Duquaine S.,North Texas Medical Center |
Kitchell E.,University of Texas Southwestern Medical Center |
Tate T.,Global Rehabilitation Hospital |
Tannen R.C.,Pulmonologist |
And 2 more authors.
Annals of Pharmacotherapy | Year: 2011
To report stroke-like symptoms and unusual central nervous system adverse effects in 2 elderly patients receiving ertapenem. CASE SUMMARY: Two patients ≥70 years of age experienced unusual mental status changes while receiving ertapenem. Patient 1 developed garbled speech and miosis 1 week after starting appropriately dosed ertapenem (1 g/day) for sacral osteomyelitis. Symptoms resolved upon ertapenem discontinuation but recurred upon rechallenge. Patient 2, a cachectic male with acute renal insufficiency, became delirious and progressively obtunded 5 days after starting ertapenem 1 g/day. Nine days after initiation of therapy, he required intubation and mechanical ventilation; ertapenem was discontinued at that time. Within 2 days of ertapenem discontinuation, his mental state cleared and the ventilator was removed. DISCUSSION: Carbapenems, including ertapenem, have been implicated in causing central nervous system toxicity, including hallucinations and seizures. However, published reports of other, nonseizure-related central nervous system events are limited. Considerable resources were expended on extensive medical interventions before ertapenem was identified as a potential cause of the delirium in our patients. When applied to our patients, the Naranjo probability scale indicated a highly probable relationship for patient 1 and a probable relationship for patient 2 between the adverse effects and ertapenem use. CONCLUSIONS: Clinicians should be cognizant of ertapenem's potential to induce profound changes in mental status that may mimic other conditions in elderly patients.
Del Alcazar C.R.G.,University of Texas Southwestern Medical Center |
Todorova P.K.,University of Texas Southwestern Medical Center |
Habib A.A.,University of Texas Southwestern Medical Center |
Habib A.A.,North Texas Medical Center |
And 2 more authors.
Molecular Cancer Research | Year: 2016
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. To better understand the molecular basis for therapy-driven temozolomide resistance, mice bearing orthotopic GBM xenografts were subjected to protracted temozolomide treatment, and cell lines were generated from the primary (untreated) and recurrent (temozolomide-treated) tumors. As expected, the cells derived from primary tumors were sensitive to temozolomide, whereas the cells from the recurrent tumors were significantly resistant to the drug. Importantly, the acquired resistance to temozolomide in the recurrent lines was not driven by re-expression of MGMT or loss of MMR but was due to accelerated repair of temozolomideinduced DNA double-strand breaks (DSB). Temozolomide induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin temozolomide resistance in the recurrent lines, as these cells were cross-resistant to other agents that induced replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCE). Furthermore, in light of recent studies demonstrating that CDK1 and CDK2 promote HR, it was found that CDK1/2 inhibitors countered the heightened HR in recurrent tumors and sensitized these therapy-resistant tumor cells to temozolomide. Implications: Augmented HR repair is a novel mechanism underlying acquired temozolomide resistance in GBM, and this raises the possibility of improving the therapeutic response to temozolomide by targeting HR with small-molecule inhibitors of CDK1/2. © 2016 American Association for Cancer Research.
Heinicke K.,The Texas Institute |
Heinicke K.,University of Texas Southwestern Medical Center |
Taivassalo T.,McGill University |
Wyrick P.,The Texas Institute |
And 7 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011
Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low V O 2peak (28 ± 9% of predicted) and exaggerated systemic O 2 delivery relative to O 2 utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/V O 2peak, (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and VE/VCO 2peak, (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in δVE/ΔVCO 2 (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower PaCO2 and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated V E/V O 2, V E/V CO 2, and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation. © 2011 by the American Physiological Society.
Orngreen M.C.,Copenhagen Muscle Research Center |
Jeppesen T.D.,Copenhagen Muscle Research Center |
Taivassalo T.,University of Texas Southwestern Medical Center |
Hauerslev S.,Copenhagen Muscle Research Center |
And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015
Context: Patients with blocked muscle glycogen breakdown (McArdle disease) have severely reduced exercise capacity compared to healthy individuals and are not assumed to produce lactate during exercise. Objectives: The objectives were: 1) to quantify systemic and muscle lactate kinetics and oxidation rates and muscle energy utilization during exercise in patients with McArdle disease; and 2) to elucidate the role of lactate formation in muscle energy production. Design and Setting: This was a single trial in a hospital. Participants: Participants were four patients with McArdle disease and seven healthy subjects. Intervention: Patients and healthy controls were studied at rest, which was followed by 40 minutes of cycle-ergometer exercise at 60% of the patients' maximal oxygen uptake (∼35 W). Main Outcome Measures: Main outcome measures were systemic and leg skeletal muscle lactate, alanine, fatty acid, and glucose kinetics. Results: McArdle patients had a marked decrease in plasma lactate concentration at the onset of exercise, and the concentration remained suppressed during exercise. A substantial leg net lactate uptake and subsequent oxidation occurred over the entire exercise period in patients, in contrast to a net lactate release or no exchange in the healthy controls. Despite a net lactate uptake by the active leg, a simultaneous unidirectional lactate release was observed in McArdle patients at rates that were similar to the healthy controls. Conclusion: Lactate is an important energy source for contracting skeletal muscle in patients with myophosphorylase deficiency. Although McArdle patients had leg net lactate consumption, a simultaneous release of lactate was observed at rates similar to that found in healthy individuals exercising at the same very low workload, suggesting that lactate formation is mandatory for muscle energy generation during exercise. Copyright © 2015 by the Endocrine Society.
Abele M.,George hlen Va Medical Center |
Brown J.,North Texas Medical Center |
Ibrahim H.,North Texas Medical Center |
Jha M.K.,North Texas State Hospital
Academic Psychiatry | Year: 2016
Objective: The authors report on the current status of motivational interviewing education and training director attitudes about providing it to psychiatry residents. Methods: Training directors of general, child/adolescent and addiction psychiatry training programs were invited to participate in an anonymous online survey. Results: Of the 333 training directors who were invited to participate, 66 of 168 (39.3 %) general, 41 of 121 (33.9 %) child/adolescent, and 19 of 44 (43.2 %) addiction psychiatry training directors completed the survey. The authors found that 90.9 % of general, 80.5 % of child/adolescent, and 100 % of addiction psychiatry training programs provided motivational interviewing education. Most programs used multiple educational opportunities; the three most common opportunities were didactics, clinical practice with formal supervision, and self-directed reading. Most training directors believed that motivational interviewing was an important skill for general psychiatrists. The authors also found that 83.3 % of general, 87.8 % of child/adolescent, and 94.7 % of addiction psychiatry training directors reported that motivational interviewing should be taught during general psychiatry residency. Conclusions: Motivational interviewing skills are considered important for general psychiatrists and widely offered by training programs. Competency in motivational interviewing skills should be considered as a graduation requirement in general psychiatry training programs. © 2014 Academic Psychiatry.
Crooks D.R.,Georgetown University |
Crooks D.R.,U.S. National Institutes of Health |
Jeong S.Y.,U.S. National Institutes of Health |
Tong W.-H.,U.S. National Institutes of Health |
And 6 more authors.
Journal of Biological Chemistry | Year: 2012
Iron-sulfur (Fe-S) cluster cofactors are formed on the scaffold protein ISCU. ISCU myopathy is a disease caused by an intronic mutation that leads to abnormally spliced ISCU mRNA. We found that two predominant mis-spliced ISCU mRNAs produce a truncated and short-lived ISCU protein product in multiple patient cell types. Expression of the muscle-specific transcription factor MyoD further diminished normal splicing of ISCU mRNA in patient myoblasts, demonstrating that the process of muscle differentiation enhances the loss of normal ISCUmRNA splicing. ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts.Wenext treated patient cells with pro-oxidants to mimic the oxidative stress associated with muscle activity. Brief hydrogen peroxide treatment or incubation in an enriched oxygen atmosphere led to a marked further reduction of ISCU protein levels, which could be prevented by pretreatment with the antioxidant ascorbate. Thus, we conclude that skeletal muscle differentiation of patient cells causes a higher degree of abnormal ISCU splicing and that oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles.
Taivassalo T.,McGill University |
Taivassalo T.,The Texas Institute |
Ayyad K.,The Texas Institute |
Ayyad K.,North Texas Medical Center |
And 3 more authors.
Brain | Year: 2012
Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0±0.9 compared with 1.4±0.3, P<0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1±4.0ml/kg/min compared with 20.7±7.9ml/kg/min, P<0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or 'ragged-red' fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r 2=0.68, P<0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise. Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy, thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise. Furthermore, the finding of high capillary levels despite elevated tissue oxygen levels during exercise in respiration-deficient muscle fibres implies that mitochondrial metabolism activates angiogenesis in skeletal muscle by a mechanism that is independent of hypoxia. © 2011 The Author.
Jain M.K.,University of Texas Southwestern Medical Center |
Adams-Huet B.,University of Texas Southwestern Medical Center |
Terekhova D.,University of Texas Southwestern Medical Center |
Kushner L.E.,Research Center |
And 5 more authors.
Journal of Viral Hepatitis | Year: 2014
Chronic viral infections lead to persistent immune activation, which is alleviated by eradicating or suppressing the infection. To understand the effects of interferon treatment on immune system activation by chronic infections, we evaluated kinetic patterns of a broad spectrum of serum biomarkers during HCV treatment in HIV/HCV co-infected patients. HCV viral load and 50 biomarkers were analysed at baseline and 27 time points during pegylated interferon-alpha and ribavirin (IFN/RBV) treatment of 12 HIV/HCV co-infected patients. We evaluated biomarker changes from baseline for each time point and biomarker correlations with clinical parameters, treatment response and liver histopathology. IL-1α, IL-12p40, IL-1RA, IP-10, MIG, MIP-1α/1β, HGF, sCD40L, TRAIL and leptin increased in the first day. IL-12p70, IL-17A, IL-10, GROα, IL-8, MCP-3, IL-4 and M-CSF peaked later during week 1. IL-1α, HGF, IP-10, MIP-1α, TRAIL, sCD40L, IL-10, IL-12p70, MCP-3, FGFb, ENA-78, TGF-β, IL-2, IFN-γ, IL-6, IL-15, IL-7 and PDGF-BB decreased below baseline over the course of treatment. Higher BMI, baseline HCV viral load and leptin levels were associated with lack of sustained virologic response. ENA-78 was associated with sustained viral response. Positive correlations were found between liver inflammation and baseline CD4 count, sVCAM and HGF; fibrosis stage and HGF; liver steatosis, BMI and leptin. Our findings suggest IFN/RBV treatment initially increases levels of several biomarkers, but eventually leads to a decline in many immune markers. These findings shed light on the relationship between IFN treatment and immune activation by chronic viral infections, such as HCV. © 2014 John Wiley & Sons Ltd.
Sharp L.J.,University of Texas Southwestern Medical Center |
Sharp L.J.,The Texas Institute |
Haller R.G.,University of Texas Southwestern Medical Center |
Haller R.G.,The Texas Institute |
Haller R.G.,North Texas Medical Center
Neurologic Clinics | Year: 2014
Metabolic and mitochondrial myopathies encompass a heterogeneous group of disorders that result in impaired energy production in skeletal muscle. Symptoms of premature muscle fatigue, sometimes leading to myalgia, rhabdomyolysis, and myoglobinuria, typically occur with exercise that would normally depend on the defective metabolic pathway. But in another group of these disorders, the dominant muscle symptom is weakness. This article reviews the clinical features, diagnosis, and management of these diseases with emphasis on the recent literature. © 2014 Elsevier Inc.
Krainski F.,The Texas Institute |
Krainski F.,University of Texas Southwestern Medical Center |
Hastings J.L.,The Texas Institute |
Hastings J.L.,University of Texas Southwestern Medical Center |
And 12 more authors.
Journal of Applied Physiology | Year: 2014
Exposure to microgravity causes functional and structural impairment of skeletal muscle. Current exercise regimens are time-consuming and insufficiently effective; an integrated countermeasure is needed that addresses musculoskeletal along with cardiovascular health. High-intensity, short-duration rowing ergometry and supplemental resistive strength exercise may achieve these goals. Twenty-seven healthy volunteers completed 5 wk of head-down-tilt bed rest (HDBR): 18 were randomized to exercise, 9 remained sedentary. Exercise consisted of rowing ergometry 6 days/wk, including interval training, and supplemental strength training 2 days/wk. Measurements before and after HDBR and following reambulation included assessment of strength, skeletal muscle volume (MRI), and muscle metabolism (magnetic resonance spectroscopy); quadriceps muscle biopsies were obtained to assess muscle fiber types, capillarization, and oxidative capacity. Sedentary bed rest (BR) led to decreased muscle volume (quadriceps: -9 ± 4%, P < 0.001; plantar flexors: -19 ± 6%, P < 0.001). Exercise (ExBR) reduced atrophy in the quadriceps (-5 ± 4%, interaction P < 0.018) and calf muscle, although to a lesser degree (-14 ± 6%, interaction P < 0.076). Knee extensor and plantar flexor strength was impaired by BR (-14 ± 15%, P < 0.014 and -22 ± 7%, P < 0.001) but preserved by ExBR (-4 ± 13%, P < 0.238 and -13 ± 28%, P < 0.011). Metabolic capacity, as assessed by maximal O2 consumption, 31P-MRS, and oxidative chain enzyme activity, was impaired in BR but stable or improved in ExBR. Reambulation reversed the negative impact of BR. High-intensity, short-duration rowing and supplemental strength training effectively preserved skeletal muscle function and structure while partially preventing atrophy in key antigravity muscles. Due to its integrated cardiovascular benefits, rowing ergometry could be a primary component of exercise prescriptions for astronauts or patients suffering from severe deconditioning. Copyright © 2014 the American Physiological Society.