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Biomedical subjects

R M Cohen

Publications and source records attributed to R M Cohen.

At least 91 records · Page 5Linked to original sources
PubMed1992

Delayed L-phenylalanine infusion allows for simultaneous kinetic analysis and improved evaluation of specific-to-nonspecific fluorine-18-dopa uptake in brain.

The accumulation of 3-O-methyl-6-[18F]fluoro-L-DOPA (18F-30M-DOPA) in the brain from the circulation is responsible for most of the nonspecific background during 18F-DOPA positron emission tomography scanning. To increase the sensitivity of 18F-DOPA for imaging presynaptic dopamine systems, we took advantage of 18F-30M-DOPA's rapid clearance from the brain (T1/2 approximately 15-20 min). The infusion of the unlabeled amino acid L-phenylalanine, starting 75 min after 18F-DOPA administration, prevents 18F-30M-DOPA entrance into the brain through competition at the large amino acid transport system of the blood brain barrier. This method produces high specific-to-nonspecific contrast images of 18F accumulation beginning 15-30 min after onset of amino acid infusion and better sensitivity to small changes in 18F-DOPA uptake while still allowing for kinetic analysis of the data in the early time points. Kinetic and anatomical data were found to be strongly correlated.

Animals↗
PubMed1991

Reduced cerebrospinal fluid dynorphin A1-8 in Alzheimer's disease.

Cerebrospinal fluid (CSF) measures of dynorphin A were compared in three groups. Alzheimer patients (n = 9), elderly depressives (n = 9), and age-matched normal controls (n = 9). The Alzheimer patients revealed a 40% decrease in CSF dynorphin compared with controls (36 +/- 15 versus 60 +/- 21 pg/ml, p less than 0.05). In contrast, other peptide measures [Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and galanin] remained unchanged across groups. This finding was further supported when an additional 20 Alzheimer patients with similar clinical backgrounds also showed reduced CSF dynorphin (37 +/- 13 pg/ml). CSF dynorphin did not correlate significantly with clinical variables or other CSF measures of monoamine metabolites [i.e., 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)]. Given the previous report of increased kappa binding of Alzheimer brains at autopsy, the authors speculate about a possible up-regulation of opiate receptors in Alzheimer's disease and suggest ways to test this hypothesis in vivo.

Aged↗
PubMed1991

Human growth hormone stimulates proliferation of human retinal microvascular endothelial cells in vitro.

Growth hormone (GH) has been implicated in the pathogenesis of proliferative diabetic retinopathy. We sought to determine whether this could be mediated by an effect of GH on proliferation of endothelial cells, and, for this purpose, established long-term cultures of human retinal microvascular endothelial cells (hREC) from normal postmortem human eyes. High-purity (greater than 95%) hREC preparations were selected for experiments, based on immunofluorescence with acetylated low density lipoprotein (LDL) and anti-factor VIII-related antigen. Growth requirements for these cells were complex, including serum for maintenance at slow growth rates and additional mitogens for more rapid proliferation. Exposure of hREC to physiologic doses of human GH (hGH) resulted in 100% greater cell number vs. control (P less than 0.01) but could be elicited only in the presence of serum. When differing serum conditions were compared, hGH stimulated [3H]thymidine incorporation up to 1.6- to 2.2-fold under each condition and increased DNA content significantly in the presence of human, horse, and fetal calf serum. Depending on the culture conditions used, the threshold hGH concentration for significant stimulation of hREC proliferation was 0.4-4 micrograms/liter. In contrast, proliferation of human umbilical vein endothelial cells was not significantly altered by hGH added to concentrations as high as 200 micrograms/liter. In summary, hREC respond to physiologic concentrations of hGH in vitro with enhanced proliferation. This specific effect of GH on retinal microvascular endothelial cells supports the hypothesis of a role for GH in endothelial cell biology.

Cell Division↗
PubMed1991

Plasma catecholamines and their metabolites in obsessive-compulsive disorder.

Plasma catecholamines and their metabolites were sampled in 13 medication-free patients with obsessive-compulsive disorder (OCD) and 29 normal controls. In addition to severe OCD symptoms, the patients had significantly higher anxiety, tension, and resting pulse rates than the controls. Nonetheless, mean plasma concentrations of norepinephrine (NE) and epinephrine (E), the catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA), and the stress-related hormone cortisol did not differ between OCD patients and normal controls. When the patients and control populations were combined and average plasma NE and E levels calculated over 35 min, subjects with a higher mean NE output (greater than 1.1 pm/ml) had higher Profile of Mood States depression scores than subjects with a low NE output (less than 1.1 pm/ml). Altogether, these results indicate that elevated plasma catecholamine measures are not likely to be associated with the pathophysiology of OCD.

Adult↗
PubMed1991

New rapid analysis method demonstrates differences in 6-[18F] fluoro-L-dopa plasma input curves with and without carbidopa and in hemi-MPTP lesioned monkeys.

Kinetic modeling of the PET tracer 6-[18F]fluoro-L-dopa ([18F]Dopa), used to measure presynaptic dopamine function, requires the accurate determination of the plasma input curve. We have developed a new method that uses alumina extraction preceded by cation and anion exchange resins to determine the parent compound, [18F]Dopa and its critical metabolite 3-O-methyl-6-[18F]fluoro-L-dopa. Using this method we found that carbidopa increases the plasma input of [18F]Dopa while decreasing the rate of metabolite formation, and that previous drug treatment can significantly effect [18F]Dopa metabolism.

Animals↗
PubMed1991

Distribution and kinetics of 3-O-methyl-6-[18F]fluoro-L-dopa in the rhesus monkey brain.

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

Animals↗
PubMed1991

Renal aspects of therapy for human immunodeficiency virus and associated opportunistic infections.

Patients with human immunodeficiency virus infection and the acquired immunodeficiency syndrome are often treated with a variety of potentially nephrotoxic drugs. This review summarizes the renal, fluid, and electrolyte complications of drugs used to treat human immunodeficiency virus and associated opportunistic infections. The pharmacokinetics of the drugs are also briefly reviewed, and dosing guidelines for the use of these drugs in patients who have renal insufficiency or who are receiving dialysis are provided.

Anti-Bacterial Agents↗
PubMed1991

Resistance of growth hormone secretion to somatostatin in men with type I diabetes mellitus.

The effect of continuous infusions of somatostatin (SRIF) on growth hormone (GH) secretion induced by GH-releasing hormone (GHRH) bolus was compared in a dose-response manner between diabetic subjects in poor glycemic control and nondiabetic subjects to address the hypothesis that altered pituitary responsiveness to SRIF contributes to the hypersecretion of GH in diabetes mellitus in humans. Studies were conducted with a modification of the euglycemic clamp technique to minimize fluctuations in glucose and insulin. Suppression of GHRH-induced GH secretion was demonstrable in diabetic subjects only at a SRIF dose 15-fold higher than that at which suppression could be detected in nondiabetic subjects. The calculated 50% inhibitory dose (ID50) in diabetic subjects was 4-fold higher than that in nondiabetic subjects (P = 0.03). In diabetic subjects after 2 wk of intensive insulin management, the change in the dose-response curve persisted despite significant decrements in glycosylated hemoglobin and increments in plasma insulinlike growth factor I. The increment in plasma SRIF predicted at the SRIF ID50 from concentrations measured during the SRIF infusions in nondiabetic subjects would result in hypophyseal portal SRIF concentrations in the physiological range reported in recent animal studies, whereas those for the ID50 in diabetic subjects would be approximately 1.5-2.5 times the upper limit of that range. These studies indicate that pituitary resistance to the action of SRIF occurs in men with insulin-dependent (type I) diabetes at physiological concentrations of the hormone and is therefore highly likely to contribute to the hypersecretion of GH in diabetes.

Adolescent↗
PubMed1991

Postinjection L-phenylalanine increases basal ganglia contrast in PET scans of 6-18F-DOPA.

The sensitivity of 18F-DOPA positron emission tomography for imaging presynaptic dopamine systems is limited by the amount of specific-to-nonspecific accumulation of radioactivity in brain. In rhesus monkeys, we have been able to increase this ratio by taking advantage of the lag time between 18F-DOPA injection and the formation of its main metabolite, the amino acid 18F-fluoromethoxydopa, the entrance of which into brain is responsible for most of the brain's nonspecific radioactivity. By infusing an unlabeled amino acid, L-phenylalanine, starting 15 min after 18F-DOPA administration, we preferentially blocked the accumulation of 18F-fluoromethoxydopa by preventing its entrance into brain through competition at the large neutral amino acid transport system of the blood-brain barrier. This method appears as reliable as the original and more sensitive, as demonstrated by the comparison of normal and MPTP-treated animals under both conditions.

Animals↗
PubMed1991

Plasma lipoprotein peroxidation potential: a test to evaluate individual susceptibility to peroxidation.

Peroxidation of lipids is believed to play a key role in various degenerative diseases. However, few simple tests are able to detect individual susceptibility or resistance to peroxidation. Measurement of the basal concentrations of lipid peroxides in plasma is not satisfactory because they are so low. Therefore, we developed a test to determine susceptibility of whole plasma to metal/H2O2-catalyzed peroxidation. Incubation of 300-500 microL of plasma with H2O2/cupric acetate resulted in the formation of products from fatty acids (malonaldehyde, measured by thiobarbituric acid assay) and cholesterol (predominantly cholest-3,5-dien-7-one, measured by gas-liquid chromatography). In the presence of Cu2+, formation of malonaldehyde and cholest-3,5-dien-7-one increased at least 10-fold over basal values. Lipid peroxide (malonaldehyde) and cholesterol oxide concentrations after peroxidation were significantly higher (P less than 0.01) in diabetic plasma than in normal plasma. Because susceptibility to plasma peroxidation represents a balance between pro-oxidant factors and antioxidant protection, this test may be useful in determining individual susceptibility to peroxidation as influenced by nutritional and clinical status.

Adult↗
PubMed1990

Cerebral glucose metabolism in adults with hyperactivity of childhood onset.

BACKGROUND AND METHODS: The cause of childhood hyperactivity (attention deficit-hyperactivity disorder) is unknown. We investigated the hypothesis that cerebral glucose metabolism might differ between normal adults (controls) and adults with histories of hyperactivity in childhood who continued to have symptoms. Each patient was also the biologic parent of a hyperactive child. None of the adults had ever been treated with stimulant medication. To measure cerebral glucose metabolism, we administered 148 to 185 MBq (4 to 5 mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal adults and 25 hyperactive adults while they performed an auditory-attention task. Images were obtained for 30 minutes with a Scanditronix positron-emission tomograph with a resolution of 5 to 6 mm. Whole-brain and regional rates of glucose metabolism were measured with computer assistance by two trained research assistants, working independently, who were blinded to the subjects' status (control or hyperactive). RESULTS: Global cerebral glucose metabolism was 8.1 percent lower in the adults with hyperactivity than in the normal controls (mean +/- SD, 9.05 +/- 1.20 mg per minute per 100 g vs. 9.85 +/- 1.68 mg per minute per 100 g; P = 0.034). In the adults with hyperactivity, glucose metabolism was significantly reduced, as compared with the values for the controls, in 30 of 60 specific regions of the brain (P less than 0.05). Among the regions of the brain with the greatest reductions in glucose metabolism were the premotor cortex and the superior prefrontal cortex. When the seven women with hyperactivity or the six patients with learning disabilities were omitted from the analysis, the results were similar. CONCLUSIONS: Glucose metabolism, both global and regional, was reduced in adults who had been hyperactive since childhood. The largest reductions were in the premotor cortex and the superior prefrontal cortex--areas earlier shown to be involved in the control of attention and motor activity.

Adult↗
PubMed1990

Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia.

BACKGROUND AND METHODS: Fetal macrosomia occurs despite nearly normal maternal blood glucose levels in women with diabetes treated with insulin. We examined the hypothesis that it may be caused by insulin transferred as an insulin-antibody complex from the mother to her fetus. We adapted and validated a method based on high-performance liquid chromatography and used it to quantitate insulin in small volumes (0.5 to 1.0 ml) of cord serum from 51 infants born to mothers with insulin-dependent diabetes mellitus. RESULTS: In mothers receiving only human insulin (n = 6), only human insulin was detected in cord serum. Of the remaining 45 infants, whose mothers received animal insulin during pregnancy, 28 (group 1) had levels of animal (bovine or porcine) insulin (mean [+/- SE], 707 +/- 163 pmol per liter) that constituted 27.4 +/- 2.5 percent of the total insulin concentration (2393 +/- 500 pmol per liter) measured in the cord serum. The cord-serum insulin concentration in the remaining 17 infants (group 2), in whom only human insulin was detected (381 +/- 56 pmol per liter), was only 15 percent of that in group 1 (P less than 0.001). There was a significant correlation between the maternal and the cord-serum concentrations of anti-insulin antibody and the concentration of animal insulin in the baby (r = 0.77, P less than 0.01, and r = 0.76, P less than 0.001, respectively), suggesting that the animal insulin was transferred as an insulin-antibody complex. In group 1 the mean concentration of animal insulin in cord serum was higher in the 12 infants with macrosomia than in the 16 infants without the condition (1113 +/- 321 vs. 402 +/- 110 pmol per liter; P less than 0.05), and the concentration of animal insulin in cord serum correlated with birth weight (r = 0.39, P less than 0.05). The maternal glycosylated hemoglobin values and the incidence of respiratory distress syndrome were similar in groups 1 and 2. CONCLUSIONS: Considerable amounts of antibody-bound insulin are transferred from mother to fetus during pregnancy in some women with insulin-dependent diabetes mellitus; the extent of transfer correlates with the maternal concentration of anti-insulin antibody. The correlation between macrosomia and the concentrations of animal insulin in cord serum indicates that the transferred insulin has biologic activity and suggests that the formation of antibody to insulin in the mother is a determinant of fetal outcome independent of maternal blood glucose levels.

Adult↗
PubMed1990

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. Patients treated with clomipramine.

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.

Adult↗
PubMed1990

TRH attenuates scopolamine-induced memory impairment in humans.

The brain tripeptide thyrotropin-releasing hormone (TRH) has been demonstrated to facilitate cholinergic neurotransmission. To test its interaction with the cholinergic system in humans, high-dose TRH (0.5 mg/kg) or placebo was administered intravenously (IV) to normal controls pretreated with scopolamine (0.5-0.75 mg IV), a centrally active muscarinic antagonist, which has been used to model aspects of the memory impairment of normal aging and of dementia. Compared to placebo, TRH markedly attenuated scopolamine-induced impairment of some measures of memory, most notably on a selective reminding task. This cognitive study is the first in humans to suggest a neuromodulatory effect of a peptide on the cholinergic system, and suggests a facilitatory role for TRH in human memory processes.

Adult↗
PubMed1990

Estimation of cellular DNA content in cell lysates suitable for RNA isolation.

Methods presently available for the isolation of RNA are incompatible with conditions necessary for the measurement of either DNA or cell number, resulting in infrequent quantitation of messenger RNA in relation to the quantity of cells studied. In the present studies, a microfluorometric method has been modified from previous techniques to permit the quantitation of DNA in cell lysates prepared using an acid guanidinium thiocyanate-phenol (AGTP) solution from which RNA can subsequently be isolated. The lysate is incubated in alkaline EDTA, then neutralized with KH2PO4, followed by the addition of the fluorochrome bisbenzimidazole (Hoechst 33258), and measurement of fluorescence. DNA content is comparable in measurements by the present technique and by the diphenylamine method on parallel samples. DNA content per cell for human cells measured with this technique is comparable to that previously reported using other methods. The use of AGTP solution results in stability of measurable DNA in cell lysates for periods of at least 10 weeks (permitting batching of samples and retrospective measurement) and stability of fluorescence for at least 20 h after the addition of bisbenzimidazole making the timing of fluorescence measurement less critical. The technique described should permit quantitation of messenger RNA in relation to DNA (and hence indirectly to cell number) on a routine basis.

Benzimidazoles↗
PubMed1990

Alterations in circulating human chorionic gonadotropin free alpha-subunit in insulin-dependent diabetic pregnancy: correlation with maternal characteristics.

Circulating concentrations of hCG free alpha-subunit (alpha hCG) increase throughout pregnancy. To address the hypothesis that maternal plasma alpha hCG may reflect placental dysfunction and/or adverse perinatal outcome during insulin-dependent diabetic pregnancy, alpha hCG was measured serially throughout gestation, beginning before week 12, with a specific RIA using a monoclonal antibody in 54 insulin-dependent diabetic (randomly assigned to strict and customary glycemic control) and 25 nondiabetic pregnancies. alpha hCG was significantly lower in pregnant insulin-dependent diabetic subjects than in nondiabetics subjects until 24 weeks gestation, after which it was higher until delivery. Plasma alpha hCG stabilized in nondiabetics at 32 weeks, whereas it continued to increase in diabetics until delivery, at which time it was 37% greater than that in nondiabetics (mean +/- SE, 1441 +/- 90 vs. 1052 +/- 78 micrograms/L; P less than 0.002). Values in diabetic subjects assigned to strict control were intermediate between those in diabetic subjects assigned to customary control and nondiabetic subjects. alpha hCG was greater in diabetic subjects with pregestational hypertension or microvascular disease, but not in those with pregnancy-induced hypertension. These findings were independent of the assigned goals of glycemic control. alpha hCG was not correlated with the duration of diabetes or related to premature delivery, fetal distress, birth asphyxia, or macrosomia. Thus, alpha hCG is increased during the third trimester of the type I diabetic pregnancy and is associated with preexisting hypertension and maternal microangiopathy, but is not a predictor of adverse perinatal outcome. Excessive alpha hCG secretion in diabetes may share pathophysiological mechanisms in common with those underlying diabetic microangiopathy.

Adult↗