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Biomedical subjects

A Fisher

Publications and source records attributed to A Fisher.

At least 181 records · Page 10Linked to original sources
PubMed1989

(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3') quinuclidine (AF102B): a new M1 agonist attenuates cognitive dysfunctions in AF64A-treated rats.

(+-)-cis-2-Methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B), a new muscarinic agonist of utmost rigidity, exhibits a high selectivity for M1 muscarinic receptors. In rats having a cholinergic hypofunction induced by the intracerebroventricular administration of ethylcholine aziridinium (AF64A), AF102B reversed cognitive impairments in a step-through passive avoidance task and in an 8-arm radial maze. AF102B reversed cognitive impairments at significantly lower doses than those needed to induce side-effects. In addition, AF102B exhibited low toxicity. The results suggest that AF102B may prove useful for treatments of cholinergic deficiencies and cognitive impairments, like those reported in Alzheimer's disease.

Alzheimer Disease↗
PubMed1989

Natural history of acquired immunodeficiency syndrome in women in Rhode Island.

PURPOSE: Current recommendations for treatment of human immunodeficiency virus (HIV) infection and for prophylaxis against associated opportunistic infections in North America are largely based on observations of HIV infection in males. In an effort to determine whether the natural history and clinical course may be different, with implications relevant to prophylaxis against opportunistic infections, we have documented the clinical courses of the first 24 known cases of acquired immunodeficiency syndrome (AIDS) in women in Rhode Island, most of whom developed Centers for Disease Control-defined AIDS before the availability of an effective antiviral agent (i.e., zidovudine) or a well-defined approach to prophylaxis against opportunistic infections (e.g., oral trimethoprimsulfa). PATIENTS AND METHODS: The subjects in this study are 24 women with AIDS who were treated by members of the Brown University medical faculty from June 1982 through June 1988. All patients had thorough clinical evaluations and appropriate laboratory studies as they became available. All were followed at intervals no greater than two months. All opportunistic infections were treated by appropriate, specific antimicrobial therapy. When zidovudine became available, it was administered to all remaining patients in the study. All subjects were counseled about HIV infection, its modes of transmission, and the early symptoms of opportunistic infections. RESULTS: These observations yielded the following three major findings: (1) Candida esophagitis was the most common (38%) AIDS-defining event; (2) Pneumocystis carinii pneumonia was less frequently the AIDS-defining event (13%) and occurred less commonly during the illness (29%) than in North American males with AIDS; (3) Of 14 women in whom the diagnosis of AIDS was established before January 1, 1987, the mean survival time after diagnosis was greater than 20 months. CONCLUSION: More information on the natural history of HIV infection in North American women is urgently needed. If more extensive data from other geographic regions confirm the observations in this study, the optimal approach to prophylaxis against opportunistic infections in women with AIDS may be substantially different from that which is most appropriate for males.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Cholinotoxicity induced by ethylcholine aziridinium ion after intracarotid and intracerebroventricular administration.

The effect of ethylcholine aziridinium ion (AF64A) after an intracerebroventricular (icv) injection was compared to that obtained after an intravascular administration. Reductions in choline acetyltransferase (ChAT) and acetylcholinesterase activities in the hippocampus but not in the cerebral cortex or the corpus striatum were observed 10 days after bilateral injection of AF64A into the rat cerebroventricles (3 nmol/side). However, when AF64A was injected into the carotid artery (1 mumol/kg) following a unilateral opening of the blood-brain barrier by a hypertonic treatment, a significant decrease in ChAT activity was observed in the ipsilateral side of the cerebral cortex but not in hippocampus, corpus striatum, or cerebellum. High-affinity choline transport was reduced significantly 11 days after an icv injection of AF64A in all the above mentioned brain regions, and recovered 60 days post injection in the cerebral cortex and in the corpus striatum but not in the hippocampus. Our results suggest that in various brain regions, AF64A causes various degrees of damage to cholinergic neurons, depending on the quantity of the toxin that reaches the target tissue.

Acetylcholinesterase↗
PubMed1989

A comparison of glutathione reductase and glutathione peroxidase activities in patients with rheumatoid arthritis and healthy adults.

A 30% increase in erythrocyte glutathione peroxidase (GP) activity was found in patients with rheumatoid arthritis when compared with healthy controls (p = 0.001) whereas the increase in glutathione reductase (GR) was statistically insignificant. No correlation was found between the activities of the enzymes and the erythrocyte sedimentation rate (ESR). The enzyme activities were independent of age, sex, or type of drug treatment of the patients. A possible interpretation of the results is presented.

Adult↗
PubMed1988

Dual synaptic effects of activating M1-muscarinic receptors, in superior cervical ganglia of rabbits.

Postsynaptic potentials elicited by various muscarinic agonists and by preganglionic stimuli in the presence of such agonists were recorded from rabbit superior cervical ganglia using sucrose-gap and air-gap methods. While methacholine and bethanechol (both at 10(-4) M) induced biphasic potential changes, McN-A-343 and a novel synthetic compound AF-102B (10(-7) M-10(-5) M) produced only a depolarizing response which was depressed by the M1-antagonist pirenzepine (10(-7) M), but not by the M2 antagonist AF-DX 116 (same concentration), indicating that these compounds act purely as M1-muscarinic agonists in this system. These agonists selectively depressed the orthodromic slow excitatory postsynaptic potential (EPSP) in a dose-dependent manner without substantially affecting the fast EPSP; this is in accord with the view that their depolarizing action is on the same postsynaptic muscarinic receptor that mediates the slow EPSP. The slow inhibitory post synaptic potential (IPSP), on the other hand, was found potentiated in the presence of these agonists. This potentiation was antagonized not only by pirenzepine but also by yohimbine; the potentiation was itself enlarged by nomifensine (a dopamine-uptake inhibitor). We postulate that M1-muscarinic receptors are present not only on the postganglionic principal cells but also on the interneurons; the former were already known to be responsible for the generation of slow EPSP, but the latter may be on terminals of dopamine-containing small intensely fluorescent cells and regulate the orthodromic release of dopamine and are to be distinguished from the M2-receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1988

Cholinotoxicity of the ethylcholine aziridinium ion in primary cultures from rat central nervous system.

The cytotoxic effects of ethylcholine aziridinium ion (AF64A) were studied in primary cultures prepared from either whole brain, septum, or midbrain of fetal rats. AF64A, at concentrations up to 22.5 microM, significantly reduced the number of acetylcholinesterase-stained cells without affecting the number of dopaminergic neurons or their ability to take up and release [3H]dopamine. Many of the survived acetylcholinesterase-stained cells appeared with intact somata but damaged processes, indicating a retrograde degeneration starting at the nerve terminal. Higher concentrations of AF64A (greater than 22.5 microM), caused general toxicity which was expressed by degeneration of various neuronal and glial cells. Choline (500 microM), significantly protected the cells from AF64A induced cytotoxicity. The results are consistent with a previously described kinetic model, that predicted a dual action of AF64A: selective cholinotoxicity at low concentrations and non-selective cytotoxicity at higher concentrations.

Acetylcholinesterase↗
PubMed1988

Granulopoietic differentiation in long-term bone marrow cultures from children with congenital neutropenia.

The capacity of granulopoietic precursor cells (CFU-GM) to differentiate in vitro was evaluated in five children with congenital neutropenia using short-term colony assays and long-term marrow cultures. In all five children, methylcellulose assays revealed normal numbers of CFU-GM, which displayed an appropriate response to various sources of GM-CSF and differentiated up to the polymorphonuclear leukocyte state (PMN). In contrast, neutrophil PMN were not observed in long-term bone marrow cultures from three patients, despite a normal production of CFU-GM, myeloblasts, and promyelocytes during the 5-6 week culture period. Thus, in these patients, the characteristic "block" in granulocytic maturation observed in vivo was reproduced in vitro in long-term cultures. Granulocytic differentiation proceeded normally in long-term cultures from the two other patients, thus indicating heterogeneity in the expression of the defect. These results might indicate abnormal interactions between stromal and hematopoietic cells in long-term marrow cultures from some patients with congenital neutropenia. Furthermore, our results showed some correlation between the granulocytic defect in vitro and the clinical outcome in vivo.

Agranulocytosis↗
PubMed1988

Alfentanil infusions on the intensive therapy unit.

We have investigated the use of alfentanil by infusion to sedate 14 patients during controlled ventilation on the intensive therapy unit (ITU). An initial rate of 24 micrograms.kg-1.h-1 was chosen and altered thereafter according to patient response. Incremental doses of midazolam (2.5-5.0 mg) were given intravenously (i.v.) if indicated. In 4 patients, the use of a muscle relaxant was necessary to allow adequate controlled ventilation of the patient. The mean duration of infusion was 27.9 h (range 10-141 h), and the mean total dose of alfentanil was 69.3 mg (12.5-240 mg). Spontaneous ventilation was rapidly achieved in 11 patients after stopping the infusion. The mean arterial carbon dioxide tension (PaCO2) was 5.38 kPa, 15-30 min after stopping the infusion. The clinical condition of 2 patients necessitated a change in sedation technique and one patient died during the alfentanil infusion. Alfentanil by infusion caused no major cardiovascular effects and did not influence the plasma cortisol response to trauma. There was no major alteration in blood biochemistry or haematology during the infusions of alfentanil. The plasma concentrations of alfentanil during infusion showed a wide variability. These probably relate to both changes in the volume of distribution of the drug and in hepatic clearance.

Adolescent↗
PubMed1988

Characterization of murine monoclonal antibodies to HIV-1 induced by synthetic peptides.

We have used short synthetic peptides, 12 and 13 amino acids in length, conjugated to carrier proteins to develop monoclonal antibodies (MAb) to the envelope glycoprotein of 120 (kD) (gp120) and the 3' open reading frame protein (3-orf) of the human immunodeficiency virus type 1 (HIV-1). The peptides employed were chosen because of their strong hydrophilicity and in the case of the gp120 peptide because it represents a highly conserved hydrophilic region in the envelope protein. The MAb developed displayed appropriate specificities with their respective peptides and reacted with appropriate HIV-1 components (i.e., a 120 kD glycoprotein and a 27 kD protein, respectively) as determined by Western blot analysis. In indirect immunofluorescence assays the MAb strongly stained syncytia present in cultures of HTLV-3B-infected H9 cells. The MAb to the envelope component reacted with the RF isolate of HIV-1, as well as with the 3B isolate in immunofluorescence.

Amino Acid Sequence↗
PubMed1987

Complete nucleotide sequences of functional clones of the AIDS virus.

To examine the mechanism of lymphocytotoxicity induced by human T-lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV), an in vitro model has been developed. Introduction of an HTLV-III/LAV proviral clone, HXB2, into normal lymphocytes results in the production of virions and cell death. The complete nucleotide sequence of the proviral form of HXB2 has now been determined. Its structure is quite similar to that previously determined for HTLV-III/LAV clones whose biological capacities had not previously been demonstrated. The biological function of two additional clones of HTLV-III/LAV, BH10 and HXB3, are reported. Clone BH10 which lacks the 5' long terminal repeat sequences (LTR) and a portion of the 3' LTR is reconstituted by substituting the corresponding sequences of HXB2 and is shown to be capable of generating infectious cytopathic virions. Clone HXB3, which has been partially sequenced, is also found to be capable of producing lymphocytopathic virus. Clone HXB3 differs from HXB2 in its lack of a termination codon in 3' orf, demonstrating that 3' orf plays no major role in virus replication or cytopathic activity. These data provide the necessary background to allow the identification of viral determinants of replication, cytopathic activity, and antigenicity using these functional proviral clones.

Base Sequence↗
PubMed1987

Reversible and irreversible inhibition of high-affinity choline transport caused by ethylcholine aziridinium ion.

The effect of ethylcholine aziridinium ion (AF64A) on choline transport in hippocampal, striatal, and cerebrocortical synaptosomes was studied. Synaptosomes prepared from these three brain regions were equally sensitive to AF64A. Low concentrations of AF64A produced a reversible inhibition (IC50 values = 1.35-2.25 microM), whereas higher concentrations produced an irreversible inhibition (IC50 values = 25-30 microM), which started as competitive. The irreversible component of the inhibition was independent of extracellular Na+ concentration, a finding suggesting that the choline transporter is alkylated at its outward position. The kinetics of the inhibition were rapid and similar in the three brain regions examined. The high-affinity choline transport was more sensitive to the toxin than the low-affinity choline transport. Based on these results, we propose a kinetic model that explains the reversible and the irreversible inhibitions induced by AF64A. The possible relationships between the concentrations that in vitro produce reversible and irreversible inhibition and those that in vivo produce selective and nonselective cholinergic hypofunction are discussed.

Animals↗
PubMed1987

Transketolase abnormality in cultured fibroblasts from familial chronic alcoholic men and their male offspring.

We have investigated a thiamine-dependent enzyme, transketolase, in cultured fibroblasts from 41 human subjects, including patients with alcoholism-associated Wernicke-Korsakoff syndrome (n = 3), familial chronic alcoholic males (n = 7), their sons (n = 7), nonalcoholic men (n = 7), their male offspring (n = 7), and three generations of an Amish family (n = 10) without any history of alcoholism. This study was undertaken to delineate whether transketolase abnormality (i.e., high Michaelis Menton constant (Km) for thiamine pyrophosphate), previously reported in patients with Wernicke-Korsakoff syndrome is prevalent among familial chronic alcoholic men and their sons without prior history of alcohol abuse but who are at high risk for alcoholism. Our data suggest that an inborn error (i.e., high Km of transketolase for thiamine pyrophosphate) predisposing to thiamine deficiency diseases similar to those reported in Wernicke-Korsakoff syndrome may occur in the general population. However, for some as yet unexplained reason(s) this variant seems to occur more frequently among familial chronic alcoholic men and their male offspring without any history of alcoholism. The inheritance pattern of this enzyme variant as revealed from an Amish pedigree study may be autosomal recessive as previously suggested.

Adolescent↗
PubMed1987

In vivo studies with fibre components.

There are few studies in man examining the in vivo effects of dietary fibre on bile acid metabolism but divergent results have been recorded depending on the amount and type of fibre eaten. Studies in which the fibre components pectin, cellulose, and lignin were fed to normal volunteers for four weeks have been reported. The highly fermentable component pectin is associated with increased secondary bile acid formation in contrast to the partially fermentable component cellulose in which the opposite occurs. Lignin has no effect on bile acid metabolism. No component significantly alters biliary lipids. Since ordinary diets contain a mixture of different fibres the net effect will depend on the relative amounts of each. Significant changes in bile acid metabolism and biliary lipids in the longer term (greater than 4 weeks) however, are not precluded by the results of these short term studies.

Bile Acids and Salts↗