Biomedical subjects
Publications and source records attributed to M Davis.
Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex. When infused onto the spinal cord, serotonin produced a dose-dependent increase in startle. Thus the same neurotransmitter can modulate the same behavior in opposite ways, depending on which part of the central nervous system is involved.
Circulating antibodies reacting specifically with the cell membrane of hepatocytes isolated from halothane-anesthetized rabbits were detected in nine of 11 patients with fulminant hepatic failure after helothane-induced anesthesia. The immunoglobulin deposition, as revealed by immunofluorescence, showed a granular pattern on the hepatocyte surface membrane. Preincubation of halothane-pretreated, but not of control, hepatocytes with serum containing this antibody rendered them susceptible to cytotoxic effects of normal lymphocytes in vitro. Control studies using serum from subjects repeatedly exposed to halothane without the development of liver damage, and from patients with viral and toxic liver injury have confirmed the specificity of these findings to serve halothane-associated liver injury. These results provide further evidence of an immunologic component in this condition.
The IgM molecule is composed of subunits made up of two light chain and two heavy chain (mu) polypeptides. The mu chain is encoded by several gene segments--variable (V), joining (J) and constant (Cmu). The Cmu gene segment is of particular interest for several reasons. First, the mu chain must exist in two very different environments--as an integral membrane protein in receptor IgM molecules (micrometer) and as soluble serum protein in IgM molecules into the blood (mus). Second, the Cmu region in mus is composed of four homology units or domains (Cmu1, Cmu2, Cmu3 and Cmu4) of approximately 110 amino acid residues plus a C-terminal tail of 19 residues. We asked two questions concerning the organisation of the Cmu gene segment. (1) Are the homology units separated by intervening DNA sequences as has been reported for alpha (ref. 5), gamma 1 (ref. 6) and gamma 2b (ref. 7) heavy chain genes? (2) Is the C-terminal tail separated from the Cmu4 domain by an intervening DNA sequence? If so, DNA rearrangements or RNA splicing could generate hydrophilic and hydrophobic C-terminal tails for the mus and micrometer polypeptides, respectively. We demonstrate here that intervening DNA sequences separate each of the four coding regions for Cmu domains, and that the coding regions for the Cmu4 domains and the C-terminal tail are directly contiguous.
Seven of ten women with oral-contraceptive-associated liver tumours were found to have hepatocellular carcinoma. The diagnosis was often delayed, although hepatomegaly was always present on examination, and liver-function tests and erythrocyte sedimentation-rates were abnormal in most cases. Other investigations, including routine technetium liver scans and biopsy, were sometimes misleading. There were important differences in alpha-fetoprotein concentration, vascularity on angiography, and survival between liver tumours in pill users and non-users.
The effects of different doses (0.03, 0.06, 0.12, 0.25, 1.0, 2.0, 4.0, and 8.0 mg/kg body weight) of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) were tested on the acoustic startle reflex in rats. Beginning at 0.12 mg/kg, 5-MeODMT increased startle monotonically up to the highest dose used. 5-MeODMT still increased startle in acutely decerebrate rats or when infused directly onto the spinal cord. The excitatory effects of a high systemic dose of 5-MeODMT were completely blocked by cinanserin, cyproheptadine, and propranolol, but not by parachlorophenylalanine, alpha-methyl-p-tyrosine, haloperidol, sotalol, or phenoxybenzamine. The results were discussed in terms of a new theory, which suggests that stimulation of serotonin receptors in the spinal cord enhance startle whereas serotonin receptors in the forebrain inhibit startle.
We have determined the sequences of separate germline genetic elements which encode two parts of a mouse immunglobulin heavy chain variable region. These elements, termed gene segments, are heavy chain counterparts of the variable (V) and joining (J) gene segments of immunoglobulin light chains. The VH gene segment encodes amino acids 1-101 and the JH gene segment encodes amino acids 107-123 of the S107 phosphorylcholine-binding VH region. This JH gene segment and two other JH gene segments are located 5' to the mu constant region gene (Cmu) in germline DNA. We have also determined the sequence of a rearranged VH gene encoding a complete VH region, M603, which is closely related to S107. In addition, we have partially determined the VH coding sequences of the S107 and M167 heavy chain mRNAs. By comparing these sequences to the germline gene segments, we conclude that the germline VH and JH gene segments do not contain at least 13 nucleotides which are present in the rearranged VH genes. In S107, these nucleotides encode amino acids 102-106, which form part of the third hypervariable region and consequently influence the antigen-binding specificity of the immunoglobulin molecule. This portion of the variable region may be encoded by a separate germline gene segment which can be joined to the VH and JH gene segments. We term this postulated genetic element the D gene segment, referring to its role in the generation of heavy chain diversity. Essentially the same noncoding sequences are found 3' to the VH gene segment and as inverse complements 5' to two JH gene segments. These are the same conserved nucleotides previously found adjacent to light chain V and J gene segments. Each conserved sequence consists of blocks of seven and ten conserved nucleotides which are separated by a spacer of either 11 or 22 nonconserved nucleotides. The highly conserved spacing, corresponding to one or two turns of the DNA helix, maintains precise spatial orientations between blocks of conserved nucleotides. Gene segments which can join to one another (VK and JK, for example) always have spacers of different lengths. Based on these observations, we propose a model for variable region gene rearrangement mediated by proteins which recognize the same conserved sequences adjacent to both light and heavy chain immunoglobulin gene segments.
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The present review argues that the startle reflex is particularly well suited as a model system to analyze how drugs alter stimulus reactivity and reflex excitability. It then reviews all the literature to date on how drugs or lesions that are thought to alter neurochemical transmitter systems affect acoustic and/or tactile startle. Hypotheses are presented to account for how serotonin, dopamine, norepinephrine, acetylcholine, and opiates modulate startle. Effects on startle plasticity such as habituation, sensitization, and potentiation resulting from prior associative learning are also included.
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The interactions of cysteamine, N-acetylcysteine, 2-mercaptopropionylglycine and methionine with N-acetyl 4-aminophenol (paracetamol) have been examined during its metabolism to a covalently bound product in an in vitro mouse hepatic microsomal system. Of the compounds used only methionine failed to reduce the amount of covalently bound [3H]paracetamol-derived radioactivity. These results indicate that the effecitveness of methionine in reducing paracetamol hepatotoxicity in vivo is achieved by mechanisms other than those involving direct interactions with the hepatic mixed-function oxidase system or its oxidation products. In contrast, cysteamine, N-acetylcysteine and 2-mercaptopropionylglycine can directly inhibit the binding of [3H]paracetamol-derived radioactivity in vitro, and may do so by processes which affect both the formation and the subsequent binding of a reactive paracetamol metabolite.
The association between nutrient deficiencies, steroid administration, anti-flagellate therapy and giardiasis was examined using the Giardia muris/mouse model. Administration of steroids to BALB/c mice resulted in persisting high levels of infection with G. muris, whereas untreated animals were able to eliminate this parasite. In addition, steroid treatment significantly reduced the efficacy of anti-flagellate therapy. Protein-deficient mice eliminated the parasite at the same rate as mice on an optimum diet and also developed strong acquired resistance to re-infection. A similar pattern was observed in iron-deficient mice, except that the number of parasites that became established during the first 2 weeks of infection was significantly reduced. Thus, there was no evidence of synergism between iron and protein deficiency and infection in this model.
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1. The plasma elimination rate of antipyrine and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxyantipyrine were measured in five children in the acute phase of malnutrition and after recovery. The results were compared with those obtained in 3 normal children. 2. Upon nutritional rehabilitation antipyrine clearance increased from 0.65 +/- 0.14 ml min-1 kg-1 to 1.07 +/- 0.20 ml min-1 kg-1. 3. The urinary excretion of 4-hydroxy-antipyrine increased from 6.1 +/- 4.5 to 14.7 +/- 5.9%, norantipyrine from 8.8 +/- 5.7 to 14.3 +/- 5.4 and 3-hydroxy-methyl-antipyrine from 11.8 +/- 8.3 to 20.5 +/- 5.6% (% of dose/24h urine). Excretion of unchanged antipyrine decreased from 5.2 +/- 3.7 to 2.7 +/- 0.9% dose. The metabolite profile (ratio between the amounts of the various metabolites excreted) was not significantly different. 4. It is concluded that malnutrition decreases the rate of antipyrine metabolism, but it does not affect the three oxidative pathways differently.
A patient is described who suffered hypersenitivity reactions (anorexia, nausea and vomiting) as well as cholestatic jaundice from therapy with azathioprine. Evidence is given that the 2 reactions were mediated by different portions of the azathioprine molecule.
Of 45 patients with chronic active hepatitis, 17 had taken paracetamol before the onset of symptoms. There were no significant differences, however, between the two groups in abnormalities of liver function tests, nor in ease of control after paracetamol withdrawal and institution of immunosuppressive therapy. The patient who had taken more than 5 g/week was studied in greater detail, but after a challenge dose of 1 g paracetamol there was no rise in serum aminotransferases and the pattern of excretion of paracetamol metabolites was normal. A critical review of the previously published reports failed to uncover any convincing evidence that paracetamol is an initiating factor in the development of chronic active hepatitis, although it may, at therapeutic levels, cause a toxic hepatitis in those individuals at risk.
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Pima Indians have a high prevalence of hyperinsulinemia, obesity, and diabetes, but they have low plasma cholesterol levels, reduced low density lipoprotein synthesis, and little arteriosclerotic heart disease. To investigate lipoprotein metabolism further in this group, very low density lipoprotein (VLDL) metabolism was studied, using [3H]glycerol as an endogenous precursor of triglyceride (TG) synthesis, in 15 obese Pima nondiabetic males and compared to that of 10 obese and 13 normal weight, normolipidemic, nondiabetic Caucasian males. The resultant kinetic data were analyzed using a multicompartmental model which includes two pathways for VLDL-TG synthesis and a process of stepwise delipidation for VLDL catabolism. As compared to obese Caucasians, the obese Pimas had a lower rate of VLDL-TG synthesis, and a lower proportion of slow pathway for synthesis. The fractional catabolic rate in the Pimas was higher than in either Caucasian group, a larger proportion of VLDL-TG was delipidized at each step, and particle residence time was shorter. When the relation between VLDL-TG metabolism and plasma insulin was examined, plasma insulin levels in the Pima were not correlated with VLDL-TG synthetic rates, catabolic rates, or plasma pools. On the other hand VLDL-TG synthetic rates were correlated with plasma free fatty acid levels. Thus, in this population with low plasma lipids and reduced arteriosclerotic heart disease, VLDL-TG synthesis is low, VLDL-TG catabolism is accelerated, and VLDL pools appear to be insensitive to the influence of body weight and hyperinsulinemia.