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Biomedical subjects

S Shaw

Publications and source records attributed to S Shaw.

At least 487 records · Page 27Linked to original sources
PubMedDate not supplied

Frequency of hyperprolinemia in alcoholic liver cirrhosis: relationship to blood lactate.

In alcohol-induced liver injury, hyperprolinemia has been proposed as a marker of fibrogenesis probably secondary to hyperlactacidemia. However, some studies of plasma proline in alcoholics with cirrhosis have reported normal rather than increased levels. In order to evaluate the frequency of hyperprolinemia in alcoholic liver disease and its relationship to blood lactate, we measured plasma proline levels in 145 subjects including 91 alcoholics with a spectrum of liver disease as well as 22 nonalcoholics with liver injury unrelated to alcohol. We also studied baboons fed alcohol as 50% of total calories for 1 to 4 years. Among alcoholics only 21/91 had elevated proline values. Elevations were most frequent among patients with severe hepatic decompensation (3/8), in patients with alcoholic hepatitis on liver biopsy (5/17), and in those with acute alcohol-related withdrawal, with alcohol still present in the blood (4/9). Patients with liver disease unrelated to alcohol but severe in nature also has elevations in proline (3/3). Only 4/28 patients with cirrhosis due to alcohol had elevated values, and none of the baboons fed alcohol had hyperprolinemia whether withdrawn from alcohol or not. Hyperlactacidemia was associated with hyperprolinemia, but so were depressed serum albumin values and prolongations of the prothrombin time, suggesting a general association with severe liver disease. These results reveal that hyperprolinemia occurs infrequently in patients with alcohol-induced cirrhosis and therefore does not appear to be a sensitive marker of hepatic fibrosis in these patients.

Animals↗
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Lipid peroxidation as a mechanism of alcoholic liver injury: role of iron mobilization and microsomal induction.

Lipid peroxidation has been invoked as a mechanism of alcoholic liver injury but its role has been controversial and the mechanism by which it occurs is unclear. Catalytic iron is known to play an important role in cellular injury and is produced during mobilization of ferritin iron. In vivo administration of a large acute dose of ethanol (5 g/kg) which produces hepatic lipid peroxidation in chow-fed rats resulted in mobilization of non-heme iron. The generation of NADH from alcohol metabolism via ADH or superoxide from acetaldehyde-xanthine oxidase mobilized iron from horse spleen ferritin in vitro. Chronic feeding of alcohol as 36% of energy for 6 weeks does not itself produce peroxidation in the rat but potentiates acute effects of ethanol. It produced microsomal induction which enhanced iron-stimulated lipid peroxidation and increased hepatic non-heme iron. Carbon monoxide increased rather than decreased accumulation of microsomal peroxidation products in vitro suggesting that cytochrome P-450 reductase mediates peroxidation but cytochrome P-450 may metabolize products. Incubation at lowered oxygen tensions equivalent to those observed in the perivenular zone (pO2 = 24 mmHg) enhanced in vitro iron mobilization but decreased peroxidation. Lipid peroxidation and its stimulation by iron mobilization and microsomal induction may be an important contributory mechanism of alcohol-induced liver injury.

Animals↗
PubMedDate not supplied

Effect of ethanol-generated free radicals on gastric intrinsic factor and glutathione.

The oxidation of acetaldehyde (generated from the metabolism of ethanol) by oxidases such as xanthine oxidase generates free radicals which can mobilize ferritin iron, alter hepatic glutathione and produce lipid peroxidation. The stomach, a site of ethanol metabolism and rich in xanthine oxidase, was studied with respect to the effects of ethanol on intrinsic factor (IF) binding of vitamin B-12 as well as gastric glutathione (GSH). Incubations of gastric homogenates with acetaldehyde-xanthine oxidase inhibited the B-12 binding ability by IF. A large acute dose of ethanol in vivo (5 g/kg, conc. greater than 40% w/v) decreased gastric IF binding of B-12 and depressed gastric GSH; these effects were markedly attenuated by the feeding of sodium tungstate which inhibited xanthine oxidase. Changes in B-12 binding paralleled changes in gastric GSH. Scatchard plots of IF binding of B-12 for homogenates suggested decreased number of binding sites rather than altered affinity. In conclusion, the gastric metabolism of ethanol generates free radicals which alter IF binding of B-12, depress gastric GSH and may play a role in alcohol-induced gastric injury.

Animals↗
PubMedDate not supplied

Cimetidine as a scavenger of ethanol-induced free radicals.

Free radical generation and the mobilization of catalytic iron are important in the pathogenesis of alcohol-induced liver injury. Cimetidine is a free radical scavenger in thermal skin injury and cobra venom-induced lung injury, and was therefore investigated as a scavenger of ethanol-induced free radicals. In vitro cimetidine inhibited iron-mediated cleavage of DNA as well as the potentiation of such cleavage by bleomycin. Peroxidation of microsomes by xanthine-xanthine oxidase, acetaldehyde-xanthine oxidase, as well as by the addition of low-molecular weight iron chelates were inhibited (17-100%) by cimetidine (0.1-1 mM). Free radical generation due to ethanol in isolated rat hepatocytes was studied by measuring ethane and pentane production. Cimetidine (1 mM) significantly decreased ethane and pentane production due to ethanol: 1 mM (2.2 +/- 0.3 vs. 1.0 +/- 0.2 pmol ethane per 10(6) cells/h; p less than 0.01, 4.2 +/- 0.4 versus 1.6 +/- 0.3 pmole per 10(6) cells/h pentane; p less than 0.001). Similar inhibitions were observed in the isolated perfused liver. Studies of superoxide reduction of ferricytochrome-C as well as hydroxyl radical generation by Fe(+)+/EDTA/ascorbate revealed that cimetidine was an effective hydroxyl radical scavenger. In summary, in a variety of in vitro systems, as well as in isolated hepatocytes and perfused liver, cimetidine inhibits ethanol-induced free radical injury. These findings may warrant its investigation as a therapeutic agent.

Animals↗
PubMedDate not supplied

Ethanol-induced free radical injury to the hepatocyte glucagon receptor.

Plasma membrane receptors are essential in cellular homeostasis. Free radical generation and catalytic iron have been implicated in alcohol-induced liver injury; damage to plasma membrane receptors may be one important mechanisms of injury. The effect of ethanol-induced free radicals on hepatocyte receptor dysfunction was investigated in rodent models of free radical injury due to chronic alcohol administration. Receptors for glucagon and their postreceptor signal transduction pathway (cyclic AMP production [cAMP]) were investigated as sites of free radical injury in isolated perfused livers. Glucagon-stimulated cAMP decreased (15%-80%) over a range of physiological (submaximal) doses of glucagon after 6 weeks of ethanol feeding, while free radical generation (alkane evolution) increased greater than three to fourfold over baseline (ethane; 2.04 +/- 0.36 vs. 0.58 +/- 0.08 pmole/10(6) cell/hr, p < 0.01; pentane 3.15 +/- 0.30 vs. 0.91 +/- 0.16, p < 0.01). Iron loading (125 mg/kg IP) potentiated this inhibition of cAMP production (40%-95%) and further increased alkane production twofold (ethane 4.29 +/- 0.78, pentane 5.76 +/- 0.71). Scatchard analysis revealed decreased numbers of glucagon receptors paralleling cAMP responses. Free radical damage to hepatocyte cell membrane receptors may be an important mechanism of alcohol-induced liver injury.

Alkanes↗
PubMedDate not supplied

Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody.

The specificity of cytotoxic T lymphocytes (Tc) cells is conferred by an antigen-specific receptor, Ti, which in humans is physically associated with an invariant cell-surface glycoprotein, T3. Monoclonal antibodies specific for either T3 and Ti are able to elicit a variety of T-cell responses such as lymphokine production, mitogenesis and cytotoxicity. For example, human Tc cells lyse anti-T3-expressing hybridoma cells, but not cells of other specificity, presumably because anti-T3 on the hybridoma cells binds to T3 on the Tc cells and triggers lysis. Here, we have adapted approaches used in a different cytotoxic effector system, antibody-dependent cellular cytotoxicity (ADCC), to alter the specificity of Tc cell. Studies of ADCC showed that heteroaggregates containing anti-Fc receptor (Fc gamma R) antibody cross-linked to a second antibody bind to Fc gamma R on ADCC effectors and cause them to kill target cells bearing antigen recognized by the second antibody. The present studies use anti-T3-containing heteroaggregates to re-target human Tc cells to cells for which we have appropriate antibodies, including xenogeneic tumour cells and chicken erythrocytes. These results extend previous observations on the role of T3 in triggering cytotoxicity and suggest that effector cell re-targeting could be used for in vivo treatment of neoplasms and other pathogens that express distinctive surface antigens.

Animals↗
PubMedDate not supplied

Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones.

Cell-cell adhesion is essential for many immunological functions, including interaction of cytotoxic T lymphocytes (CTLs) with their targets. We have explored CTL-target interactions using well-characterized cloned human CTLs. Conjugate formation between these CTLs and many antigen-negative targets is almost as efficient as with specific target cells, but does not lead to target-cell lysis. Thus, on specific target cells, adhesion by antigen-independent pathways may occur concurrently with or precede antigen recognition. The molecules LFA-1, CD2 (T11, LFA-2) and LFA-3 have been shown to be involved in human CTL conjugation with and lysis of specific target cells. Here we describe monoclonal antibody inhibition studies using individual monoclonal antibodies and mixes which demonstrate (1) that LFA-1, CD2 and LFA-3 are involved in antigen-independent conjugate formation; and (2) suggest that CD2 and LFA-3 are involved in one pathway and LFA-1 in another. We confirmed the existence of distinct pathways by the demonstration that LFA-1-dependent adhesion requires divalent cations and is temperature-sensitive whereas CD2- and LFA-3-dependent adhesion does not require divalent cations and is temperature-insensitive. Together with previous data, our studies suggest that CD2 on the effector interacts with LFA-3 as its ligand on targets.

Antibodies, Monoclonal↗
PubMedDate not supplied

The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3.

CD2 (known also as T11 (ref. 1), LFA-2 (ref. 2) and the erythrocyte rosette receptor (ref. 3] is a functionally important T lymphocyte surface glycoprotein of relative molecular mass 50,000 to 58,000 (Mr 50-58 K) which appears early in thymocyte ontogeny and is present on all mature T cells. Monoclonal antibodies to CD2 inhibit cytotoxic T-lymphocyte (CTL)-mediated killing by binding to the T lymphocyte and blocking adhesion to the target cell. Such antibodies also inhibit T helper cell responses including antigen-stimulated proliferation, interleukin-2 (IL-2) secretion, and IL-2 receptor expression. Certain combinations of monoclonal antibodies to CD2 epitopes trigger proliferation of peripheral blood T lymphocytes, cytotoxic effector function and expression of IL-2 receptors by thymocytes, resulting in thymocyte proliferation in the presence of exogenous IL-2 (ref. 11). These findings suggest that CD2 can function in signalling as well as being an adhesion molecule. To understand the role of CD2 in T-cell adhesion and activation, it is essential to define its natural ligand. Our previous observation that purified CD2 inhibits rosetting of T lymphocytes with sheep erythrocytes and can be absorbed by sheep erythrocytes suggested it also might bind with detectable affinity to human cells. We now report that CD2 binds to a cell-surface antigen known as lymphocyte function-associated antigen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with LFA-3.

Antibodies, Monoclonal↗
PubMedDate not supplied

Survival of a preterm twin following infarction of the right hepatic lobe.

Survival following hemorrhagic necrosis of a lobe of the liver in preterm infants is very uncommon. We present the clinical and radiologic findings of such a case, discuss the clinical management of the hemorrhage that resulted in the infant's survival, and present a basis for the evolution of the liver pathology.

Diseases in Twins↗
PubMedDate not supplied

Preparing nurse leaders for the new millennium: The ICN Leadership for Change project.

Now in its fourth year, the ICN Leadership For Change (LFC) project has reached 145 nurses from 44 countries. Hundreds of additional nurses are influenced by LFC programmes through participant projects developed and implemented at the country level. The LFC project is offered in the Caribbean, the South Pacific, Latin America, and in the countries of East, Central and Southern Africa. The Asian region is also included through a new program underway in Singapore. ICN Nurse Consultant Sally Shaw, BN, BA (Hons), MPH, who manages the LFC project, describes its successes.

Education, Nursing↗
PubMedDate not supplied

Increase in circulating insulin induced by atrial natriuretic peptide in normal humans.

To search for possible metabolic interactions of alpha-human-atrial natriuretic peptide (alpha hANP), we evaluated in 20 normal subjects blood levels of alpha hANP, glucose, insulin, cortisol, electrolytes, catecholamines, free fatty acids, carnitine and amino acids, blood pressure (BP), and heart rate before, during, and after a 45-min infusion of synthetic alpha hANP. Group A [n = 10] was studied on liberal and Group B on three consecutive sodium (Na) intakes of 17, 140, and 310 mM/day. Plasma alpha hANP was slightly but not significantly higher following 5 days on "normal" or high than on low Na+ intakes. alpha hANP infused at 0.1 microgram/kg/min produced on all Na+ intakes comparable percentage increases in plasma insulin (+34 to 63%, p less than 0.001), norepinephrine (+76 to 155%, p less than 0.001) and heart rate (p less than 0.001), and a similar fall in diastolic BP (p less than 0.001). Plasma glucose tended to be decreased slightly and cortisol was reduced; epinephrine, dopamine, and potassium levels were not significantly modified. As evaluated in group A, serum free fatty acids were increased (p less than 0.01), plasma free carnitine levels were reduced (p less than 0.001), and amino acids were not consistently altered. These findings indicate that in normal humans alpha hANP may, on various sodium intakes, modulate insulin secretion and/or metabolism and elicit a possibly baroreflex-mediated sympathetic activation and lipolysis.

Adult↗
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Association between low plasma tryptophan and blackouts in male alcoholic patients.

Alcohol has been observed to alter various aspects of memory function. Some of the most extreme forms of memory impairment experienced by alcoholics are blackouts. There are at present very few data on the biological mechanisms underlying alcohol-related memory impairment. A variety of mechanisms including the cholinergic and catecholaminergic systems have been implicated in learning and memory. More recently, however, the importance of the serotonergic system in memory function has been demonstrated. We investigated whether patients with a history of blackouts had lower plasma levels of the serotonin precursor tryptophan than patients without such a history. Tryptophan values were significantly lower in patients who had experienced blackouts than in patients who had not. No significant differences between the two group of patients were observed for other amino acids sharing with tryptophan the same transport carrier into the brain. Drinking history variables did not differentiate among the two patient groups. Our data suggest that a decrease in plasma tryptophan (and concomitant lowered brain serotonin) could increase the vulnerability of certain individuals to manifestations of various aspects of memory impairment including one of its most extreme forms, the blackout.

Adult↗
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Altered endothelin-1 levels in acute lower limb ischemia and reperfusion.

Tourniquet-induced ischemia is often used in orthopedic and reconstructive procedures. This is associated with muscle damage and dysfunction, which limits tourniquet application time. Endothelin-1 (ET-1) is a potent vasoconstrictor, which has been implicated in ischemic conditions and ischemia-reperfusion injury. This study aimed to investigate the role of ET-1 in human skeletal muscle subjected to tourniquet-induced acute ischemia and reperfusion. Thirteen patients undergoing total knee replacement were studied. Plasma and muscle ET-1 concentrations were measured at the start of surgery, after an hour of acute ischemia, and 15 minutes following reperfusion. ET-1 receptor binding was also studied by use of autoradiography, and ET-1 mRNA expression investigated by use of real-time polymerase chain reaction (RT-PCR). Tissue ET-1 increased following the period of acute ischemia and persisted during reperfusion. ET-1 was associated with microvessels and macrophages in the muscle. No changes in circulating ET-1 levels, ET-1 mRNA expression, or ET-1 receptor binding were found. It is concluded that the ET-1 pathway is involved in acute ischemia and reperfusion and it may contribute to the muscle injury that occurs during surgical procedures.

Acute Disease↗
PubMedDate not supplied

Abnormal liver function tests as biological markers for alcoholism in narcotic addicts.

Liver Function Test (LFT) abnormalities are frequently observed in narcotic addicts. However, the role of alcohol in producing such changes remains unclear. In order to evaluate the effects of alcohol in producing LFT elevations as well as the use of routine LFTs to serve as biochemical markers for alcoholism in narcotic addicts, 612 addicts participating in a randomized control trial of intervention in alcoholism were studied. Baseline parameters including LFTs and history of alcohol use were obtained on entry into the study and subsequently periodically during follow-up which varied from 6 months to 2 1/2 years (mean 13.5 months). On entry to the study, 104 of 612 (17%) of addicts were classified as alcoholics. Mean values of LFTs (SGOT, SGPT, Alkaline phosphatase, GGTP) in the alcoholic cohort were significantly increased compared to those among nonalcoholics (p less than 0.01 to less than 0.001 for individual tests). Mean values of LFTs did not significantly change during methadone maintenance in either group. Although a greater proportion of alcoholic addicts had elevated LFTs, the predictive values for each test (18 to 35%) were sufficiently low to prevent them from being used as biochemical markers of alcoholism. These findings suggest that although elevations in LFTs are frequently present in narcotic addicts and are significantly greater among addicts who are also alcoholic, most elevations are not specifically due to alcohol. Conventional LFTs are therefore of limited value in assessing alcoholism among narcotic addicts.

Alcoholism↗
PubMedDate not supplied

'Tomlinson' in Scotland.

The Management Executive (ME) in Scotland has recently announced that between 3000 and 7000 acute sector beds are to be lost in Scotland by the year 2001, for many of the same reasons that the Tomlinson report recommended beds be cut in London. Health boards are developing plans to restructure hospital services but issues of public and professional support for the plans they produce, and questions of funding, will determine the final outcome.

Efficiency↗