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Biomedical subjects

Robert D Stevens

Publications and source records attributed to Robert D Stevens.

At least 19 recordsLinked to original sources
PubMed2006

The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease.

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.

Aged↗
PubMed2006

A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion.

Glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in beta-cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS.

Animals↗
PubMed2006

Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics.

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n = 14-15 per group, 59-60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABA(A) and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.

Analysis of Variance↗
PubMed2006

The spectrum of encephalopathy in critical illness.

Beyond the cerebral impact of cardiac arrest, recent research indicates a high prevalence of neurological disturbances such as delirium and coma among patients admitted to the intensive care unit (ICU). These disturbances, grouped here under the term "encephalopathy," may be overlooked while attention is devoted to reversing life-threatening imbalances in cardiac and pulmonary function. Nevertheless, there is ample evidence that encephalopathy is an independent predictor of mortality. Factors associated with encephalopathy include primary cerebral disorders such as stroke, trauma, and meningitis, or systemic derangements including sepsis, organ failure, and exposure to pharmacological agents and toxins. Although encephalopathy may resolve with treatment of the underlying disorder, there is mounting evidence that cerebral dysfunction persists beyond the acute phase of critical illness. ICU survivors often suffer chronic impairments in cognitive ability, suggesting occult brain injury. The pathogenesis and natural history of encephalopathy, still poorly understood, need further clarification to spur the development of effective preventive and therapeutic interventions.

Brain Diseases, Metabolic↗
PubMed2006

Approach to the comatose patient.

BACKGROUND: Coma is a medical emergency and may constitute a diagnostic and therapeutic challenge for the intensivist. OBJECTIVE: To review currently available data on the etiology, diagnosis, and outcome of coma. To propose an evidence-based approach for the clinical management of the comatose patient. DATA SOURCE: Search of Medline and Cochrane databases; manual review of bibliographies from selected articles and monographs. DATA SYNTHESIS AND CONCLUSIONS: Coma and other states of impaired consciousness are signs of extensive dysfunction or injury involving the brainstem, diencephalon, or cerebral cortex and are associated with a substantial risk of death and disability. Management of impaired consciousness includes prompt stabilization of vital physiologic functions to prevent secondary neurologic injury, etiological diagnosis, and the institution of brain-directed therapeutic or preventive measures. Neurologic prognosis is determined by the underlying etiology and may be predicted by the combination of clinical signs and electrophysiological tests.

Brain Death↗
PubMed2006

Controversies in the management of aneurysmal subarachnoid hemorrhage.

BACKGROUND: The care of patients with aneurysmal subarachnoid hemorrhage has evolved significantly with the advent of new diagnostic and therapeutic modalities. Although it is believed that these advances have contributed to improved outcomes, considerable uncertainty persists regarding key areas of management. OBJECTIVE: To review selected controversies in the management of aneurysmal subarachnoid hemorrhage, with a special emphasis on endovascular vs. surgical techniques for securing aneurysms, the diagnosis and therapy of cerebral vasospasm, neuroprotection, antithrombotic and anticonvulsant agents, cerebral salt wasting, and myocardial dysfunction, and to suggest venues for further clinical investigation. DATA SOURCE: Search of MEDLINE and Cochrane databases and manual review of article bibliographies. DATA SYNTHESIS AND CONCLUSIONS: Many aspects of care in patients with aneurysmal subarachnoid hemorrhage remain highly controversial and warrant further resolution with hypothesis-driven clinical or translational research. It is anticipated that the rigorous evaluation and implementation of such data will provide a basis for improvements in short- and long-term outcomes.

Brain Ischemia↗
PubMed2005

New PEG-ylated Mn(III) porphyrins approaching catalytic activity of SOD enzyme.

Two new tri(ethyleneglycol)-derivatized Mn(III) porphyrins were synthesized with the aim of increasing their bioavailability, and blood-circulating half-life. These are Mn(III) tetrakis(N-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)pyridinium-2-yl)porphyrin, MnTTEG-2-PyP5+ and Mn(III) tetrakis(N,N'-di(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)imidazolium-2-yl)porphyrin, MnTDTEG-2-ImP5+. Both porphyrins have ortho pyridyl or di-ortho imidazolyl electron-withdrawing substituents at meso positions of the porphyrin ring that assure highly positive metal centered redox potentials, E1/2 = +250 mV vs. NHE for MnTTEG-2-PyP5+ and E1/2 = + 412 mV vs. NHE for MnTDTEG-2-ImP5+. As expected, from established E1/2 vs. log kcat(O2 *-) structure-activity relationships for metalloporphyrins (Batinic-Haberle et al., Inorg. Chem., 1999, 38, 4011), both compounds exhibit higher SOD-like activity than any meso-substituted Mn(III) porphyrins-based SOD mimic thus far, log kcat = 8.11 (MnTTEG-2-PyP5+) and log kcat = 8.55 (MnTDTEG-2-ImP5+), the former being only a few-fold less potent in disproportionating O2*- than the SOD enzyme itself. The new porphyrins are stable to both acid and EDTA, and non toxic to E. coli. Despite elongated substituents, which could potentially lower their ability to cross the cell wall, MnTTEG-2-PyP5+ and MnTDTEG-2-ImP5+ exhibit similar protection of SOD-deficient E. coli as their much smaller ethyl analogues MnTE-2-PyP5+ and MnTDE-2-ImP5+, respectively. Consequently, with anticipated increased blood-circulating half-life, these new Mn(III) porphyrins may be more effective in ameliorating oxidative stress injuries than ethyl analogues that have been already successfully explored in vivo.

Escherichia coli↗
PubMed2005

Glucocorticoid therapy in neurologic critical care.

BACKGROUND: The pivotal role of inflammation and edema across the spectrum of central nervous system injury has driven extensive investigation into the therapeutic potential of glucocorticoids. OBJECTIVE: To review the experimental and clinical data relating to the efficacy and adverse effects of glucocorticoids in conditions encountered in critical neurologic and neurosurgical illness. DATA SOURCE: Search of MEDLINE and Cochrane databases, manual review of article bibliographies. DATA SYNTHESIS AND CONCLUSIONS: The efficacy of glucocorticoids is well established in ameliorating edema associated with brain tumors and in improving outcome in subsets of patients with bacterial meningitis. Despite frequently encouraging experimental results, clinical trials of glucocorticoids in ischemic stroke, intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and traumatic brain injury have not shown a definite therapeutic effect. The evidence supporting glucocorticoid therapy for spinal cord injury is controversial; however methylprednisolone continues to be widely employed in this setting.

Brain Edema↗
PubMed2005

Spurious hypoxemia.

OBJECTIVE: To discuss the pathophysiology and clinical implications of spurious hypoxemia in the setting of hyperleukocytosis. DESIGN: Case report and review of the literature. SETTING: A 22-bed, adult neurosciences critical care unit at a tertiary care hospital. PATIENT: A 49-yr-old male with chronic myelogenous leukemia. INTERVENTIONS: Administration of hydroxyurea and imatinib mesylate. MEASUREMENTS AND MAIN RESULTS: The patient was admitted to the neurosciences critical care unit with an acute nontraumatic subdural hematoma that required emergent surgical evacuation. His clinical course was notable for neurologic deterioration, sepsis, hyperleukocytosis, severe hypoxemia, and prolonged mechanical ventilation. An inverse relationship was observed between arterial oxygen tension and the magnitude of hyperleukocytosis. Hypoxemia resolved after the institution of chemotherapy and normalization of white cell count. Pulse oximeter saturation was normal throughout. CONCLUSIONS: Patients with hyperleukocytosis are at risk for severe hypoxemia, which may be real or spurious. Failure to recognize spurious hypoxemia can lead to unnecessary diagnostic tests and therapeutic interventions, exposing patients to avoidable risk. A diagnostic algorithm is proposed.

Algorithms↗
PubMed2004

Nitric oxide represses the Arabidopsis floral transition.

The correct timing of flowering is essential for plants to maximize reproductive success and is controlled by environmental and endogenous signals. We report that nitric oxide (NO) repressed the floral transition in Arabidopsis thaliana. Plants treated with NO, as well as a mutant overproducing NO (nox1), flowered late, whereas a mutant producing less NO (nos1) flowered early. NO suppressed CONSTANS and GIGANTEA gene expression and enhanced FLOWERING LOCUS C expression, which indicated that NO regulates the photoperiod and autonomous pathways. Because NO is induced by environmental stimuli and constitutively produced, it may integrate both external and internal cues into the floral decision.

Arabidopsis↗
PubMed2004

New class of potent catalysts of O2.-dismutation. Mn(III) ortho-methoxyethylpyridyl- and di-ortho-methoxyethylimidazolylporphyrins.

Three new Mn(III) porphyrin catalysts of O2.-dismutation (superoxide dismutase mimics), bearing ether oxygen atoms within their side chains, were synthesized and characterized: Mn(III) 5,10,15,20-tetrakis[N-(2-methoxyethyl)pyridinium-2-yl]porphyrin (MnTMOE-2-PyP(5+)), Mn(III)5,10,15,20-tetrakis[N-methyl-N'-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP(5+)) and Mn(III) 5,10,15,20-tetrakis[N,N'-di(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTDMOE-2-ImP(5+)). Their catalytic rate constants for O2.-dismutation (disproportionation) and the related metal-centered redox potentials vs. NHE are: log k(cat)= 8.04 (E(1/2)=+251 mV) for MnTMOE-2-PyP(5+), log k(cat)= 7.98 (E(1/2)=+356 mV) for MnTM,MOE-2-ImP(5+) and log k(cat)= 7.59 (E(1/2)=+365 mV) for MnTDMOE-2-ImP(5+). The new porphyrins were compared to the previously described SOD mimics Mn(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)), Mn(III) 5,10,15,20-tetrakis(N-n-butylpyridinium-2-yl)porphyrin (MnTnBu-2-PyP(5+)) and Mn(III) 5,10,15,20-tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin (MnTDE-2-ImP(5+)). MnTMOE-2-PyP(5+) has side chains of the same length and the same E(1/2), as MnTnBu-2-PyP(5+)(k(cat)= 7.25, E(1/2)=+ 254 mV), yet it is 6-fold more potent a catalyst of O2.-dismutation , presumably due to the presence of the ether oxygen. The log k(cat)vs. E(1/2) relationship for all Mn porphyrin-based SOD mimics thus far studied is discussed. None of the new compounds were toxic to Escherichia coli in the concentration range studied (up to 30 microM), and protected SOD-deficient E. coli in a concentration-dependent manner. At 3 microM levels, the MnTDMOE-2-ImP(5+), bearing an oxygen atom within each of the eight side chains, was the most effective and offered much higher protection than MnTE-2-PyP(5+), while MnTDE-2-ImP(5+) was of very low efficacy.

Catalysis↗
PubMed2004

Strategies in the high-risk cardiac patient undergoing non-cardiac surgery.

The risk of perioperative myocardial infarction or cardiac death in patients undergoing non-cardiac surgery may be estimated by clinical risk factor analysis and by myocardial stress testing. While stress testing modalities accurately delineate reversible myocardial ischaemia, their positive predictive value is low, and it is not clear whether their implementation improves outcome when compared to risk stratification alone. Similarly, it remains to be shown that preoperative coronary revascularization is an effective strategy in reducing perioperative risk. Recent reports indicate that surgery undertaken in the first weeks after percutaneous coronary interventions may be associated with a significantly increased rate of major complications. Administration of beta-blockers and alpha2-adrenergic agonists to high-risk patients reduces surgical morbidity and mortality, and the benefits observed with beta-blockers may extend long after the operative period. In high-risk patients undergoing major surgery, pulmonary artery catheter-guided haemodynamic optimization has not been associated with better outcomes, whereas use of regional anesthetic techniques decreases the incidence of postoperative pulmonary, but not cardiac, complications.

Adrenergic beta-Antagonists↗
PubMed2003

Analysis of a glucose tetrasaccharide elevated in Pompe disease by stable isotope dilution-electrospray ionization tandem mass spectrometry.

Patients with glycogen storage disease type II (GSD II) typically excrete increased amounts of a glycogen-derived glucose tetrasaccharide, Glcalpha1-6Glcalpha1-4Glcalpha1-4Glc (Glc(4)), in the urine. With the advent of a new enzyme replacement therapy for GSD II, there is a need for early identification of patients with this disease and for monitoring the efficacy of treatment. Glc(4) is a good candidate biomarker for GSD II. A simple and robust method using stable isotope dilution-electrospray ionization-tandem mass spectrometry for the analysis of Glc(4) in biological samples was developed. A 13C(6)-labeled stable isotope internal standard was synthesized by transglycosylation using a recombinant alpha-amylase. Butyl 4-aminobenzoate derivatives of Glc(4) and the internal standard were analyzed using multiple reaction monitoring. This method was shown to be accurate and precise by the repeated analysis of calibrators and quality control samples in urine and plasma. There was good agreement with a high-performance liquid chromatography-UV method for urine samples, whereas there was less agreement with plasma samples. Accurate determination from dried urine spot samples was also demonstrated. This method is amenable to high-throughput analysis, a necessary prerequisite for mass screening for GSD II.

Biomarkers↗
PubMed2003

A comparison of in vitro acylcarnitine profiling methods for the diagnosis of classical and variant short chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Homozygosity and compound heterozygosity for the short chain acyl-CoA dehydrogenase (SCAD) gene sequence variants 625G-->A and 511C-->T are associated with ethylmalonic aciduria (EMA), a biochemical indicator of SCAD deficiency. The clinical and biochemical implications of these variants are not fully understood. The effect of these variants on the accumulation of butyrylcarnitine by fibroblasts in culture was studied. METHODS: In vitro acylcarnitine profiling in fibroblasts was carried out using [U-13C]-labeled or unlabeled palmitate in the presence of excess L-carnitine, with or without a medium chain acyl-CoA dehydrogenase (MCAD) inhibitor. Acylcarnitines were analyzed using tandem mass spectrometry. 625G/625G (wild type), 625G/625A and 625A/625A (variant) control fibroblasts were compared with fibroblasts from patients homozygous for inactivating SCAD mutations (SCAD deficient) and from patients with EMA who were homozygous or compound heterozygous for the SCAD variants. RESULTS: Variant control and patient fibroblasts accumulated moderate amounts of butyrylcarnitine compared with wild-type controls and in contrast to the significant amount of butyrylcarnitine accumulated by SCAD deficient fibroblasts, regardless of incubation conditions. CONCLUSIONS: Moderately reduced SCAD activity associated with SCAD variants can be detected using in vitro acylcarnitine profiling methods, which may be used as an indirect measure of SCAD activity.

Acyl-CoA Dehydrogenase↗
PubMed2003

myGrid: personalised bioinformatics on the information grid.

MOTIVATION: The (my)Grid project aims to exploit Grid technology, with an emphasis on the Information Grid, and provide middleware layers that make it appropriate for the needs of bioinformatics. (my)Grid is building high level services for data and application integration such as resource discovery, workflow enactment and distributed query processing. Additional services are provided to support the scientific method and best practice found at the bench but often neglected at the workstation, notably provenance management, change notification and personalisation. RESULTS: We give an overview of these services and their metadata. In particular, semantically rich metadata expressed using ontologies necessary to discover, select and compose services into dynamic workflows.

Computational Biology↗
PubMed2003

Critical care and perioperative management in traumatic spinal cord injury.

Traumatic spinal cord injury is frequently associated with brain injury and with alterations in respiratory and cardiovascular function that require critical care management. Complications include respiratory failure, atelectasis, pneumonia, neurogenic shock, autonomic dysreflexia, venous thromboembolism, and sepsis. While complications may be managed with supportive care, the goal of ameliorating neurologic outcome has proved elusive. Methylprednisolone, when instituted <8 hours after traumatic spinal cord injury, was associated in two clinical trials with statistically significant improvements in motor scores at 6 months and 1 year; however, critical reappraisal of these data raises questions about their validity and clinical relevance. Until more evidence of clinically effective therapies is available, acute management must be driven by pathophysiologic principles, with emphasis on interventions that attenuate secondary neurologic injury; these include the rational use of immobilization, cautious airway management, and promotion of cord perfusion and oxygenation with the appropriate level of hemodynamic and respiratory support. Clinical trials of pharmacologic neuroprotection have yielded disappointing results, but the ongoing elucidation of spinal cord repair and regenerative mechanisms suggests new therapeutic prospects.

Critical Care↗
PubMed2003

Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review.

A number of drugs have been tested in clinical trials to decrease cardiac complications in patients undergoing noncardiac surgery. To compare the results of these studies, we conducted a quantitative systematic review. Medline, Embase, and Cochrane databases were searched for randomized trials that assessed myocardial ischemia, myocardial infarction, 30-day cardiac mortality, and adverse effects. Data were combined using a fixed-effect model and expressed as Peto odds ratios (OR) with 95% confidence interval (CI) and as numbers-needed-to-treat/harm (NNT/H). Twenty-one trials involving 3646 patients were included: 11 trials using beta-blockers (6 drugs; 866 patients), 6 clonidine or mivazerol (614 patients), 3 diltiazem or verapamil (121 patients), and 1 nitroglycerin (45 patients). All trials had an inactive control; there were no direct comparisons. beta-blockers decreased ischemic episodes during surgery (7.6% versus 20.2% with placebo; OR 0.32 [95% CI, 0.17-0.58]; NNT 8) and after surgery (15.2% versus 27.9% with control; OR 0.46 [95% CI, 0.26-0.81]; NNT 8). alpha(2)-agonists decreased ischemia during surgery only (19.4% versus 32.8%; OR 0.47 [95% CI, 0.33-0.68]; NNT 7). beta-blockers reduced the risk of myocardial infarction (0.9% versus 5.2%; OR 0.19 [95% CI, 0.08-0.48]; NNT 23) but only when 2 trials with high-risk patients were included. The effect of alpha(2)-agonists on myocardial infarction was not significant (6.1% versus 7.3%; OR 0.85 [95% CI, 0.62-1.14]). beta-blockers significantly decreased the risk of cardiac death from 3.9% to 0.8% (OR 0.25 [95% CI, 0.09-0.73], NNT 32). alpha(2)-agonists significantly decreased the risk of cardiac death from 2.3% to 1.1% (OR 0.50 [95% CI, 0.28-0.91], NNT 83). For calcium channel blockers and nitroglycerin, evidence of any benefit was lacking. The most common adverse effect was bradycardia, which occurred in 24.5% of patients receiving a beta adrenergic blocker versus 9.1% of controls (OR 3.76 [95% CI, 2.45-5.77], NNH 6).

Adrenergic alpha-Agonists↗