Biomedical subjects
Publications and source records attributed to S Shaw.
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The virus specificity of human in vitro cytotoxic T cell responses to influenza virus was studied with the use of peripheral blood mononuclear leukocytes from normal adult volunteers. Previous natural exposure of these donors to a variety of type A influenza viruses was documented by HI antibody titers. Cells sensitized in vitro with A/HK or A/PR8 were cytotoxic for autologous target cells infected with A/HK, A/PR8, or A/JAP 305 type A influenza viruses, but not for B/HK-infected or uninfected cells. B/HK-sensitized effector cells lysed target cells infected with B/HK but not targets infected with type A viruses. A/HK- and A/PR8-immune effector populations were shown to recognize cross-reactive antigens on A/HK- and A/PR8-infected target cells by cold target competition. Influenza-immune effector cells were cytotoxic for virus-infected autologous targets but much less so for virus-infected allogeneic targets. This self-restriction suggested that the cytotoxicity was largely T cell-mediated and was confirmed by cell separation analysis. Thus, the human secondary cytotoxic T cell response in vitro to influenza viruses is predominantly directed against cross-reactive determinants on cells infected with serologically distinct type A influenza viruses.
The specificity of in vitro induced human influenza-immune cytotoxic effector cells was analyzed with respect to recognition of HLA-A and -B-linked gene products. The influenza-immune cytotoxic activity observed on panels of virus-infected targets demonstrated that virus-immune effectors preferentially lyse targets with which they share HLA-A or -B specificities. Virus-immune effectors from certain donors recognized virus in conjunction with some, but not all, of their self HLA-A and -B antigens. Among donors who share a given HLA antigen (such as A2 or B7), there are differences in the ability of their virus-immune T cells to recognize the shared antigen. Virus-infected target cells from HLA-A2 or -B7 "nonresponder" donors could be lysed by virus-immune T cells obtained from other donors who shared only the HLA-A2 or -B7 antigen with these target cells. These observations suggest that the absence of cytotoxic T cell responses by some donors to influenza virus in conjunction with HLA-A2 or -B7 is not due to control by the structural genes that code for these HLA antigens, but rather may result from control by regulatory genes that act at the level of the responder and/or stimulator cell. The results are discussed in the context of Ir gene regulation of human T cell responses.
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The measurement of AANB relative to leucine was found to be a useful biochemical test for the detection of chronic alcohol consumption. This test, in combination with GGTP determinations, provided a sensitive means of detection (81% positive) for chronic alcohol consumption with a minimum of false positive determinations (2%).
Plasma amino acid abnormalities are common in alcoholics, but the respective role of alcoholism, nutrition, and liver injury in producing these abnormalities is unknown. To elucidate this question, amino acids were measured in 56 alcoholics and 32 nonalcoholics with liver disease, and in an experimental model of alcoholic liver injury in the baboon. Dietary protein deficiency depressed branched-chain amino acids with a tendency to decreased alpha-amino-n-butyric acid. By contrast, chronic alcoholic consumption selectively increased these amino acids both in short term (2 to 4 weeks) studies in human beings and in 1 to 4-year studies in baboons. Moderate liver injury had no significant effects on these amino acids whereas advanced cirrhosis depressed branched-chain amino acids. Thus, plasma branched-chain amino acids and alpha-amino-n-butyric acid in the alcoholic are affected by at least three variables: dietary protein deficiency and advanced cirrhosis which tend to decrease these amino acids, and chronic alcohol consumption which tends to increase them.
Recently developed tests that measure levels of alpha-amino-n-butyric acid (AANB) and serum glutamic dehydrogenase (GDH) may improve screening for early detection of heavy drinking and liver injury, respectively. With these tests, a "three-level" approach to the problem is now possible: (1) detection of heavy drinking on the basis of a biochemical marker (such as AANB); (2) detection of liver injury (necrosis and inflammation) on the basis of serum liver tests (such as GDH); and (3) detection of alcoholics in whom cirrhosis is prone to develop by the screening of liver biopsy specimens for precirrhotic lesions (such as pericentral sclerosis).
The effects of ethanol upon amino acid metabolism represent a complex interaction of ethanol metabolism and its products, nutritional abnormalities and pathological alterations in various organs especially the liver. The effects of chronic alcohol consumption upon amino acid absorption, digestion and transport appear largely of theoretical interest without significant impact on nitrogen balance, hepatic urea or protein synthesis or plasma amino acid patterns. Marked alterations in amino acid metabolism in the liver and other organs are observed in human alcoholics. These result in changes in plasma and tissue levels of amino acids and may explain or contribute to hepatic encephalopathy by altering levels of intermediate products such as catecholamines and neurotransmitters. Plasma amino acid changes due to ethanol may also provide a biochemical marker for the assessment of ethanol consumption in an objective fashion. Amino acid requirements in the diet may be altered in the alcoholic along with lowered protein tolerance. Administration of selected proteins or mixtures of amino acids may provide a means for maintaining nitrogen balance while avoiding or improving hepatic encephalopathy in such patients.
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Human PBML can generate cytotoxic responses to autologous cells that have been chemically modified with TNP or DNP. The cytotoxic effectors have precise hapten specificity. The DNP-specific effectors recognize DNP in association with cell surface alloantigens, which appear to be at least partially associated with HLA-A and -B. The TNP-specific effectors recognize TNP in association with several classes of determinants--some of which are HLA-linked alloantigens that are incompletely associated with HLA-A and -B, while other determinants are widely shared among humans.
A patient with chronic myeloid leukaemia treated with busulphan for 4-5 years, developed signs of busulphan toxicity and portal hypertension with ascites, oesophageal varices and jaundice. At post-mortem there was minimal leukaemic infiltration but there were alterations in the liver architecture sufficient to explain the portal hypertension. The pathogenesis of the liver changes and their possible relationship to splenomegaly and busulphan toxicity are considered.
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Enzyme "panels," in which creatine kinase and lactate dehydrogenase activities in serum are measured, are useful indicators of myocardial infarction. We examined a further enzyme, glyceraldehyde-phosphate dehydrogenase (EC 1.2.1.12), by comparison with creatine kinase (EC 2.7.3.2), in the early diagnosis of such infarctions. Results indicate that this total dehydrogenase appears in the serum before total creatine kinase activity; however, the lack of cardio-specificity relating to the dehydrogenase isoenzyme fraction 2 in comparison to the creatine kinase MB band is a major disadvantage, as is its relatively poor in vitro stability. We conclude that measurement of this dehydrogenase does not allow a substantially earlier diagnosis of myocardial infarction.
The plasma ratio of alpha-amino-n-butyric acid to leucine was elevated in ambulatory and hospitalized alcoholics as well as in baboons fed alcohol along with an adequate diet. There was a statistically significant positive correlation between this ratio and the degree of alcoholism assessed by three separate medical and psychological criteria in patients maintained on methadone.
We investigated the role of serum bactericidal activity in Hemophiplus influenzae type b infections in infants with meningitis and in a rat model. In infected infants, 13/22 admission sera had bactericidal activity against the infecting strain, and bacteremia was as frequent in those with bactericidal activity (54%) as those without (56%). The coexistence of bactericidal activity and bacteremia was reproduced and studied in experimentally infected weanling rats. Serum from such rats kills in vitro 95% of conventionally broth-grown bacteria within 10 min, but does not kill organisms obtained from the infected animals. Thus bactericidal activity as conventionally determined for H. influenzae b may have no relevance in vivo, Incubation of broth-grown bacteria in normal rat serum for 30 min at 37 degrees C produces a resistance like that of in vivo organisms. This phenotypic conversion depends on factors that are of molecular weight less than 1,000, stable to 100 degrees C, but destroyed by ashing. When injected intravenously into nonimmune animals, broth-grown bacteria are quickly cleared, while serum-preincubated bacteria are not. The latter, however, are cleared when injected into bacteremic rats (half-life 30 min). Bacteremia in the rats may persist despite this capacity for clearance because bacteria are entering the blood from extravascular fluids, which contain greater than 90% of the total bacterial burden.