genome sequence information. Here, I identify neglected areas of biology and describe how both targeted species sequencing and more broad taxonomic surveys of the tree of life can address important biological questions. I enumerate the significant benefits that would accrue from sequencing a broader range of taxa, as well as discuss the technical advances in sequencing and assembly methods that would allow for wide-ranging application of whole-genome analysis. Finally, I suggest that in addition to 'big science' survey initiatives to sequence the tree of life, a modified infrastructure-funding paradigm would better support reference genome sequence generation for research communities most in need. © 2015 Elsevier Ltd. Source


Zhi D.,University of Alabama at Birmingham | Chen R.,Baylor College of Medicine
PLoS ONE | Year: 2012

Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work. © 2012 Zhi, Chen. Source


Blumenthal-Barby J.S.,Baylor College of Medicine | Krieger H.,University of Houston
Medical Decision Making | Year: 2015

Background. The role of cognitive biases and heuristics in medical decision making is of growing interest. The purpose of this study was to determine whether studies on cognitive biases and heuristics in medical decision making are based on actual or hypothetical decisions and are conducted with populations that are representative of those who typically make the medical decision; to categorize the types of cognitive biases and heuristics found and whether they are found in patients or in medical personnel; and to critically review the studies based on standard methodological quality criteria. Method. Data sources were original, peer-reviewed, empirical studies on cognitive biases and heuristics in medical decision making found in Ovid Medline, PsycINFO, and the CINAHL databases published in 1980-2013. Predefined exclusion criteria were used to identify 213 studies. During data extraction, information was collected on type of bias or heuristic studied, respondent population, decision type, study type (actual or hypothetical), study method, and study conclusion. Results. Of the 213 studies analyzed, 164 (77%) were based on hypothetical vignettes, and 175 (82%) were conducted with representative populations. Nineteen types of cognitive biases and heuristics were found. Only 34% of studies (n = 73) investigated medical personnel, and 68% (n = 145) confirmed the presence of a bias or heuristic. Each methodological quality criterion was satisfied by more than 50% of the studies, except for sample size and validated instruments/questions. Limitations are that existing terms were used to inform search terms, and study inclusion criteria focused strictly on decision making. Conclusions. Most of the studies on biases and heuristics in medical decision making are based on hypothetical vignettes, raising concerns about applicability of these findings to actual decision making. Biases and heuristics have been underinvestigated in medical personnel compared with patients. © The Author(s) 2014. Source


Eknoyan G.,Baylor College of Medicine
Seminars in Dialysis | Year: 2012

The endeavor to understand the workings of the human body is as old as civilization; but it is in the intellectual movement of the Renaissance that its actual scientific study began in earnest and has not ceased growing since then. It was in the 16th century that the study of organs was launched and with it that of the kidney, which was then conceived as an accessory organ to clear the excess water ingested with food. The study of the structural basis of kidney function was launched by Bartolomeo Eustachio (1514-1574); the elements of its physiology and pathology were promulgated by Jean Fernel (1497-1558), and that of the chemical study of urine and of the principal cause of kidney disease then, calculi, instigated by Joan Baptista Van Helmont (1577-1644). The methodological approaches of these and their contemporary investigators, which were crystallized and formulated by Francis Bacon (1561-1626), opened the gates of the Scientific Revolution that followed in the 17th century, beginning with that of describing the circulation in 1628 by William Harvey (1564-1657) that would finally free the kidney from the shackles imposed on it as a mere accessory organ to the liver in Galen's physiology. © 2012 Wiley Periodicals, Inc.. Source


Lapillonne A.,University of Paris Descartes | Lapillonne A.,Baylor College of Medicine | Griffin I.J.,University of California at Davis
Journal of Pediatrics | Year: 2013

Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the influence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have significant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post-term has no significant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization significantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance. Source


Lee L.J.,University of Houston | Lupo P.J.,Baylor College of Medicine
Pediatric Cardiology | Year: 2013

Although a previous metaanalysis indicated that maternal smoking during pregnancy increased the risk of congenital heart defects (CHD) in offspring, the effect of smoking on individual CHD subtypes was not determined. Because CHDs are anatomically, clinically, epidemiologically, and developmentally heterogeneous, the authors conducted a systematic review and metaanalysis of the association between maternal smoking during pregnancy and the risk of CHDs, including CHD subtypes among offspring. Two types of summary relative risk (RR) estimates (any smoking vs no smoking and increasing categories of smoking, i.e., light, medium, and heavy) were calculated for CHDs as a group and for a number of CHD subtypes using both fixed- and random-effects models. Random effects estimates were reported if there was evidence of heterogeneity among the studies. Consistent with the previous metaanalysis, the authors observed a positive association between maternal smoking during pregnancy and the risk of CHDs as a group (RR, 1.11; 95 % confidence interval [CI], 1.02-1.21; number of cases [n] = 18,282). Additionally, women who smoked during pregnancy were more likely to have a child with 12 (71 %) of 17 CHD subtypes analyzed compared with women who did not smoke. The highest risk was for septal defects as a group (RR, 1.44; 95 % CI, 1.16-1.79; n = 2977). The evidence of dose response was observed for septal defects as a group, atrial septal defects, and atrioventricular septal defects. This systematic review and metaanalysis suggests that maternal smoking is modestly associated with an increased risk of CHDs and some CHD subtypes. © 2012 Springer Science+Business Media, LLC. Source


Gramatges M.M.,Baylor College of Medicine
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

A 16-year-old female diagnosed with acute myeloid leukemia (AML) with inversion 16, a favorable prognostic indicator, has persistent neutropenia after her fourth cycle of dose-intensified chemotherapy. She was recently admitted for treatment with empiric antibiotics for febrile neutropenia, and an astute intern noticed a new lesion on her right foot with a dark necrotic center. A biopsy of the lesion showed spreading hyphae, consistent with Aspergillus. Despite her compliance with fluconazole fungal prophylaxis, computed tomography imaging revealed disseminated aspergillosis involving her lungs, liver, and kidneys. Amphotericin was started, but systemic fungemia and the development of multiorgan failure resulted in her death. You are in the difficult position of having to explain to her parents that she died in remission from chemotherapy-related complications. All of those involved in this unfortunate scenario wonder if something could have been done to prevent her death. Source


Friedman E.M.,Baylor College of Medicine
New England Journal of Medicine | Year: 2016

Successful removal of a foreign body from the external auditory canal or the nasal passage depends on the size, shape, texture, and composition of the object, the length of time the object has been lodged, the patient's anatomy, the presence or absence of infection, and the number and nature of any previous attempts at removal. The likelihood of success for retrieval in an outpatient setting decreases with each additional attempt. It is important to keep the patient still by means of passive restraint or sedation and to use appropriate equipment with excellent illumination. Experience by the operator in the removal of foreign objects will increase confidence, improve technical skills, and increase the likelihood of success. © 2016 Massachusetts Medical Society. All rights reserved. Source


There have been hundreds of H. pylori eradication trials and yet doubt remains regarding the best regimen for any situation. With most regimens, treatment failure is the result of resistance to one component (e.g., clarithromycin). Thus, if one knows the treatment success with two groups (all with susceptible and with all with resistant infections), one can construct a normogram that provides a reliable estimate of the outcome at any prevalence of resistance. The same data can be used to estimate the prevalence of resistance in any clinical trial, the effects duration of therapy, and effects of any procedures to improve outcome (e.g., increasing the proton-pump inhibitor dose, the duration of therapy, etc.). Because the Hp-normo-graham can reliably predict the outcome of clinical trials, it can also obviate the need for many clinical trials in populations where resistance is common. Here, we illustrate the construction of Hp-normo-graham and its use to describe the effects of resistance, duration of therapy, attempts to improve results, and the prevalence of resistance and to obviate the need for many clinical trials. © 2016 John Wiley & Sons Ltd. Source


Bauer V.P.,Baylor College of Medicine
Clinics in Colon and Rectal Surgery | Year: 2013

Evidence-based perioperative care plans after colorectal surgery serve to improve quality outcome, decrease complications, and reduce medical cost. The benefits of routine nasogastric decompression and prolonged enteral restriction after bowel resection are not supported in this new era of evidence-based surgical care. Prophylactic nasogastric decompression fails to improve bowel function, length of stay, and prevent anastomotic leak, wound complications (infection, fascial dehiscence, incisional hernia), pulmonary complications (atelectasis, aspiration, pneumonia, fever, pharyngolaryngitis), and abdominal discomfort (distension, nausea, vomiting). Patients have earlier return of bowel function without the use of a nasogastric tube (NGT). Early refeeding within 24 hours after bowel resection is well tolerated in 80 to 90% of patients, and associated with earlier hospital discharge, decreased risk of infection, and improved postoperative hyperglycemic control. Abdominal discomfort is the most common complication observed in patients treated with early feeding and without a NGT, but does not result in higher therapeutic nasogastric intubation, postoperative ileus, aspiration, or other complications. The use of multimodal adjuncts in combination with these guidelines should be considered to improve outcome. The current literature is reviewed with suggestions for achieving better outcomes after colorectal resection. © 2013 by Thieme Medical Publishers, Inc. Source


Nasseri F.,Baylor College of Medicine | Eftekhari F.,University of Texas M. D. Anderson Cancer Center
Radiographics | Year: 2010

At imaging, the thymus appears in a variety of shapes and sizes, even in the same individual. It gradually involutes with age and may acutely shrink during periods of bodily stress. During the recovery period, it grows back to its original size or even larger, a phenomenon known as thymic rebound hyperplasia. These anatomic variations and dynamic changes appear to be the main source of confusion with pathologic conditions. In turn, these misinterpretations may lead to prolongation or alteration of the chemotherapy regimen or to unnecessary radiation therapy, biopsy, or thymectomy. Familiarity with the embryology, anatomy, and dynamic physiology of the thymus is essential to avoid unnecessary imaging or invasive procedures. Radiologists play a major role in differentiating normal thymic variants, ectopic thymic tissue, and nonneoplastic thymic conditions such as rebound hyperplasia from neoplastic conditions. Knowledge of the imaging findings of thymic tumors and their mimics may help radiologists arrive at the correct diagnosis. © RSNA, 2010. Source


Dobrev D.,University of Duisburg - Essen | Wehrens X.H.T.,Baylor College of Medicine
Circulation Research | Year: 2014

Cardiac ryanodine receptor type 2 plays a key role in excitation- contraction coupling. The ryanodine receptor type 2 channel protein is modulated by various post-translational modifications, including phosphorylation by protein kinase A and Ca2+/calmodulin protein kinase II. Despite extensive research in this area, the functional effects of ryanodine receptor type 2 phosphorylation remain disputed. In particular, the potential involvement of increased ryanodine receptor type 2 phosphorylation in the pathogenesis of heart failure and arrhythmias remains a controversial area, which is discussed in this review article. © 2014 American Heart Association, Inc. Source


Fowler J.C.,Baylor College of Medicine
Psychotherapy | Year: 2013

The treatment of suicidal individuals requires special attention to therapist interventions that promote a viable treatment alliance in the context of shared responsibilities for patient safety. Three core principles in the treatment process (alliance building, enhancing curiosity about the function of suicidal thoughts and urges, as well as enhancing experience and expression of intense emotions) are articulated and brief case vignettes are used to illuminate the principles. Results from open trails and randomized control trials involving suicidal patients are examined to support the evidence-based practice of these principles. The overarching principle undergirding the utility of the principles is a collaborative joining with the patient to decrease isolation and alienation when facing intense and overwhelming emotions. © 2013 American Psychological Association. Source


Barnes A.S.,Baylor College of Medicine | Kimbro R.T.,Rice University
Journal of General Internal Medicine | Year: 2012

BACKGROUND: Interventions to address obesity and weight loss maintenance among African Americans have yielded modest results. There is limited data on African Americans who have achieved successful longterm weight loss maintenance. OBJECTIVE: To identify a large sample of African American adults who intentionally achieved clinically significant weight loss of 10 %; to describe weight-loss and maintenance efforts of African Americans through a cross-sectional survey; to determine the feasibility of establishing a registry of African American adults who have successfully lost weight. DESIGN, SETTING, AND PARTICIPANTS: African American volunteers from the United States ≥ 18 years of age were invited to complete a cross-sectional survey about weight, weight-loss, weight-loss maintenance or regain. Participants were invited to submit contact information to be maintained in a secure registry. MAIN MEASURES: Percentage of participants who achieved long-term weight-loss maintenance reporting various dietary and physical activity strategies, motivations for and social-cognitive influences on weight loss and maintenance, current eating patterns, and selfmonitoring practices compared to African Americans who lost weight but regained it. Participants also completed the Short International Physical Activity Questionnaire. KEY RESULTS: Of 3,414 individuals screened, 1,280 were eligible and completed surveys. Ninety-percent were women. This descriptive analysis includes 1,110 women who lost weight through non-surgical means. Over 90 % of respondents had at least some college education. Twenty-eight percent of respondents were weight-loss maintainers. Maintainers lost an average of 24 % of their body weight and had maintained ≥ 10 % weight loss for an average of 5.1 years. Maintainers were more likely to limit their fat intake, eat breakfast most days of the week, avoid fast food restaurants, engage in moderate to high levels of physical activity, and use a scale to monitor their weight. CONCLUSIONS: Influences and practices differ among educated African American women who maintain weight loss compared to those who regain it. © Society of General Internal Medicine 2012. Source


Alan Harris R.,Baylor College of Medicine
Epigenetics | Year: 2013

Metastable epialleles (MEs) are mammalian genomic loci where epigenetic patterning occurs before gastrulation in a stochastic fashion leading to systematic interindividual variation within one species. Importantly, periconceptual nutritional influences may modulate the establishment of epigenetic changes, such as DNA methylation at MEs. Based on these characteristics, we exploited Infinium HumanMethylation450 BeadChip kits in a 2-tissue parallel screen on peripheral blood leukocyte and colonic mucosal DNA from 10 children without identifiable large intestinal disease. This approach led to the delineation of 1776 CpG sites meeting our criteria for MEs, which associated with 1,013 genes. The list of ME candidates exhibited overlaps with recently identified human genes (including CYP2E1 and MGMT, where methylation has been associated with Parkinson disease and glioblastoma, respectively) in which perinatal DNA methylation levels where linked to maternal periconceptual nutrition. One hundred and eighteen (11.6%) of the ME candidates overlapped with genes where DNA methylation correlated (r > 0.871; p < 0.055) with expression in the colon mucosa of 5 independent control children. Genes involved in homophilic cell adhesion (including cadherin-associated genes) and developmental processes were significantly overrepresented in association with MEs. Additional filtering of gene expression-correlated MEs defined 35 genes, associated with 2 or more CpG sites within a 10 kb genomic region, fulfilling the ME criteria. DNA methylation changes at a number of these genes have been linked to various forms of human disease, including cancers, such as asthma and acute myeloid leukemia (ALOX12), gastric cancer (EBF3), breast cancer (NAV1), colon cancer and acute lymphoid leukemia (KCNK15), Wilms tumor (protocadherin gene cluster; PCDHAs) and colorectal cancer (TCERG1L), suggesting a potential etiologic role for MEs in tumorigenesis and underscoring the possible developmental origins of these malignancies. The presented compendium of ME candidates may accelerate our understanding of the epigenetic origins of common human disorders. © 2013 Landes Bioscience. Source


Dupont H.L.,Baylor College of Medicine
Alimentary Pharmacology and Therapeutics | Year: 2016

Background Disruption of the gut microbiota through use of systemic antimicrobials or activation of the mucosal inflammatory response by pathogens can cause dysregulation of the intestinal mucosa. Aim To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea (TD). Methods A literature search was performed using the terms 'rifaximin' and 'L/105' in combination with the terms 'in vitro activity', 'diarrhea', 'microbiota' and 'gut flora'. Results Rifaximin has been traditionally identified as a nonsystemic, broad-spectrum, bactericidal antibiotic. Evidence shows that the activity of rifaximin against enteropathogens in this setting is likely enhanced by its increased solubility in the presence of bile acids in the small intestine. Results of clinical studies show that although rifaximin is efficacious in TD, a clinical cure often occurs without apparent bacterial eradication and with minimal effect on the gut microbiota, suggesting an effect of rifaximin other than direct antibiotic activity. Conclusions Although definitive studies on the effect of rifaximin on the gut microbiota in large cohorts of healthy volunteers or patients have not been published, pre-clinical studies provide some insight. These studies have shown that rifaximin may have effects on both the pathogen and host, including direct effects on pathogenic bacteria (such as reducing the expression of bacterial virulence factors) and indirect effects on the host (such as inhibiting bacterial attachment and internalisation at the intestinal mucosa and reducing mucosal inflammation). © 2015 John Wiley & Sons Ltd. Source


The formation of single-stranded DNA (ssDNA) at double-strand break (DSB) ends is essential in repair by homologous recombination and is mediated by DNA helicases and nucleases. Here we estimated the length of ssDNA generated during DSB repair and analyzed the consequences of elimination of processive resection pathways mediated by Sgs1 helicase and Exo1 nuclease on DSB repair fidelity. In wild-type cells during allelic gene conversion, an average of 2-4 kb of ssDNA accumulates at each side of the break. Longer ssDNA is formed during ectopic recombination or break-induced replication (BIR), reflecting much slower repair kinetics. This relatively extensive resection may help determine sequences involved in homology search and prevent recombination within short DNA repeats next to the break. In sgs1Delta exo1Delta mutants that form only very short ssDNA, allelic gene conversion decreases 5-fold and DSBs are repaired by BIR or de novo telomere formation resulting in loss of heterozygosity. The absence of the telomerase inhibitor, PIF1, increases de novo telomere pathway usage to about 50%. Accumulation of Cdc13, a protein recruiting telomerase, at the break site increases in sgs1Delta exo1Delta, and the requirement of the Ku complex for new telomere formation is partially bypassed. In contrast to this decreased and alternative DSB repair, the efficiency and accuracy of gene targeting increases dramatically in sgs1Delta exo1Delta cells, suggesting that transformed DNA is very stable in these mutants. Altogether these data establish a new role for processive resection in the fidelity of DSB repair. Source


The high prevalence neglected tropical diseases (NTDs) exhibit a global disease burden that exceeds malaria, tuberculosis, and other better known global health conditions; they also represent a potent force in trapping the world's poorest people in poverty. Through extremely low cost national programs of disease mapping and mass drug administration (MDA) for the seven most common NTDs, integrated NTD control and elimination efforts are now in place in more than 14 countries through the support of the United States Agency for International Development (USAID), the British Department for International Development (DFID), and the Global Network for NTDs and its partners. The World Health Organization (WHO) estimates that in 2008 some 670 million people in 75 countries received NTD treatments through these and other sponsored programs. With continued successes the next decade could witness the global elimination of blinding trachoma, human Africa trypanosomiasis (HAT), lymphatic filariasis (LF), onchocerciasis, trachoma, and leprosy as public health problems, in addition to the eradication of dracunculiasis. For other high prevalence NTDs, including hookworm infection, schistosomiasis, Chagas disease and leishmaniasis, new drugs and vaccines may still be required. Increasingly it is recognized that the high prevalence NTDs exhibit extensive geographic overlap and polyparasitism is commonly found throughout the world's low income countries. Therefore, global elimination will also require integrated packages of drugs together with vaccine-linked chemotherapy. Ultimately, the global elimination of the high prevalence NTDs will require continued large-scale support from the U.S. Government and selected European governments, however, the emerging market economies, such as Brazil, China, India, Mexico, and Nigeria, and wealthy countries in the Middle East will also have to substantially contribute. © 2011 Elsevier Ltd. Source


Marini J.C.,Baylor College of Medicine
Journal of Nutrition | Year: 2012

Recent isotopic tracer studies in mice, piglets, and humans have produced conflicting results as to the main carbon skeleton precursor for citrulline and arginine synthesis. This may be due in part to the different tracers infused and models used to interpret the stable isotope data. Furthermore, previous studies usually investigated a single precursor, which prevented the direct comparison among multiple precursors. To further elucidate the contribution of different precursors to citrulline synthesis, all possible enteral and plasma precursors of citrulline were studied in a mouse model during the postabsorptive and postprandial period using multitracer protocols. In addition, three different models were used to interpret the stable isotope data. The utilization of the classic precursor-product equation, developed for i.v. infused tracers but also used to include i.g. tracers, grossly overestimated the contribution of enteral precursors. Regardless of the model employed, dietary and plasma arginine were the main precursors for citrulline synthesis during feeding and plasma arginine during feed deprivation. The contribution of arginine was directly at the site of citrulline synthesis and through plasma ornithine. The predominant role of arginine and ornithine seen in this study supports the observations in mice, piglets, and humans suggesting that ornithine amino transferase is a pivotal enzyme in this pathway. © 2012 American Society for Nutrition. Source


McNeil J.C.,Baylor College of Medicine
Infection and Drug Resistance | Year: 2014

Children with immunocompromising conditions represent a unique group for the acquisition of antimicrobial resistant infections due to their frequent encounters with the health care system, need for empiric antimicrobials, and immune dysfunction. These infections are further complicated in that there is a relative paucity of literature on the clinical features and management of Staphylococcus aureus infections in immunocompromised children. The available literature on the clinical features, antimicrobial susceptibility, and management of S. aureus infections in immunocompromised children is reviewed. S. aureus infections in children with human immunodeficiency virus (HIV) are associated with higher HIV viral loads and a greater degree of CD4 T-cell suppression. In addition, staphylococcal infections in children with HIV often exhibit a multidrug resistant phenotype. Children with cancer have a high rate of S. aureus bacteremia and associated complications. Increased tolerance to antiseptics among staphylococcal isolates from pediatric oncology patients is an emerging area of research. The incidence of S. aureus infections among pediatric solid organ transplant recipients varies considerably by the organ transplanted; in general however, staphylococci figure prominently among infections in the early posttransplant period. Staphylococcal infections are also prominent pathogens among children with a number of immunodeficiencies, notably chronic granulomatous disease. Significant gaps in knowledge exist regarding the epidemiology and management of S. aureus infection in these vulnerable children. © 2014 McNeil. Source


Rejeski W.J.,Wake forest University | Ip E.H.,Wake forest University | Bertoni A.G.,Wake forest University | Bray G.A.,Louisiana State University | And 3 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND:Adults with type 2 diabetes mellitus often have limitations in mobility that increase with age. An intensive lifestyle intervention that produces weight loss and improves fitness could slow the loss of mobility in such patients. METHODS:We randomly assigned 5145 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes to either an intensive lifestyle intervention or a diabetes support-and-education program; 5016 participants contributed data. We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline. The primary outcome was self-reported limitation in mobility, with annual assessments for 4 years. RESULTS:At year 4, among 2514 adults in the lifestyle-intervention group, 517 (20.6%) had severe disability and 969 (38.5%) had good mobility; the numbers among 2502 participants in the support group were 656 (26.2%) and 798 (31.9%), respectively. The lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group (odds ratio, 0.52; 95% confidence interval, 0.44 to 0.63; P<0.001). Both weight loss and improved fitness (as assessed on treadmill testing) were significant mediators of this effect (P<0.001 for both variables). Adverse events that were related to the lifestyle intervention included a slightly higher frequency of musculoskeletal symptoms at year 1. CONCLUSIONS:Weight loss and improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT00017953.) Copyright © 2012 Massachusetts Medical Society. Source


Tolle M.A.,Baylor College of Medicine
Journal of the American Board of Family Medicine | Year: 2010

Every year, millions of children travel internationally with their families, many to developing countries. Although the vast majority experience uneventful travel and return home well, it is not uncommon for children to present as ill during or after travel. Although the majority of travel-associated illness is mild and self-limited, serious conditions regularly occur. Almost all life-threatening conditions after travel present with fever, and malaria is the most important of these to rapidly exclude. Gastrointestinal symptoms are common after travel in the developing world, and most diarrhea in child travelers has a bacterial source. Children who have a rash in association with fever or who appear ill should receive a priority work-up focused on ruling out serious conditions. Many children traveling internationally experience respiratory illness during or shortly after travel, mainly common upper respiratory infections, yet serious conditions, such as tuberculosis, may occur. Eosinophilia is common in the returned pediatric traveler, particularly those with prolonged stays in the tropics. Not all eosinophilia is caused by parasitic infection; drug reactions, asthma, and other allergic conditions are also common causes. With a focus first on ruling out life-threatening disease and subsequently on an informed and efficient path to diagnosis and treatment, clinicians may confidently provide care for this challenging group of patients. Source


Scaglia F.,Baylor College of Medicine
Developmental Disabilities Research Reviews | Year: 2010

Mitochondrial respiratory chain disorders are a group of genetically and clinically heterogeneous disorders caused by the biochemical complexity of mitochondrial respiration and the fact that two genomes, one mitochondrial and one nuclear, encode the components of the respiratory chain. These disorders can manifest at birth or present later in life. They result, at least in part, in defective production of ATP. Typically, mitochondrial disorders affect tissues with high energetic demands such as skeletal muscle, cardiac muscle, and the central nervous system. Neurological dysfunction is the most frequent clinical presentation of these disorders. The central nervous system is highly dependent on oxidative metabolism, and particular mitochondrial disorders are accompanied by focal brain necrosis (Leigh disease), dementia, or static encephalopathy. Furthermore, many children with mitochondrial encephalomyopathies present with more subtle and indolent signs including focal cognitive deficits of memory, perception, and language. Some subjects with mitochondrial disorders may also exhibit nonverbal cognitive impairment, compromised visuospatial abilities, and short-term memory deficits associated with working memory that likely reflect defects in synaptic plasticity. Psychiatric features are found within the clinical spectrum of mitochondrial syndromes. It is increasingly recognized that mitochondrial dysfunction may be associated with neuropsychiatric abnormalities such as dementia, major depression, and bipolar disorder. Furthermore, several lines of evidence suggest that there is involvement of mitochondrial dysfunction in schizophrenia, including documented alterations in brain energy metabolism, electron transport chain activity, and expression of genes involved in mitochondrial function. The purpose of this review article is to summarize the psychiatric features observed in mitochondrial cytopathies and discuss possible mechanisms of dysfunctional cellular energy metabolism that underlie the pathophysiology of major subsets of psychiatric disorders. © 2010 Wiley-Liss, Inc. Source


Jankovic J.,Baylor College of Medicine
Movement Disorders | Year: 2013

Medications such as anticholinergic drugs, dopamine modulators, baclofen, muscle relaxants, and other pharmacologic agents have been used for a long time to treat dystonia, but the introduction of botulinum toxin and deep brain stimulation clearly revolutionized the symptomatic treatment of this neurological movement disorder. Therapy of dystonia can be divided into the following categories: (1) physical, supportive, and ancillary therapy; (2) pharmacologic treatment; (3) chemodenervation with botulinum toxin; and (4) peripheral and central surgery (deep brain stimulation). Except in some cases of secondary dystonia, pathogenesis-targeted or disease-modifying therapy is currently not available. This review focuses on evidence-based medical treatment of dystonia, highlighting recent advances, with emphasis on individualized approach. © 2013 Movement Disorder Society. Source


Lamb D.J.,Baylor College of Medicine
Asian Journal of Andrology | Year: 2010

Sperm function testing, once commonly performed for the infertile couple before employing assisted reproductive technology (ART), has fallen out of favour in many reproductive medicine centers throughout the world. Indeed, the most recent addition of the 'World Health Organisation (WHO) Laboratory Manual for the Examination and Processing of Human Semen' now groups many of these procedures into a section termed Research Procedures. In large part, this reflects the current clinical practice of bypassing the in-depth evaluation of the male partner, while assuming that if a spermatozoon can be found for intracytoplasmic sperm injection (ICSI), it must be a healthy cell capable of achieving fertilization. Nevertheless, sperm function testing can provide valuable clinical insights into defects causing male infertility. Admittedly, in some cases, functional sperm deficiencies can be overcome using an ART. In other cases, couples will be empowered by the knowledge of the cause of their infertility, and for some couples, perhaps even the likelihood of ICSI success (relative to the spermatozoa). The knowledge allows them to make truly informed reproductive decisions, including (perhaps) the decision to seek donor insemination, to adopt or to remain childless. Knowledge of the cause of their infertility may provide closure for couples and a sense of confidence regarding their choice of reproductive treatment. © 2010 AJA, SIMM & SJTU. Source


Orange J.S.,Baylor College of Medicine
Journal of Allergy and Clinical Immunology | Year: 2013

Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation. © 2013 American Academy of Allergy, Asthma & Immunology. Source


Stewart S.A.,University of Washington | Bertuch A.A.,Baylor College of Medicine
Cancer Research | Year: 2010

The fourth AACR Special Conference on The Role of Telomeres and Telomerase in Cancer Research was held February 27 to March 2, 2010 in Fort Worth, TX. The meeting was organized to bring together those interested in the basic molecular mechanisms that govern telomere dynamics and stability with those interested in the clinical implications of telomere dysfunction and the use of telomeres and telomerase as therapeutic targets. The meeting was extremely successful as evidenced by the attendance and quality of the presentations. Indeed, several important themes emerged including (a) the intricate connection between the DNA replication and repair machineries in basic telomere replication and stability, (b) the complex interplay between the telomere-specific shelterin components and DNA repair proteins, (c) the nontelomeric functions of TERT in numerous cell types including stem cells, (d) a growing appreciation for the connection that exists between telomere maintenance deficiency states and diverse conditions such as idiopathic pulmonary fibrosis and hematopoietic malignancies, and (e) the successful progression of agents targeting telomerase directly and immunologically to phase III clinical trials. Evident at the meeting was the vibrant energy that permeates the telomere field and the important biological and medical findings that it continues to yield. ©2010 AACR. Source


Sifers R.N.,Baylor College of Medicine
Proceedings of the American Thoracic Society | Year: 2010

α(1)-Antitrypsin (AAT) secreted from hepatocytes is an inhibitor of neutrophil elastase. Its normal circulating concentration functions to maintain the elasticity of the lung by preventing the hydrolytic destruction of elastin fibers. Severely diminished circulating concentrations of AAT, resulting from the impaired secretion of genetic variants that exhibit distinct polypeptide folding defects, can function as an etiologic agent for the development of chronic obstructive pulmonary disease. In addition, the inappropriate accumulation of structurally aberrant AAT within the hepatocyte endoplasmic reticulum can contribute to the etiology of liver disease. This article focuses on the discovery and characterization of a biosynthetic quality control system that contributes to the secretion of AAT by first facilitating its proper structural maturation, and then by orchestrating the selective elimination of those molecules that fail to attain structural maturation. Mechanistic elucidation of these interconnected quality control events recently led to the identification of an underlying genetic modifier capable of accelerating the onset of end-stage liver disease by impairing the efficiency of an initial step in the protein disposal process. Source


Zoghbi H.Y.,Howard Hughes Medical Institute | Zoghbi H.Y.,Baylor College of Medicine | Bear M.F.,Howard Hughes Medical Institute
Cold Spring Harbor Perspectives in Biology | Year: 2012

The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Moyer V.A.,Baylor College of Medicine
Annals of Internal Medicine | Year: 2011

Description: Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for bladder cancer. Methods: The USPSTF performed a targeted literature search for new evidence on the benefits and harms of screening, the accuracy of primary care-feasible screening tests, and the benefits and harms of treatment. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for bladder cancer in asymptomatic adults (I statement). © 2011 American College of Physicians. Source


Epstein R.M.,University of Rochester | Street Jr. R.L.,Baylor College of Medicine
Annals of Family Medicine | Year: 2011

In the context of serious illness, individuals usually rely on others to help them think and feel their way through difficult decisions. To help us to understand why, when, and how individuals involve trusted others in sharing information, deliberation, and decision making, we offer the concept of shared mind- ways in which new ideas and perspectives can emerge through the sharing of thoughts, feelings, perceptions, meanings, and intentions among 2 or more people. We consider how shared mind manifests in relationships and organizations in general, building on studies of collaborative cognition, attunement, and sensemaking. Then, we explore how shared mind might be promoted through communication, when appropriate, and the implications of shared mind for decision making and patient autonomy. Next, we consider a continuum of patient-centered approaches to patient-clinician interactions. At one end of the continuum, an interactional approach promotes knowing the patient as a person, tailoring information, constructing preferences, achieving consensus, and promoting relational autonomy. At the other end, a transactional approach focuses on knowledge about the patient, information-as-commodity, negotiation, consent, and individual autonomy. Finally, we propose that autonomy and decision making should consider not only the individual perspectives of patients, their families, and members of the health care team, but also the perspectives that emerge from the interactions among them. By drawing attention to shared mind, clinicians can observe in what ways they can promote it through bidirectional sharing of information and engaging in shared deliberation. Source


Soltani A.,California Institute of Technology | Soltani A.,Baylor College of Medicine | Koch C.,California Institute of Technology
Journal of Neuroscience | Year: 2010

The primate visual system continuously selects spatial proscribed regions, features or objects for further processing. These selection mechanisms- collectively termed selective visual attention-are guided by intrinsic, bottom-up and by task-dependent, top-down signals. While much psychophysical research has shown that overt and covert attention is partially allocated based on saliency-driven exogenous signals, it is unclear how this is accomplished at the neuronal level. Recent electrophysiological experiments in monkeys point to the gradual emergence of saliency signals when ascending the dorsal visual stream and to the influence of top-down attention on these signals. To elucidate the neural mechanisms underlying these observations, we construct a biologically plausible network of spiking neurons to simulate the formation of saliency signals in different cortical areas. We find that saliency signals are rapidly generated through lateral excitation and inhibition in successive layers of neural populations selective to a single feature. These signals can be improved by feedback from a higher cortical area that represents a saliency map. In addition, we show how top-down attention can affect the saliency signals by disrupting this feedback through its action on the saliency map. While we find that saliency computations require dominant slow NMDA currents, the signal rapidly emerges from successive regions of the network. In conclusion, using a detailed spiking network model we find biophysical mechanisms and limitations of saliency computations which can be tested experimentally. Copyright © 2010 the authors. Source


Goldstein S.L.,Baylor College of Medicine | Chawla L.S.,George Washington University
Clinical Journal of the American Society of Nephrology | Year: 2010

Small elevations in serum creatinine may reflect significant kidney damage and be associated with poor patient outcomes, thus rendering creatinine to be a late marker of acute kidney injury (AKI). AKI researchers refer to the AKI biomarker quest as the "search for the renal troponin I," implying that such putative earlier AKI biomarker use could allow for earlier intervention. We consider the analogy to troponin I and its acceptance to prompt evaluation and therapeutic intervention to treat myocardial ischemia and prevent myocardial infarction an informative and potentially applicable model to the AKI field. Because AKI does not hurt, there is no validated equivalent of chest pain or anginal equivalent to increase suspicion for AKI presence on the part of the clinician. So, although biomarkers may ultimately be validated to detect AKI early, unless nephrologists and intensivists can define "renal angina" to initiate "renal troponin I" assessments, AKI biomarkers may never realize their full potential to improve patient care and outcomes. The purpose of this article is to review both adult and pediatric AKI literature to devise a definition for a renal anginal syndrome equivalent. Copyright © 2010 by the American Society of Nephrology. Source


Zitnik M.,University of Ljubljana | Zupan B.,University of Ljubljana | Zupan B.,Baylor College of Medicine
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2015

For most problems in science and engineering we can obtain data sets that describe the observed system from various perspectives and record the behavior of its individual components. Heterogeneous data sets can be collectively mined by data fusion. Fusion can focus on a specific target relation and exploit directly associated data together with contextual data and data about system's constraints. In the paper we describe a data fusion approach with penalized matrix tri-factorization (DFMF) that simultaneously factorizes data matrices to reveal hidden associations. The approach can directly consider any data that can be expressed in a matrix, including those from feature-based representations, ontologies, associations and networks. We demonstrate the utility of DFMF for gene function prediction task with eleven different data sources and for prediction of pharmacologic actions by fusing six data sources. Our data fusion algorithm compares favorably to alternative data integration approaches and achieves higher accuracy than can be obtained from any single data source alone. © 2014 IEEE. Source


Jankovic J.,Baylor College of Medicine | Clarence-Smith K.,KM Pharmaceuticals Consulting
Expert Review of Neurotherapeutics | Year: 2011

Tetrabenazine (TBZ; Xenazine ®) is a potent, selective, reversible depletor of monoamines from nerve terminals. TBZ inhibits the vesicular monoamine transporter type 2 which, in humans, is expressed nearly exclusively in the brain. TBZ is rapidly metabolized in the liver by carbonyl reductase to stereoisomers of hydrotetrabenazine, some of which are potent inhibitors of vesicular monoamine transporter type 2. Initially developed in the 1950s for schizophrenia, since the 1970s several publications have reported on the efficacy of TBZ in the treatment of various hyperkinetic movement disorders. Although quite effective in controlling the involuntary movements, there were considerable inter-individual differences in the optimal dose, defined as the dose judged by the investigator to provide the greatest efficacy with minimal or tolerable adverse events. This variability is in part owing to differences in severity and mechanism of the target symptoms and to variable activity of the enzyme carbonyl reductase that metabolizes TBZ to its active metabolites. Dose-limiting adverse events, consisting mainly of sedation, parkinsonism, akathisia and depression, are usually rapidly reversible upon dosage reduction. In addition to its established antichorea efficacy in Huntington's disease, the drug has been reported to also be effective in a variety of other hyperkinetic movement disorders, including tardive dyskinesia and tics associated with Tourette's syndrome. © 2011 Expert Reviews Ltd. Source


Dupont H.L.,Baylor College of Medicine
Expert Opinion on Pharmacotherapy | Year: 2011

Introduction: Rifaximin is increasingly being used to treat acute and chronic gastrointestinal infections and disorders. The drug exerts its beneficial effect through a variety of gut-selective mechanisms involving the host intestinal microbiota. Areas covered: Abstracts of all publications listed in PubMed on the topic of rifaximin are reviewed to determine their potential value in the understanding of mechanisms of rifaximin activity. The author's extensive file on the drug is also used in the review. Expert opinion: Rifaximin inhibits a broad spectrum of bacteria in the bile-rich small bowel and susceptible bacteria in the aqueous colon, and alters microbial virulence and epithelial cell function. The different mechanisms of action of rifaximin potentially explain the use of the drug in widely varied diseases and syndromes. © 2011 Informa UK, Ltd. Source


Ondo W.G.,Baylor College of Medicine
Handbook of Clinical Neurology | Year: 2011

Hemichorea and generalized chorea are well-recognized syndromes associated with nonketotic hyperglycemia. This condition usually occurs in older age, affects females more than men, and often heralds a new diagnosis of diabetes, usually type 2. It may resolve over days with treatment of the underlying hyperglycemia or persist for years. Magnetic resonance imaging is very characteristic, and shows T1 hyperdensity in the striatum. The underlying pathophysiology is not clear, but recent evidence suggests that the imaging may represent zinc, as opposed to calcium. Tetrabenazine has worked well when symptomatic treatment is required. Other rare causes of metabolic choreas include hypoparathyroid abnormalities, hypoglycemia, and hypernatremia. © 2011 Elsevier B.V. Source


Golding I.,Baylor College of Medicine | Golding I.,Urbana University
Annual Review of Biophysics | Year: 2011

The life cycle of bacteriophage lambda serves as a simplified paradigm for cell-fate decisions. The ongoing quantitative, high-resolution experimental investigation of this life cycle has produced some important insights in recent years. These insights have to do with the way cells choose among alternative fates, how they maintain long-term memory of their gene-expression state, and how they switch from one stable state to another. The recent studies have highlighted the role of spatiotemporal effects in cellular processes and the importance of distinguishing chemical stochasticity from possible hidden variables in cellular decision making. © 2011 by Annual Reviews. All rights reserved. Source


Wang C.,Baylor College of Medicine
Current Opinion in Urology | Year: 2010

Purpose of review: Benign prostatic hyperplasia (BPH) is prevalent in old men and often results in lower urinary tract symptoms (LUTS). Phosphodiesterase-5 (PDE5) inhibitors increase intracellular concentrations of cyclic guanosine monophosphate. PDE5 inhibitors (sildenafil, tadalafil, vardenafil, etc.) are first-line treatments for erectile dysfunction. Recently, PDE5 inhibitors have been found to regulate smooth muscle tone in human prostate. This article focuses on the use of PDE5 inhibitors for BPH/LUTS treatment and highlights the clinical significance. Recent findings: Preclinical and clinical studies have provided promising evidence that PDE5 inhibitors may be an effective and well tolerated treatment option for BPH/LUTS. Combination therapy using PDE5 inhibitors and α1-adrenergic blockers resulted in greater improvements in BPH/LUTS than did either drug alone. Summary: There has been increasing interest in the use of PDE5 inhibitors to treat BPH/LUTS. Combination of PDE5 inhibitors and α1-adrenergic blockers may have an additive beneficial effect on BPH/LUTS compared with monotherapy. Mechanisms of action of nitric oxide/cyclic guanosine monophosphate/PDE5 pathway in the treatment of BPH/LUTS deserve further investigations. Larger-scale, well designed clinical trials in future are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5 inhibitors in the treatment of LUTS secondary to BPH. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Qin L.,Baylor College of Medicine | Zhang M.,Northwestern University
Journal of Biological Chemistry | Year: 2010

Maspin has been identified as a potent angiogenesis inhibitor. However, the molecular mechanism responsible for its anti-angiogenic property is unclear. In this study, we examined the effect of maspin on endothelial cell (EC) adhesion and migration in a cell culture system. We found that maspin was expressed in blood vessels ECs and human umbilical vein endothelial cells (HUVECs). Maspin significantly enhanced HUVEC cell adhesion to various matrix proteins. This effect was dependent on the activation of integrin β1, which subsequently led to distribution pattern changes of vinculin and F-actin. These results indicated that maspin affects cell adhesion and cytoskeleton reorganization through an integrin signal transduction pathway. Analysis of HUVECs following maspin treatment revealed increased integrin-linked kinase activities and phosphorylated FAK levels, consistent with increased cell adhesion. Interestingly, when HUVECs were induced to migrate by migration stimulatory factor bFGF, active Rac1 and cdc42 small GTPase levels were decreased dramatically at 30 min following maspin treatment. Using phosphorylated FAK at Tyr397 as an indicator of focal adhesion disassembly, maspin-treated HUVECs had elevated FAK phosphorylation compared with the mock treated control. The results were a reduction in focal adhesion disassembly and the retardation in EC migration. This study uncovers a mechanism by which maspin exerts its effect on EC adhesion and migration through an integrin signal transduction pathway. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Moffett J.M.,Baylor College of Medicine
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | Year: 2011

To summarize the indications and techniques for parathyroid autotransplantation and to explore other aspects of the field that warrant further research and discussion. Review of relevant literature with focus on parathyroid autotransplantation and cryopreservation. Parathyroid autotransplantation is an important technique used by surgeons to circumvent postoperative hypoparathyroidism. Immediate autotransplantation is used intraoperatively, most commonly in the setting of total thyroidectomy or during total parathyroidectomy in a patient with parathyroid hyperplasia. Delayed autotransplantation with cryopreservation is typically used in patients with persistent or recurrent hyperparathyroidism who require repeated cervical exploration. The success rate of autotransplantation in preventing postoperative hypoparathyroidism reported in the literature is highly variable and is dependent on timing, disease, and duration of tissue storage. Ultimately, surgical planning for patients with hyperparathyroidism involves finding a balance between decreasing a patient's symptoms, increasing the time of eucalcemia, and avoiding the complications of permanent hypoparathyroidism. Source


Bree A.F.,Baylor College of Medicine | Shah M.R.,Saint Louis University
American Journal of Medical Genetics, Part A | Year: 2011

The first international colloquium on basal cell nevus syndrome (BCNS) was held at Saint Louis University School of Medicine and supported by the Basal Cell Carcinoma Nevus Syndrome (BCCNS) Life Support Network (). The foremost goal of the conference was to review and revise the prior diagnostic criteria and define the surveillance recommendations for affected pediatric and adult patients to allow for early intervention. The invited consensus group participants included geneticists, dermatologists, orthopedists, neurologists, and dental/oral medicine specialists, who treat patients with BCNS or related disorders. This group also included individuals who have a research interest in BCNS and who additionally serve on the medical advisory board of the BCCNS Life Support Network. Expert opinion was based on the collective clinical and research experience of the consensus group participants after presentation and review of the previously published literature regarding diagnosis and treatment of BCNS. A consensus was achieved and agreed upon by open roundtable discussion of the group participants. The consensus statement outlines the proposed diagnostic and management protocols that will hopefully limit morbidity and mortality for affected individuals until more specific and targeted therapies are widely available. © 2011 Wiley-Liss, Inc. Source


Gluck S.,University of Miami | Arteaga C.L.,Vanderbilt University | Osborne C.K.,Baylor College of Medicine
Clinical Cancer Research | Year: 2011

The recent incremental advances made in the treatment of metastatic breast cancer have elicited potential for survival extension in this treatable, yet incurable, population of breast cancer patients. Clinicians have focused on targeted therapies, which aim at signaling receptors such as the human epidermal receptor superfamily, the estrogen receptor, VEGF, the insulin-like growth factor receptor, the hepatocyte growth factor receptor (cMET), phosphoinositide 3-kinase, mTOR, and many others. ©2011 AACR. Source


Matoba A.Y.,Baylor College of Medicine
Cornea | Year: 2012

PURPOSE: To report 5 cases of culture-proven fungal keratitis that resolved with moxifloxacin monotherapy. METHODS: Case reports and review of medical literature. Five patients with fungal keratitis were treated with topical moxifloxacin. RESULTS: All 5 patients had resolution of their infection with topical moxifloxacin monotherapy. CONCLUSIONS: Topical fluoroquinolone agents may have significant antifungal properties. However, the vast majority of fungal keratitis patients cannot be cured with fluoroquinolone monotherapy. An initial response of keratitis to topical fluoroquinolone therapy should not lead to the assumption that the infection is bacterial because the possibility of fungal infection cannot be ruled out on that basis. © 2012 by Lippincott Williams & Wilkins. Source


Zhao W.,Methodist Hospital Research Institute | Li Q.,Methodist Hospital Research Institute | Ayers S.,Methodist Hospital Research Institute | Gu Y.,Methodist Hospital Research Institute | And 5 more authors.
Cell | Year: 2013

Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process. © 2013 Elsevier Inc. Source


Kao C.,Baylor College of Medicine
American journal of physiology. Endocrinology and metabolism | Year: 2013

In enterocytes, glutamine serves as the major source of energy; another metabolic fate of glutamine is conversion to citrulline. Because sepsis can affect gut function and integrity, alterations in glutamine metabolism may exist and lead to decreased citrulline production. This study aimed to investigate how sepsis affects glutamine metabolism, including its conversion to citrulline, by measuring glutamine and citrulline flux, fractional splanchnic extraction of glutamine and leucine, and the contribution of glutamine nitrogen to citrulline in septic patients and healthy controls. Eight patients with severe sepsis and 10 healthy controls were given primed, constant intravenous infusion of [(2)H2]citrulline and sequential administration of intravenous and enteral [α-(15)N]glutamine and [(13)C]leucine in the postabsorptive state. The results showed that, compared with healthy controls, septic patients had a significantly lower whole body citrulline flux and plasma concentration, higher endogenous leucine flux, and higher glutamine clearance. Fractional splanchnic extraction of leucine was higher in septic patients than in controls, but fractional extraction of glutamine was not different. The majority of the (15)N label transferred from glutamine to citrulline was found at the α-position. These results demonstrate that lower glutamine plasma concentrations in sepsis were a result of increased glutamine clearance. Despite adequate splanchnic uptake of glutamine, there is decreased production of citrulline, suggesting a defect in the metabolic conversion of glutamine to citrulline, decreased uptake of glutamine by the enterocyte but increased uptake by the liver, and/or shunting of glutamine to other metabolic pathways. Source


Montgomery R.R.,Yale University | Murray K.O.,Baylor College of Medicine
Expert Review of Anti-Infective Therapy | Year: 2015

West Nile virus (WNV) is a mosquito-borne enveloped positive-strand RNA virus that emerged in North America in 1999 in New York City. Over the past 15 years, WNV has become established throughout the USA and has spread into Canada, Mexico and the Caribbean. CDC reports indicate >41,000 clinical cases, including more than 1700 fatalities. An estimated 3 million people in the USA may have been infected to date. Infection with WNV is dependent on many factors including climate, mosquito habitats and immunologically naïve bird populations. In addition, variations within individuals contribute to the risk of severe disease, in particular, advanced age, hypertension, immunosuppression and critical elements of the immune response. Recent advances in technology now allow detailed analysis of complex immune interactions relevant to disease susceptibility. © 2015 Informa UK, Ltd Source


Ma C.X.,University of Washington | Reinert T.,Instituto Nacional Of Cancer Inca | Chmielewska I.,Medical University of Lublin | Ellis M.J.,Baylor College of Medicine
Nature Reviews Cancer | Year: 2015

Oestrogen receptor-positive (ER +) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER + breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Igbokwe A.,Molecular Pathology Laboratory | Lopez-Terrada D.H.,Baylor College of Medicine
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. Objective.-To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. Data Sources.-Original research articles, review articles, and the authors' personal practice experience. Conclusions.-Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care. Source


Human decomposition is a mosaic system with an intimate association between biotic and abiotic factors. Despite the integral role of bacteria in the decomposition process, few studies have catalogued bacterial biodiversity for terrestrial scenarios. To explore the microbiome of decomposition, two cadavers were placed at the Southeast Texas Applied Forensic Science facility and allowed to decompose under natural conditions. The bloat stage of decomposition, a stage easily identified in taphonomy and readily attributed to microbial physiology, was targeted. Each cadaver was sampled at two time points, at the onset and end of the bloat stage, from various body sites including internal locations. Bacterial samples were analyzed by pyrosequencing of the 16S rRNA gene. Our data show a shift from aerobic bacteria to anaerobic bacteria in all body sites sampled and demonstrate variation in community structure between bodies, between sample sites within a body, and between initial and end points of the bloat stage within a sample site. These data are best not viewed as points of comparison but rather additive data sets. While some species recovered are the same as those observed in culture-based studies, many are novel. Our results are preliminary and add to a larger emerging data set; a more comprehensive study is needed to further dissect the role of bacteria in human decomposition. Source


Bouchier-Hayes L.,Center for Cell and Gene Therapy | Bouchier-Hayes L.,Baylor College of Medicine | Green D.R.,St Jude Childrens Research Hospital
Cell Death and Differentiation | Year: 2012

Despite an abundance of literature on the role of caspase-2 in apoptosis, there exists much controversy about this protease making it difficult to place caspase-2 correctly in the apoptotic cascade, and hence its role in apoptosis remains unclear. The identification of the PIDDosome as a signaling platform for caspase-2 activation prompted intense investigation into the true role of this orphan caspase. What has emerged is the idea that caspase-2 may not be mandatory for apoptosis and that activation of this caspase in response to some forms of stress has other effects on the cell such as regulation of cell cycle progression. This idea is particularly relevent to the discovery that caspase-2 may act as a tumor suppressor. Here, we discuss the proposed mechanisms through which caspase-2 signals, in particular those involving PIDD, and their impact on cellular fate. © 2012 Macmillan Publishers Limited All rights reserved. Source


Panyi G.,Debrecen University | Beeton C.,Baylor College of Medicine | Felipe A.,University of Barcelona
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

The outcome of a malignant disease depends on the efficacy of the immune system to destroy cancer cells. Key steps in this process, for example the generation of a proper Ca2+ signal induced by recognition of a specific antigen, are regulated by various ion channel including voltage-gated Kv1.3 and Ca2+activated KCa3.1 K+ channels, and the interplay between Orai and STIM to produce the Ca2+-release-activated Ca2+ (CRAC) current required for T-cell proliferation and function. Understanding the immune cell subset-specific expression of ion channels along with their particular function in a given cell type, and the role of cancer tissue-dependent factors in the regulation of operation of these ion channels are emerging questions to be addressed in the fight against cancer disease. Answering these questions might lead to a better understanding of the immunosuppression phenomenon in cancer tissue and the development of drugs aimed at skewing the distribution of immune cell types towards killing of the tumour cells. © 2014 The Author(s) Published by the Royal Society. Source


Rogers J.,Baylor College of Medicine
ILAR Journal | Year: 2013

The field of nonhuman primate genomics is undergoing rapid change and making impressive progress. Exploiting new technologies for DNA sequencing, researchers have generated new whole-genome sequence assemblies for multiple primate species over the past 6 years. In addition, investigations of within-species genetic variation, gene expression and RNA sequences, conservation of non-protein-coding regions of the genome, and other aspects of comparative genomics are moving at an accelerating speed. This progress is opening a wide array of new research opportunities in the analysis of comparative primate genome content and evolution. It also creates new possibilities for the use of nonhuman primates as model organisms in biomedical research. This transition, based on both new technology and the new information being generated in regard to human genetics, provides an important justification for reevaluating the research goals, strategies, and study designs used in primate genetics and genomics. © The Author 2013. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. Source


Guven A.,Rice University | Rusakova I.A.,University of Houston | Lewis M.T.,Baylor College of Medicine | Wilson L.J.,Rice University
Biomaterials | Year: 2012

The use of chemotherapeutic drugs in cancer therapy is often limited by problems with administration such as insolubility, inefficient biodistribution, lack of selectivity, and inability of the drug to cross cellular barriers. To overcome these limitations, various types of drug delivery systems have been explored, and recently, carbon nanotube (CNT) materials have also garnered attention in the area of drug delivery. In this study, we describe the preparation, characterization, and in vitro testing of a new ultra-short single-walled carbon nanotube (US-tube)-based drug delivery system for the treatment of cancer. In particular, the encapsulation of cisplatin (CDDP), a widely-used anticancer drug, within US-tubes has been achieved, and the resulting CDDP@US-tube material characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and inductively-coupled optical emission spectrometry (ICP-OES). Dialysis studies performed in phosphate-buffered saline (PBS) at 37 °C have demonstrated that CDDP release from CDDP@US-tubes can be controlled (retarded) by wrapping the CDDP@US-tubes with Pluronic-F108 surfactant. Finally, the anticancer activity of pluronic-wrapped CDDP@US-tubes has been evaluated against two different breast cancer cell lines, MCF-7 and MDA-MB-231, and found to exhibit enhanced cytotoxicity over free CDDP after 24 h. These studies have laid the foundation for developing US-tube-based delivery of chemotherapeutics, with drug release mainly limited to within cancer cells only. © 2011 Elsevier Ltd. Source


Ma W.J.,Baylor College of Medicine
Vision Research | Year: 2010

The juxtaposition of established signal detection theory models of perception and more recent claims about the encoding of uncertainty in perception is a rich source of confusion. Are the latter simply a rehash of the former? Here, we make an attempt to distinguish precisely between optimal and probabilistic computation. In optimal computation, the observer minimizes the expected cost under a posterior probability distribution. In probabilistic computation, the observer uses higher moments of the likelihood function of the stimulus on a trial-by-trial basis. Computation can be optimal without being probabilistic, and vice versa. Most signal detection theory models describe optimal computation. Behavioral data only provide evidence for a neural representation of uncertainty if they are best described by a model of probabilistic computation. We argue that single-neuron activity sometimes suffices for optimal computation, but never for probabilistic computation. A population code is needed instead. Not every population code is equally suitable, because nuisance parameters have to be marginalized out. This problem is solved by Poisson-like, but not by Gaussian variability. Finally, we build a dictionary between signal detection theory quantities and Poisson-like population quantities. © 2010 Elsevier Ltd. Source


Neilson J.R.,Baylor College of Medicine | Sandberg R.,Karolinska Institutet
Experimental Cell Research | Year: 2010

Precisely directed cleavage and polyadenylation of mRNA is a fundamental part of eukaryotic gene expression. Yet, 3′ end heterogeneity has been documented for thousands of mammalian genes, and usage of one cleavage and polyadenylation signal over another has been shown to impact gene expression in many cases. Building upon the rich biochemical and genetic understanding of the 3′ end formation, recent genomic studies have begun to suggest that widespread changes in mRNA cleavage and polyadenylation may be a part of large, dynamic gene regulatory programs. In this review, we begin with a modest overview of the studies that defined the mechanisms of mammalian 3′ end formation, and then discuss how recent genomic studies intersect with these more traditional approaches, showing that both will be crucial for expanding our understanding of this facet of gene regulation. © 2010 Elsevier Inc. Source


Hartig S.M.,Baylor College of Medicine
Current Protocols in Molecular Biology | Year: 2013

Image analysis methods have been developed to provide quantitative assessment of microscopy data. In this unit, basic aspects of image analysis are outlined, including software installation, data import, image processing functions, and analytical tools that can be used to extract information from microscopy data using ImageJ. Step-by-step protocols for analyzing objects in a fluorescence image and extracting information from two-color tissue images collected by bright-field microscopy are included. © 2013 by John Wiley & Sons, Inc. Source


Evans R.W.,Baylor College of Medicine
Headache | Year: 2015

The symptoms of migraine are non-specific and can be present in many other primary and secondary headache disorders, which are reviewed. Even experienced headache specialists may be challenged at times when diagnosing what appears to be first or worst, new type, migraine status, and chronic migraine. © 2015 American Headache Society. Source


Congenital cytomegalovirus (CMV) infection has been called “the elephant in our living room” because it is a major public health problem that for decades has been unrecognized and unaddressed. Congenital CMV infection is a common cause of sensorineural hearing loss, vision loss, neurodevelopment disabilities, liver disease, and growth failure. Diagnostic tests are now widely available to identify newborns with congenital CMV infection, congenitally infected newborns now can be easily assessed for evidence of organ involvement, and there are now antiviral treatments and other interventions available to improve the outcome in children with congenital CMV disease. A licensed vaccine to prevent CMV infection is not yet available; however, a “CMV knowledge vaccine,” composed of “an ounce of CMV awareness and three simple precautions” and that is endorsed by the Centers for Disease Control and Prevention is available for pregnant women who wish to reduce their contact with potentially CMV-infected secretions and therefore reduce their risk of acquiring CMV during pregnancy. Medical experts in the field of congenital CMV have been called upon for a consensus statement for diagnosis and treatment, and nonprofit organizations of families affected by congenital CMV from around the world have formed a collaborative coalition to facilitate the spread of CMV knowledge and awareness. © SLACK Incorporated. Source


Neul J.L.,Neurology | Neul J.L.,Baylor College of Medicine | Neul J.L.,The Texas Institute
Dialogues in Clinical Neuroscience | Year: 2012

Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders. © 2012, LLS SAS. Source


Zhang G.,University of Texas Health Science Center at Houston | Jin B.,Baylor College of Medicine | Li Y.-P.,University of Texas Health Science Center at Houston
EMBO Journal | Year: 2011

Upregulation of ubiquitin ligase atrogin1/MAFbx and muscle wasting are hallmarks of cancer cachexia; however, the underlying mechanism is undefined. Here, we describe a novel signalling pathway through which Lewis lung carcinoma (LLC) induces atrogin1/MAFbx upregulation and muscle wasting. C2C12 myotubes treated with LLC-conditioned medium (LCM) rapidly activates p38 MAPK and AKT while inactivating FoxO1/3, resulting in atrogin1/MAFbx upregulation, myosin heavy chain loss, and myotube atrophy. The p38α/β MAPK inhibitor SB202190 blocks the catabolic effects. Upon activation, p38 associates with C/EBPβ resulting in its phosphorylation and binding to a C/EBPβ-responsive cis-element in the atrogin1/MAFbx gene promoter. The promoter activity is stimulated by LCM via p38β-mediated activation of the C/EBPβ-responsive cis-element, independent of the adjacent FoxO1/3-responsive cis-elements in the promoter. In addition, p38 activation is observed in the muscle of LLC tumour-bearing mice, and SB202190 administration blocks atrogin1/MAFbx upregulation and muscle protein loss. Furthermore, C/EBPβ -/- mice are resistant to LLC tumour-induced atrogin1/MAFbx upregulation and muscle wasting. Therefore, activation of the p38β MAPKĝ€"C/EBPβ signalling pathway appears a key component of the pathogenesis of LLC tumour-induced cachexia. © 2011 European Molecular Biology Organization | All Rights Reserved. Source


Buchanan E.P.,Baylor College of Medicine
Plastic and reconstructive surgery | Year: 2014

After studying this article, the participant should be able to: 1. Recognize the clinical presentations of commonly seen craniofacial syndromes. 2. Understand the most serious complications associated with each syndrome. 3. Formulate the best age-appropriate surgical plans. Craniofacial syndromes fall into two major categories-those associated with craniosynostosis, and those associated with clefts. Each has a different set of potential complications requiring a unique approach for surgical management. Craniosynostosis is a congenital disorder in which one or more of the cranial sutures fuses prematurely. The most common syndromes associated with this condition include Crouzon, Apert, Pfeiffer, Muenke, and Saethre-Chotzen syndromes. Surgical management of these children requires a multidisciplinary approach and close involvement of the family. Operations must take into consideration the growing potential of the bony structures. Common syndromes associated with clefts include Pierre Robin, Treacher Collins, Nager, Binder, and Stickler syndromes. Many of these children have severe airway issues requiring immediate address before operative reconstruction. As with syndromes associated with craniosynostosis, the key to management is a multidisciplinary approach focused on the right timing. The purpose of this article is to review the clinical presentation, care, and treatment of these patients. Source


Frank S.,Boston University | Jankovic J.,Baylor College of Medicine
Drugs | Year: 2010

There is inevitable physical, cognitive and behavioural decline in Huntingtons disease (HD), a dominantly inherited progressive neurological disorder. The hallmark of the disease is chorea, an involuntary brief movement that tends to flow between body regions. HD is diagnosed clinically with genetic confirmation. Predictive testing is available; however, it should be undertaken with caution in patients at risk for the disease but without clinical disease expression. Ongoing observational trials have identified not only early subtle motor signs, but also striatal volume, verbal memory and olfaction as possible early manifestations of clinical disease. Multiple areas of the brain degenerate, with dopamine, glutamate and GABA being the predominant neurotransmitters affected in HD. Although many pharmacotherapies have been evaluated targeting these neurotransmitters, few well conducted trials for symptomatic or neuroprotective interventions have yielded positive results. Tetrabenazine is one of the better studied and more effective agents for reducing chorea, although with a risk of potentially serious adverse effects. Newer antipsychotic agents such as olanzapine and aripiprazole may have adequate efficacy with a more favourable adverse-effect profile than older antipsychotics for treating chorea and psychosis. In this review, the pathogenesis, epidemiology and diagnosis of HD are discussed as background for understanding potential pharmacological treatment options. Potential strategies to delay the progression of HD that have been studied and are planned for the future are summarized. Although there is no current method to change the course of this devastating disease, education and symptomatic therapies are effective tools available to clinicians and the families affected by HD. © 2010 Adis Data Information BV. All rights reserved. Source


Lopez-Terrada D.,Baylor College of Medicine | Zimmermann A.,University of Bern
Pediatric Blood and Cancer | Year: 2012

Systematic histopathologic examination of hepatoblastoma specimens from patients enrolled in therapeutic protocols has allowed the identification of clinically relevant histologic subtypes that are being incorporated into risk stratification systems. Genetic and molecular studies have documented recurrent chromosomal abnormalities and aberrant activation of developmental, and oncogenic signaling pathways in hepatoblastoma. Molecular profiling has also identified molecular subclasses and gene signatures that could be used to stratify hepatoblastoma patients. Future international collaboration is needed to develop consensus pathology classifications, and to progressively incorporate genetic and molecular biomarkers into therapeutic pediatric liver tumors protocols. © 2012 Wiley Periodicals, Inc. Source


Garber A.J.,Baylor College of Medicine
The American journal of managed care | Year: 2010

In addition to the hypoglycemia and weight gain associated with many treatments for type 2 diabetes, alpha-glucosidase inhibitors, thiazolidinediones, metformin, sulfonylureas, and the glinides do not address all of the multiple defects existing in the pathophysiology of the disease. Cumulatively, these oral agents address the influx of glucose from the gastrointestinal tract, impaired insulin activity, and acute beta-cell dysfunction in type 2 diabetes; however, until recently, there were no means to deal with the inappropriate hyperglucagonemia or chronic beta-cell-decline characteristic of the disease. The recently introduced incretin-based therapies serve to address some of the challenges associated with traditionally available oral antidiabetic agents. In addition to improving beta-cell function, stimulating insulin secretion, and inhibiting glucagon secretion, these agents reduce appetite, thereby stabilizing weight and/or promoting weight loss in patients with type 2 diabetes. Of the incretin-based therapies, both the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and inhibit glucagon secretion. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 receptor agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and saxagliptin. Earlier and more frequent use of these incretin-based therapies is recommended in the treatment of type 2 diabetes, based on their overall safety and ability to achieve the glycosylated hemoglobin level goal. As such, both the American Diabetes Association and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) treatment algorithms recommend the use of incretin-based therapy in both treatment-naive and previously treated patients. The AACE/ACE guidelines clearly state that these agents should not be limited to third- or fourth-line therapy. Source


Vijayan K.V.,Baylor College of Medicine
Blood | Year: 2015

In this issue of Blood, Bruneau et al1 provide evidence that disruption of diacylglycerol kinase e isoform (DGKe) does not upregulate complement activation, but rather induces endothelial damage via the activation of p38 mitogen-activated protein kinase (MAPK). These in vitro findings may support a new pathophysiologic mechanism for atypical hemolytic uremic syndrome (aHUS) in a subset of patients with DGKE gene mutations. © 2015 by The American Society of Hematology. Source


Soletsky B.,Baylor College of Medicine | Feig D.I.,University of Alabama at Birmingham
Hypertension | Year: 2012

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy. © 2012 American Heart Association, Inc. Source


Coe B.P.,University of Washington | Girirajan S.,University of Washington | Eichler E.E.,Baylor College of Medicine
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2012

Despite detailed clinical definition and refinement of neurodevelopmental disorders and neuropsychiatric conditions, the underlying genetic etiology has proved elusive. Recent genetic studies have revealed some common themes: considerable locus heterogeneity, variable expressivity for the same mutation, and a role for multiple disruptive events in the same individual affecting genes in common pathways. Recurrent copy number variation (CNV), in particular, has emphasized the importance of either de novo or essentially private mutations creating imbalances for multiple genes. CNVs have foreshadowed a model where the distinction between milder neuropsychiatric conditions from those of severe developmental impairment may be a consequence of increased mutational burden affecting more genes. © 2012 Wiley Periodicals, Inc. Source


DuPont H.L.,Baylor College of Medicine
Mayo Clinic Proceedings | Year: 2015

Emerging preclinical and clinic evidence described herein suggests that the mechanism of action of rifaximin is not restricted to direct antibacterial effects within the gastrointestinal tract. Data from this study were derived from general and clinical trial-specific PubMed searches of English-language articles on rifaximin available through December 3, 2014. Search terms included rifaximin alone and in combination (using the Boolean operation "AND") with travelers' diarrhea, hepatic encephalopathy, liver cirrhosis, irritable bowel syndrome, inflammatory bowel disease, and Crohn's disease. Rifaximin appears to reduce bacterial virulence and pathogenicity by inhibiting bacterial translocation across the gastrointestinal epithelial lining. Rifaximin was shown to decrease bacterial adherence to epithelial cells and subsequent internalization in a bacteria- and cell type-specific manner, without an alteration in bacterial counts, but with a down-regulation in epithelial proinflammatory cytokine expression. Rifaximin also appears to modulate gut-immune signaling. In animal models of inflammatory bowel disease, rifaximin produced therapeutic effects by activating the pregnane X receptor and thereby reducing levels of the proinflammatory transcription factor nuclear factor κB. Therefore, for a given disease state, rifaximin may act through several mechanisms of action to exert its therapeutic effects. Clinically, rifaximin 600 mg/d significantly reduced symptoms of travelers' diarrhea (eg, time to last unformed stool vs placebo [32.0 hours vs 65.5 hours, respectively; P=.001]). For the prevention of hepatic encephalopathy recurrence, data indicate that treating 4 patients with rifaximin 1100 mg/d for 6 months would prevent 1 episode of hepatic encephalopathy. For diarrhea-predominant irritable bowel syndrome, a significantly greater percentage (40.7%) of patients treated with rifaximin 1650 mg/d for 2 weeks experienced adequate global irritable bowel syndrome symptom relief vs placebo (31.7%; P<.001). Rifaximin may be best described as a gut microenvironment modulator with cytoprotection properties, and further studies are needed to determine whether these putative mechanisms of action play a direct role in clinical outcomes. © 2015 Mayo Foundation for Medical Education and Research. Source


Edwards M.S.,Baylor College of Medicine | Gonik B.,Wayne State University
Vaccine | Year: 2013

The development of a group B streptococcal (GBS) glycoconjugate vaccine and its upcoming evaluation in a phase 3 trial in pregnant women highlight the importance of defining the anticipated impact of GBS vaccination upon the broad spectrum of GBS-related perinatal morbidity and mortality. We present the specific pregnancy-associated and neonatal conditions attributable, at least in part, to GBS in high and lower income countries. We offer a rationale to support our contention that implementation of GBS glycoconjugate immunization during pregnancy will reduce the global burden of GBS-related morbidity and mortality in pregnant women and their infants. © 2012 Elsevier Ltd. Source


Caulfield T.,University of Alberta | McGuire A.L.,Baylor College of Medicine
Annual Review of Medicine | Year: 2012

Direct-to-consumer (DTC) genetic testing has attracted a great amount of attention from policy makers, the scientific community, professional groups, and the media. Although it is unclear what the public demand is for these services, there does appear to be public interest in personal genetic risk information. As a result, many commentators have raised a variety of social, ethical, and regulatory issues associated with this emerging industry, including privacy issues, ensuring that DTC companies provide accurate information about the risks and limitations of their services, the possible adverse impact of DTC genetic testing on healthcare systems, and concern about how individuals may interpret and react to genetic risk information. © 2012 by Annual Reviews. All rights reserved. Source


Hotez P.J.,Baylor College of Medicine | Hotez P.J.,The Texas Institute | Hotez P.J.,Rice University
PLoS Neglected Tropical Diseases | Year: 2013

The concept of the neglected tropical diseases (NTDs) was established in the aftermath of the Millennium Development Goals. Here, we summarize the emergence of several new post-2010 global health documents and policies, and how they may alter the way we frame the world's major NTDs since they were first highlighted. These documents include a new Global Burden of Disease 2010 Study that identifies visceral leishmaniasis and food-borne trematode infections as priority diseases beyond the seven NTDs originally targeted by preventive chemotherapy, a London Declaration for access to essential medicines, and a 2013 World Health Assembly resolution on NTDs. Additional information highlights an emerging dengue fever pandemic. New United Nations resolutions on women and the non-communicable diseases (NCDs) have not yet embraced NTDs, which may actually be the most common afflictions of girls and women and represent a stealth cause of NCDs. NTDs also have important direct and collateral effects on HIV/AIDS and malaria, and there is now a robust evidence base and rationale for incorporating NTDs into the Global Fund to Fight AIDS, Tuberculosis, and Malaria. "Blue marble health" is an added concept that recognizes a paradoxical NTD disease burden among the poor living in G20 (Group of Twenty) and other wealthy countries, requiring these nations to take greater ownership for both disease control and research and development. As we advance past the year 2015, it will be essential to incorporate global NTD elimination into newly proposed Sustainable Development Goals. © 2013 Peter J. Hotez. Source


Kosten T.A.,Baylor College of Medicine
Pharmacology Biochemistry and Behavior | Year: 2011

Genetic studies indicate that alcohol consumption associates with expression of the P2rx4 gene, a gene that codes for the P2X 4 receptor. This receptor is a subtype in the purinergic system of ligand-gated ion channels that when activated exerts excitatory effects in CNS. P2X 4 function is inhibited by alcohol and P2X 4 receptors are modulated positively by the antiparasitic agent, ivermectin. Two experiments were performed to test the ability of ivermectin to alter the behavioral effects of alcohol in rats. After alcohol exposure was achieved via the "drinking in the dark" procedure, separate groups of Sprague-Dawley rats were trained to lever press for either alcohol (10% ethanol/2% sucrose) or sucrose (3%) solutions in operant chambers. Rats were tested for maintenance of operant self-administration under a progressive ratio condition (Experiment 1) and for reinstatement of extinguished responding induced by solution presentation (Experiment 2) after ivermectin (0; 1-10 mg/kg; IP) administration. Ivermectin decreased the amount of work that the animal performed to obtain reinforcers in the maintenance study, particularly in the group reinforced with alcohol, and tended to decrease reinstated lever press responding. Conditioned approach behavior (head entries) was significantly reduced by ivermectin in both experiments. Reduction in motor activity was seen during the longer maintenance sessions but not in the shorter reinstatement sessions. Results suggest some support for ivermectin-like drugs as potential treatment agents for alcohol dependence. Caution is warranted due to modest specificity on behavior reinforced by alcohol, some reduction in general activity levels, and the lack of dose-response effects. © 2011 Elsevier Inc. All rights reserved. Source


Shetty M.K.,Baylor College of Medicine
Seminars in Ultrasound, CT and MRI | Year: 2010

This article reviews the radiation risks to the developing fetus when exposed in utero to diagnostic radiological procedures. The discussion focuses primarily on abdominal computed tomography as this is the examination that delivers the highest radiation dose to the fetus among the diagnostic radiological procedures performed during pregnancy. The review describes the common indications for abdominal computed tomography, the biological risks to the developing fetus, radiation dose, and dose modulation techniques as well as the need for establishing a pregnancy policy to guide performance of radiological investigations in pregnancy. © 2010 Elsevier Inc. All rights reserved. Source


Street Jr. R.L.,Texas A&M University | Street Jr. R.L.,Baylor College of Medicine | Haidet P.,Pennsylvania State University
Journal of General Internal Medicine | Year: 2011

BACKGROUND: An important feature of patient-centered care is physician understanding of their patients' health beliefs and values. OBJECTIVE: Determine physicians' awareness of patients' health beliefs as well as communication, relationship, and demographic factors associated with better physician understanding of patients' illness perspectives. DESIGN: Cross-sectional, observational study. RESEARCH PARTICIPANTS: A convenience sample of 207 patients and 29 primary care physicians from 10 outpatient clinics. APPROACH AND MEASURES: After their consultation, patients and physicians independently completed the CONNECT instrument, a measure that assesses beliefs about the degree to which the patient's condition has a biological cause, is the patient's fault, is one the patient can control, has meaning for the patient, can be treated with natural remedies, and patient preferences for a partnership with the physician. Physicians completed the measure again on how they thought the patient responded. Active patient participation (frequency of questions, concerns, acts of assertiveness) was coded from audio-recordings of the consultations. Physicians' answers for how they thought the patient responded to the health belief measure were compared to their patients' actual responses. Degree of physician understanding of patients' health beliefs was computed as the absolute difference between patients' health beliefs and physicians' perception of patients' health beliefs. KEY RESULTS: Physicians' perceptions of their patients' health beliefs differed significantly (P<0.001) from patients' actual beliefs. Physicians also thought patients' beliefs were more aligned with their own. Physicians had a better understanding of the degree to which patients believed their health conditions had personal meaning (p=0.001), would benefit from natural remedies (p=0.049), were conditions the patient could control (p=0.001), and wanted a partnership with the doctor (p=0.014) when patients more often asked questions, expressed concerns, and stated their opinions. Physicians were poorer judges of patients' beliefs when patients were African-American (desire for partnership) (p=0.013), Hispanic (meaning) (p=0.075), or of a different race (sense of control) (p=0.024). CONCLUSIONS: Physicians were not good judges of patient's health beliefs, but had a substantially better understanding when patients more actively participated in the consultation. Strategies for increasing physicians' awareness of patients' health beliefs include preconsultation assessment of patients' beliefs, implementing culturally appropriate patient activation programs, and greater use of partnership-building to encourage active patient participation. © 2010 Society of General Internal Medicine. Source


Samson S.L.,Baylor College of Medicine
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | Year: 2014

Cushing's disease is a rare condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma and associated with debilitating complications and excess mortality. Transsphenoidal adenomectomy is generally first-line treatment but is contraindicated in some patients and associated with significant post-surgical recurrence. While there are few data to support long-term use of most pharmacologic treatments, pasireotide (a multireceptor-targeted somatostatin analog) recently demonstrated sustained benefit in a 12-month, multicenter, Phase III trial and in 2 long-term extension studies. The Phase III trial (N=162) demonstrated reductions in urinary free cortisol in most patients, with durable treatment effect over 12 months. Biochemical improvement was generally paralleled by reductions in Cushing's-related signs and symptoms and enhanced health-related quality of life. Long-term treatment was evaluated in 58 patients who entered a planned 12-month extension phase. Reductions in urinary free cortisol remained stable throughout the extension, with further improvements noted in clinical signs and symptoms. Similar results were reported in the smaller Phase II extension (N=18; median treatment duration, 9.7 months; range, 2 months-4.8 years). Case reports have recently emerged demonstrating sustained disease control for upto 7 years in some patients. Safety considerations for long-term medical treatment with pasireotide are generally similar to those for other somatostatin analogs, except for the incidence and severity of hyperglycemia. Most patients experience new or worsening hyperglycemia with pasireotide treatment. Expert recommendations for treatment of pasireotide-associated hyperglycemia have recently been published and new studies are planned to elucidate the optimal treatment approach for pasireotide-associated hyperglycemia. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York. Source


Garber A.J.,Baylor College of Medicine
Diabetes Care | Year: 2011

The results achieved with long-acting GLP-1 receptor agonists appear to be superior to those achieved with short-acting GLP-1 receptor agonists, with greater improvements in glycemic control after once-daily liraglutide treatment compared with twice-daily exenatide. Furthermore, exenatide LAR provided better glycemic control than exenatide with comparable weight loss. Trials are ongoing to evaluate the efficacy of exenatide LAR when compared with insulin glargine in patients with type 2 diabetes on a metformin background with or without prior sulfonylurea treatment (DURATION-3; NCT00641056) or used as monotherapy in drug-naive patients (DURATION-4; NCT00676338). As a drug class, long-acting GLP-1 receptor agonists increase glycemic control in patients with type 2 diabetes with a low risk of hypoglycemia because of their glucose-dependent mechanism of action. This drug class has also been demonstrated to promote weight loss and reduce SBP, which could be of benefit to patients with type 2 diabetes, reducing their cardiovascular risk. Furthermore, although nausea is a common side effect with long-acting GLP-1 receptor agonists, it tends to be transient and, overall, long-acting GLP-1 receptor agonists are generally well tolerated. Thus, long-acting GLP-1 receptor agonists may provide an effective therapeutic option for individuals with type 2 diabetes and are well placed to meet the standard of care guidelines set by the ADA in treating more than just blood glucose. © 2011 by the American Diabetes Association. Source


Goodell M.A.,Baylor College of Medicine
Blood | Year: 2013

Genetic analysis of hematologic malignancies over the past 5 years has revealed abundant mutations in epigenetic regulators in all classes of disorders. Here, we summarize the observations made within our review series on the role of epigenetics in hematology. We highlight the clinical implications of mutations in epigenetic regulators and outline what we envision are some of the major areas that merit future research. Recent findings may have immediate prognostic value, but also offer new targets for drug development. However, the pleiotropic action of these regulators indicates caution is warranted and argues for investment in understanding of their underlying mechanisms of action as we proceed to exploit these findings for the benefit of patients. Source


Nakata P.A.,Baylor College of Medicine
Frontiers in Biology | Year: 2012

Crystals of calcium oxalate have been observed among members from most taxonomic groups of photosynthetic organisms ranging from the smallest algae to the largest trees. The biological roles for calcium oxalate crystal formation in plant growth and development include high-capacity calcium regulation, protection against herbivory, and tolerance to heavy metals. Using a variety of experimental approaches researchers have begun to unravel the complex mechanisms controlling formation of this biomineral. Given the important roles for calcium oxalate formation in plant survival and the antinutrient and pathological impact on human health through its presence in plant foods, researchers are avidly seeking a more comprehensive understanding of how these crystals form. Such an understanding will be useful in efforts to design strategies aimed at improving the nutritional quality and production of plant foods. © 2012 Higher Education Press and Springer-Verlag Berlin Heidelberg. Source


Vierling J.M.,Baylor College of Medicine
Clinical Gastroenterology and Hepatology | Year: 2015

Autoimmune hepatitis (AIH) occurs globally and afflicts children and adults of all ethnicities and races. 1,2 The current hypothesis is that AIH results from hepatocyte injury (caused by environmental exposure to viruses or xenobiotics) that triggers a dysregulated, adaptive immune attack against hepatocyte autoantigens in immunogenetically susceptible persons. 3-5 AIH is characterized by female predilection, elevated aminotransferases, non-species or organ-specific autoantibodies, increased levels of ?-globulin or immunoglobulin (Ig) G, and interface hepatitis on liver biopsy. 1,3,6 AIH presents rarely as acute liver failure (ALF) and infrequently as acute hepatitis. At diagnosis, 70%-80% of patients have chronic hepatitis, and approximately 33% have cirrhosis, 1,7 indicating that AIH commonly progresses undiagnosed and untreated for prolonged periods. Cirrhotic patients are at risk for complications of portal hypertension, liver failure, and, in a minority, hepatocellular carcinoma (HCC). AIH is divided into types 1 and 2 (Table 1), which are based on signature expressions of autoantibodies (Table 2). Autoantigenic B- and T-cell epitopes have been identified only for the less frequent type 2. Type 1 AIH can present at any age but is increasingly diagnosed in older women.8 In contrast, the peak incidence of type 2 AIH occurs in children and adolescents. 9 In European adults, the prevalence of type 2 AIH is higher in the South than in the North. 10 Neither the incidence nor prevalence of type 2 AIH in the United States is known, largely because of failure to test for anti-liver-kidney microsomal antibody 1 (LKM1). 3 A minority of AIH patients develop putative overlap syndromes (OS) with the cholestatic diseases primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), 3,6,11 but both diagnostic criteria and therapy remain controversial.12. Source


Singal A.G.,University of Texas Southwestern Medical Center | El-Serag H.B.,Baylor College of Medicine
Clinical Gastroenterology and Hepatology | Year: 2015

The epidemiology of hepatocellular carcinoma (HCC) is characterized by dynamic temporal trends, several major established (i.e., HCV, HBV, alcohol) and emerging (i.e., diabetes, obesity, NAFLD) risk factors. Epidemiologic studies and clinical trials have identified additional demographic, clinical, pharmacological, genetic and life style factors that further affect or modify the likelihood of HCC and can be used in clinical practice to identify at-risk patients (i.e., risk stratification or prognostic algorithms) that can be targeted for prevention and early detection programs. These studies have also paved the way toward several well established preventive measures including HBV vaccination, HBV treatment, HCV treatment and HCC surveillance, and potential chemoprevention using statins, metformin or coffee. However, the effectiveness of HCC prevention in clinical practice and at the population level has lagged behind due to patient, provider, system, and societal factors. The Quality in the Continuum of Cancer Care model provides a framework for evaluating the HCC prevention processes, including potential failures that create a gap between efficacy and effectiveness. © 2015 AGA Institute. Source


Lapteva N.,Baylor College of Medicine | Huang X.F.,University of Southern California
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: To date cancer immunotherapy has only achieved limited clinical efficacy, thus more efficient immunotherapeutic approaches need to be explored. The CC chemokine CCL5 plays a role in chemoattraction and activation of immune cells implying its potential clinical application as an adjuvant for boosting anti-tumor immunity, although an effect on carcinogenesis and tumor cell invasiveness is also reported to be associated with CCL5. Areas covered in this review: Recent progress in exploiting CCL5 as an adjuvant for cancer prevention and treatment, and updated understanding on how CCL5 is involved in tumor invasiveness and carcinogenesis. What the reader will gain: CCL5 represents a natural adjuvant for enhancing anti-tumor immune responses. However, animal experiments and clinical reports suggest that CCL5 plays a role in carcinogenesis and invasiveness of tumor cells. Therefore, a CCL5-based cancer therapeutic approach needs to avoid the CCL5-associated potential detrimental effects. Take home message: CCL5 has a pre-eminent role in chemotaxis and activation of a wide spectrum of immune cells. CCL5 functions as an adjuvant to boost anti-tumor immunity by diverse protocols such as co-immunization of recombinant CCL5 protein with tumor-associated antigen, vaccination with CCL-5-expressing tumor cells, or viral vector delivery of CCL5 cDNA into growing tumor. CCL5 may also promote tumor cell survival, proliferation and invasion by different mechanisms. © 2010 Informa UK Ltd. Source


An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development. Source


Renin-angiotensin-aldosterone system (RAAS) inhibitors in combination with other antihypertensive drugs (eg, calcium channel blockers [CCBs] and/or diuretics) are a preferred treatment option for managing uncontrolled hypertension in high-risk patients with chronic kidney disease (CKD), diabetes, or heart failure because RAAS inhibitors provide cardiorenal benefits in addition to lowering blood pressure (BP). However, when prescribing antihypertensive therapies to high-risk patients, physicians must be aware of the risks of treatment-related adverse events of hyperkalemia and peripheral edema associated with RAAS inhibitors and CCBs, respectively. This review discusses the use of single-pill combination antihypertensive therapy to optimize BP control in high-risk patients with CKD, diabetes, and/or heart failure and provides strategies for preventing and managing hyperkalemia and peripheral edema in this group. Single-pill combination therapy can utilize different classes of antihypertensive drugs to reduce BP while mitigating the risks of treatment-related adverse events, reducing pill burden, lowering medical cost, and improving patient compliance. © 2012 Wiley Periodicals, Inc. Source


Muntz J.,Baylor College of Medicine
American Journal of Surgery | Year: 2010

Background: Venous thromboembolism (VTE) is a major cause of mortality and morbidity in patients after major surgery. The US Acting Surgeon General issued a "call to action" to reduce the number of VTE cases nationwide. Data sources: PubMed literature searches were performed to identify original studies. Results and conclusions: Noncompliance with VTE guidelines is common in clinical practice. Thromboprophylaxis is frequently stopped on discharge, not meeting recommendations for standard-duration prophylaxis (710 days) because of shorter hospital stays or for extended-duration prophylaxis (1035 days). Appropriate pharmacologic prophylaxis options for orthopedic surgery patients include the lowmolecular-weight heparins (LMWHs), fondaparinux, or warfarin (1035 days). For patients undergoing abdominal surgery for cancer, the LMWHs are recommended beyond hospitalization (up to 28 days). Performance measures should help establish VTE-prevention policies that close the gap between guideline recommendations and clinical practice in a greater number of hospitals. © 2010 Elsevier Inc. Source


El-Serag H.B.,Baylor College of Medicine
Gastroenterology | Year: 2012

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. © 2012 AGA Institute. Source


Marino J.S.,University of Toledo | Xu Y.,Baylor College of Medicine | Hill J.W.,University of Toledo
Trends in Endocrinology and Metabolism | Year: 2011

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. © 2011 Elsevier Ltd. Source


Timchenko L.,Baylor College of Medicine
International Journal of Biochemistry and Cell Biology | Year: 2013

Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in patients' tissues by targeting RNA-binding proteins such as CUG-binding protein 1 (CUGBP1) and Muscle blind-like protein 1 (MBNL1). Despite overwhelming evidence showing the critical role of RNA-binding proteins in DM1 and DM2 pathologies, the downstream pathways by which these RNA-binding proteins cause muscle wasting and muscle weakness are not well understood. This review discusses the molecular pathways by which DM1 and DM2 mutations might cause muscle atrophy and describes progress toward the development of therapeutic interventions for muscle wasting and weakness in DM1 and DM2. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved. Source


Davila J.A.,Baylor College of Medicine
American Journal of Gastroenterology | Year: 2010

Known risk factors for hepatocellular carcinoma (HCC) include hepatitis C, hepatitis B, and alcoholic liver disease. Several studies have examined diabetes as a risk factor for HCC because of its association with fatty liver disease and non-alcoholic steatohepatitis. The current study by Tung et al. found that neither diabetes nor overweight was a risk factor for HCC. Results were consistent using both a cross-sectional and a case-control study approach. Findings from this study suggest that diabetes and overweight alone are not adequate to increase the risk of HCC in the absence of concomitant viral hepatitis or liver disease. © 2010 by the American College of Gastroenterology. Source


Fram N.R.,University of California at Los Angeles | Masket S.,University of California at Los Angeles | Wang L.,Baylor College of Medicine
Ophthalmology | Year: 2015

Purpose To compare the accuracy of intraoperative aberrometry technology and the Fourier-domain optical coherence tomography (OCT)-based intraocular lens (IOL) formula for IOL power calculation in eyes undergoing cataract surgery after previous laser vision correction (LVC) compared with established methods. Design Retrospective consecutive case series. Participants Patients undergoing cataract surgery with a history of LASIK or photorefractive keratectomy. Methods The IOL power was estimated preoperatively using the IOLMaster 500 (Carl Zeiss Meditec, Dublin, CA) to calculate the Haigis-L and Masket regression formulae (when prior data were available), and the Optovue RTVue (Optovue Inc, Fremont, CA) spectral domain OCT was used to obtain the Fourier-domain OCT-based IOL formula. The Optiwave Refractive Analysis (ORA) System (WaveTec Vision Systems Inc, Aliso Viejo, CA) wavefront aberrometer measured aphakic refractive measurements intraoperatively and calculated the IOL power with a modified vergence formula. Comparative analysis was done for predictive accuracy of IOL power determination using 2 conventional methods and 2 new technologies: the Haigis-L formula, Masket regression formula, ORA intraoperative aberrometry, and Optovue RTVue Fourier-domain OCT-based IOL formula. Patients without historical data (N = 39) were compared using 3 methods (Haigis-L, ORA, and Optovue), and patients with historical data (N = 20) were compared using all methods (Masket regression formula, Haigis-L, ORA, and Optovue). Main Outcome Measures Median absolute error (MedAE), mean absolute error (MAE), and percentage of eyes within ±0.25, ±0.50, ±0.75, and ±1.00 diopters (D) of refractive prediction error. Results A total of 39 eyes of 29 patients without historical data were analyzed separately from 20 eyes of 20 patients with historical data. In the group without historical data (N = 39), 49% of eyes were within ±0.25 D, 69% to 74% of eyes were within ±0.50 D, 87% to 97% of eyes were within ±0.75 D, and 92% to 97% of eyes were within ±1.00 D of targeted refractive IOL power prediction error. The MedAE was 0.26 D for Haigis-L, 0.29 D for ORA, and 0.28 D for Optovue. The MAE was 0.37 D for Haigis-L, 0.34 D for ORA, and 0.39 D for Optovue. In the group with historical data (N = 20), 35% to 70% of eyes were within ±0.25 D, 60% to 85% of eyes were within ±0.50 D, 80% to 95% of eyes were within ±0.75 D, and 90% to 95% of eyes were within ±1.00 D of targeted refractive IOL power prediction error. The MedAE was 0.21 D for the Masket regression formula, 0.22 D for the Haigis-L formula, 0.25 D for ORA, and 0.39 for Optovue. The MAE was 0.28 D for the Masket regression formula, 0.31 D for the Haigis-L formula, 0.37 D for ORA, and 0.44 D for Optovue. There was no statistically significant difference among the methods. Conclusions Newer technology to estimate IOL power calculations in eyes after LVC shows promising results when compared with established methods. © 2015 American Academy of Ophthalmology. Source


Dietrich J.E.,Baylor College of Medicine
Current Opinion in Obstetrics and Gynecology | Year: 2010

PURPOSE OF REVIEW: Limited evidence is available on the diagnosis and management of adenomyosis in adolescents. This review highlights the postulated pathophysiologic mechanisms, the prevalence of the condition among adult women and new reports of adenomyosis or adenomyotic cysts occurring in adolescents. Diagnostic criteria as well as treatment options are discussed. RECENT FINDINGS: Very few cases of adenomyosis conditions are reported in the literature, and management schemes differed with regard to medical versus surgical approaches. It is clear from reports in adolescents presenting with severe refractory dysmenorrhea that MRI can help establish a diagnosis of adenomyosis, possibly avoiding or delaying surgery to allow for medical management in some cases. SUMMARY: Adenomyosis may be present during adolescence. Because mechanisms of disease appear to be similar, goals of treatment in the adolescent are toward fertility preservation. Medical management appears to be a good option for certain types of adenomyosis, although surgery may be appropriate in the case of well circumscribed adenomyotic cysts, adenomyomas or noncommunicating horns. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Ziats M.N.,U.S. National Institutes of Health | Ziats M.N.,University of Cambridge | Ziats M.N.,Baylor College of Medicine | Rennert O.M.,U.S. National Institutes of Health
Molecular Psychiatry | Year: 2014

We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders. © 2014 Macmillan Publishers Limited All rights reserved. Source


Liu K.,University of Wisconsin - Madison | Liu K.,Baylor College of Medicine | Bittner A.N.,University of Wisconsin - Madison | Wang J.D.,University of Wisconsin - Madison
Current Opinion in Microbiology | Year: 2015

Bacteria produce guanosine tetraphosphate and pentaphosphate, collectively named (p)ppGpp, in response to a variety of environmental stimuli. These two remarkable molecules regulate many cellular processes, including the central dogma processes and metabolism, to ensure survival and adaptation. Work in Escherichia coli laid the foundation for understanding the molecular details of (p)ppGpp and its cellular functions. As recent studies expand to other species, it is apparent that there exists considerable variation, with respect to not only (p)ppGpp metabolism, but also to its mechanism of action. From an evolutionary standpoint, this diversification is an elegant example of how different species adapt a particular regulatory network to their diverse lifestyles. © 2015 Elsevier Ltd. Source


El Sahly H.,Baylor College of Medicine
Expert Review of Vaccines | Year: 2010

Approximately 70 years passed between the licensing of alum salts as vaccine adjuvants and that of MF59™ MF59, an oil-in-water emulsion, is currently licensed for use in the elderly as an adjuvant in seasonal influenza vaccines. Its mechanism of action is not fully understood, but enhancement of the interaction between the antigen and the dendritic cell seems to be involved. When used with seasonal influenza vaccines, an increase occurs in the hemagglutination inhibition antibody titers against some, but not all, seasonal vaccine influenza strains. The adjuvant effect is more pronounced when MF59 is combined with novel influenza antigens such as H9 and H5. The use of the adjuvant is associated with an increase in the frequency of local and systemic early post-vaccine adverse events (3-7 days), but no increase in adverse events was observed thereafter. Currently, MF59 is under evaluation as an adjuvant with other antigens such as pandemic influenza antigens and cytomegalovirus antigens. © 2010 Expert Reviews Ltd. Source


Shah T.,Baylor College of Medicine
Methodist DeBakey cardiovascular journal | Year: 2013

Peripartum cardiomyopathy is a rare and potentially fatal disease. Though approximately half of the patients recover, the clinical course is highly variable and some patients develop refractory heart failure and persistent left ventricular systolic dysfunction. It is diagnosed when women present with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. Etiology remains unclear, and treatment is similar to other cardiomyopathies and includes evidence-based standard heart failure management strategies. Experimental strategies such as intravenous immunoglobulin and bromocriptine await further clinical validation. Source


Greenbaum M.P.,Baylor College of Medicine
Cold Spring Harbor perspectives in biology | Year: 2011

Stable intercellular bridges are a conserved feature of gametogenesis in multicellular animals observed more than 100 years ago, but their function was unknown. Many of the components necessary for this structure have been identified through the study of cytokinesis in Drosophila; however, mammalian intercellular bridges have distinct properties from those of insects. Mammalian germ cell intercellular bridges are composed of general cytokinesis components with additional germ cell-specific factors including TEX14. TEX14 is an inactive kinase essential for the maintenance of stable intercellular bridges in gametes of both sexes but whose loss specifically impairs male meiosis. TEX14 acts to impede the terminal steps of abscission by competing for essential component CEP55, blocking its interaction in nongerm cells with ALIX and TSG101. Additionally, TEX14-interacting protein RBM44, whose localization in stabile intercellular bridges is limited to pachytene and secondary spermatocytes, may participate in processes such as RNA transport but is nonessential to the maintenance of intercellular bridge stability. Source


Thompson D.,Baylor College of Medicine
Journal of Diabetes Science and Technology | Year: 2012

Serious video games for health are designed to entertain while changing a specific health behavior. This article identifies behavioral principles that can guide the development of serious video games focused on changing a variety of health behaviors, including those attempting to decrease risk of obesity and type 2 diabetes. Guidelines discussed include how to develop video games that provide a solid foundation for behavior change by enhancing a player's knowledge and skill, ways in which personal mastery experiences can be incorporated into a video game environment, using game characters and avatars to promote observational learning, creating personalized experiences through tailoring, and the importance of achieving a balance between "fun-ness" and "seriousness." The article concludes with suggestions for future research needed to inform this rapidly growing field. © Diabetes Technology Society. Source


Goldberg D.S.,Baylor College of Medicine
Perspectives in Biology and Medicine | Year: 2010

Many ethical and policy analyses of the devastating undertreatment of chronic pain leave unaddressed the role played by stigma, even though the notion that such stigma exists is well documented.This article examines the social and cultural roots of the stigma of chronic pain in American society. I document the long history of illness stigma in Western societies as a way of illustrating the power of this meaningmaking construct, and I use the Book of Job as a framework for understanding the deep link between sin and suffering in the context of illness and chronic pain in the United States. Unfortunately, while illness stigma can be ameliorated, there is little evidence of such progress in the undertreatment and stigmatization of chronic pain sufferers, and I explain some of the reasons why the best evidence does not demonstrate much improvement. I conclude by sketching some recommendations for diminishing the stigmatization of the chronic pain sufferer, and warn that the focus on altering the opioid regulatory regime is unlikely to have the desired impact in reducing the suffering of millions of Americans. © 2010 by The Johns Hopkins University Press. Source


Melcher A.,St Jamess Hospital | Parato K.,Ottawa Hospital Research Institute | Rooney C.M.,Baylor College of Medicine | Bell J.C.,Ottawa Hospital Research Institute
Molecular Therapy | Year: 2011

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers. Source


Wilhelmus K.R.,Baylor College of Medicine
Cochrane database of systematic reviews (Online) | Year: 2010

Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis. To compare the relative effectiveness of antiviral agents, interferon, and corneal débridement in the treatment of acute HSV epithelial keratitis. We searched CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (January 1950 to October 2010), EMBASE (January 1980 to October 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2010), Zetoc (British Library's Electronic Table of Contents), System for Information on Grey Literature in Europe (openSIGLE), Biosciences Information Service (BIOSIS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), Japan Information Center of Science and Technology (JICST-EPlus), and China Academic Journals database (CAJ) via China National Knowledge Infrastructure (CNKI) with citations confirmed using China/Asia On Demand (COAD). There were no language or date restrictions in the search for trials. All databases except CNKI and COAD were last searched on 27 October 2010, CNKI and COAD were searched on 1 April 2010. We also searched literature digests, conference proceedings and reference lists. Of 152 eligible studies,106 comparative treatment trials involving 5872 eyes with dendritic or geographic epithelial keratitis were analysed for corneal healing over two weeks. Interventions were compared at 14 days after trial enrolment by calculating a risk ratio (RR) that was adjusted with indirect RR, assessed by an inconsistency index (I(2) ) and supplemented by a seven-day RR and a hazard ratio (HR). Idoxuridine, though uncertainly better in healing outcome than control because of few trials with 14-day follow up, allowed earlier corneal re-epithelialisation. Vidarabine resulted in a significantly better outcome than placebo in one trial (RR 1.96; 95% CI 1.10 to 3.49). Compared to idoxuridine, in combined direct and indirect analyses, vidarabine (RR 1.11; 95% CI 1.03 to 1.19), trifluridine (RR 1.31; 95% CI 1.20 to 1.42), acyclovir (RR 1.23; 95% CI 1.16 to 1.31), brivudine (RR 1.38; 95% CI 1.18 to 1.61), and ganciclovir (RR 1.40; 95% CI 1.25 to 1.57) were significantly more effective. Trifluridine (RR 1.12; 95% CI 1.04 to 1.21) and acyclovir (RR 1.11; 95% CI 1.05 to 1.19) appeared more effective than vidarabine. No significant differences were found in comparisons between acyclovir, trifluridine and brivudine. The comparison of ganciclovir to acyclovir was limited by heterogeneity and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as topical antiviral therapy. Compared to antiviral monotherapy, the combination of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with débridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes but may have accelerated healing. The corneal epithelial healing outcome was improved when antiviral therapy was added to débridement (RR 1.21; 95% CI 1.04 to 1.42). Trifluridine and acyclovir are more effective than idoxuridine or vidarabine, and similar in therapeutic effectiveness. Brivudine and ganciclovir are at least as effective as acyclovir. While not improving outcome, the combination of interferon and an antiviral agent may speed healing. The effectiveness of corneal epithelial débridement is improved by an antiviral agent. Source


Giordano T.P.,Baylor College of Medicine
Topics in Antiviral Medicine | Year: 2011

Poor retention in HIV disease care is a common, modifiable risk factor associated with poor outcomes, including higher rates of antiretroviral therapy failure, increased HIV transmission risk behaviors, and worse survival. Predictors of poor retention include younger age, female sex, racial or ethnic minority status, low socioeconomic status, no usual source of health care, less advanced HIV disease, fewer non-HIV-related comorbidities, and greater unmet psychosocial needs. Thus far, there have been few published randomized trials of interventions to improve retention. The fact that most clinics are understaffed and underresourced in a flat funding environment raises serious questions about the translation, dissemination, and sustainability of interventions found to be successful in the research setting. Efforts to improve retention in care should incorporate informational, motivational, and behavioral skills components. Practical steps can be taken by clinics to improve retention. This article summarizes a lecture by Thomas P. Giordano, MD, MPH, at the 13th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in Washington, DC, in August 2010. © 2011, IAS-USA. Source


Tamimi A.,Pfizer | Serdarevic D.,Pfizer | Hanania N.A.,Baylor College of Medicine
Respiratory Medicine | Year: 2012

Asthma and COPD are two chronic inflammatory disorders of the airway characterized by airflow limitation. While many similarities exist between these two diseases, they are pathologically distinct due to the involvement of different inflammatory cells; predominantly neutrophils, CD8 lymphocytes in COPD and eosinophils and CD4 lymphocytes in asthma. Cigarette smoking is associated with accelerated decline of lung function, increased mortality, and worsening of symptoms in both asthma and COPD. Furthermore, exposure to cigarette smoke can alter the inflammatory mechanisms in asthma to become similar to that seen in COPD with increasing CD8 cells and neutrophils and may therefore alter the response to therapy. Cigarette smoke exposure has been associated with a poor response to inhaled corticosteroids which are recommended as first line anti-inflammatory medications in asthma and as an add-on therapy in patients with severe COPD with history of exacerbations. While the main proposed mechanism for this altered response is the reduction of the histone deacetylase 2 (HDAC2) enzyme system, other possible mechanisms include the overexpression of GR-β, activation of p38 MAPK pathway and increased production of inflammatory cytokines such as IL-2, 4, 8, TNF-α and NF-Kß. Few clinical trials suggest that leukotriene modifiers may be an alternative to corticosteroids in smokers with asthma but there are currently no drugs which effectively reduce the progression of inflammation in smokers with COPD. However, several HDAC2 enhancers including low dose theophylline and other potential anti-inflammatory therapies including PDE4 inhibitors and p38 MAPK inhibitors are being evaluated. © 2011 Elsevier Ltd. All rights reserved. Source


Vaezi M.F.,Vanderbilt University | Pandolfino J.E.,Northwestern University | Vela M.F.,Baylor College of Medicine
American Journal of Gastroenterology | Year: 2013

Achalasia is a primary motor disorder of the esophagus characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis. This results in patients' complaints of dysphagia to solids and liquids, regurgitation, and occasional chest pain with or without weight loss. Endoscopic finding of retained saliva with puckered gastroesophageal junction or barium swallow showing dilated esophagus with birds beaking in a symptomatic patient should prompt appropriate diagnostic and therapeutic strategies. In this ACG guideline the authors present an evidence-based approach in patients with achalasia based on a comprehensive review of the pertinent evidence and examination of relevant published data. © 2013 by the American College of Gastroenterology. Source


Graham D.Y.,Baylor College of Medicine
Clinical Gastroenterology and Hepatology | Year: 2010

As an infectious disease, the approach to anti- Helicobacter pylori therapy differs from other common gastrointestinal conditions because treatment success of more than 90% to 95% should be expected and the reasons for treatment failure can always be understood. Neither comparisons with another regimen nor randomization are required to identify a highly successful therapy. Treatment success should be judged first in relation to outcome (ie, ≥95% or grade A). Inclusion of a known inferior regimen in a clinical trial is generally unethical. If the use of a known inferior drug is required by a regulatory agency, subjects must be given full and accurate information regarding expectations with each regimen; there can be no deceptions. Comparative trials should be restricted to highly successful treatments (ie, comparisons of different doses, durations, compliance, cost, and so forth). Success should be judged as ordered categories such as <85%, 85%-89%, 90%-94%, or ≥95% and statistically equivalent regimens with the same grade success (ie, 90%-94% [Grade B]) are inferior to those higher category (ie, ≥95% [Grade A]) regimens. Only grade A or B regimens should be prescribed. Here we discuss anti- H pylori eradication studies from the prospective of an infectious disease with the goal of providing recommendations regarding changes in approach and in reporting that should help resolve the ethical issues and make the results of clinical trials more useful to clinicians. © 2010 AGA Institute. Source


Trautner B.W.,Baylor College of Medicine
Nature Reviews Urology | Year: 2012

Asymptomatic bacteriuria (ABU) is a condition in which bacteria are present in a noncontaminated urine sample collected from a patient without signs or symptoms related to the urinary tract. ABU must be distinguished from symptomatic UTI by the absence of signs and symptoms compatible with UTI or by clinical determination that a nonurinary etiology accounts for the patient's symptoms. Interactions between the organism, the host, and the bladder environment determine whether bacteriuria leads to ABU or to UTI. ABU is a very common condition that is often treated unnecessarily with antibioticsg - it should be detected and treated in pregnant women and patients undergoing urologic surgery, but in most other patient groups, treatment does not confer benefit and can be harmful. A change in prescribing behavior for ABU has been achieved through several fairly high-intensity interventions, such as interactive educational sessions for physicians, but whether these improvements persist beyond the study period is not known. Further research is needed to determine whether screening for and treatment of ABU is beneficial in patients with renal transplants, patients with orthotopic neobladders, patients undergoing prosthetic joint implantation, and patients with neutropenia. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Hadzic N.,Kings College | Finegold M.J.,Baylor College of Medicine
Clinics in Liver Disease | Year: 2011

Management of pediatric liver tumors has significantly improved over the last 2 decades. The management options for hepatocelluar carcinoma (HCC) are not well defined. In the pediatric context, the main clinical aims are to reduce chemotherapy toxicity (predominantly ototoxicity and nephrotoxicity) in children treated for hepatoblastoma and to investigate additional modes of treatment for HCC. An increasing number of children develop HCC in the background of chronic liver disease, and screening methods need to be better observed. © 2011 Elsevier Inc. Source


Becher A.,Oxford PharmaGenesis Ltd | El-Serag H.,Baylor College of Medicine
Alimentary Pharmacology and Therapeutics | Year: 2011

Background: Some patients with gastro-oesophageal reflux disease (GERD) experience persistent reflux symptoms on proton pump inhibitor (PPI) therapy. The relationship between persistent reflux symptoms and health-related quality of life (HRQoL) is unclear. Aim: To assess the relationship between persistent reflux symptoms on PPI therapy and HRQoL in patients with GERD. Methods: Systematic searches were conducted in PubMed and Embase. Eligible studies had to have used psychometrically evaluated patient reported outcome instruments to assess HRQoL. Results: Nine studies were included; supplementary data were obtained for four of these. The effect of persistent reflux symptoms despite PPI therapy on physical HRQoL was assessed in seven studies and that on mental HRQoL in five studies. Compared with patients whose reflux symptoms responded to PPIs, those with persistent symptoms had, on average, 8-16% lower scores for physical health (five studies) and 2-12% lower scores for mental health (three studies). Three studies included data on the effect of baseline HRQoL on subsequent symptomatic response to PPI therapy. Patients with persistent symptoms had clinically relevant lower psychological well-being at baseline compared with those whose symptoms responded to PPIs (average score difference: 7%; two studies). High anxiety levels at baseline seemed to be an important aspect of persistent symptoms. Conclusions: Persistent reflux symptoms on PPI therapy are associated with reduced physical and mental HRQoL, while reduced mental HRQoL at baseline seems to impair symptomatic response to PPIs. HRQoL may need to be considered alongside reflux symptom frequency and severity when making decisions about disease management. © 2011 Blackwell Publishing Ltd. Source


Only a few decades ago, most experts, including this writer, would have recommended against AVR for asymptomatic patients with AS because the risk of early surgery exceeded its benefit. However, since then, we have become capable of recognizing asymptomatic patients at higher than average risk for whom AVR appears prudent, whereas the risk of both AVR and of postoperative valve-related complications has diminished. Thus, it appears reasonable to perform AVR for asymptomatic patients with an aortic valve area <0.8 cm 2 who also have any of the following: (1) A positive exercise test, (2) heavy valve calcification, (3) documented rapid progression of AS from serial measurements, (4) excessive LVH, or (5) rising natriuretic peptides, providing the patient is referred to a surgical team with an established track record of excellent operative outcomes. Ultimately, a randomized trial could answer the question, but until such a trial is performed, we will have to continually wrestle with this issue using our best judgment on a case-by-case basis. © 2012 American Heart Association, Inc. Source


Wong L.-J.C.,Baylor College of Medicine
Seminars in Neurology | Year: 2012

White matter involvement has recently been recognized as a common feature in patients with multisystem mitochondrial disorders that may be caused by molecular defects in either the mitochondrial genome or the nuclear genes. It was first realized in classical mitochondrial syndromes associated with mitochondrial DNA (mtDNA) mutations, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Leigh's disease, and Kearns-Sayre's syndrome. Deficiencies in respiratory chain complexes I, II, IV, and V often cause Leigh's disease; most of them are due to nuclear defects that may lead to severe early-onset leukoencephalopathies. Defects in a group of nuclear genes involved in the maintenance of mtDNA integrity may also affect the white matter; for example, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by thymidine phosphorylase deficiency, Navajo neurohepatopathy (NNH) due to MPV17 mutations, and Alpers syndrome due to defects in DNA polymerase gamma (POLG). More recently, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) has been reported to be caused by autosomal recessive mutations in a mitochondrial aspartyl-tRNA synthetase, DARS2 gene. A patient with leukoencephalopathy and neurologic complications in addition to a multisystem involvement warrants a complete evaluation for mitochondrial disorders. A definite diagnosis may be achieved by molecular analysis of candidate genes based on the biochemical, clinical, and imaging results. © 2012 by Thieme Medical Publishers, Inc. Source


Morey L.C.,Texas A&M University | Skodol A.E.,University of Arizona | Oldham J.M.,The Menninger Clinic | Oldham J.M.,Baylor College of Medicine
Journal of Abnormal Psychology | Year: 2014

This study compared the perceived clinical utility of DSM-IV-TR personality disorder diagnoses (retained in DSM-5) with the alternative model presented in DSM-5 Section III, using a national sample of clinicians applying both systems to their own patients. A sample of 337 mental health clinicians (26% psychiatrists, 63% psychologists, and 11% other professional disciplines) provided a complete assessment of all personality disorder features listed in DSM-IV-TR and DSM-5 Section III. After applying each diagnostic model, clinicians evaluated the clinical utility of that model with respect to communication with patients and with other professionals, comprehensiveness, descriptiveness, ease of use, and utility for treatment planning. These perceptions were compared across DSM-IV-TR and the 3 components of the DSM-5 Section III model, and between psychiatrists and nonpsychiatrists. Although DSM-IV-TR was seen as easy to use and useful for professional communication, in every other respect the DSM-5 Section III model was viewed as being equally or more clinically useful than DSM-IV-TR. In particular, the DSM-5 dimensional trait model was seen as more useful than DSM-IV-TR in 5 of 6 comparisons-by psychiatrists as well as other professionals. Although concerns were expressed about the clinical utility of the DSM-5 personality disorder system during its development, these criticisms were offered without data on the proposed system. The results of this study demonstrate that aside from the current familiarity of the DSM-IV-TR approach, it offers little advantage in perceived clinical utility over the DSM-5 Section III system, whereas the latter is viewed as being more useful in several respects. © 2014 American Psychological Association. Source


Gargollo P.C.,Baylor College of Medicine
Urologic Clinics of North America | Year: 2015

Minimally invasive techniques are rapidly being developed and integrated into urologic surgery. Over the past 5years, the urologic literature is abound with novel techniques and adaptations to conventional laparoscopy. Pediatric urology is no exception to this trend, and the benefits of minimally invasive surgery may be accentuated in children given the relatively more confined working spaces and also a heightened awareness of cosmesis for the pediatric population. Increasingly, complex pediatric urologic procedures are being performed with robot assistance. The feasibility of nephrectomy, pyeloplasty, ureteral reimplantation, and bladder surgery has been clearly established. © 2015 Elsevier Inc. Source


Dunleavy K.,U.S. National Cancer Institute | Bollard C.M.,Baylor College of Medicine
Blood | Year: 2013

In this issue of Blood, Liapis et al investigate the characteristics of the tumor microenvironment as well as the role of viral components in AIDS-related diffuse large B-cell lymphoma (AR-DLBCL) and compare these findings with sporadic cases of DLBCL. Copyright 2011 by The American Society of Hematology; all rights reserved. Source


McGuire A.L.,Baylor College of Medicine | Evans B.J.,University of Houston | Caulfield T.,University of Alberta | Burke W.,University of Washington
Science | Year: 2010

International cooperation and postmarket regulation are needed for Internet-based direct-to-consumer genome tests. Source


Highlander S.K.,Baylor College of Medicine
Animal health research reviews / Conference of Research Workers in Animal Diseases | Year: 2012

Analysis of microbial communities using high throughput sequencing methods began in the mid 2000s permitting the production of 1000s to 10,000s of sequence reads per sample and megabases of data per sequence run. This then unprecedented depth of sequencing allowed, for the first time, the discovery of the 'rare biosphere' in environmental samples. The technology was quickly applied to studies in several human subjects. Perhaps these early studies served as a reminder that though the microbes that inhabit mammals are known to outnumber host cells by an order of magnitude or more, most of these are unknown members of our second genome, or microbiome (as coined by Joshua Lederberg), because of our inability to culture them. High throughput methods for microbial 16S ribosomal RNA gene and whole genome shotgun (WGS) sequencing have now begun to reveal the composition and identity of archaeal, bacterial and viral communities at many sites, in and on the human body. Surveys of the microbiota of food production animals have been published in the past few years and future studies should benefit from protocols and tools developed from large-scale human microbiome studies. Nevertheless, production animal-related resources, such as improved host genome assemblies and increased numbers and diversity of host-specific microbial reference genome sequences, will be needed to permit meaningful and robust analysis of 16S rDNA and WGS sequence data. Source


Mary Healy C.,Baylor College of Medicine
Clinical Obstetrics and Gynecology | Year: 2012

Successful maternal immunization requires consideration of maternal and infant disease burden, biological factors affecting immune response and placental transport of antibodies, optimal timing of immunization, safety and acceptability. Tetanus, inactivated influenza and acellular pertussis vaccines are recommended during pregnancy; others are recommended when maternal risk of infection is high. The development of new conjugate vaccines for use in adults may reduce global maternal and infant disease burden. Maternal immunization against group B streptococcus is projected to be superior to current preventative strategies in decreasing disease. Further evaluation of maternal immunization strategies to prevent maternal and infant infections is needed. © 2012, Lippincott Williams & Wilkins. Source


Bruce C.R.,Baylor College of Medicine
Aging and Disease | Year: 2013

This article reviews some of the complex ethical issues that accompany the diffusion of ventricular assist devices (VADs) for heart failure patients, with a particular emphasis on issues unique to older adults. In doing so, the ethical issues are centered on three decision points: (a) patient selection; (b) informed consent (i.e., initiation of the device); and (c) end of life (i.e., deactivation of the device.) It is contended that, with the technological improvements in heart failure treatments and new indications, the decision making process for VAD placement and deactivation has become more clinically and ethically challenging, particularly for older adults. Areas for potential future research are identified. Source


Thomas S.S.,Baylor College of Medicine | Mitch W.E.,ABBR R705
Clinical and Experimental Nephrology | Year: 2013

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions. © Japanese Society of Nephrology 2012. Source


Huang H.,Baylor College of Medicine
PLoS biology | Year: 2014

Membrane-embedded prenyltransferases from the UbiA family catalyze the Mg2+-dependent transfer of a hydrophobic polyprenyl chain onto a variety of acceptor molecules and are involved in the synthesis of molecules that mediate electron transport, including Vitamin K and Coenzyme Q. In humans, missense mutations to the protein UbiA prenyltransferase domain-containing 1 (UBIAD1) are responsible for Schnyder crystalline corneal dystrophy, which is a genetic disease that causes blindness. Mechanistic understanding of this family of enzymes has been hampered by a lack of three-dimensional structures. We have solved structures of a UBIAD1 homolog from Archaeoglobus fulgidus, AfUbiA, in an unliganded form and bound to Mg2+ and two different isoprenyl diphosphates. Functional assays on MenA, a UbiA family member from E. coli, verified the importance of residues involved in Mg2+ and substrate binding. The structural and functional studies led us to propose a mechanism for the prenyl transfer reaction. Disease-causing mutations in UBIAD1 are clustered around the active site in AfUbiA, suggesting the mechanism of catalysis is conserved between the two homologs. Source


Ludtke S.J.,Baylor College of Medicine | Serysheva I.I.,University of Houston
Current Opinion in Structural Biology | Year: 2013

Few tools are available to determine the structure of large integral membrane proteins such as intracellular Ca2+ release channels, RyRs and IP3Rs. Single particle cryo-EM can readily determine the structure of such channels to intermediate resolution, and can be used to quantitatively assess conformational variability. However, due to the, often low, image contrast of these cryospecimens, methods for validation are critical to insure the accuracy of such structures, and to put limits on their interpretability. The low-resolution structure of RyR has been well established for some time, but high-resolution has been slow to emerge. The structure of IP3R channel by cryo-EM had a number of false-starts, but improved validation methods have recently lead to a demonstrably accurate reconstruction. © 2013 Elsevier Ltd. Source


Lee J.,Baylor College of Medicine | Maunsell J.H.R.,Howard Hughes Medical Institute
Journal of Neurophysiology | Year: 2010

It remains unclear how attention affects the tuning of individual neurons in visual cerebral cortex. Some observations suggest that attention preferentially enhances responses to low contrast stimuli, whereas others suggest that attention proportionally affects responses to all stimuli. Resolving how attention affects responses to different stimuli is essential for understanding the mechanism by which it acts. To explore the effects of attention on stimuli of different contrasts, we recorded from individual neurons in the middle temporal visual area (MT) of rhesus monkeys while shifting their attention between preferred and nonpreferred stimuli within their receptive fields. This configuration results in robust attentional modulation that makes it possible to readily distinguish whether attention acts preferentially on low contrast stimuli. We found no evidence for greater enhancement of low contrast stimuli. Instead, the strong attentional modulations were well explained by a model in which attention proportionally enhances responses to stimuli of all contrasts. These data, together with observations on the effects of attention on responses to other stimulus dimensions, suggest that the primary effect of attention in visual cortex may be to simply increase the strength of responses to all stimuli by the same proportion. Copyright © 2010 The American Physiological Society. Source


Objective: To provide rationale for testosterone replacement therapy (TRT) in older men with low testosterone levels and symptoms consistent with testosterone deficiency.Methods: The relevant literature was reviewed using PubMed.Results: Cross-sectional and longitudinal population-based studies indicate that total and free testosterone levels fall with aging, and they may be accompanied by symptoms consistent with androgen deficiency. Testosterone treatment of younger men with very low testosterone levels and hypothalamic, pituitary, or testicular disease is associated with improvements in symptoms, body composition, bone density, and hematocrit/hemoglobin. Studies evaluating testosterone treatment of older men with low testosterone levels are limited, but they suggest some increase in fat free mass, some decrease in fat mass, and some increase in bone density of the lumbar spine and femoral neck.Conclusion: The Testosterone Trial should provide definitive information regarding the potential benefits of TRT in men ≥65 years of age. If efficacy is confirmed, we will still need more information regarding the risks of TRT in older men. © 2013 AACE. Source


Roshanravan H.,University of Houston | Dryer S.E.,University of Houston | Dryer S.E.,Baylor College of Medicine
American Journal of Physiology - Renal Physiology | Year: 2014

Extracellular ATP may contribute to Ca2+ signaling in podocytes during tubuloglomerular feedback (TGF) and possibly as a result of local tissue damage. TRPC6 channels are Ca2+-permeable cationic channels that have been implicated in the pathophysiology of podocyte diseases. Here we show using whole cell recordings that ATP evokes robust activation of TRPC6 channels in mouse podocyte cell lines and in rat podocytes attached to glomerular capillaries in ex vivo glomerular explants. The EC50 for ATP is ~ 10 μM and is maximal at 100 μM, and currents were blocked by the P2 antagonist suramin. In terms of maximal currents that can be evoked, ATP is the strongest activator of podocyte TRPC6 that we have characterized to date. Smaller currents were observed in response to ADP, UTP, and UDP. ATP-evoked currents in podocytes were abolished by TRPC6 knockdown and by pretreatment with 10 μM SKF-96365 or 50 μM La3+. ATP effects were also abolished by inhibiting G protein signaling and by the PLC/PLA2 inhibitor D-609. ATP effects on TRPC6 were also suppressed by knockdown of the slit diaphragm scaffolding protein podocin, and also by tempol, a membrane-permeable quencher of reactive oxygen species. Modulation of podocyte TRPC6 channels, especially in foot processes, could provide a mechanism for regulation of glomerular function by extracellular nucleotides, possibly leading to changes in permeation through slit diaphragms. These results raise the possibility that sustained ATP signaling could contribute to foot process effacement, Ca2+-dependent changes in gene expression, and/or detachment of podocytes. © 2014 the American Physiological Society. Source


In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.206. © 2015 Macmillan Publishers Limited Source


Malkova A.,Indiana University - Purdue University Indianapolis | Ira G.,Baylor College of Medicine
Current Opinion in Genetics and Development | Year: 2013

Break-induced replication (BIR) is the pathway of homologous recombination (HR) conserved from phages to eukaryotes that serves to repair DNA breaks that have only one end. BIR contributes to the repair of broken replication forks and allows telomere lengthening in the absence of telomerase. Nonallelic BIR may lead to translocations and other chromosomal rearrangements. In addition, BIR initiated at sites of microhomology can generate copy number variations (CNVs) and complex chromosomal changes. The level of mutagenesis associated with DNA synthesis in BIR is significantly higher than during normal replication. These features make BIR a likely pathway to promote bursts of genetic changes that fuel cancer progression and evolution. © 2013 Elsevier Ltd. Source


Milone M.,Mayo Medical School | Wong L.-J.,Baylor College of Medicine
Molecular Genetics and Metabolism | Year: 2013

Mitochondria are ubiquitous organelles and play crucial roles in vital functions, most importantly, the oxidative phosphorylation and energy metabolism. Therefore, mitochondrial dysfunction can affect multiple tissues, with muscle and nerve preferentially affected. Mitochondrial myopathy is a common clinical phenotype, which is characterized by early fatigue and/or fixed muscle weakness; rhabdomyolysis can seldom occur. Muscle biopsy often identifies signs of diseased mitochondria by morphological studies, while biochemical analysis may identify respiratory chain deficiencies. The clinical, morphological and biochemical data guide molecular analysis. Being the mitochondrial function under the control of both mitochondrial DNA and nuclear DNA, the search for mitochondrial DNA mutations and mitochondrial DNA quantitation, may not be sufficient for the molecular diagnosis of mitochondrial myopathies. Approximately 1500 nuclear genes can affect mitochondrial structure and function and the targeting of such genes may be necessary to reach the diagnosis. The identification of causative molecular defects in nuclear or mitochondrial genome leads to the definite diagnosis of mitochondrial myopathy. © 2013 Elsevier Inc. Source


Wong L.-J.C.,Baylor College of Medicine
Mitochondrion | Year: 2013

Mitochondrial disorders are by far the most genetically heterogeneous group of diseases, involving two genomes, the 16.6. kb mitochondrial genome and ~. 1500 genes encoded in the nuclear genome. For maternally inherited mitochondrial DNA disorders, a complete molecular diagnosis requires several different methods for the detection and quantification of mtDNA point mutations and large deletions. For mitochondrial disorders caused by autosomal recessive, dominant, and X-linked nuclear genes, the diagnosis has relied on clinical, biochemical, and molecular studies to point to a group of candidate genes followed by stepwise Sanger sequencing of the candidate genes one-by-one. The development of Next Generation Sequencing (NGS) has revolutionized the diagnostic approach. Using massively parallel sequencing (MPS) analysis of the entire mitochondrial genome, mtDNA point mutations and deletions can be detected and quantified in one single step. The NGS approach also allows simultaneous analyses of a group of genes or the whole exome, thus, the mutations in causative gene(s) can be identified in one-step. New approaches make genetic analyses much faster and more efficient. Huge amounts of sequencing data produced by the new technologies brought new challenges to bioinformatics, analytical pipelines, and interpretation of numerous novel variants. This article reviews the clinical utility of next generation sequencing for the molecular diagnoses of complex dual genome mitochondrial disorders. © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. Source


RNA sequencing (RNA-seq) has become a major tool for biomedical research. A key step in analyzing RNA-seq data is to infer the origin of short reads in the source genome, and for this purpose, many read alignment/mapping software programs have been developed. Usually, the majority of mappable reads can be mapped to one unambiguous genomic location, and these reads are called unique reads. However, a considerable proportion of mappable reads can be aligned to more than one genomic location with the same or similar fidelities, and they are called "multireads". Allocating these multireads is challenging but critical for interpreting RNA-seq data. We recently developed a Bayesian stochastic model that allocates multireads more accurately than alternative methods (Ji et al. Biometrics 2011). In order to serve a greater biological community, we have implemented this method in a stand-alone, efficient, and user-friendly software package, BM-Map. BM-Map takes SAM (Sequence Alignment/Map), the most popular read alignment format, as the standard input; then based on the Bayesian model, it calculates mapping probabilities of multireads for competing genomic loci; and BM-Map generates the output by adding mapping probabilities to the original SAM file so that users can easily perform downstream analyses. The program is available in three common operating systems, Linux, Mac and PC. Moreover, we have built a dedicated website, http://bioinformatics.mdanderson.org/main/BM-Map, which includes free downloads, detailed tutorials and illustration examples. We have developed a stand-alone, efficient, and user-friendly software package for accurately allocating multireads, which is an important addition to our previous methodology paper. We believe that this bioinformatics tool will greatly help RNA-seq and related applications reach their full potential in life science research. Source


Morris P.B.,Medical University of South Carolina | Ballantyne C.M.,Baylor College of Medicine | Birtcher K.K.,University of Houston | Dunn S.P.,University of Virginia | Urbina E.M.,Cincinnati Childrens Hospital Medical Center
Journal of the American College of Cardiology | Year: 2014

Managing risk related to low-density lipoprotein (LDL) is vital in therapy for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events given its important etiologic role in atherogenesis. Despite decades of research showing reduction of ASCVD risk with multiple approaches to lowering of LDL cholesterol, there continue to be significant gaps in care with inadequate numbers of patients receiving standard of care lipid-lowering therapy. Confusion regarding implementation of the multiple published clinical practice guidelines has been identified as one contributor to suboptimal management of LDL-related risk. This review summarizes the current guidelines for reduction of LDL-related cardiovascular risk provided by a number of major professional societies, which have broad applicability to diverse populations worldwide. Statements have varied in the process and methodology of development of recommendations, the grading system for level and strength of evidence, the inclusion or exclusion of expert opinion, the suggested ASCVD risk assessment tool, the lipoproteins recommended for risk assessment, and the lipoprotein targets of therapy. The similarities and differences among important guidelines in the United States and internationally are discussed, with recommendations for future strategies to improve consistency in approaches to LDL-related ASCVD risk and to reduce gaps in implementation of evidence-based therapies. © 2014 By The American College of Cardiology Foundation Published By Elsevier Inc. Source


Zhao W.,Baylor College of Medicine
Oncogene | Year: 2015

Progesterone receptor (PR) is usually co-localized with estrogen receptor (ER) in normal mammary cells. It is not known whether ER/PR-negative human breast cancer arises from an ER/PR-negative cell or from an ER/PR-positive cell that later lost ER/PR. Using intraductal injection of a lentivirus to deliver both an oncogene (ErbB2) and a floxed green fluorescent protein (GFP) in PRCre/+mice, whose Cre gene is under the control of the PR promoter, we were able to trace the PR status of the infected cells as they progressed to cancer. We found that the resulting early lesions stained negative for PR in most of the cells and usually retained GFP. The resulting tumors lacked ER and PR, and 75% (15/20) of them retained the GFP signal in all tumor cells, suggesting PR was never expressed throughout the evolution of a majority of these tumors. In conclusion, our data demonstrate that ErbB2-initiated ER/PR-negative mammary tumors primarily originate from the subset of the mammary epithelium that is negative for PR and probably ER as well. These findings also provide an explanation for why antihormonal therapy fails to prevent ER-negative breast cancers.Oncogene advance online publication, 7 December 2015; doi:10.1038/onc.2015.465. © 2015 Macmillan Publishers Limited Source


Khalaf N.,Baylor College of Medicine
Discovery medicine | Year: 2012

Clostridium difficile is emerging as an important enteric pathogen in children. Historically considered as an asymptomatic colonizer of the gastrointestinal tract, C. difficile infection (CDI) has not been well-studied in pediatric populations. While asymptomatic carriage remains high among infants, recent epidemiological surveillance has demonstrated a rise in the prevalence of CDI in both healthcare and community settings, particularly in children 1-5 years of age. The pathogenesis of pediatric CDI, including the factors underlying the absence of toxin-mediated effects among colonized infants, remains ill-defined. Studies suggest that traditional adult CDI risk factors such as antibiotic and healthcare exposure may not be as important for children who acquire CDI in the community. As recognition of the significant impact of CDI in children increases, the pressing need for deepening our understanding of this disease and identifying optimal therapeutic and preventative strategies is becoming apparent. Source


Fowler J.C.,Baylor College of Medicine
Psychotherapy | Year: 2012

This practice review focuses on the challenges of conducting sensitive and accurate assessments of the relative risk for suicide attempts and completed suicides. Suicide and suicide attempts are a frequently encountered clinical crisis, and the assessment, management, and treatment of suicidal patients is one of the most stressful tasks for clinicians. An array of risk factors, warning signs, and protective factors associated with suicide risk are reviewed; however, we are not yet in possession of evidence-based diagnostic tests that can accurately predict suicide risk on an individual level without also creating an inordinate number of false-positive predictions. Given the current limitations of assessment strategies, clinicians are advised to keep in mind that patients contemplating suicide are under enormous psychological distress, requiring sensitive and thoughtful engagement during the assessment process. An overarching goal of these assessments should be conducted within the therapeutic frame, in which efforts are made to enhance the therapeutic alliance by negotiating a collaborative approach to assessing risk and understanding why thoughts of suicide are so compelling. Within this treatment heuristic, the Suicide Assessment Five-step Evaluation and Triage (SAFE-T) is recommended as a pragmatic multidimensional assessment protocol incorporating the best known risk and protective factors. © 2012 American Psychological Association. Source


Xi Y.,Baylor College of Medicine
Nature Structural and Molecular Biology | Year: 2016

Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing has been observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover an essential role of the human SIRT6 enzyme in pericentric transcriptional silencing, and we show that this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, residue K18 of histone H3 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, depletion of these transcripts through RNA interference rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and regulation of acetylated H3K18 at heterochromatin, and demonstrate the pathogenic role of deregulated pericentric transcription in aging- and cancer-related cellular dysfunction. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Deng H.,Central South University | Gao K.,Central South University | Jankovic J.,Baylor College of Medicine
Movement Disorders | Year: 2013

Parkinson's disease (PD), the second most common age-related neurodegenerative disease, is characterized by loss of dopaminergic and nondopaminergic neurons, leading to a variety of motor and nonmotor symptoms. In addition to environmental factors, genetic predisposition and specific gene mutations have been shown to play an important role in the pathogenesis of this disorder. Recently, the identification of the vacuolar protein sorting 35 homolog gene (VPS35), linked to autosomal dominant late-onset PD, has provided new clues to the pathogenesis of PD. Here we discuss the VPS35 gene, its protein function, and various pathways involved in Wnt/β-catenin signaling and in the role of DMT1 mediating the uptake of iron and iron translocation from endosomes to the cytoplasm. Further understanding of these mechanisms will undoubtedly provide new insights into the pathogenic mechanisms of PD and may lead to prevention and better treatment of the disorder. © 2013 Movement Disorder Society. Source


Abbott D.H.,University of Wisconsin - Madison | Bacha F.,Baylor College of Medicine
Fertility and Sterility | Year: 2013

Polycystic ovary syndrome (PCOS) is a prevalent hyperandrogenic infertility and cardiometabolic disorder that increases a woman's lifetime risk of type 2 diabetes mellitus. It is heritable and intensely familial. Progress toward a cure has been delayed by absence of an etiology. Evidence is mounting, however, for in utero T excess, together with gestational hyperglycemia, contributing to either early differentiation of PCOS or phenotypic amplification of its genotypes. Abnormal endocrine, ovarian, and hyperinsulinemic traits are detectable as early as 2 months of age in daughters of women with PCOS, with adiposity enhancement of hyperinsulinemia during childhood potentially contributing to hyperandrogenism and LH excess by adolescence. These findings encourage increasing clinical focus on early childhood markers for adiposity and hyperinsulinemia accompanying ovarian and adrenal endocrine abnormalities that precede a diagnosable PCOS phenotype. They raise the possibility for lifestyle or therapeutic intervention before and during pregnancy or during childhood and adolescence alleviating the manifestations of a familial genetic predisposition to PCOS. Copyright © 2013 Published by Elsevier Inc. Source


Munoz F.M.,Baylor College of Medicine
American Journal of Obstetrics and Gynecology | Year: 2012

Prevention of influenza in pregnant women and their newborns through maternal immunization is a safe and effective intervention during seasonal epidemics and a priority during a pandemic. While influenza vaccination of pregnant women has been routine in the United States since the 1950s, coverage rates increased significantly only after the 2009 H1N1 influenza pandemic. Epidemiologic and clinical studies support the safety of inactivated influenza vaccines in pregnant women and their infants. Safety barriers to the use of vaccines during pregnancy can be addressed through research, active surveillance, and education. © 2012 Mosby, Inc. Source


Deng H.,Central South University | Gao K.,Central South University | Jankovic J.,Baylor College of Medicine
Nature Reviews Neurology | Year: 2014

The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders. © 2014 Macmillan Publishers Limited. All rights reserved. Source


Hamill R.J.,Baylor College of Medicine
Drugs | Year: 2013

Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3-6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV-infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile. © 2013 Springer International Publishing Switzerland (outside the USA). Source


Chen J.J.,Loma Linda University | Marsh L.,Baylor College of Medicine
Therapeutic Advances in Neurological Disorders | Year: 2014

Anxiety disturbances are recognized as common psychiatric comorbidities in Parkinson's disease (PD) and contribute to significant impairments in areas of cognitive, functional, motor and social performance. Anxiety in PD results in reduced quality of life, higher levels of care dependency and increased caregiver burden. Surprisingly, there is a paucity of treatment data. In one randomized, controlled study, bromazepam was found to be effective for anxiety in PD. However, usage of benzodiazepines in the PD population is limited by potential risk of confusion and falls. There are no controlled studies of selective serotonin reuptake inhibitors (SSRIs) for anxiety in PD. However, results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD, although in these studies anxiety outcomes were secondary. This review underscores that, given the high prevalence of anxiety disturbances in PD, there is a significant paucity of treatment data for this population. Additional studies are warranted. In the meantime, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions. Cognitive and behavioral therapies (with or without pharmacotherapy) have demonstrated efficacy and warrant consideration. When feasible, a targeted and individualized multimodal approach utilizing psychotherapeutic interventions along with pharmacologic therapies should be considered. © The Author(s), 2013. Source


Acosta S.,Rice University | Acosta S.,Baylor College of Medicine
Computer Methods in Applied Mechanics and Engineering | Year: 2015

The formulation of the on-surface radiation condition (OSRC) is extended to handle wave scattering problems in the presence of multiple obstacles. The new multiple-OSRC simultaneously accounts for the outgoing behavior of the wave fields, as well as, the multiple wave reflections between the obstacles. Like boundary integral equations (BIE), this method leads to a reduction in dimensionality (from volume to surface) of the discretization region. However, as opposed to BIE, the proposed technique leads to boundary integral equations with smooth kernels. Hence, these Fredholm integral equations can be handled accurately and robustly with standard numerical approaches without the need to remove singularities. Moreover, under weak scattering conditions, this approach renders a convergent iterative method which bypasses the need to solve single scattering problems at each iteration.Inherited from the original OSRC, the proposed multiple-OSRC is generally a crude approximate method. If accuracy is not satisfactory, this approach may serve as a good initial guess or as an inexpensive pre-conditioner for Krylov iterative solutions of BIE. © 2014 Elsevier B.V. Source


Paysse E.A.,Baylor College of Medicine
Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus | Year: 2012

Refractive surgery has now been used successfully to treat severe anisometropia and isoametropia associated with amblyopia in children who cannot wear standard spectacles or contact lenses. Extraocular techniques include photorefractive keratectomy, laser-assisted subepithelial keratomileusis, and laser-assisted in situ keratomileusis. Intraocular techniques include refractive lensectomy and phakic intraocular lenses and are still being investigated in children for refractive errors outside the treatment dose capabilities of the excimer laser. This workshop discusses the various techniques, how and when to use each, and their risks and benefits. Newer techniques currently being used in adults that may someday be used in children are also introduced. Copyright © 2012 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved. Source


Zheng H.,Baylor College of Medicine | Koo E.H.,University of California at San Diego
Molecular Neurodegeneration | Year: 2011

The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease in large part due to the sequential proteolytic cleavages that result in the generation of -amyloid peptides (A). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP. © 2011 Zheng and Koo; licensee BioMed Central Ltd. Source


Gomes-Pereira M.,University of Paris Descartes | Cooper T.A.,Baylor College of Medicine | Gourdon G.,University of Paris Descartes
Trends in Molecular Medicine | Year: 2011

DNA repeat expansions can result in the production of toxic RNA. RNA toxicity has been best characterised in the context of myotonic dystrophy. Nearly 20 mouse models have contributed significant and complementary insights into specific aspects of this novel disease mechanism. These models provide a unique resource to test pharmacological, anti-sense, and gene-therapy therapeutic strategies that target specific events of the pathobiological cascade. Further proof-of-principle concept studies and preclinical experiments require critical and thorough analysis of the multiple myotonic dystrophy transgenic lines available. This review provides in-depth assessment of the molecular and phenotypic features of these models and their contribution towards the dissection of disease mechanisms, and compares them with the human condition. More importantly, it provides critical assessment of their suitability and limitations for preclinical testing of emerging therapeutic strategies. © 2011 Elsevier Ltd. Source


Kushner J.A.,Baylor College of Medicine | Kushner J.A.,Texas Childrens Diabetes and Endocrinology Center
Journal of Clinical Investigation | Year: 2013

Preservation and regeneration of β cell endocrine function is a long-sought goal in diabetes research. Defective insulin secretion from β cells underlies both type 1 and type 2 diabetes, thus fueling considerable interest in molecules capable of rebuilding β cell secretion capacity. Though early work in rodents suggested that regeneration might be possible, recent studies have revealed that aging powerfully restricts cell cycle entry of β cells, which may limit regeneration capacity. Consequently, aging has emerged as an enigmatic challenge that might limit β cell regeneration therapies. This Review summarizes recent data regarding the role of aging in β cell regeneration and proposes models explaining these phenomena. Source


Erez A.,Baylor College of Medicine | Erez A.,Weizmann Institute of Science
Genetics in Medicine | Year: 2013

In the early 1930s, phenylketonuria was among the first metabolic diseases to be defined. In the following years, multiple attempts to correlate genotype and phenotype in several inherited metabolic diseases, including phenylketonuria, were encountered with difficulties. It is becoming evident that the phenotype of metabolic disorders is often more multifaceted than expected from the disruption of a specific enzyme function caused by a single-gene disorder. Undoubtedly, revealing the factors contributing to the discrepancy between the loss of a single enzymatic function and the wide spectrum of clinical consequences would allow clinicians to optimize treatment for their patients. This article discusses several possible contributors to the unique, complex phenotypes observed in inherited metabolic disorders, using argininosuccinic aciduria as a disease model. Source


El-Hattab A.W.,King Saud bin Abdulaziz University for Health Sciences | Scaglia F.,Baylor College of Medicine
Neurotherapeutics | Year: 2013

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results. © 2013 The American Society for Experimental NeuroTherapeutics, Inc. Source


Liu H.,Baylor College of Medicine
Molecular Therapy | Year: 2015

Safety switches are becoming relevant for the clinical translation of T-cell–based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells.Molecular Therapy (2016); doi:10.1038/mt.2015.217. © 2015 American Society of Gene & Cell Therapy Source


Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.Molecular Therapy (2015); doi:10.1038/mt.2015.199. © 2015 American Society of Gene & Cell Therapy Source


Massaad C.A.,Baylor College of Medicine | Klann E.,New York University
Antioxidants and Redox Signaling | Year: 2011

The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age- or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function. © 2011 Mary Ann Liebert, Inc. Source


McKenna N.J.,Baylor College of Medicine
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

Nuclear receptors (NRs) are a superfamily of ligand-regulated transcription factors that interact with coregulators and other transcription factors to direct tissue-specific programs of gene expression. Recent years have witnessed a rapid acceleration of the output of high-content data platforms in this field, generating discovery-driven datasets that have collectively described: the organization of the NR superfamily (phylogenomics); the expression patterns of NRs, coregulators and their target genes (transcriptomics); ligand- and tissue-specific functional NR and coregulator sites in DNA (cistromics); the organization of nuclear receptors and coregulators into higher order complexes (proteomics); and their downstream effects on homeostasis and metabolism (metabolomics). Significant bioinformatics challenges lie ahead both in the integration of this information into meaningful models of NR and coregulator biology, as well as in the archiving and communication of datasets to the global nuclear receptor signaling community. While holding great promise for the field, the ascendancy of discovery-driven research in this field brings with it a collective responsibility for researchers, publishers and funding agencies alike to ensure the effective archiving and management of these data. This review will discuss factors lying behind the increasing impact of discovery-driven research, examples of high-content datasets and their bioinformatic analysis, as well as a summary of currently curated web resources in this field. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. © 2010 Elsevier B.V. Source


Peniche A.G.,University of Texas Medical Branch | Savidge T.C.,Baylor College of Medicine | Dann S.M.,University of Texas Medical Branch
Current Opinion in Infectious Diseases | Year: 2013

Purpose of Review: Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in the healthcare setting. An emerging consensus suggests that CDI is caused by pathogenic toxin production, gut microbial dysbiosis and altered host inflammatory responses. The aim of this review is to summarize and highlight recent advances focused on CDI pathogenic mechanisms. Recent Findings: Potential paradigm shifts relating to the mechanisms of toxin action and inhibition have recently been reported, with new insights into spore germination and surface protein function also gaining traction. Multiomic analysis of microbiome dysbiosis has identified important CDI-associated microbial community shifts that may form the basis of future targeted bacteriotherapy, and functional metabolite biomarkers that require further characterization. Classical innate and adaptive immunity against CDI is rapidly being delineated, with novel innate S-nitrosylation signals also being identified. Summary: Studies in patients and animal disease models are shedding new light on the critical roles of the microbiota, metabolome and host responses in primary and recurrent CDI. An improved understanding of the CDI disease pathogenesis will provide the basis for developing new therapies for treating disease and preventing recurrence. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Zhou X.,Baylor College of Medicine
Molecular Therapy | Year: 2015

Activation of the inducible caspase 9 (iC9) safety gene by a dimerizing drug (chemical inducer of dimerization (CID) AP1903) effectively resolves the symptoms and signs of graft-versus-host disease (GvHD) in haploidentical stem cell transplant (HSCT) recipients. However, after CID treatment, 1% of iC9-T cells remain and can regrow over time; although these resurgent T cells do not cause recurrent GvHD, it remains unclear whether repeat CID treatments are a safe and feasible way to further deplete residual gene-modified T cells should any other adverse effects associated with them occur. Here, we report a patient who received an infusion of haploidentical iC9-T cells after HSCT and subsequently received three treatments with AP1903. There was a mild (grade 2) and transient pancytopenia following each AP1903 administration but no non-hematological toxicity. Ninety five percent of circulating iC9-T cells (CD3+CD19+) were eliminated after the first AP1903 treatment. Three months later, the residual cells had expanded more than eightfold and had a lower level of iC9 expression. Each repeated AP1903 administration eliminated a diminishing percentage of the residual repopulating cells, but elimination could be enhanced by T-cell activation. These data support the safety and efficiency of repeated CID treatments for persistent or recurring toxicity from T-cell therapies.Molecular Therapy (2016); doi:10.1038/mt.2015.234. © 2015 American Society of Gene & Cell Therapy Source


Garber A.J.,Baylor College of Medicine
Expert Opinion on Investigational Drugs | Year: 2012

Introduction: GLP-1 receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, exenatide, was approved in the mid-2000s, other agents with longer durations of action (that do not require twice-daily dosing) are now being developed. Indeed, liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, and more recently, a once-weekly formulation of exenatide was approved in 2011. This review considers the mechanism of action of GLP-1 receptor agonists and considers the various agents in this class. Areas covered: The importance of GLP-1 itself in glycemic control and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the five GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide and taspoglutide) since 2005 is provided and their mechanisms of action, efficacy in terms of glycemic control and weight loss, and tolerability are reviewed. Expert opinion: GLP-1 receptor agonists result in clinically meaningful weight loss in addition to their beneficial effects on glucose homeostasis. These agents provide substantial clinical benefits for patients compared with sulfonylureas or DPP-4 inhibitors and will, therefore, become one of the major therapeutic choices for patients with T2DM. © 2012 Informa UK, Ltd. Source


Lua R.C.,Baylor College of Medicine
Bioinformatics | Year: 2012

Summary: Understanding the differences between knotted and unknotted protein structures may offer insights into how proteins fold. To characterize the type of knot in a protein, we have developed PyKnot, a plugin that works seamlessly within the PyMOL molecular viewer and gives quick results including the knot's invariants, crossing numbers and simplified knot projections and backbones. PyKnot may be useful to researchers interested in classifying knots in macromolecules and provides tools for students of biology and chemistry with which to learn topology and macromolecular visualization. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Brunetti-Pierri N.,Telethon Institute of Genetics and Medicine | Brunetti-Pierri N.,University of Naples Federico II | Ng P.,Telethon Institute of Genetics and Medicine | Ng P.,Baylor College of Medicine
Human Molecular Genetics | Year: 2011

Helper-dependent adenoviral (HDAd) vectors devoid of all viral-coding sequences are promising non-integrating vectors for liver-directed gene therapy because they have a large cloning capacity, can efficiently transduce a wide variety of cell types from various species independent of the cell cycle and can result in long-term transgene expression without chronic toxicity. The main obstacle preventing clinical applications of HDAd for liver-directed gene therapy is the host innate inflammatory response against the vector capsid proteins that occurs shortly after intravascular vector administration resulting in acute toxicity, the severity of which is dependent on vector dose. Intense efforts have been focused on elucidating the factors involved in this acute response and various strategies have been investigated to improve the therapeutic index of HDAd vectors. These strategies have yielded encouraging results with the potential for clinical translation. © The Author 2011. Published by Oxford University Press. All rights reserved. Source


Liu D.J.,University of Michigan | Leal S.M.,Baylor College of Medicine
Bioinformatics | Year: 2012

Motivation: Next-generation sequencing greatly increases the capacity to detect rare-variant complex-trait associations. However, it is still expensive to sequence a large number of samples and therefore often small datasets are used. Given cost constraints, a potentially more powerful two-step strategy is to sequence a subset of the sample to discover variants, and genotype the identified variants in the remaining sample. If only cases are sequenced, directly combining sequence and genotype data will lead to inflated type-I errors in rare-variant association analysis. Although several methods have been developed to correct for the bias, they are either underpowered or theoretically invalid. We proposed a new method SEQCHIP to integrate genotype and sequence data, which can be used with most existing rare-variant tests. Results: It is demonstrated using both simulated and real datasets that the SEQCHIP method has controlled type-I errors, and is substantially more powerful than all other currently available methods. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Palzkill T.,Baylor College of Medicine
Annals of the New York Academy of Sciences | Year: 2013

β-Lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site that, in turn, is dependent on the subclass of β-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-β-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes. © 2012 New York Academy of Sciences. Source


Riehle K.,Baylor College of Medicine
BMC bioinformatics | Year: 2012

Microbial metagenomic analyses rely on an increasing number of publicly available tools. Installation, integration, and maintenance of the tools poses significant burden on many researchers and creates a barrier to adoption of microbiome analysis, particularly in translational settings. To address this need we have integrated a rich collection of microbiome analysis tools into the Genboree Microbiome Toolset and exposed them to the scientific community using the Software-as-a-Service model via the Genboree Workbench. The Genboree Microbiome Toolset provides an interactive environment for users at all bioinformatic experience levels in which to conduct microbiome analysis. The Toolset drives hypothesis generation by providing a wide range of analyses including alpha diversity and beta diversity, phylogenetic profiling, supervised machine learning, and feature selection. We validate the Toolset in two studies of the gut microbiota, one involving obese and lean twins, and the other involving children suffering from the irritable bowel syndrome. By lowering the barrier to performing a comprehensive set of microbiome analyses, the Toolset empowers investigators to translate high-volume sequencing data into valuable biomedical discoveries. Source


Baranowski T.,Baylor College of Medicine | Lytle L.,University of North Carolina at Chapel Hill
Obesity Reviews | Year: 2015

The Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study evaluated with a large sample a comprehensive carefully planned obesity prevention intervention targeting multiple levels of influence that were culturally adapted to the situations in eight European countries. Despite the great effort and attention to detail, the IDEFICS study did not achieve its targeted adiposity or behaviour change objectives. Should we be surprised that the IDEFICS trial did not have its intended effects? We think not, and would have been surprised if it did. Recent research has revealed the lack of consistent meaningful relationships between several apparently obesogenic behaviours and adiposity, weak or no relationships among behavioural change procedures, mediating variables and targeted behaviours and inadequate attention to moderating effects. Future obesity prevention interventions would benefit from a more thorough understanding of the complex relationships that have been hypothesized and the interrelationships with biological factors. While systems modelling has been proposed as providing the solution, important less complex identification of new constructs, new relationships and community interventions are still needed, both to find innovative solutions and to provide input into the systems models. We should question results from cross-sectional studies and be satisfied only with longitudinal or experimental tests of relationships. © 2015 World Obesity. Source


Maximum likelihood has been widely used for over three decades to infer phylogenetic trees from molecular data. When reticulate evolutionary events occur, several genomic regions may have conflicting evolutionary histories, and a phylogenetic network may provide a more adequate model for representing the evolutionary history of the genomes or species. A maximum likelihood (ML) model has been proposed for this case and accounts for both mutation within a genomic region and reticulation across the regions. However, the performance of this model in terms of inferring information about reticulate evolution and properties that affect this performance have not been studied. In this paper, we study the effect of the evolutionary diameter and height of a reticulation event on its identifiability under ML. We find both of them, particularly the diameter, have a significant effect. Further, we find that the number of genes (which can be generalized to the concept of "non-recombining genomic regions") that are transferred across a reticulation edge affects its detectability. Last but not least, a fundamental challenge with phylogenetic networks is that they allow an arbitrary level of complexity, giving rise to the model selection problem. We investigate the performance of two information criteria, the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), for addressing this problem. We find that BIC performs well in general for controlling the model complexity and preventing ML from grossly overestimating the number of reticulation events. Our results demonstrate that BIC provides a good framework for inferring reticulate evolutionary histories. Nevertheless, the results call for caution when interpreting the accuracy of the inference particularly for data sets with particular evolutionary features. Source


Musher D.M.,Baylor College of Medicine
Mayo Clinic Proceedings | Year: 2016

Medical guidelines tend to convey a sense of unanimity of opinion that may not reflect the deliberations of the experts who wrote them. Using, as an example, an analysis of the recently published recommendations on administering pneumococcal conjugate vaccine to adults, the present article raises the question of whether official recommendations and guidelines should include dissenting opinions, analogous to decisions issued by the US Supreme Court. The argument that such a policy would lead to confusion in our profession is addressed in 2 ways: (1) the current system, in which different professional societies publish conflicting recommendations, as in the case of breast or prostate cancer screening, can be far more confusing, and (2) in the long run, greater transparency will lead to more thoughtful and higher-quality medical care. Perhaps the most important point of this paper is the suggestion that it is far better to bring dissent into the recommendation process than to act as if it is not there. © 2016 Mayo Foundation for Medical Education and Research. Source


Levin H.S.,Michael bakey Veterans Affairs Medical Center | Levin H.S.,Baylor College of Medicine | Diaz-Arrastia R.R.,Uniformed Services University of the Health Sciences
The Lancet Neurology | Year: 2015

Concussion and mild traumatic brain injury (TBI) are interchangeable terms to describe a common disorder with substantial effects on public health. Advances in brain imaging, non-imaging biomarkers, and neuropathology during the past 15 years have required researchers, clinicians, and policy makers to revise their views about mild TBI as a fully reversible insult that can be repeated without consequences. These advances have led to guidelines on management of mild TBI in civilians, military personnel, and athletes, but their widespread dissemination to clinical management in emergency departments and community-based health care is still needed. The absence of unity on the definition of mild TBI, the scarcity of prospective data concerning the long-term effects of repeated mild TBI and subconcussive impacts, and the need to further develop evidence-based interventions to mitigate the long-term sequelae are areas for future research that will improve outcomes, reduce morbidity and costs, and alleviate delayed consequences that have only recently come to light. © 2015 Elsevier Ltd. Source


Rossi L.,Baylor College of Medicine
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Hematopoietic stem cells (HSCs) are defined by the capabilities of multi-lineage differentiation and long-term self-renewal. Both these characteristics contribute to maintain the homeostasis of the system and allow the restoration of hematopoiesis after insults, such as infections or therapeutic ablation. Reconstitution after lethal irradiation strictly depends on a third, fundamental property of HSCs: the capability to migrate under the influence of specific chemokines. Directed by a chemotactic compass, after transplant HSCs find their way to the bone marrow, where they eventually home and engraft. HSCs represent a rare population that primarily resides in the bone marrow with an estimated frequency of 0.01% of total nucleated cells. Separating HSCs from differentiated cells that reside in the bone marrow has been the focus of intense investigation for years. In this chapter, we will describe in detail the strategy routinely used by our laboratory to purify murine HSCs, by exploiting their antigenic phenotype (KSL), combined with the physiological capability to efficiently efflux the vital dye Hoechst 33342, generating the so-called Side Population, or SP. Source


Graham D.Y.,Baylor College of Medicine
Gastroenterology | Year: 2015

Helicobacter pylori infection contributes to the development of diverse gastric and extragastric diseases. The infection is necessary but not sufficient for the development of gastric adenocarcinoma. Its eradication would eliminate a major worldwide cause of cancer death, therefore there is much interest in identifying how, if, and when this can be accomplished. There are several mechanisms by which H pylori contributes to the development of gastric cancer. Gastric adenocarcinoma is one of many cancers associated with inflammation, which is induced by H pylori infection, yet the bacteria also cause genetic and epigenetic changes that lead to genetic instability in gastric epithelial cells. H pylori eradication reduces both. However, many factors must be considered in determining whether treating this bacterial infection will prevent cancer or only reduce its risk - these must be considered in designing reliable and effective eradication therapies. Furthermore, H pylori infection has been proposed to provide some benefits, such as reducing the risks of obesity or childhood asthma. When tested, these hypotheses have not been confirmed and are therefore most likely false. © 2015 by the AGA Institute. Source


Park S.-K.,University of Texas Southwestern Medical Center | Xiang Y.,University of Texas Southwestern Medical Center | Xiang Y.,Tianjin Medical University | Feng X.,Baylor College of Medicine | Garrard W.T.,University of Texas Southwestern Medical Center
Genes and Development | Year: 2014

To understand the relationships between nuclear organization and gene expression in a model system, we employed three-dimensional imaging and chromatin immunoprecipitation (ChIP)-chromosome conformation capture (3C) techniques to investigate the topographies of the immunoglobulin (Ig) genes and transcripts during B-cell development. Remarkably, in plasma cells, when antibody synthesis peaks, active Ig genes residing on three different chromosomes exhibit pronounced colocalizations in transcription factories, often near the nuclear periphery, and display trans-chromosomal enhancer interactions, and their transcripts frequently share interchromatin trafficking channels. Conceptually, these features of nuclear organization maximize coordinated transcriptional and transcript trafficking control for potentiating the optimal cytoplasmic assembly of the resulting translation products into protein multimers. © 2014 Park et al. Source


Petit C.J.,Baylor College of Medicine
Congenital Heart Disease | Year: 2011

Outcomes for staged palliation for single-ventricle heart disease have improved over the past two decades. As outcomes improve, parental expectations for survival and quality of life have risen accordingly. Nevertheless, the number of interventions and complications these patients must endure remain high. The final surgical destination of the single-ventricle patient, the total cavopulmonary connection (or Fontan operation) successfully separates systemic venous and pulmonary venous blood flow but does so at great cost. Fontan patients remain at significant risk of complications despite what are perceived to be "favorable" hemodynamics. The outcomes in this population are discussed in this review, with particular attention to the history behind our current strategies as well as to recent salient studies. © 2011 the Author. Congenital Heart Disease © 2011 Wiley Periodicals, Inc. Source


Rangwala S.,Baylor College of Medicine | Tsai K.Y.,University of Texas M. D. Anderson Cancer Center
British Journal of Dermatology | Year: 2011

Over the past several decades, there has been increasing interest in understanding the roles of the immune system in the development and progression of cancer. The importance of the immune system in human skin cancer has been long recognized based primarily upon the increased incidence of skin cancers in organ transplant recipients and mechanisms of ultraviolet (UV) radiation-mediated immunomodulation. In this review, we integrate multiple lines of evidence highlighting the roles of the immune system in skin cancer. First, we discuss the concepts of cancer immunosurveillance and immunoediting as they might relate to human skin cancers. We then describe the clinical and molecular mechanisms of skin cancer development and progression in the contexts of therapeutic immuno-suppression in organ transplant recipients, viral oncogenesis, and UV radiation-induced immunomodulation with a primary focus on basal cell carcinoma and squamous cell carcinoma. The clinical evidence supporting expanding roles for immunotherapy is also described. Finally, we discuss recent research examining the functions of particular immune cell subsets in skin cancer and how they might contribute to both antitumour and protumour effects. A better understanding of the biological mechanisms of cancer immunosurveillance holds the promise of enabling better therapies. © 2011 British Association of Dermatologists. Source


Chiang S.,Rice University | Haneef Z.,Baylor College of Medicine | Haneef Z.,Medical Center
Clinical Neurophysiology | Year: 2014

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. © 2014 International Federation of Clinical Neurophysiology. Source


Although patients with chronic schizophrenia have substantially higher smoking rates than either the general population or patients with other mental illnesses, drug-naive patients with a first episode of schizophrenia have received little systemic study. This study examined smoking rates, the association between smoking and symptom severity and cognitive function in Chinese first-episode schizophrenia (FES) patients using cross-sectional and case-control designs. Two hundred and forty-four drug-naive FES patients and 256 healthy controls matched for gender, age and education completed the Fagerström Test for Nicotine Dependence (FTND) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients were also rated on the Positive and Negative Symptom Scale (PANSS). The rate and quantity of smoking were not significantly higher among FES patients compared to the general population. Among patients, smokers scored higher than non-smokers on the total PANSS and the positive symptom subscale scores. There were no significant associations between cognitive function and smoking in either FES patients or healthy controls. In contrast to studies in patients with chronic schizophrenia, drug-naive FES patients did not smoke more frequently than the general population. Furthermore, patients with psychotic disorders who smoked did not exhibit significant cognitive differences compared with those who did not smoke. However, smoking may have other detrimental effects on physical and mental health, for example on positive symptoms. Source


Schlomer B.J.,Baylor College of Medicine | Copp H.L.,University of California San Francisco
Journal of Pediatric Urology | Year: 2014

Objective Augmentation cystoplasty (AC) is a major surgery that can be associated with long-term morbidity. This study aimed to describe the cumulative incidence of outcomes and urologic procedures in a large cohort of children who underwent AC, identify significant sources of morbidity, and to evaluate baseline factors associated with outcomes of interest. Methods Children ≤18 years who underwent AC in the Pediatric Health Information System from 1999 to 2010 were included. All follow-up encounters up to June 2012 were included. Cumulative incidences for 15 outcomes and urologic procedures were calculated using non-informative censoring. Sensitivity analyses were performed to determine effect of censoring assumptions and including hospitals without complete datasets. As an exploratory analysis, baseline patient factors were evaluated for associations with outcomes and urologic procedures of interest using multivariable Cox proportional hazards models adjusted for clustering by hospital. Results 2831 AC patients were identified. Based on cumulative incidence calculations and sensitivity analyses; the cumulative incidence ranges of outcomes and procedures at 1, 3, 5, and 10 years were calculated. Examples of 10-year cumulative incidence ranges are given for the following outcomes and procedures: bladder rupture (2.9-6.4%), small bowel obstruction (5.2-10.3%), bladder stones (13.3-36.0%), pyelonephritis (16.1-37.1%), cystolithopaxy (13.3-35.1%), and reaugmentation (5.2-13.4%). The development of chronic kidney disease was strongly associated with a diagnosis of lower urinary tract obstruction (HR 13.7; 95% CI 9.4-19.9). Bladder neck surgery and stoma creation at time of AC were associated with an increased hazard of bladder rupture (HR 1.9; 95% CI 1.1-3.3) and bladder stones (HR 1.4; 95% CI 1.1-1.8) respectively. Conclusions Outcomes of interest and urologic procedures after AC are common. Results from this large cohort can be used to counsel patients and families about expectations after AC. Pyelonephritis, chronic kidney disease, further reconstructive surgery, and calculus disease appear to cause significant morbidity. Collaborative efforts are needed to further reduce morbidity in this patient population. © 2014 Journal of Pediatric Urology Company. Source


Matsueda S.,Kurume University | Graham D.Y.,Baylor College of Medicine
World Journal of Gastroenterology | Year: 2014

Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved. Source


It has been well documented that cocaine and methamphetamine use can lead to the onset of psychotic symptoms similar to schizophrenia. However, the research and literature on gender differences and stimulant-induced psychosis have been mixed. The primary aim of this study was to investigate gender differences in the reporting of psychotic symptoms in cocaine- versus methamphetamine-dependent individuals. Participants were recruited from the Los Angeles, California, community via radio and newspaper advertisements. All met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for cocaine or methamphetamine dependence, and all reported either methamphetamine or cocaine as their primary drug of abuse. During a screening interview, participants answered questions from the Psychotic Symptom Assessment Scale, which characterizes various types of psychotic symptoms during drug use ("while high") or during periods of nonuse ("while abstinent"). Participants included 42 cocaine-dependent individuals (27 men, 15 women) and 43 methamphetamine-dependent individuals (25 men, 18 women). Among cocaine users, there were no significant differences between men and women with regard to ethnicity, years of use, route of administration, and amount used in the past week, though they differed significantly with regard to age (P = 0.029). In the "while abstinent" condition, women were significantly more likely than men to report experiencing auditory hallucinations (13% vs 0%, respectively; P = 0.050) and tactile hallucinations (20% vs 0%; P = 0.016), whereas men were more likely to report delusions of grandeur (48% vs 6%; P = 0.006). During the "while high" condition, women were significantly more likely than men to report delusions of grandeur (13% vs 0%, respectively; P = 0.050), tactile hallucinations (33% vs 0%; P = 0.001), and olfactory hallucinations (13% vs 0%; P = 0.050). Among methamphetamine users, there were no significant differences between men and women with regard to age, ethnicity, years of use, route of administration, or amount used in the past week. In the "while abstinent" condition, women were significantly more likely than men to report feeling that something was wrong with the way a part of their body looked (72% vs 32%, respectively; P = 0.009), olfactory hallucinations (39% vs 8%; P = 0.010) and dressing inappropriately (22% vs 0%; P = 0.010). During the "while high" condition, women were more likely than men to report delusions of grandeur (33% vs 16%, respectively; P = 0.030), paranoia (50% vs 16%; P = 0.017), and tactile hallucinations (61% vs 32%; P = 0.050). The findings of the present study revealed that cocaine- and methamphetamine-dependent women were more likely than their male counterparts to report experiencing various psychotic symptoms. This information may be useful for clinicians and mental health professionals, who should take these symptoms into account as potential barriers that may impede effective treatment. Copyright © 2010 Excerpta Medica Inc. All rights reserved. Source


Deng H.,Central South University | Liang H.,Central South University | Jankovic J.,Baylor College of Medicine
Archives of Neurology | Year: 2013

Parkinson disease is one of the most common neurodegenerative diseases associated with aging. At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. Among them, PARK15-associated parkinsonism, also referred to as parkinsonianpyramidal disease (PPD), was found to be caused by mutations in the F-box only protein 7 gene (FBXO7). Parkinsonian-pyramidal disease differs from typical Parkinson disease chiefly by juvenile onset and the presence of spasticity. Four mutations have been identified and a pattern of autosomal recessive inheritance has been proposed in all reported PPD families. The FBXO7 protein is a member of the Skp1-Cullin-F-box-type E3 ubiquitin ligases, which play important roles in targeting proteins for ubiquitination. Although PPD is a relatively rare parkinsonian disorder, understanding its genetic and pathological mechanisms may lead to new insights into the pathogenesis of Parkinson disease and development of therapeutic strategies not only for PPD but also for other parkinsonian disorders. © 2013 American Medical Association. Source


Graham D.Y.,Baylor College of Medicine | Lee Y.,National Taiwan University | Wu M.,National Taiwan University
Clinical Gastroenterology and Hepatology | Year: 2014

Data are available such that choice of Helicobacter pylori therapy for an individual patient can be reliably predicted. Here, treatment success is defined as a cure rate of 90% or greater. Treatment outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with the knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). We provide the formula for predicting outcome and we illustrate the calculations. Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete; neither should continue to be used as empiric therapies (ie, 7- and 14-day triple therapies fail when clarithromycin resistance exceeds 5% and 15%, respectively, and 10-day sequential therapy fails when metronidazole resistance exceeds 20%). Therapy should be individualized based on prior history and whether the patient is in a high-risk group for resistance. The preferred choices for Western countries are 14-day concomitant therapy, 14-day bismuth quadruple therapy, and 14-day hybrid sequential-concomitant therapy. We also provide details regarding the successful use of fluoroquinolone-, rifabutin-, and furazolidone-containing therapies. Finally, we provide recommendations for the efficient development (ie, identification and optimization) of new regimens, as well as how to prevent or minimize failures. The trial-and-error approach for identifying and testing regimens frequently resulted in poor treatment success. The described approach allows outcome to be predicted and should simplify treatment and drug development. © 2014. Source


Wang X.H.,Emory University | Mitch W.E.,Baylor College of Medicine
Nature Reviews Nephrology | Year: 2014

In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin-proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications. © 2014 Macmillan Publishers Limited. Source


Harpavat S.,Hepatology and Nutrition | Finegold M.J.,Baylor College of Medicine | Karpen S.J.,Hepatology and Nutrition
Pediatrics | Year: 2011

OBJECTIVES: Healthy infants are thought to acquire biliary atresia (BA) in the first weeks of life. Because those diagnosed earlier have better outcomes, we were interested in determining the earliest time BA could be detected. We started by examining the immediate postnatal period, hypothesizing that newborns would not yet have acquired disease and still have normal direct/conjugated bilirubin (DB/CB) levels. PATIENTS AND METHODS: Newborn DB/CB levels were obtained retrospectively from birth hospitals. Subjects with BA were born between 2007 and 2010 and cared for at Texas Children's Hospital. Those with BA splenic malformation syndrome or born prematurely were excluded. Control subjects were term newborns who later never developed neonatal liver disease. RESULTS: Of the 61 subjects with BA, 56% had newborn DB/CB levels measured. All DB/CB levels exceeded laboratory norms and rose over time. At 24 to 48 hours of life, subjects with BA had mean DB levels significantly higher than those of controls (1.4 ± 0.43 vs. 0.19 ± 0.075 mg/dL, P < .0001), even while their mean total bilirubin (TB) levels remained below phototherapy limits. Finally, despite the elevated DB/CB levels, the majority of patients (79%) had normal DB:TB ratios ≤0.2. CONCLUSIONS: Patients with BA have elevated DB/CB levels shortly after birth. To detect affected infants earlier and improve outcomes, the results suggest two possibilities: (1) screen all newborns for elevated DB/CB levels, rather than just those who appear jaundiced; and then (2) follow all newborns with elevated DB/CB levels, rather than just those with DB:TB ratios >0.2. Copyright © 2011 by the American Academy of Pediatrics. Source


Jimenez-Shahed J.,Baylor College of Medicine
Neuropsychiatric Disease and Treatment | Year: 2012

Dystonia is a movement disorder of uncertain pathogenesis that is characterized by involuntary and inappropriate muscle contractions which cause sustained abnormal postures and movements of multiple or single (focal) body regions. The most common focal dystonias are cervical dystonia (CD) and blepharospasm (BSP). The first-line recommended treatment for CD and BSP is injection with botulinum toxin (BoNT), of which two serotypes are available: BoNT type A (BoNT/A) and BoNT type B (BoNT/B). Conventional BoNT formulations include inactive complexing proteins, which may increase the risk for antigenicity, possibly leading to treatment failure. IncobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a BoNT/A agent that has been recently Food and Drug Administration-approved for the treatment of adults with CD and adults with BSP previously treated with onabotulinumtoxinA (Botox®; Allergen, Inc, Irvine, CA) - a conventional BoNT/A. IncobotulinumtoxinA is the only BoNT product that is free of complexing proteins. The necessity of complexing proteins for the effectiveness of botulinum toxin treatment has been challenged by preclinical and clinical studies with incobotulinumtoxinA. These studies have also suggested that incobotulinumtoxinA is associated with a lower risk for stimulating antibody formation than onabotulinumtoxinA. In phase 3 noninferiority trials, incobotulinumtoxinA demonstrated significant improvements in CD and BSP symptoms in both primary and secondary measures, compared with baseline, and met criteria for noninferiority versus onabotulinumtoxinA. In placebo-controlled trials, incobotulinumtoxinA also significantly improved the symptoms of CD and BSP, with robust outcomes in both primary and secondary measures. The use of incobotulinumtoxinA has been well tolerated in all trials, with an adverse event profile similar to that of onabotulinumtoxinA. Based on these data, incobotulinumtoxinA is a safe and effective BoNT/A for the treatment of CD and BSP, and may pose a lower risk for immunogenicity leading to treatment failure compared with other available BoNT agents. This paper reviews the treatment of focal dystonias with BoNTs, in particular, incobotulinumtoxinA. Controlled trials from the existing incobotulinumtoxinA literature are summarized. © 2012 Jimenez-Shahed, publisher and licensee Dove Medical Press Ltd. Source


Jarjour I.T.,Clinic for Autonomic Dysfunction | Jarjour I.T.,Baylor College of Medicine
Seminars in Pediatric Neurology | Year: 2013

Postural tachycardia syndrome is a chronic condition with frequent symptoms of orthostatic intolerance or sympathetic activation and excessive tachycardia while standing, without significant hypotension. Orthostatic symptoms include dizziness, lightheadedness, blurring of vision, near faints, weakness in legs, poor concentration, nausea, and headaches. Somatic symptoms include fatigue, sleep disorder, widespread pain, abdominal pain, and menstrual irregularities. Psychological problems may overlap with physical complaints. This review discusses the normal physiology of orthostatic change, different pathophysiological mechanisms of postural tachycardia syndrome, including hypovolemia, venous pooling, autonomic neuropathy, and hyperadrenergic responses. In addition, an outline for management tailored to the patient's clinical syndrome is presented, along with concluding thoughts on future research needs. © 2013 Elsevier Inc. Source


Arrese M.,University of Santiago de Chile | Karpen S.J.,Baylor College of Medicine
Clinical Pharmacology and Therapeutics | Year: 2010

Members of the nuclear receptor (NR) superfamily of ligandactivated transcription factors are players of substantial relevance in the regulation of hepatic gene expression. NRs direct normal physiology and metabolism, adaptations to liver disease, and responses to inflammation and toxins. They also contribute to the regenerative response. In this review, we summarize currently available experimental and clinical data, focusing on the role of NRs in cholestasis and nonalcoholic fatty liver disease (NAFLD). We also highlight the potential of NRs as targets for safe and effective therapeutic interventions. © 2010 American Society2010 American Society for Clinical Pharmacology and Therapeutics. Source


Yazdanbakhsh K.,New York Blood Center | Ware R.E.,Baylor College of Medicine | Noizat-Pirenne F.,French Institute of Health and Medical Research
Blood | Year: 2012

Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication. © 2012 by The American Society of Hematology. Source


Gee A.P.,Baylor College of Medicine
Cancer Gene Therapy | Year: 2015

Compliance with Food and Drug Administration regulations relating to initiating early phase clinical trials of new cellular therapy products often presents a hurdle to new investigators. One of the biggest obstacles is the requirement to manufacture the therapeutic products under current Good Manufacturing Practices - a system that is usually poorly understood by both basic researchers and clinicians. This article reviews the major points that must be addressed when manufacturing genetically modified T cells for therapeutic use. © 2015 Nature America, Inc. Source


Dietrich J.E.,Baylor College of Medicine
Hormone and Metabolic Research | Year: 2015

The incidence and prevalence of conditions of the reproductive tract varies. This is related to both the complexity and spectrum of underlying and associated conditions. In some cases, only retrospective or case data are available, and likely under-reporting occurs, contributing to a lower than expected prevalence. Given the complex nature in which the reproductive tract develops in the fetus, it is important to understand the embryology, especially in situations of congenital anatomic differences. It is interesting to note not only patterns of conditions, but patterns of concurrent conditions or anomalies such as those occurring with isolated Müllerian anomalies, in conjunction with disorders of sexual differentiation or with cloacal malformations. This review will address typical presentation of these conditions, highlights of management and point to areas of research need, including clinical outcomes and genetic implications. © Georg Thieme Verlag KG Stuttgart. New York. Source


Adrogue H.J.,Baylor College of Medicine | Adrogue H.J.,Veterans Affairs Medical Center | Madias N.E.,Tufts University | Madias N.E.,St Elizabeths Medical Center
Journal of the American Society of Nephrology | Year: 2012

Treatment of hypotonic hyponatremia often challenges clinicians on many counts. Despite similar serum sodium concentrations, clinical manifestations can range from mild to life threatening. Some patients require active management, whereas others recover without intervention. Therapeutic measures frequently yield safe correction, yet the same measures can result in osmotic demyelination. To address this challenge, we present a practical approach to managing hyponatremia that centers on two elements: a diagnostic evaluation directed at the pathogenesis and putative causes of hyponatremia, the case-specific clinical and laboratory features, and the associated clinical risk; and a management plan tailored to the diagnostic findings that incorporates quantitative projections of fluid therapy and fluid losses on the patient's serum sodium, balances potential benefits and risks, and emphasizes vigilant monitoring. These principles should enable the clinician to formulate a management plan that addresses expeditiously three critical questions: Which of the determinants of the serum sodium are deranged and what is the underlying culprit? How urgent is the need for intervention? What specific therapy should be instituted and which are the associated pitfalls? Copyright © 2012 by the American Society of Nephrology. Source


Jefferies J.L.,Baylor College of Medicine | Towbin J.A.,The Heart Institute
The Lancet | Year: 2010

Dilated cardiomyopathy is characterised by left ventricular dilation that is associated with systolic dysfunction. Diastolic dysfunction and impaired right ventricular function can develop. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be exercise-induced or persistent at rest. Many patients are asymptomatic. Chronically treated patients sometimes present acutely with decompensated heart failure. Other life-threatening risks are ventricular arrhythmias and atrioventricular block, syncope, and sudden death. Genetic inheritance arises in 30-48% of patients, and inflammatory disorders such as myocarditis or toxic effects from medications, alcohol, or illicit drugs also result in dilated cardiomyopathy. Genes that cause dilated cardiomyopathy generally encode cytoskeletal and sarcomeric (contractile apparatus) proteins, although disturbance of calcium homeostasis also seems to be important. In children, disrupted mitochondrial function and metabolic abnormalities have a causal role. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress. Arrhythmia therapy and prevention of sudden death continue to be mainstays of treatment. Despite progress over the past 10 years, outcomes need to be improved. © 2010 Elsevier Ltd. All rights reserved. Source


Horton T.,Baylor College of Medicine
Blood | Year: 2015

In this issue of Blood, Jing et al have identified 2 novel pathways involved in the dexamethasone response in pediatric B-precursor acute lymphoblastic leukemia (ALL). © 2015 by The American Society of Hematology. Source


Redell M.S.,Baylor College of Medicine
Blood | Year: 2016

The transcription factor signal transducer and activator of transcription 3 (STAT3) is perhaps best known for its prosurvival effects in a wide variety of cancers, but for some, including acute myeloid leukemia (AML), its role in immune evasion may be just as important. In this issue of Blood, Zhang et al1 report the development of an engineered STAT3 decoy oligodeoxynucleotide (dODN) that is stable in serum, is taken up specifically by target cells, and exerts its antileukemia effects largely by restoring the host anti-AML immune response. Source


Lam W.,Baylor College of Medicine
Methodist DeBakey cardiovascular journal | Year: 2011

Improved surgical outcomes in children have led to a growing population of adults with congenital heart disease. Rhythm disturbances in the adult congenital heart disease (ACHD) patient can be intrinsic to the anomaly or acquired after palliation. Tachyarrhythmias, either supraventricular or ventricular, and bradyarrhythmias, either sinus node dysfunction or atrioventricular block, may occur frequently. Technological advances in intervention and surgical approaches have led to prophylactic and therapeutic reduction in arrhythmias. In order of escalation, this article addresses medical management, catheter ablation, device therapy for antitachycardia pacing and defibrillation, and surgical intervention. There are now an estimated one million-plus ACHD patients living in the United States. An estimated 45% of those have simple defects (e.g., atrial septal defects), 40% have moderately complex defects (e.g., tetralogy of Fallot, or ToF), and 15% have severely complex defects (e.g., single ventricle anatomy or surgical palliations for transposition of the great arteries [TGA]). The moderate and severe categories have a high incidence of arrhythmia. Of older repaired ToF patients, 34% develop symptomatic atrial or supraventricular tachycardias, 8.5% develop high-grade ventricular tachycardia (VT), and there are an increasing number of implantable defibrillators due to a sudden-death estimate of 2% per decade. Thus, an estimated 50,000 adults with repaired ToF will require electrophysiology follow-up with 100 sudden deaths per year nationally. Roughly 3% of all congenital heart surgeries requiring cardiopulmonary bypass have post-operative AV block, and 1% will require permanent pacing. Older atriopulmonary Fontans have up to an estimated 50% incidence of atrial tachycardia within a decade of palliation due to suture lines and elevated atrial pressures. Patients who have undergone an atrial switch operation (e.g., Mustard or Senning operations) are rarely exclusively in sinus rhythm a decade after repair, thus posing problems for rhythm control and anticoagulation. Catheter ablation in congenital heart disease is often more challenging than structurally normal hearts because of abnormal anatomy (congenital and/or post-surgical) and thicker chamber walls due to unfavorable hemodynamics. In preparation, review of noninvasive imaging, previous catheterization angiography, and surgical palliation reports are paramount prior to a procedure. Fortunately, to meet the growing challenge, newer software with 3-D packages allow for improved mapping. In addition, advances with larger-tipped and irrigated-tip catheters allow for deeper, more effective lesions to be placed. Several advances in surgical approach have led to a reduction in arrhythmias. For example, the arterial switch operation for d-transposition of the great arteries instead of the aforementioned atrial switch operation eliminates the use of a systemic right ventricle that can later develop intra-atrial reentrant tachycardia and sinus node dysfunction. Other advances include paying careful attention to minimizing ventriculotomies in ToF and ventricular septal defect (VSD) repairs, earlier complete repairs, and valve sparing to reduce pulmonary insufficiency. Finally, completion of the extra-cardiac Fontan procedure (e.g., total cavopulmonary connection) for single ventricles avoids extensive suture lines in the right atrium, thereby reducing scarring and higher pressures that lead to IART and sinus node dysfunction. Extracardiac (EC) conduits and lateral tunnel (LT) Fontans are preferred today, and the Fontan conversion procedure (converting prior atriopulmonary Fontans to the EC or LT type) can be performed to reduce arrhythmia and thromboembolic events. Source


Chen D.,Columbia University | Shan J.,Columbia University | Zhu W.-G.,Peking University | Qin J.,Baylor College of Medicine | Gu W.,Columbia University
Nature | Year: 2010

The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Rimawi M.F.,Baylor College of Medicine
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)- amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy. Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone-releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery. Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; ypT0-is) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease (ypT1a-b) was 22% (ER positive, 33%; ER negative, 4%). In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study. Source


Siddiq D.M.,Baylor College of Medicine | Darouiche R.O.,Michael bakey Veteran Affairs Medical Center
Nature Reviews Urology | Year: 2012

Catheter-associated urinary tract infection (CAUTI) is the most common health-care-associated infection worldwide. Although not all cases of bacteriuria result in clinical infection, several hundred thousand episodes of CAUTI occur each year in the USA alone. The milieu in which the catheter is placed is highly conducive to bacterial colonization, biofilm formation on the catheter surface, and inevitable catheter-associated bacteriuria. A multitude of novel methods of CAUTI prevention have been described, including established approaches that are routinely recommended, such as the use of a secured, closed, silicone urinary catheter drainage system that mimics normal voiding, and newer strategies focusing on biocompatible catheter materials that cause minimal host inflammatory response and retard biofilm formation. Much recent research has focused on modification of the catheter surface by either coating or impregnation with antimicrobials or antiseptics. However, clinical trials that analyse cost-effectiveness and rates of antimicrobial resistance are awaited. More recently, innovative use of iontophoresis, vibroacoustic stimulation, bacterial interference and bacteriophage cocktails has been reported. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Lerner S.P.,Baylor College of Medicine | Goh A.,Houston Methodist Hospital
Cancer | Year: 2015

Advances in endoscopic imaging technology may improve sensitivity for the detection of bladder cancer and provide a more complete understanding of the urothelial landscape, and it also may lead to improved short-term and long-term cancer control. Fluorescence cystoscopy requires intravesical administration of a photosensitizing agent (5-aminolevulinic acid or hexaminolevulinate), and imaging with a blue-light endoscopy system demonstrably improves the detection of papillary and flat bladder lesions compared with conventional white-light cystoscopy. Prospective phase 3 clinical trials have demonstrated improved diagnostic ability, enhanced tumor resection, and a small but significant reduction in recurrence-free survival. Optical coherence tomography delineates subsurface microarchitecture information about bladder lesions in real time and has the ability to discriminate between noninvasive and invasive cancers. Narrow-band imaging may augment white-light cystoscopy by providing increased contrast between normal and abnormal tissue on the basis of neovascularity. Confocal laser endoscopy has been applied to the urinary tract using thinner probes adapted from use in gastrointestinal malignancies and provides exquisite images at microscopic resolution. More technology is on the horizon that may further enhance our ability to detect and accurately stage bladder tumors and distinguish benign from malignant or dysplastic lesions. © 2014 American Cancer Society. Source


Hughes S.O.,Baylor College of Medicine | Shewchuk R.M.,University of Alabama at Birmingham
International Journal of Behavioral Nutrition and Physical Activity | Year: 2012

Background: Associations between parent and child characteristics and how they influence the approach parents take toward children in the feeding environment have not been examined extensively, especially in low-income minority families who are at a higher risk for obesity. The primary aim of the study was to examine positive and negative parent emotions as potential mediators of the relationship between child temperament and parents' perceptions of strategy effectiveness and problems encountered in feeding children fruit and vegetables.Methods: Participants were low-income families (n = 639, 73% minority, children aged 3-5 years) participating in Head Start programs in two states. Parents completed the Children's Behavior Questionnaire (CBQ), Positive and Negative Affect Schedule (PANAS), and measures of strategy effectiveness (teachable moments, practical methods, restriction, and enhanced availability) and problems encountered (vegetable characteristics, child attributions for dislike, external influences, and parental demands) in feeding children fruit and vegetables.Results: Positive parent emotions partially mediated the relationship between child Effortful Control and strategy effectiveness and fully mediated the relationship between Surgency and strategy effectiveness. Although negative parent emotions were associated with increased perception of problems in feeding children fruit and vegetables, the relationship between Negative Affectivity and problems in feeding was partially mediated by negative parent emotions.Conclusions: Positive parent emotions facilitated perceived effectiveness of feeding strategies, with child Effortful Control and Surgency instrumental to this process. Understanding mechanisms in parent-child feeding is important when developing interventions designed to promote healthy child eating behaviors. © 2012 Hughes and Shewchuk; licensee BioMed Central Ltd. Source


Antebi A.,Max Planck Institute for Biology of Ageing | Antebi A.,University of Cologne | Antebi A.,Baylor College of Medicine
Current Topics in Developmental Biology | Year: 2013

Hormones play a critical role in driving major stage transitions and developmental timing events in many species. In the nematode C. elegans the steroid hormone receptor, DAF-12, works at the confluence of pathways regulating developmental timing, stage specification, and longevity. DAF-12 couples environmental and physiologic signals to life history regulation, and it is embedded in a rich architecture governing diverse processes. Here, we highlight the molecular insights, extraordinary circuitry, and signaling pathways governing life stage transitions in the worm and how they have yielded fundamental insights into steroid regulation of biological time. © 2013 Elsevier Inc. Source


Zhang L.,Baylor College of Medicine
Neurobiology of aging | Year: 2012

The nuclear receptor related 1 (Nurr1) transcription factor contributes to the development and maintenance of dopamine (DA) neurons in the brain. We found that heterozygous Nurr1 knockout (Nurr1 +/-) influenced the age-dependent decline in the number of DA neurons and influenced DA signaling. We examined the DA marker, tyrosine hydroxylase, using immunohistochemistry, and we measured DA signaling using fast-scan cyclic voltammetry in 3 age groups of wild-type (Nurr1 +/+) and mutant (Nurr1 +/-) mice: 3-6, 9-12, and 15-23 mo old. Prior to significant loss of DA neurons and to the onset of parkinsonian symptoms, young Nurr1 +/- mice (3-6 mo) exhibited a decrease in peak evoked DA release that was partially countered by a decrease in the rate of DA reuptake. As peak evoked DA release declined with age for both the wild-type and Nurr1 +/- mice, both genotypes manifested decreased DA reuptake. As the DA release fell further with age, decreased DA reuptake eventually could not adequately compensate the Nurr1 +/- mice. The results indicated that Nurr1 deficiency led to impaired DA release even before significant DA neuron loss. Copyright © 2012 Elsevier Inc. All rights reserved. Source


Tavyev Asher Y.J.,Cedars Sinai Medical Center | Scaglia F.,Baylor College of Medicine
European Journal of Medical Genetics | Year: 2012

Epilepsy can be a challenging diagnosis to make in the neonatal and infantile periods. Seizures in this age group may be due to a serious underlying cause that results in an epileptic encephalopathy. Early infantile epileptic encephalopathy (EIEE) is a progressive neurologic condition that exhibits concomitant cognitive and motor impairment, and is often associated with severe intellectual disability. This condition belongs to the group of age-dependent epileptic encephalopathies, and thus the clinical and electro-encephalographic features change with age as the central nervous system evolves. The molecular bases and the clinical spectrum associated with the early infantile epileptic encephalopathies continue to expand as new genetic discoveries are made. This review will highlight the molecular etiologies of early infantile epileptic encephalopathy, and the clinical and electro-encephalographic changes that take place in these epileptic phenotypes as the brain develops. © 2012 Elsevier Masson SAS. Source


Foster B.A.,University of Texas Health Science Center at San Antonio | Tom D.,University of Texas Health Science Center at San Antonio | Hill V.,Baylor College of Medicine
Journal of Pediatrics | Year: 2014

Objective To determine whether the use of hypotonic vs isotonic maintenance fluids confers an increased risk of hyponatremia in hospitalized children. Study design A search of MEDLINE (1946 to January 2013), the Cochrane Central Registry (1991 to December 2012), Cumulative Index for Nursing and Allied Health Literature (1990 to December 2012), and Pediatric Academic Societies (2000-2012) abstracts was conducted using the terms "hypotonic fluids/saline/solutions" and "isotonic fluids/saline/solutions," and citations were reviewed using a predefined protocol. Data on the primary and secondary outcomes were extracted from original articles by 2 authors independently. Meta-analyses of the primary and secondary outcomes were performed when possible. Results A total of 1634 citations were screened. Ten studies (n = 893) identified as independent randomized controlled trials were included. Five studies examined subjects in the intensive care unit setting, including 4 on regular wards and 1 in a mixed setting. In hospitalized children receiving maintenance intravenous fluids, hyponatremia was seen more often in those receiving hypotonic fluids than in those receiving isotonic fluids, with an overall relative risk of 2.37 (95% CI, 1.72-3.26). Receipt of hypotonic fluids was associated with a relative risk of moderate hyponatremia (<130 mmol/L) of 6.1 (95% CI, 2.2-17.3). A subgroup analysis of hypotonic fluids with half-normal saline found a relative risk of hyponatremia of 2.42 (95% CI, 1.32-4.45). Conclusion In hospitalized children in intensive care and postoperative settings, the administration of hypotonic maintenance fluids increases the risk of hyponatremia when compared with administration of isotonic fluids. For patients on general wards, insufficient data are available based on the reviewed studies, and individual risk factors must be assessed. © 2014 Elsevier Inc. All rights reserved. Source


Sardiello M.,Baylor College of Medicine
Annals of the New York Academy of Sciences | Year: 2016

The lysosome is the main catabolic hub of the cell. Owing to its role in fundamental processes such as autophagy, plasma membrane repair, mTOR signaling, and maintenance of cellular homeostasis, the lysosome has a profound influence on cellular metabolism and human health. Indeed, inefficient or impaired lysosomal function has been implicated in the pathogenesis of a number of degenerative diseases affecting various organs and tissues, most notably the brain, liver, and muscle. The discovery of the coordinated lysosomal expression and regulation (CLEAR) genetic program and its master controller, transcription factor EB (TFEB), has provided an unprecedented tool to study and manipulate lysosomal function. Most lysosome-based processes—including macromolecule degradation, autophagy, lysosomal exocytosis, and proteostasis—are under the transcriptional control of TFEB. Interestingly, impaired TFEB signaling has been suggested to be a contributing factor in the pathogenesis of several degenerative storage diseases. Preclinical studies based on TFEB exogenous expression to reinstate TFEB activity or promote CLEAR network–based lysosomal enhancement have highlighted TFEB as a candidate therapeutic target for the treatment of various degenerative storage diseases. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences. Source


Wang X.H.,Emory University | Mitch W.E.,Baylor College of Medicine
International Journal of Biochemistry and Cell Biology | Year: 2013

Purpose: Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions. Major findings: Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1,E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle. Summary: In CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved. Source


Raft S.,U.S. National Institutes of Health | Groves A.K.,Baylor College of Medicine
Cell and Tissue Research | Year: 2015

The vertebrate inner ear is composed of multiple sensory receptor epithelia, each of which is specialized for detection of sound, gravity, or angular acceleration. Each receptor epithelium contains mechanosensitive hair cells, which are connected to the brainstem by bipolar sensory neurons. Hair cells and their associated neurons are derived from the embryonic rudiment of the inner ear epithelium, but the precise spatial and temporal patterns of their generation, as well as the signals that coordinate these events, have only recently begun to be understood. Gene expression, lineage tracing, and mutant analyses suggest that both neurons and hair cells are generated from a common domain of neural and sensory competence in the embryonic inner ear rudiment. Members of the Shh, Wnt, and FGF families, together with retinoic acid signals, regulate transcription factor genes within the inner ear rudiment to establish the axial identity of the ear and regionalize neurogenic activity. Close-range signaling, such as that of the Notch pathway, specifies the fate of sensory regions and individual cell types. We also describe positive and negative interactions between basic helix-loop-helix and SoxB family transcription factors that specify either neuronal or sensory fates in a context-dependent manner. Finally, we review recent work on inner ear development in zebrafish, which demonstrates that the relative timing of neurogenesis and sensory epithelial formation is not phylogenetically constrained. © 2014, Springer-Verlag Berlin Heidelberg. Source


Hotez P.J.,Baylor College of Medicine | Gurwith M.,Georgetown University
International Journal of Infectious Diseases | Year: 2011

Objectives: To review the