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Biomedical subjects

M J Lewis

Publications and source records attributed to M J Lewis.

At least 19 recordsLinked to original sources
PubMed1998

Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team.

CONTEXT: Contaminated pharmaceutical products can result in substantial morbidity and mortality and should be included in the differential diagnosis of deaths of unknown origin. OBJECTIVE: To investigate an outbreak of deaths among children from acute renal failure in Haiti to determine the etiology and institute control measures. DESIGN: Case-control study, cohort study, and laboratory toxicologic evaluation. SETTING: Pediatric population of Haiti. PARTICIPANTS: Cases were defined as Haitian residents younger than 18 years with idiopathic anuria or severe oliguria for 24 hours or longer. Febrile hospitalized children without renal failure were enrolled as control subjects. MAIN OUTCOME MEASURE: The odds of exposure to suspected etiologic agents among cases and controls. RESULTS: We identified 109 cases of acute renal failure among children. The clinical syndrome included renal failure, hepatitis, pancreatitis, central nervous system impairment, coma, and death. Of 87 patients with follow-up information who remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients transported to the United States for intensive care unit management died before hospital discharge. A locally manufactured acetaminophen syrup was highly associated with disease (odds ratio, 52.7; 95% confidence interval, 15.2-197.2). Diethylene glycol (DEG) was found in patients' bottles in a median concentration of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42 mL/kg). Glycerin, a raw material imported to Haiti and used in the acetaminophen formulation, was contaminated with 24% DEG. CONCLUSIONS: An epidemic of severe systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred in Haiti. Good manufacturing practice regulations should be used by all pharmaceutical manufacturers to prevent such tragedies.

Acetaminophen↗
PubMed1998

Identification and molecular characterization of human T lymphotropic virus type II infections in intravenous drug abusers in the former South Vietnam.

Previous serological studies have demonstrated that some 60% of intravenous drug abusers (IVDAs) in urban areas of the former South Vietnam are infected with HTLV-II. In the present report we have attempted to characterize the viruses using restriction fragment length polymorphism (RFLP) and nucleotide sequence analysis of the provirus long terminal repeat (LTR) region. RFLP analysis of nine samples demonstrated that all were infected with the HTLV-IIb subtype. The HTLV-IIa subtype was not detected. Phylogenetic analysis of the nucleotide sequences demonstrated that the viruses clustered closely with HTLV-IIb isolates present in IVDAs from the New York City area. The present molecular analysis together with the previously reported absence of HTLV-II infection in North Vietnam supports the view that HTLV-II may have been introduced from the United States to this part of Asia by military personnel during the Vietnam conflict.

HTLV-II Infections↗
PubMed1998

Bran: may irritate irritable bowel.

The irritable gut is known to be hypersensitive, and it is reasonable to suspect that patients with the disorder might be hyperreactive to agents that stimulate or irritate it. This appears to be a possible explanation for the adverse effects of bran on hospital patients with this disorder, but we do not yet know how this product affects community IBS sufferers. We cannot ignore the fact that fiber and bran have major beneficial effects in other areas, not least in the reduction of colonic carcinoma. In conclusion, it is probably best to recommend that patients with IBS be left to judge for themselves whether bran helps or exacerbates their symptoms, but there is enough evidence to suggest that the current dogma of routinely treating all IBS sufferers with bran should be challenged. Proprietary sources of fiber, such as ispaghula, may be more appropriate for those IBS subjects (for example, constipated) for whom fiber supplementation is believed justified.

Colonic Diseases, Functional↗
PubMed1998

Influence of clinical mastitis during early lactation on reproductive performance of Jersey cows.

The purpose of this study was to determine the influence of clinical mastitis on reproductive performance of high producing Jersey cows. Cows (n = 102) with clinical mastitis during the first 150 d of lactation were evaluated. Groups were balanced according to lactation number and days of lactation and sub-divided as follows: group 1, clinical mastitis before first artificial insemination (AI) (n = 48); group 2, clinical mastitis between first AI and pregnancy (n = 14); group 3, clinical mastitis after confirmed pregnancy (n = 40); and group 4, control cows (n = 103) with no clinical mastitis. No differences in reproductive performance were detected because of milk production or mastitis caused by Gram-positive or Gram-negative pathogens. The number of days to first AI was significantly greater for cows with clinical mastitis before first AI (93.6 d) than for all other groups (71.0 d). Artificial inseminations per conception were significantly greater for cows with clinical mastitis after first AI (2.9) than for cows with clinical mastitis before first AI (1.6), cows with no clinical mastitis, or cows with clinical mastitis after confirmed pregnancy (1.7). The number of days to conception for cows with clinical mastitis after first AI (136.6 d) was significantly greater than that for control cows and that for cows that developed clinical mastitis after confirmed pregnancy (92.1 d). Clinical mastitis during early lactation markedly influenced reproductive performance of Jersey cows.

Animals↗
PubMed1997

A novel SNARE complex implicated in vesicle fusion with the endoplasmic reticulum.

Intracellular vesicular traffic is controlled in part by v- and t-SNAREs, integral membrane proteins which allow specific interaction and fusion between vesicles (v-SNAREs) and their target membranes (t-SNAREs). In yeast, retrograde transport from the Golgi complex to the ER is mediated by the ER t-SNARE Ufe1p, and also requires two other ER proteins, Sec20p and Tip20p, which bind each other. Although Sec20p is not a typical SNARE, we show that both it and Tip20p can be co-precipitated with Ufe1p, and that a growth-inhibiting mutation in Ufe1p can be compensated by a mutation in Sec20p. Furthermore, Sec22p, a v-SNARE implicated in forward transport from ER to Golgi, co-precipitates with Ufe1p and Sec20p, and SEC22 acts as an allele-specific multicopy suppressor of a temperature-sensitive ufe1 mutation. These results define a new functional SNARE complex, with features distinct from the plasma membrane and cis-Golgi complexes previously identified. They also show that a single v-SNARE can be involved in both anterograde and retrograde transport, which suggests that the mere presence of a particular v-SNARE may not be sufficient to determine the preferred target for a transport vesicle.

Amino Acid Sequence↗
PubMed1997

Regulation of left ventricular relaxation in the isolated guinea-pig heart by endogenous endothelin.

OBJECTIVE: TO examine the effects of endogenous endothelin-1 on cardiac contraction in the isolated heart using endothelin receptor antagonists. METHODS: Isolated ejecting guinea-pig hearts were perfused with Krebs buffer (1 microM indomethacin) at 37 degrees C, constant loading and heart rate, and high-fidelity left ventricular pressure was monitored by an apical 2F Millar catheter. The effects of the following interventions on left ventricular performance and coronary flow were determined: (a) no treatment (i.e., time controls) (n = 8); (b) the specific ETA receptor antagonist, BQ123 (1 microM, n = 8); (c) the specific ETB receptor antagonist, IRL 1038 (0.1 microM, n = 4; 1 microM, n = 6); (d) exogenous endothelin-1 (0.01 nM, n = 6; 0.1 nM, n = 6); (e) the specific ETB receptor agonist, BQ3020 (5 nM, n = 8). RESULTS: All parameters were stable in control (untreated) hearts. BQ123 induced progressive acceleration of early left ventricular pressure decline and a fall in left ventricular end-diastolic pressure with no effect on peak left ventricular pressure, dP/dtmax, stroke volume or coronary flow. IRL 1038 had no effect on any of these parameters. In contrast, exogenous endothelin-1 exerted potent vasoconstrictor effects associated with a fall in peak left ventricular pressure, dP/dtmax and stroke volume. Similar changes were observed with BQ3020. Concentrations of endothelin-1 < 0.1 nM, which had no vasoconstrictor effect, produced no change in LV function. CONCLUSIONS: These data indicate that basal intracardiac release of endothelin-1 significantly delays LV relaxation in the isolated guinea-pig heart, but has no effect on coronary flow. The contrasting effects of endogenous endothelin-1 (elicited by BQ123) and exogenous endothelin-1 are likely to reflect differences in their site of action and in their effective concentrations at these sites.

Animals↗
PubMed1997

Antibiotic residues and prevalence of mastitis pathogen isolation in heifers during early lactation following prepartum antibiotic therapy.

The present study was conducted to determine if antibiotic treatment of heifer mammary glands earlier in the prepartum period reduced the occurrence of residues in milk without compromising efficacy in treatment of intramammary infections. Heifers were assigned randomly to two groups: 1. untreated negative control (n = 42); and 2. intramammary infusion of 200 mg cephapirin sodium (n = 40) 14 days prior to expected calving. Mammary secretions were collected before treatment and during early lactation, and were analyzed for residues by the Bacillus stearothermophilus disc assay. Only four of 127 samples (3.1%) obtained from cephapirin-treated mammary glands at 3 days after calving were positive for residues and most (three of four) were from a heifer that calved within 3 days of treatment. Mammary secretions were also collected before treatment, and at 3 and 30 days after calving for microbiological evaluation. For untreated control heifers, mastitis pathogens were isolated from 67.3% of samples obtained from mammary glands 14 days prior to expected calving, 55.6% obtained 3 days after calving and 36.4% of samples obtained 30 days postpartum. A similar percentage of samples (63.8%) was positive for mastitis pathogens at 14 days before expected calving prior to antibiotic treatment. However, only 15.1% of samples obtained at 3 days after calving and 7.9% of samples obtained 30 days postpartum from mammary glands of antibiotic-treated heifers contained mastitis pathogens. Coagulase-negative staphylococci were isolated most frequently. Intramammary infusion of antibiotics earlier in the prepartum period markedly reduced the occurrence of residues in milk during early lactation without affecting efficacy.

Animals↗
PubMed1997

Redistribution of von Willebrand factor in porcine carotid arteries after balloon angioplasty.

von Willebrand factor (VWF) is a well-characterized multimeric glycoprotein present in platelets and plasma and synthesized by vascular endothelial cells and megakaryocytes. Its role in platelet-vessel wall interactions has been studied extensively, but its involvement in intravascular events after balloon angioplasty has not been clarified. VWF antigen is not present in porcine arterial endothelium (except for the pulmonary artery) but is readily detected in porcine venous endothelial cells. We have examined the localization of VWF in porcine vessel walls during neointima formation after bilateral carotid balloon-angioplasty. Endothelium was denuded by balloon injury but regenerated by 7 days and was fully confluent by 42 days. VWF was detected at the site of injury in localized, adherent platelet aggregates at 10 minutes after angioplasty that were not present at later time points. A well-demarcated homogeneous layer of VWF was observed on the luminal surface from 30 minutes to day 7, but there was a progressive shift of positive staining from the lumen to the outer media from days 1 to 7. VWF was also strongly detected at sites proximal and distal to the balloon injury from 30 minutes to day 7, although endothelial disruption was minimal and the monolayer remained substantially intact at these sites. Regrowing endothelial cells appeared to contain granular VWF from days 12 to 21, but this was not readily evident at later time points. The results suggest that balloon injury is associated with deposition and medial absorption of plasma or platelet VWF in this porcine model over a time period that precedes and overlaps vascular smooth muscle proliferation and endothelial recoverage. The findings provide evidence to support the concept of a wider role for VWF in tissue injury responses.

Angioplasty, Balloon↗
PubMed1997

Effects of sulphydryl- and non-sulphydryl-containing ACE inhibitors on left ventricular relaxation in the isolated guinea pig heart.

ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (e.g remodelling, diastolic dysfunction). We have previously reported that the ACE inhibitor captopril induces selective left ventricular (LV) relaxant effects in the isolated ejecting guinea pig heart. The aim of the present study was to further investigate the mechanism of the captopril-induced changes in early LV relaxation by comparing the effects of two sulphydryl and two non-sulphydryl containing ACE inhibitors in the same experimental preparation. Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter transducer inserted in the LV cavity. The sulphydryl-containing ACE inhibitors captopril and zofenaprilat enhanced early LV relaxation, whereas the non-sulphydryl-containing ACE inhibitors lisinopril and quinaprilat did not. The effects of captopril and zofenaprilat were attenuated both by the nitric oxide-scavenger haemoglobin and the bradykinin B2-kinin receptor antagonist HOE 140. Neither the oxygen free-radical scavenger superoxide dismutase nor the sulphydryl-containing compound N-acetyl cysteine administered together with lisinopril had any effect on LV relaxation. These data demonstrate that inhibition of intra-cardiac ACE activity may acutely modulate LV relaxation through increased activity of the bradykinin-nitric oxide pathway. The presence of a sulphydryl group on the relevant ACE inhibitor appears to be essential for this LV relaxant effect.

Acetylcysteine↗
PubMed1996

SNARE-mediated retrograde traffic from the Golgi complex to the endoplasmic reticulum.

Operation of the secretory pathway in eukaryotic cells requires the selective docking and fusion of transport vesicles with the appropriate target organelle. This is mediated in part by integral membrane proteins termed v-SNAREs (on vesicles) and t-SNAREs (on the target membranes). We describe a novel yeast t-SNARE that resides on the endoplasmic reticulum and mediates retrograde traffic from the Golgi complex. Mutation of this protein prevents both the HDEL receptor and a membrane protein bearing a dibasic retrieval signal from recycling to the endoplasmic reticulum. Forward traffic is also blocked, but only indirectly. Comparison with other yeast mutants indicates that Sec21p (gamma-COP) and Sec20p (an endoplasmic reticulum membrane protein) are also involved primarily, if not exclusively, in retrograde transport.

Biological Transport↗
PubMed1996

Feed-back regulation of gibberellin biosynthesis and gene expression in Pisum sativum L.

Treatment of tall and dwarf (3 beta-hydroxylase impaired) genotypes of pea (Pisum sativum L.) with the synthetic, highly active gibberellin (GA), 2,2-dimethyl GA4, reduced the shoot contents of C19-GAs, including GA1, and increased the concentration of the C20-GA, GA19. In shoots of the slender (la crys) mutant, the content of C19-GAs was lower and GA19 content was higher than in those of the tall line. Metabolism of GA19 and GA20 in leaves of a severe (na) GA-deficient dwarf mutant was reduced by GA treatment. The results suggest feed-back regulation of the 20-oxidation and 3 beta-hydroxylation reactions. Feed-back regulation of GA 20-oxidation was studied further using a cloned GA 20-oxidase cDNA from pea. The cDNA, Ps074, was isolated using polymerase chain reaction with degenerate oligonucleotide primers based on pumpkin and Arabidopsis 20-oxidase sequences. After expression of this cDNA clone in Escherichia coli, the product oxidized GA12 to GA15, GA24 and the C19-GA, GA9, which was the major product. The 13-hydroxylated substrate GA53 was similarly oxidized, but less effectively than GA12, giving mainly GA44 with low yields of GA19 and GA20. Ps074 hybridized to polyadenylated RNA from expanding shoots of pea. Amounts of this transcript were less in the slender genotype than in the tall line and were reduced in GA-deficient genotypes by treatment with GA3, suggesting that there is feed-back regulation of GA 20-oxidase gene expression.

Amino Acid Sequence↗
PubMed1996

Identification of three C20-gibberellins: GA97 (2 beta-hydroxy-GA53), GA98 (2 beta-hydroxy-GA44) and GA99 (2 beta-hydroxy-GA19).

Three new C20-gibberellins, GA97 (2 beta-hydroxy-GA53), GA98 (2 beta-hydroxy-GA44) and GA99 (2 beta-hydroxy-GA19), have all been isolated from spinach, GA97 also from tomato root cultures and pea pods, and GA98 from maize pollen. The structures of these compounds were established by GC-mass spectrometric comparisons of the trimethylsilylated methyl esters with authentic samples prepared from gibberellic acid (GA3).

Gibberellins↗
PubMed1996

Alcohol reinforcement and neuropharmacological therapeutics.

The pleasant subjective effects produced by alcohol undoubtedly reinforce drinking behaviour. Alcohol positively reinforces or rewards drinking by producing a mild euphoria. Alcohol also has anxiolytic effects that negatively reinforce drinking. The reinforcing effects of alcohol are mediated by several neurochemical systems, with dopamine and serotonin playing major roles in reward and the gamma-aminobutyric acid-benzodiazepine receptor system playing a major role in negative reinforcement. Research from our laboratory suggests that the behavioural effects of alcohol change when blood alcohol levels are changing and that these changes correspond to alterations of specific neurochemical systems. Behavioural activation and reward effects appear to occur as blood alcohol concentrations (BACs) increase. Depressive and aversive effects of alcohol occur during the period when BACs decrease. The observed correlation between behavioural and neuropharmacological changes and alcohol consumption suggest that alcohol produces a unique cascade over time that may provide clues to its long-sought specific mechanisms of action. In alcohol-dependent individuals, chronic exposure to alcohol may alter the function and communication between the liver, brain and other vital organ systems involved in hunger and the maintenance of nutrition. Under such conditions, the importance of alcohol in the diet may be enhanced such that hunger signals in the alcohol-dependent individual motivate the consumption of alcohol. Therefore, hunger for alcohol may provide an additional source of reinforcement. Endogenous opioid mechanisms may be important in this form of alcohol reinforcement.

Alcohol Deterrents↗
PubMed1995

Endothelial control of arterial distensibility is impaired in chronic heart failure.

BACKGROUND: Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF). METHODS AND RESULTS: Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10(-7) to 10(-5) mol/L) or adenosine (2 x 10(-7) to 2 x 10(-5) mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (-5%, -15%, and -26%) but not in CHF patients (3%, 1%, -4%, P < .01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 micrograms). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and -4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients. CONCLUSIONS: These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.

Acetylcholine↗
PubMed1995

Enhancement of left ventricular relaxation in the isolated heart by an angiotensin-converting enzyme inhibitor.

BACKGROUND: ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (eg, remodeling, diastolic dysfunction) in experimental studies and in patients. They inhibit the formation of angiotensin II as well as the degradation of endogenous bradykinin. We recently reported that bradykinin induces selective left ventricular (LV) relaxant effects in isolated hearts via the release of nitric oxide. The present study examined the direct effects of interaction between the ACE inhibitor captopril and endogenous bradykinin on cardiac contractile function. METHODS AND RESULTS: Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter. Captopril (1 mumol/L, n = 9) caused a progressive acceleration of LV relaxation without significantly affecting early systolic parameters (eg, LV dP/dtmax) or coronary flow. These effects were inhibited by the nitric oxide scavenger hemoglobin (1 mumol/L, n = 5) or by the B2-kinin receptor antagonist HOE140 (10 nmol/L, n = 5). In the presence of captopril, bradykinin (0.1 nmol/L, n = 6) markedly accelerated LV relaxation (significantly more than captopril alone), whereas bradykinin alone (0.1 nmol/L, n = 6) had no effect. CONCLUSIONS: These data indicate that the ACE inhibitor captopril causes an acute and selective enhancement of LV relaxation independent of changes in coronary flow, probably via an endogenous bradykinin/nitric oxide pathway.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

A SNARE-like protein required for traffic through the Golgi complex.

The secretory pathway of eukaryotic cells comprises several distinct membrane-bound compartments which are interconnected by transport vesicles that pinch off from one membrane and fuse with the next. Targeting of these vesicles is mediated in part by interactions between integral membrane proteins on the vesicles and target organelles (soluble NSF attachment protein receptors (SNAREs)), termed v-SNAREs and t-SNAREs, respectively. SNAREs required for endoplasmic reticulum (ER)-Golgi transport and for fusion of vesicles with the plasma membrane are already known. Here we identify two yeast membrane proteins that show genetic interactions with Sed5p, which is the t-SNARE for ER-Golgi traffic. One of these membrane proteins, Sft1p, is structurally similar to the known v-SNAREs and is required for transport from an early to a later Golgi compartment. Our results indicate that a single t-SNARE can control more than one transport step, and provide the first candidate for a SNARE involved in intra-Golgi traffic.

Amino Acid Sequence↗
PubMed1995

Kinetics of smooth muscle cell proliferation and intimal thickening in a pig carotid model of balloon injury.

Restenosis as a result of neointimal smooth muscle cell accumulation is an important limitation to the effectiveness of balloon angioplasty as a treatment for end-stage atherosclerosis. Quantitative animal models allow the definition of pathophysiological mechanisms and the evaluation of new therapeutic strategies. In this study we quantified the time course of neointima formation by morphometry, and smooth muscle cell (SMC) proliferation by immunocytochemistry for proliferating cell nuclear antigen (PCNA), in the pig carotid artery 0-28 days following balloon injury. This led to two distinct kinds of injury observed also in clinical studies, namely medial dilatation or deep medial tearing with rupture of the internal elastic lamina. Dilatation injury alone led to medial enlargement and neointima formation by 7 days, which did not increase further up to 28 days. Medial enlargement was similar following rupture of the internal elastic lamina; however the sum of neointima formation plus the area of medial repair ('neomedia') increased progressively up to 21 days after balloon injury. Balloon injury increased the PCNA index of smooth muscle cells in the media underlying an intact internal elastic lamina maximally after 3 days. The PCNA index in the neointima and especially in the neomedia was greater and maximal after 7 days. Endothelial regrowth occurred by 21 days in the presence or absence of medial tears. Our results establish a quantitative pig model of balloon injury which will allow the assessment of new therapeutic strategies directed at two clinically relevant types of injury. Medial tearing is associated with an enhanced and localized proliferative response and may therefore be especially important in human restenosis.

Angioplasty, Balloon↗