Insula and obsessive-compulsive disorder.
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Astrocytoma↗
Biomedical subjects
T Flynn
Publications and source records attributed to T Flynn.
Developmental effects of combined exposure to ethanol and vitamin A.
The potential for ethanol (EtOH) to influence the developmental toxicity of vitamin A was investigated. 11 groups of approximately 31 FDA-bred Osborne-Mendel rats received either a control or isocaloric 6.4% EtOH liquid diet (containing 4000 IU vitamin A/litre) ad lib. The vehicle control, EtOH and pair-fed (pair-fed against the EtOH group) groups received corn oil (the vehicle) by gavage. Vitamin A was administered by gavage without EtOH at 40,000, 80,000, 120,000 or 160,000 IU/kg daily. Vitamin A was administered by gavage at 10,000, 20,000, 40,000 or 80,000 IU/kg with EtOH ad lib., daily throughout the study. Combined EtOH and vitamin A resulted in significant reductions in maternal diet consumption and body weight when doses of vitamin A were as low as 10,000 IU/kg. The most severe effects on overall (days 0-20) maternal body weight gain were observed in the groups receiving 120,000 or 160,000 IU vitamin A/kg alone or EtOH in combination with 80,000 IU vitamin A/kg. The overall diet consumption (days 0-20) paralleled the overall weight gain. In general, pups exposed to ethanol and vitamin A had a tendency to weigh less than those exposed to vitamin A alone, but to weigh more than those exposed to EtOH alone. EtOH combined with vitamin A at 80,000 IU/kg resulted in an increased incidence of cleft palate relative to the vehicle control or either treatment alone. The incidence of exencephaly and protruding tongue was significantly greater in the group given vitamin A at 160,000 IU/kg, compared with the vehicle control group. The most consistent statistically significant skeletal finding in the groups receiving combined treatment was a treatment-related increased incidence of supernumerary ribs [14th rib (C7), 14th rib bud (L1) and 15 ribs]. In addition, the incidence of misshapen zygomatic arch was also significantly increased in the group exposed to EtOH and vitamin A at 80,000 IU/kg. The incidence of moderately enlarged renal pelvis and severely enlarged ureter proximal to the kidney was increased in the group exposed to EtOH and vitamin A at 80,000 IU/kg relative to the vehicle control, or either treatment alone. Therefore, for some of the endpoints examined in this investigation, it would appear that ethanol potentiates the developmental effects of vitamin A.
Abnormalities, Drug-Induced↗
Effect of ethanol and vitamin A excess on vitamin A status in the liver, plasma and foetuses of pregnant rats.
The effect of maternal consumption of dietary ethanol and high doses of vitamin A by gavage was investigated by evaluating plasma, liver and foetal vitamin A in Osborne-Mendel pregnant rats with a view to assessing whether ethanol modulated the potential toxicity of excess vitamin A. All groups received 4000 IU vitamin A/litre in a liquid diet. Ethanol-exposed groups also received 6.4% (v/v) ethanol in the liquid diet. Vitamin A was administered by gavage once per day in corn oil in doses ranging from 10,000 to 160,000 IU/kg body weight. Plasma vitamin A levels in ethanol-exposed groups were similar to levels in a pair-fed group. Plasma vitamin A levels were similar in the group given ethanol plus 40,000 IU vitamin A/kg and the group given 40,000 IU vitamin A/kg only, but were higher in the group receiving ethanol plus 80,000 IU vitamin A/kg than in the group given 80,000 IU vitamin A/kg only. Retinyl esters were present in the plasma of animals receiving 160,000 IU vitamin A/kg only, indicating possible saturation of the liver with vitamin A. Retinyl palmitate levels in female foetuses of the group administered ethanol plus 80,000 IU vitamin A/kg were significantly higher than those of the group administered 80,000 IU vitamin A/kg only; no significant differences in levels of retinyl palmitate in male foetuses were observed between these two groups. This observation suggests a possible sex difference in the modulation of vitamin A toxicity by ethanol in the foetus.
Administration, Oral↗
Retinal pathologic changes in multiple sclerosis.
PURPOSE: To describe the ocular pathologic changes in multiple sclerosis (MS), with attention to its effects on the uveal tract and retinal veins. METHODS: Cases of 26 patients with MS and 3 patients with neuromyelitis optica were reviewed; retinal trypsin digestion was performed on remaining wet tissue for 20 of these patients. Eyes were specifically examined for inflammation of the retinal vessels, uveal tract, retina, optic nerve, and pars plana. Specimens were also examined for atrophy of the optic nerve, ganglion cell, and nerve fiber layers. RESULTS: Atrophy of the nerve fiber and ganglion cell layers was present in 73% of the cases with MS and correlated with optic nerve atrophy; choroiditis was present in 11.5%; bilateral cyclitis without other foci of inflammation was present in 1 case; and retinal phlebitis was present in 20% (most of which were only identified after trypsin digestion). Optic nerve inflammation was present in two of the patients with neuromyelitis optica. CONCLUSION: Uveitis and retinal phlebitis are manifestations of MS. Trypsin digestion with microscopic examination is a sensitive method of testing for phlebitis, which may explain why the frequency found in this series is higher than in others. These lesions are similar to the perivenular cuffing that occurs in the central nervous system in MS.
Adult↗
Regulation of mannitol biosynthesis and degradation by Cryptococcus neoformans.
Cryptococcus neoformans, an encapsulated yeast that is an opportunistic pathogen of AIDS patients, produced and secreted mannitol when incubated with an appropriate carbon source. Glucose, fructose, and mannose were good growth substrates and were converted to mannitol. Maltose and xylose were good growth substrates but were not converted to mannitol. Cells of C. neoformans that were grown on a non-mannitol-generating carbon source, such as peptone or xylose, were able to convert glucose to mannitol only after a prolonged lag period in the presence of glucose. It was concluded that the enzymes of the mannitol biosynthetic pathway were not constitutively expressed but were induced in response to glucose or to a glucose metabolite. Enzymes required to catabolize mannitol, however, were constitutively expressed. The production of mannitol was inhibited by anaerobiosis, by the respiratory poison rotenone, and by polyethylenesulfonate, a specific inhibitor of fungal NADP-dependent dehydrogenases. When cells were incubated with deuterated glucose, the deuterium content of the mannitol produced was much lower than that of the glucose precursor, indicating that the glucose was diluted by an intracellular pool of an intermediate. We had previously shown that C. neoformans contains a large intracellular pool of glucose 6-phosphate, and we now conclude that this pool of glucose 6-phosphate is metabolically active.
Cryptococcus neoformans↗
A potent specific inhibitor of 6-phosphogluconate dehydrogenase of Cryptococcus neoformans and of certain other fungal enzymes.
A particular lot of the zwitterionic buffer, 2(N-morpholino) ethane sulfonic acid (MES), contained a contaminant that inhibited a number of fungal NADP-dependent dehydrogenases. Enzymes that were particularly sensitive include 6-phosphogluconate dehydrogenases from Cryptococcus neoformans and Schizophyllum commune and glucose-6-phosphate dehydrogenase from Schizophyllum commune. A number of NADP-dependent dehydrogenases of animal origin were tested and all were completely insensitive to inhibition except for rat liver 6-phosphogluconate dehydrogenase, which was 10-fold less sensitive than the Cryptococcal enzyme. The pattern of inhibition in all cases was linear competitive versus NADP. The inhibitor has been purified and identified as an ethylenesulfonic acid oligomer. This inhibitor holds promise as a model compound for the development of a specific antifungal agent.
Adenosine Monophosphate↗
Substrate oxidation errors during combined indirect calorimetry-hyperinsulinemic glucose clamp studies.
The procedure of indirect calorimetry is often combined with the hyperinsulinemic, euglycemic clamp technique so that intracellular rates of glucose oxidation (Gox), fat oxidation (Fox), and energy expenditure (EE) can be determined at different insulin concentrations and rates of whole-body glucose uptake. In order to perform these calculations, rates of protein oxidation (Pox) must be known and are usually estimated from urinary nitrogen (N) excretion. The use of urinary N assumes that this measurement accurately reflects Pox and is unaltered by the glucose clamp technique. To examine these assumptions and determine potential errors in rates of Gox, Fox, and EE with this method, eight healthy subjects each had basal urinary N excretion determined on 4 different days and during a 300 pmol/m2/min hyperinsulinemic, euglycemic clamp. Mean basal urinary N excretion was 6.4 +/- 1.6 mg/min. Within individuals, basal urinary N was highly variable on the 4 different days with a mean coefficient of variation (CV) of 36% +/- 18%. Over the range of basal respiratory quotient (RQ) values in this study (0.78 to 0.85) the day-to-day variation in basal urinary N resulted in potential errors of 11% to 23% for Gox, 16% to 24% for Fox, but minimal effects (less than or equal to 1%) on EE. During the hyperinsulinemic, euglycemic clamp, RQ increased to 0.95 or greater, while urinary N excretion, rather than decreasing as expected, increased by 47% (6.4 +/- 1.6 to 9.4 +/- 2.8 mg/min) due in part to increases in urea clearance from 37.5 +/- 6.7 to 75.2 +/- 12.4 mL/min (P less than .025). This increased urinary N excretion had minimal influence on Fox and EE, but underestimated Gox by up to 5% at RQ less than 0.95. A more accurate estimate of urinary N excretion during hyperinsulinemic clamps may be obtained by correcting for changes in urea clearance. These results indicate that basal urinary N excretion is highly variable and influenced by hyperinsulinemic glucose clamps. Thus, urinary N excretion, particularly during the basal state, may not accurately reflect changes in Pox and can lead to substantial errors in Gox and Fox.
Adult↗
Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor.
A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.
Animals↗
Thienotriazolodiazepines as platelet-activating factor antagonists. Steric limitations for the substituent in position 2.
The preparations of thienotriazolodiazepines bearing a substituted ethynyl group at the 2-position, and the corresponding cis-olefins and fully saturated analogues are described. The compounds were evaluated as potential antagonists of platelet-activating factor (PAF) in in vitro and in vitro test models. The new thienotriazolodiazepines are compared with known related compounds such as WEB 2086 (compound 6) and the phenylethyl derivatives 27 and 28.
Animals↗
Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial.
STUDY OBJECTIVE: To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex. DESIGN: Open label, escalating dosage, phase I-II tolerance trial. SETTING: Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. INSTRUCTIONS: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days. MEASUREMENTS AND MAIN RESULTS: Recombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages. CONCLUSIONS: Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.
AIDS-Related Complex↗
A double-blind, placebo-controlled study of oral acyclovir in postherpetic neuralgia.
Twenty-one patients with postherpetic neuralgia of two- to 84-months duration participated in a double-blind, placebo-controlled study of oral acyclovir. Pain perception was assessed with the Melzack Pain Questionnaire at baseline and at two-to six-week intervals during the ensuing six months. Clinically significant pain reduction occurred in eight patients: four received acyclovir, and four received a placebo. Several treatment strategies have been advocated for relief of postherpetic neuralgia. Results of the present study demonstrate the need for a double-blind, placebo-controlled paradigm to substantiate the efficacy of new clinical approaches. The same caveat applies to the more common syndromes encountered in psychiatric practice.
Acyclovir↗
Panic attacks and related disorders in alcohol-dependent, depressed, and nonclinical samples.
Although several studies have indicated that a substantial portion of alcoholics have an anxiety disorder, relatively little information exists specifically regarding panic disorders. In addition, prior studies have been marred by the absence of appropriate contrast groups. The present investigation compared the lifetime prevalence of panic attacks and panic-related disorders diagnosed according to DSM-III criteria in a group of 79 alcohol-dependent patients, 64 depressed patients, and 70 nonclinical subjects. Panic attacks, panic disorder, and agoraphobia with panic attacks were more prevalent in the alcohol-dependent and depressed samples than among nonclinical subjects. Men in both clinical samples were more likely than women to have had nonagoraphobic panic disorder, but male alcoholics were less likely to have developed agoraphobia than were female alcoholics or depressed patients of either sex. No consistent chronological relationship between onset of panic attacks and alcohol abuse was found. Results indicate that there is an unusually high prevalence of panic attacks and panic-related disorders among alcoholics, but comparable prevalence rates can be found in depressed and perhaps some other psychiatric populations. Implications for the assessment and treatment of alcohol-dependent and panic-disordered patients are discussed.
Adolescent↗
Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.
Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.
Administration, Oral↗
Metabolic effects of hyperglycemia and hyperinsulinemia on fate of intracellular glucose in NIDDM.
Hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) stimulates peripheral glucose uptake, which tends to compensate for impaired insulin-mediated glucose uptake. The metabolic fate of glucose and suppression of fat oxidation may differ, however, when glucose uptake is stimulated primarily by insulin or hyperglycemia. To address this issue, three hyperinsulinemic glucose-clamp studies were performed in combination with indirect calorimetry in seven nonobese subjects with NIDDM. In the first two experiments, when glucose uptake was matched at approximately 8 mg.kg-1 fat-free mass (FFM).min-1 with primarily hyperinsulinemia (1350 +/- 445 pM) or hyperglycemia (20.8 +/- 1.8 mM), identical rates of glucose oxidation (3.21 +/- 0.29 and 3.10 +/- 0.23 mg.kg-1 FFM.min-1, NS) and nonoxidative glucose metabolism (5.19 +/- 0.75 and 5.46 +/- 0.61 mg.kg-1 FFM.min-1, NS) were achieved. When glucose uptake was increased further to 11.11 +/- 0.36 mg.kg-1 FFM.min-1 with less insulin (625 +/- 70 pM) and hyperglycemia, glucose oxidation (3.85 +/- 0.26 mg.kg-1 FFM.min-1) and nonoxidative glucose metabolism (7.26 +/- 0.51 mg.kg-1 FFM.min-1) rose significantly (both P less than 0.05 from matched studies at lower rates of glucose uptake). During all glucose-clamp studies, free fatty acids were comparably suppressed by 40-46% (all P less than 0.005 vs. basal values), whereas fat oxidation was suppressed by 70-80% (all P less than 0.005 vs. basal values). A strong negative correlation was observed between rates of glucose and fat oxidation (r = -0.88, P less than 0.001) when all studies were combined.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
The Beth Johnson Foundation.
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Foundations↗
Absence of infectious HIV-1 in the urine of seropositive viremic subjects.
Urine and peripheral blood samples from 48 human immunodeficiency virus type 1 (HIV-1) seropositive individuals (38 adults and 10 children) were evaluated for the presence of HIV-1 by cocultivation and for HIV-1 p24 antigen by ELISA. None of the urine samples contained replication-competent HIV-1; 41 (85%) of 48 simultaneously obtained peripheral blood mononuclear cell samples contained replication-competent HIV-1. None of 26 urine samples available for analysis contained HIV-1 p24 antigen as determined by ELISA; 12 (34%) of 35 simultaneously obtained peripheral blood samples had detectable serum HIV-1 p24 antigen. Two of the individuals studied had HIV nephropathy, three had pyuria, and five had microscopic hematuria. Culture sensitivity was maximal when mycostatin (and not amphotericin B) was used as an antifungal agent. Our findings indicate that urine from HIV-1-seropositive individuals is unlikely to contain infectious HIV-1. This would imply that the risk of transmission of HIV-1 by urine is low to nonexistent.
Adult↗
Vibrio sepsis in a cirrhotic patient.
Vibrio vulnificus should be suspected in any soft tissue infection occurring after exposure to the marine environment. Early recognition followed by appropriate antibiotic therapy and debridement of involved tissue are essential features in the treatment of these infections.
Amputation, Surgical↗
Association of thrombotic thrombocytopenia purpura (TTP) and human immunodeficiency virus (HIV) infection.
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HIV Seropositivity↗