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Biomedical subjects

M J Stevens

Publications and source records attributed to M J Stevens.

At least 55 records · Page 3Linked to original sources
PubMed1996

Modulation of basal nitric oxide-dependent cyclic-GMP production by ambient glucose, myo-inositol, and protein kinase C in SH-SY5Y human neuroblastoma cells.

Defective tissue perfusion and nitric oxide production and altered myo-inositol metabolism and protein kinase C activation have been invoked in the pathogenesis of diabetic complications including neuropathy. The precise cellular compartmentalization and mechanistic interrelationships of these abnormalities remain obscure, and nitric oxide possesses both neurotransmitter and vasodilator activity. Therefore the effects of ambient glucose and myo-inositol on nitric oxide-dependent cGMP production and protein kinase C activity were studied in SH-SY5Y human neuroblastoma cells, a cell culture model for peripheral cholinergic neurons. D-Glucose lowered cellular myo-inositol content, phosphatidylinositol synthesis, and phosphorylation of an endogenous protein kinase C substrate, and specifically reduced nitric oxide-dependent cGMP production a time- and dose-dependent manner with an apparent IC50 of approximately 30 mM. The near maximal decrease in cGMP induced by 50 mM D-glucose was corrected by the addition of protein kinase C agonists or 500 microM myo-inositol to the culture medium, and was reproduced by protein kinase C inhibition or downregulation, or by myo-inositol deficient medium. Sodium nitroprusside increased cGMP in a dose-dependent fashion, with low concentrations (1 microM) counteracting the effects of 50 mM D-glucose or protein kinase C inhibition. The demonstration that elevated D-glucose diminishes basal nitric oxide-dependent cGMP production by myo-inositol depletion and protein kinase C inhibition in peripheral cholinergic neurons provides a potential metabolic basis for impaired nitric oxide production, nerve blood flow, and nerve impulse conduction in diabetes.

Base Sequence↗
PubMed1996

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat.

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl-L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin-induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (MI) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not -insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC or affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Acetylcarnitine↗
PubMed1996

Unilateral facial pain and lung cancer.

The symptom of unilateral facial pain as a non-metastatic presentation of lung cancer is rare. This report describes a patient in whom unilateral face pain preceded the diagnosis of lung cancer by 9 months. The neural mechanism of this syndrome is discussed and the literature reviewed.

Adenocarcinoma↗
PubMed1995

Hypofractionated irradiation for inoperable non-small cell lung cancer.

A policy of palliative intent thoracic irradiation was prospectively evaluated in 38 consecutive patients referred for treatment of inoperable non-small cell lung cancer at a single institution. A target dose of 1700 cGy in two fractions 1 week apart was delivered. Characteristics of the treatment group revealed most (87%; 33/38) to be of good-excellent performance status with minimal weight loss before irradiation. Although three patients (8%) had initial metastatic disease, all had symptoms referable to the thorax with cough (71%), dyspnoea (55%), haemoptysis (39%), and chest wall pain (34%) being dominant. Following treatment, the relative risk of maintaining complete response with regard to each of these symptoms was 0.91, 0.40, 0.92 and 0.78, respectively. Overall 70% of patients maintained complete symptomatic response to time of death or last review. Uncorrected median survival was 35 weeks and was comparable to best international end-results for either palliative intent or curative intent radiation schedules. We conclude that the radiation regimen employed is safe, efficacious and eminently resource conscious. Recognition of patient groups who overwhelmingly derive no benefit from conventional fractionation schedules will streamline access to radiotherapy services of patients suitable for radical treatment.

Aged↗
PubMed1995

Nitric oxide as a potential bridge between the metabolic and vascular hypotheses of diabetic neuropathy.

Both metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, nerve blood flow, and (Na+, K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. Nitric oxide may be the 'bridge' linking these divergent hypotheses of diabetic neuropathy. We propose a model for the pathogenesis of neuropathy invoking metabolic defects both at a vascular and neurochemical level. Early after the induction of experimental diabetes, metabolic defects may lead to a decrease in synthesis of nitric oxide in either the vascular endothelium or the sympathetic ganglia leading to decreased nerve blood flow. In addition, nitric oxide may be involved in more distal defects of somatic nerve metabolism which impair the activity of the nerve Na/K-ATPase by a mechanism involving phosphoinositide signaling and diacyl glycerol and may therefore affect nerve conduction velocity independently of ischaemia. Improved understanding of the effects of hyperglycaemia on nitric oxide metabolism, may provide important clues elucidating the mechanisms underlying the pathogenesis of diabetic neuropathy.

Animals↗
PubMed1995

The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects.

A combination of metabolic and vascular defects have been implicated in the pathogenesis of diabetic neuropathy. Animal studies have demonstrated that a reduction in nerve blood flow may be an important early defect and that vasodilators can prevent or ameliorate nerve dysfunction. The potential factors contributing to nerve ischaemia include structural defects in the endoneurial microvasculature together with rheological abnormalities, abnormalities in vasoactive agents which regulate nerve blood flow including nitric oxide and the eicosanoids, and alterations in tone of the autonomic innervation of the nerve vasculature. The principle metabolic defects which have been implicated include disruption of the polyol pathway, altered lipid metabolism, advanced glycosylated end-product formation, increased oxidative stress, and diabetes-induced defects in growth factors. The demonstration that activation of the polyol pathway in experimental diabetes may affect nerve blood flow, and conversely that vasoactive agents appear to be important in regulating some aspects of nerve metabolism, has highlighted the interdependence of the metabolic and vascular defects in the pathogenesis of this condition. Thus, selective intervention aimed at a key defect early in this cascade may subsequently correct a number of later abnormalities offering therapeutic hope in this chronic debilitating complication.

Aldehyde Reductase↗
PubMed1995

Prognostic significance of early serum tumor marker half-life in metastatic testicular teratoma.

PURPOSE: To determine whether the initial regression rates of serum tumor marker concentration (alpha-fetoprotein [AFP] and beta-human chorionic gonadotrophin [HCG]) were important prognostic factors after chemotherapy for germ cell tumors. PATIENTS AND METHODS: The analysis was confined to patients with at least two precise marker assay results between days 7 and 22 from start of platinum-based combination chemotherapy, with at least 7 days between markers. One hundred eighty-three patients were eligible and marker half-life (MHL) was evaluated for AFP in 142 and for HCG in 111 cases. MHL was calculated from the following formula: MHL = Ln1/2/G, where G was the gradient of the marker slope on a plot of Ln marker concentration versus time. MHL was regarded as prolonged if more than 3 days for HCG or more than 7 days for AFP. RESULTS: The median AFP MHL was 6 days (range, 2.7 to 237) and the median HCG MHL was 2.6 days (range, 1.7 to 37.5). Forty-nine of 142 patients (35%) had a prolonged AFP MHL; 39 of 111 patients (35%) had a prolonged HCG-MHL. A prolonged MHL did not identify relapse after front-line chemotherapy. The positive predictive value of MHL tests in identifying patients who progressed after front-line therapy was 18% for HCG, 20% for AFP, and 18% for either marker. A prolonged MHL did indicate a higher risk of mortality (hazards ratio [HR], 2.4; P = .016), but again the positive predictive value of this test was only 23%. CONCLUSION: Early evaluation of MHL by this method does not predict patients at higher risk of progression after front-line chemotherapy, and also is a poor guide to long-term prognosis.

Adolescent↗
PubMed1994

Clinical testing in diabetic peripheral neuropathy.

Diabetic polyneuropathy is a complex disease of progressive nerve fiber loss. Initial screening and diagnosis in clinical practice usually depend on assessment of subjective complaints. A need exists for objective, simple, and reproducible assessment tools that can be readily used in clinical practice. The importance of early diagnosis is highlighted by the recent North American Diabetes Control and Complications Trial where intensive insulin therapy reduced the risk of developing diabetic neuropathy by 61%. At the University of Michigan, we have developed an outpatient neuropathy program. Patients are given a questionnaire and a brief screening examination, designated the Neuropathy Screening Instrument. Diabetic neuropathy is confirmed and staged in patients with a positive Neuropathy Screening Instrument, by a quantitative neurologic examination and nerve conduction studies, designated the Diabetic Neuropathy Score. The Michigan program has been compared with well-established instruments and has been found to be sensitive and reproducible for screening and diagnosis. We believe the program provides a valuable tool for the clinician in the practice setting and should allow diagnosis and intervention earlier in the course of diabetic neuropathy.

Diabetic Neuropathies↗
PubMed1994

Prognosis of testicular teratoma differentiated.

OBJECTIVE: To determine whether the clinical course of patients with testicular teratoma differentiated (TD) and those with testicular teratoma undifferentiated justify a different follow-up protocol. PATIENTS AND METHODS: Between 1979 and 1989, 16 adult patients with testicular TD were treated at the Royal Marsden Hospital. These represented 2.7% of the 592 testicular teratoma patients seen during this period. With the exception of a propensity to involve the right testis (76%), there were no differences in clinical presentation between TD and non-TD histological subtypes. RESULTS: The mean follow-up was 55 months (range 7-137). Seven of the 16 patients had Stage I disease and were entered into surveillance programmes; one relapsed at 7 months. Ten men were treated with cisplatin or carboplatin-based chemotherapy for metastases, of whom three had had prior chemotherapy at other hospitals and were referred after relapse. In the seven previously-untreated chemotherapy group two patients failed. In the concurrent era, 375 patients with other subtypes of metastatic testicular non-seminoma were treated with chemotherapy and 47 (12.5%) failed (Progress Free Survival chi square (chi 2) = 2.73, P = 0.01). Although no difference in progression-free survival was demonstrated between TD and non-TD patients, the former had a worse overall survival probability (chi 2 = 9.02, P = 0.003); this may be an artefact due to the small number of events. CONCLUSION: Despite the apparently more benign histology, it is recommended that the management of adult TD should not deviate from the general principles established for other histological subtypes of testicular teratoma.

Adult↗
PubMed1994

The value of the Neurometer in assessing diabetic neuropathy by measurement of the current perception threshold.

The Neurometer is a relatively new device for assessing neuropathy by measuring current perception threshold (CPT). The study aim was to assess the ability of the Neurometer to distinguish between different types of nerve fibre damage by using different frequencies (2000 Hz, 250 Hz, and 5 Hz) of electric stimulus (high frequencies for large fibres and low frequencies for small fibres) and comparing the results with standard sensory tests of vibration perception threshold (VPT) and thermal perception threshold (TPT). CPT was determined on index finger and great toe of 51 patients with diabetic neuropathy and 28 non-diabetic control subjects, age and sex matched. CPT in neuropathic patients could be distinguished from controls at all three frequencies in both feet and hands (p < 0.05). The best correlation was found between CPT at 2000 Hz and VPT (r = 0.48, p < 0.001) in the feet suggesting a degree of neuroselectivity. Internal correlations between CPT at the three frequencies showed the weakest correlation between CPT at 2000 Hz and 5 Hz (r = 0.27, p < 0.005), suggesting also that possibly different types of fibres were examined. CPT reproducibility was better in control (CV = 6.4-27.7%), than in neuropathic subjects (CV = 28.4-52.3%), although the coefficient of variation was comparable to that of standard tests of sensory function, VPT and TPT. The Neurometer is a simple instrument to use in clinical practice. It has a degree of neuroselectivity but like all subjective sensory tests has a large variability.

Adult↗
PubMed1994

Effects of glucose on sorbitol pathway activation, cellular redox, and metabolism of myo-inositol, phosphoinositide, and diacylglycerol in cultured human retinal pigment epithelial cells.

Sorbitol (aldose reductase) pathway flux in diabetes perturbs intracellular metabolism by two putative mechanisms: reciprocal osmoregulatory depletion of other organic osmolytes e.g., myo-inositol, and alterations in NADPH/NADP+ and/or NADH/NAD+. The "osmolyte" and "redox" hypotheses predict secondary elevations in CDP-diglyceride, the rate-limiting precursor for phosphatidylinositol synthesis, but through different mechanisms: the "osmolyte" hypothesis via depletion of intracellular myo-inositol (the cosubstrate for phosphatidylinositol-synthase) and the "redox" hypothesis through enhanced de novo synthesis from triose phosphates. The osmolyte hypothesis predicts diminished phosphoinositide-derived arachidonyl-diacylglycerol, while the redox hypothesis predicts increased total diacylglycerol and phosphatidic acid. In high aldose reductase expressing retinal pigment epithelial cells, glucose-induced, aldose reductase inhibitor-sensitive CDP-diglyceride accumulation and inhibition of 32P-incorporation into phosphatidylinositol paralleled myo-inositol depletion (but not cytoplasmic redox, that was unaffected by glucose) and depletion of arachidonyl-diacylglycerol. 3 mM pyruvate added to the culture medium left cellular redox unaltered, but stimulated Na(+)-dependent myo-inositol uptake, accumulation, and incorporation into phosphatidylinositol. These results favor myo-inositol depletion rather than altered redox as the primary cause of glucose-induced aldose reductase-related defects in phospholipid metabolism in cultured retinal pigment epithelial cells.

Aldehyde Reductase↗
PubMed1994

The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.

Aldehyde Reductase↗
PubMed1994

A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.

OBJECTIVE: Early diagnosis of distal symmetric sensorimotor polyneuropathy, a common complication of diabetes, may decrease patient morbidity by allowing for potential therapeutic interventions. We have designed an outpatient program to facilitate diagnosis of diabetic neuropathy. RESEARCH DESIGN AND METHODS: Patients are initially administered a brief questionnaire and screening examination, designated the Michigan Neuropathy Screening Instrument (MNSI). Diabetic neuropathy is confirmed in patients with a positive assessment by a quantitative neurological examination coupled with nerve conduction studies, designated the Michigan Diabetic Neuropathy Score (MDNS). In this study, 56 outpatients with confirmed type I or II diabetes were administered the standardized quantitative components required to diagnose and stage diabetic neuropathy according to the San Antonio Consensus Statement (1) and the Mayo Clinic protocol (2). These same patients were then assessed with the MNSI and the MDNS. RESULTS: Of 29 patients with a clinical MNSI score > 2, 28 had neuropathy. Twenty-eight patients with an MDNS of > or = 7 had neuropathy, while 21 non-neuropathic patients had a score < or = 6. Of 35 patients with diabetic neuropathy, 34 had > or = 2 abnormal nerve conductions. Twenty-one normal patients and one patient with neuropathy had < or = 1 abnormal nerve conduction. CONCLUSIONS: The results indicate that the MNSI is a good screening tool for diabetic neuropathy and that the MDNS coupled with nerve conductions provides a simple means to confirm this diagnosis.

Adult↗
PubMed1993

Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography.

OBJECTIVES: The purpose of this investigation was to evaluate the sympathetic nervous system of the heart by positron emission tomographic (PET) imaging in patients with diabetes mellitus with and without diabetic autonomic neuropathy. BACKGROUND: The clinical assessment of cardiac involvement in diabetic autonomic neuropathy has been limited to cardiovascular reflex testing. With the recent introduction of radiolabeled catecholamines such as carbon (C)-11 hydroxyephedrine, the sympathetic innervation of the heart can be specifically visualized with PET imaging. METHODS: Positron emission tomographic imaging was performed with C-11 hydroxyephedrine and rest myocardial blood flow imaging with nitrogen-13 ammonia. Three patient groups were studied, including healthy volunteers as control subjects, diabetic patients with normal autonomic function testing and diabetic patients with varying severity of autonomic neuropathy. Homogeneity of cardiac tracer retention as well as absolute tracer retention was determined by relating myocardial tracer retention to an arterial C-11 activity input function. RESULTS: Abnormal regional C-11 hydroxyephedrine retention was seen in seven of eight patients with autonomic neuropathy. Relative tracer retention was significantly reduced in apical, inferior and lateral segments. The extent of the abnormality correlated with the severity of conventional markers of autonomic dysfunction. Absolute myocardial tracer retention index measurements showed a 45 +/- 21% decrease in distal compared with proximal myocardial segments in autonomic neuropathy (0.069 +/- 0.037 min-1 vs. 0.13 +/- 0.052 min-1, p = 0.02). CONCLUSIONS: This study demonstrates a heterogeneous pattern of neuronal abnormalities in patients with diabetic cardiac neuropathy. The extent of this abnormality correlated with the severity of neuropathy assessed by conventional tests. Future studies in larger groups of patients are required to define the relative sensitivity of this imaging approach in detecting cardiac neuropathy and to determine the clinical significance of these scintigraphic findings in comparison with conventional markers of autonomic innervation.

Adult↗
PubMed1993

Ambient glucose and aldose reductase-induced myo-inositol depletion modulate basal and carbachol-stimulated inositol phospholipid metabolism and diacylglycerol accumulation in human retinal pigment epithelial cells in culture.

Physiological hyperglycemia has been speculated to alter phosphoinositide (PPI; inositol phospholipid) signal transduction in cells prone to diabetic complications by two separate mass-action mechanisms with antiparallel putative effects on diacylglycerol (DAG): (i) sorbitol-induced depletion of myo-inositol leads to diminished PPI synthesis and turnover and DAG release, and (ii) elevated glucose-derived DAG precursors enhance de novo DAG synthesis. Because the first mechanism is mediated by aldose reductase (AR2), which converts glucose to sorbitol, the effects of glucose on basal and stimulated PPI signaling were explored in lines of cultured human retinal pigment epithelial cells differing widely in their basal AR2 gene expression and enzymatic activity. The results suggest that the effects of glucose on PPI signaling vary inversely with the level of AR2 activity and parallel the extent of AR2-induced myo-inositol depletion.

Aldehyde Reductase↗
PubMed1993

Comparison of MMPI-2 scores of foreign Chinese and Caucasian-American students.

MMPI-2 scores of foreign Chinese students (n = 25) were compared to those of a matched sample of Caucasian students (n = 21) and to normative data on American college students. Although responses for all groups were within normal limits, Chinese men appeared more socially introverted than Caucasian men. Relative to Caucasian women, Chinese women were more defensive, depressed, unaware of somatic and psychosocial problems, and gender astereotypic in interests. These tentative findings are discussed in terms of ethnicity and adjustment.

Acculturation↗