Mi S.,Clinical Immunobiology Correlative Studies Laboratory |
Stinson S.,General Clinical Research Center |
Kalos M.,University of Pennsylvania |
Lacey S.F.,Clinical Immunobiology Correlative Studies Laboratory |
And 2 more authors.
Science Translational Medicine | Year: 2010
AIDS patients who develop lymphoma are often treated with transplanted hematopoietic progenitor cells. As a first step in developing a hematopoietic cell-based gene therapy treatment, four patients undergoing treatment with these transplanted cells were also given gene-modified peripheral blood-derived (CD34+) hematopoietic progenitor cells expressing three RNA-based anti-HIV moieties (tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme). In vitro analysis of these gene-modified cells showed no differences in their hematopoietic potential compared with nontransduced cells. In vitro estimates of successful expression of the anti-HIV moieties were initially as high as 22% but declined to ∼1% over 4 weeks of culture. Ethical study design required that patients be transplanted with both gene-modified and unmanipulated hematopoietic progenitor cells obtained from the patient by apheresis. Transfected cells were successfully engrafted in all four infused patients by day 11, and there were no unexpected infusion-related toxicities. Persistent vector expression in multiple cell lineages was observed at low levels for up to 24 months, as was expression of the introduced small interfering RNA and ribozyme. Therefore, we have demonstrated stable vector expression in human blood cells after transplantation of autologous gene-modified hematopoietic progenitor cells. These results support the development of an RNA-based cell therapy platform for HIV.
Chao T.-F.,Taipei Veterans General Hospital |
Chao T.-F.,National Yang Ming University |
Lip G.Y.H.,University of Birmingham |
Liu C.-J.,National Yang Ming University |
And 18 more authors.
Stroke | Year: 2016
Background and Purpose - The age threshold for an increased stroke risk for patients with atrial fibrillation may be different for Asians and non-Asians. We hypothesized that a modified CHA 2 DS 2 -VASc (congestive heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female) scheme, mCHA 2 DS 2 -VASc, which assigned one point for patients aged 50 to 74 years, may perform better than CHA 2 DS 2 -VASc score for stroke risk stratification in Asians. Methods - This study used the Taiwan National Health Insurance Research Database, which included 224 866 newly diagnosed atrial fibrillation patients. The predictive accuracies of ischemic stroke of CHA 2 DS 2 -VASc and mCHA 2 DS 2 -VASc scores were compared among 124 271 patients without antithrombotic therapies. From the whole cohort, 15 948 patients had a CHA 2 DS 2 -VASc score 0 (males) or 1 (females), and 8654 patients had an mCHA 2 DS 2 -VASc score 1 (males) or 2 (females). The latter were categorized into 3 groups, that is, no treatment, antiplatelet therapy, and warfarin, and the risks of ischemic stroke and intracranial hemorrhage (ICH) were compared. Results - During a follow-up of 538 653 person-years, 21 008 patients experienced ischemic stroke. The mCHA 2 DS 2 -VASc performed better than CHA 2 DS 2 -VASc score in predicting ischemic stroke assessed by C indexes and net reclassification index. For 8654 patients having an mCHA 2 DS 2 -VASc score of 1 (males) or 2 (females) because of the resetting of the age threshold, use of warfarin was associated with a 30% lower risk of ischemic stroke and a similar risk of ICH compared with nontreatment. Net clinical benefit analyses also favored the use of warfarin in different weighted models. Conclusions - In this Asian atrial fibrillation cohort, the mCHA 2 DS 2 -VASc score performed better than the CHA 2 DS 2 -VASc and would further identify atrial fibrillation patients who may derive a positive net clinical benefit from oral anticoagulation. © 2016 American Heart Association, Inc.
News Article | November 2, 2016
BOSTON - While schizophrenia is best known for episodes of psychosis - a break with reality during which an individual may experience delusions and hallucinations - it is also marked by chronic neurocognitive deficits, such as problems with memory and attention. A multi-site cognition study led by psychologists at Beth Israel Deaconess Medical Center (BIDMC) found that these neurocognitive symptoms are evident prior to the onset of psychosis in a high-risk stage of the disorder called the prodromal phase. Published today online in advance of print in JAMA Psychiatry, the findings suggest that these impairments may serve as early warning signs of schizophrenia, as well as potential targets for intervention that could mitigate the onset of the psychotic disorder and significantly improve cognitive function. "To our knowledge, this is the largest and most definitive study of cognition in the high-risk period before onset of for psychosis/schizophrenia," said corresponding author Larry J. Seidman, PhD, a psychologist at BIDMC and professor of psychology at Harvard Medical School. "This is part of a paradigm shift in the way we are focusing on the earlier, prodromal phase of the disorder in an effort to identify those most likely to develop psychosis." Seidman and colleagues collected neurocognitive functioning data from participants at eight university-based, outpatient programs in the United States and Canada over the course of four years. The observational study compared 689 males and females deemed at clinical high risk (CHR) of developing psychosis to 264 male and female healthy controls (HC). Using 19 standard tests of executive and visuospatial abilities, attention and working memory, verbal abilities and declarative memory, the researchers found that the high-risk group performed significantly worse than the control group on all 19 measures. Among the high-risk individuals only, those who later progressed to a psychotic disorder performed significantly worse than their high-risk peers who did not develop psychosis during the study. "Currently, when mental health professionals assess people coming in for evaluation, we don't know who will eventually develop schizophrenia," said Seidman. "Our group's focus is on identifying early warning signs and then developing interventions to improve a person's chances for not getting it, making it milder or delaying it." Impaired working memory (the ability to hold information like a phone number in mind for a short time while it's in use) and declarative memory (the ability to recall things learned in the last few minutes) turned out to be the key neurocognitive functions that are impaired in the high-risk, prodromal phase prior to the onset of full-blown psychosis. These findings, said Seidman, are in keeping with the experiences of many people with schizophrenia who report sudden difficulties reading, concentrating or remembering things in the earliest days of the disorder. Schizophrenia "conjures up dread" in our culture, Seidman said, but he notes that it is likely these cognitive deficits - not the delusions and hallucinations people fear so much - that keep roughly 80 percent of people with schizophrenia out of work or school. Recent focus on the prodromal period and the growing promise of early intervention is giving patients and their families more realistic hope that better outcomes are possible, he added. "People can hear voices and still function pretty well, but they basically cannot function at all when their cognition is impaired," he said. "We are also testing a number of cognitive remediation and enhancement treatments to determine their role in the evolution of the illness. There's more evidence suggesting that early intervention reduces the number of people who transition to schizophrenia." This study represented the second phase of the North American Prodrome Longitudinal Study (NAPLS), the multi-site research consortium formed in 2003 to focus on early intervention and prevention of schizophrenia. By pooling their data, NAPLS researchers have been able to identify individuals at high risk for developing a psychotic disorder as well as the biological risk factors associated with converting to psychosis. This summer, the collaborators, led by researchers at Yale, published a risk calculator that can help professionals predict patients' risk of developing psychosis. In addition to BIDMC and Yale, the other NAPLS sites are based at Emory University, the University of Calgary, University of California Los Angeles (UCLA), University of California San Diego (UCSD), University of North Carolina Chapel Hill, University of San Francisco, and Zucker Hillside Hospital. "A significant number of people are able to remain in or go back to work and school," Seidman said. "This early intervention approach is giving people more hope, and that really matters." Study coauthors include Daniel I. Shapiro, PhD; Williams S. Stone, PhD; Kristen A. Woodberry, MSW, PhD; and Ashley Ronzio, BS, all of BIDMC; Barbara A. Cornblatt, PhD, MBA, of Zucker Hillside Hospital, Queens, NY; Jean Addington, PhD, of the University of Calgary, Calgary, Alberta; Carrie E. Bearden, PhD; of UCLA; Kristin S. Cadenhead, MD, and Ming T. Tsuang, MD, PhD, DSc, of UC San Diego; Tyrone D. Cannon, PhD, Thomas H. McGlashan, MD, and Scott W. Woods, MD, of Yale University; Daniel H. Mathalon, PhD, MD, of UC San Francisco; Diana O. Perkins, MD, of UNC, Chapel Hill; and Elaine F. Walker, PhD, of Emory University. This work was supported by grants from the National Institute of Mental Health (U01MH081928, P50 MH080272, R01 MH096027, U01 MH081857, U01 MH081984, P50 MH066286, R01 MH60720, U01 MH082022, K24 MH76191, U01 MH081902, U01 MH082004, U01 MH081988, U01 MH082022); grant SCDMH82101008006 from the Commonwealth of Massachusetts; Clinical Translational Science Award UL1RR025758 and General Clinical Research Center Grant M01RR01032 from the National Center for Research Resources to Harvard University at Beth Israel Deaconess Medical Center; and by grant P41RR14075 from the National Center for Research Resources. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .
Basu A.,Oklahoma State University |
Sanchez K.,Oklahoma State University |
Leyva M.J.,General Clinical Research Center |
Wu M.,The University of Oklahoma Health Sciences Center |
And 3 more authors.
Journal of the American College of Nutrition | Year: 2010
Objective: To compare the effects of supplementation of green tea beverage or green tea extracts with controls on body weight, glucose and lipid profile, biomarkers of oxidative stress, and safety parameters in obese subjects with metabolic syndrome. Design: Randomized, controlled prospective trial. Setting: General Clinical Research Center (GCRC) at University of Oklahoma Health Sciences Center (OUHSC). Subjects: Thirty-five subjects with obesity and metabolic syndrome were recruited in age- and gendermatched trios and were randomly assigned to the control (4 cups water/d), green tea (4 cups/d), or green tea extract (2 capsules and 4 cups water/d) group for 8 weeks. The tea and extract groups had similar dosing of epiogallocatechin-3-gallate (EGCG), the active compound in green tea. Methods: Anthropometrics, blood pressure, fasting glucose and lipids, nuclear magnetic resonance (NMR)-based lipid particle size, safety parameters, biomarkers of oxidative stress (oxidized low-density lipoprotein [LDL], myeloperoxidase [MPO], malondialdehyde and hydroxynonenals [MDA and HNE]), and free catechins were analyzed at screen and at 4 and 8 weeks of the study. Results: Pairwise comparisons showed green tea beverage and green tea extracts caused a significant decrease in body weight and body mass index (BMI) versus controls at 8 weeks (-2.5 ± 0.7 kg, p < 0.01, and -1.9 ± 0.6, p < 0.05, respectively). Green tea beverage showed a decreasing trend in LDL-cholesterol and LDL/high-density lipoprotein (HDL) versus controls (p < 0.1). Green tea beverage also significantly decreased MDA and HNE (-0.39 ± 0.06 μM, p < 0.0001) versus controls. Plasma free catechins were detectable in both beverage and extract groups versus controls at screen and at 8 weeks, indicating compliance and bioavailability of green tea catechins. Conclusions: Green tea beverage consumption (4 cups/d) or extract supplementation (2 capsules/d) for 8 weeks significantly decreased body weight and BMI. Green tea beverage further lowered lipid peroxidation versus age- and gender-matched controls, suggesting the role of green tea flavonoids in improving features of metabolic syndrome in obese patients.
Van Deventer H.E.,U.S. National Institutes of Health |
Mendu D.R.,General Clinical Research Center |
Remaley A.T.,U.S. National Institutes of Health |
Soldin S.J.,U.S. National Institutes of Health |
And 2 more authors.
Clinical Chemistry | Year: 2011
BACKGROUND: Accurate measurement of free thyroxine (FT4) is important for diagnosing and managing thyroid disorders. Most laboratories measure FT4 by direct analogue immunoassay methods. The validity of these methods have recently been questioned. The inverse log-linear relationship between FT4 and thyroidstimulating hormone (TSH) is well described and provides a physiological rationale on which to base an evaluation of FT 4 assays. METHODS: The study included 109 participants for whom FT4 measurement was requested by their clinician. Samples were selected for inclusion to reflect a wide spectrum of TSH and albumin results. FT4 and TSH were measured by use of the Siemens Immulite immunoassay (IA). FT4 was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/ MS) (MS-FT4). RESULTS: The inverse log-linear correlation coefficient between TSH and FT4 was significantly better (P<0.0001) for MS-FT4 (0.84, 95% CI, 0.77- 0.88) than for IA-FT4 (0.45, 95% CI, 0.29-0.59). IA-FT4 showed a significant correlation with albumin (Spearman correlation coefficient 0.45, 95% CI, 0.29-0.5, P<0.0001) and thyroxine-binding globulin (TBG) (Spearman correlation coefficient 0.23, 95% CI, 0.05- 0.41, P<0.02). In contrast, FT4 measurement by LC-MS/MS did not show a significant correlation with albumin or TBG. CONCLUSIONS: The inverse log-linear relationship between FT4 and TSH was significantly better for FT4 measured by LC-MS/MS than by IA. The MS-FT4method therefore provides FT 4 results that agree clinically with those obtained for TSH. Additionally, the significant correlation between IA-FT4 with albumin and TBG suggests that this FT4 method depends on binding protein concentrations and consequently does not accurately reflect FT4. © 2010 American Association for Clinical Chemistry.
Richey P.A.,University of Tennessee Health Science Center |
Richey P.A.,General Clinical Research Center |
Disessa T.G.,General Clinical Research Center |
Somes G.W.,University of Tennessee Health Science Center |
And 5 more authors.
American Journal of Hypertension | Year: 2010
Background Children with hypertension (HTN) are at increased risk for left ventricular hypertrophy (LVH). Increased left ventricular (LV) mass (LVM) by the process of remodeling in response to volume or pressure loading may be eccentric (increased LV diameter) or concentric (increased wall thickness). Our objective was to classify LV geometry among children with primary HTN and examine differences in ambulatory blood pressure (ABP). Methods Subjects aged 7-18 years with suspected HTN were enrolled in this cross-sectional study. ABP and LVM index (LVMI) were measured within the same 24-h period. LV geometry was classified as normal, concentric remodeling, concentric LVH, or eccentric LVH. Results Children with LVH had significantly higher ambulatory systolic BP (SBP) and diastolic blood pressure (BP) (DBP) levels and body mass index (BMI) Z-score. Sixty-eight children had HTN based upon ABP monitoring (ABPM). Thirty-eight percent of the hypertensive subjects had LVH, with equal distribution in the concentric and eccentric groups. There were significant differences in the 24-h DBP parameters when the eccentric LVH group was compared to the normal geometry and concentric LVH groups. Relative wall thickness (RWT) was inversely associated with night time DBP parameters. These relationships persisted after controlling for BMI Z-score. Conclusions Although the risk for LVH is associated with increased SBP and BMI Z-score, those with eccentric LVH had significantly higher DBP. © 2010 American Journal of Hypertension, Ltd.
Horvath P.,University of California at Irvine |
Horvath P.,Clinical Translational Science Institute |
Oliver S.R.,University of California at Irvine |
Oliver S.R.,Clinical Translational Science Institute |
And 7 more authors.
Journal of Investigative Medicine | Year: 2013
Introduction: Cardiovascular complications are the leading cause of mortality in type 2 diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes [Gc], monocytes [Mc]), as reflected by increased CD11b, CD66b, and other surface markers, increases their endothelial and cytokines/chemokines release. Whereas this inflammatory activation seems inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. Methods: Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous fasting euglycemia or hyperglycemia both at baseline and after 30, 90, and 240 minutes of incubation at room temperature. Results: Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity compared with the euglycemic patients with T2DM whose values were similar to those of the healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. Conclusion: Our data suggest that whereas the presence of diabetes per se may have a proinflammatory effect, hyperglycemia seems to further acutely exacerbate innate cell inflammatory status and their consequent endothelial adhesion and vascular damage potential. Copyright © 2013 by The American Federation for Medical Research.
Avery E.,University of Connecticut Health Center |
Kleppinger A.,University of Connecticut Health Center |
Feinn R.,General Clinical Research Center |
Kenny A.M.,University of Connecticut Health Center
Journal of the American Medical Directors Association | Year: 2010
Objective: To determine what variables separate community-dwelling elders from assisted living-dwelling elders. Design: Cross-sectional. Setting: Community and assisted living facilities in Connecticut. Participants: 114 individuals (77 community dwelling, 37 assisted living). Assessments: Nutritional survey, 6-minute walk, Mini-Mental Status Exam (MMSE), Center of Epidemiologic Studies (CES)-Depression Scale, 25-OH vitamin D. Results: At baseline, assisted living-dwelling elders appeared to have lower serum 25-OH vitamin D levels, lower MMSE scores, higher CES-depression scale scores, and walked shorter distances in the 6-minute walk. Serum 25-OH vitamin D levels and 6-minute walk were significantly different between the 2 groups using logistic regression analysis. As serum 25-OH vitamin D levels increased, the probability of an elder living in an assisted living facility decreased, and as distance walked during the 6-minute walk increased, the probability of an elder living in an assisted living facility decreased. Conclusions: Elders living in assisted living facilities had significantly lower 25-OH vitamin D levels and walked shorter distances during the 6-minute walk. These variables can be used to predict the probability of an elder living in an assisted living facility. The lack of effect of nutrition suggests that the role of vitamin D in this setting is in physical function. © 2010 American Medical Directors Association.