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Biomedical subjects

H Powell

Publications and source records attributed to H Powell.

At least 19 recordsLinked to original sources
PubMed2000

Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi.

Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2((-/-))). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2((+/+))) mice and GstP1/P2((-/-)) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2((+/+)) and GstP1/P2((-/-)) mice, GSH levels only recovered in the GstP1/P2((-/-)) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of GST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity.

Acetaminophen↗
PubMed2000

Psychosocial experiences of cardiac patients in early recovery: a community-based study.

OBJECTIVE: To report on the nature, incidence and severity of problems commonly experienced by cardiac patients in the early months of recovery, and to test the hypotheses that there exist differences in the incidences of these problems depending on age and sex. METHODS: 1124 emergency cardiac patients discharged from hospital with acute myocardial infarction, unstable angina, stable angina pectoris, chronic ischaemic heart disease or heart failure were surveyed 4 months after discharge. They were asked to indicate how often during the previous 2 weeks they had experienced each of a range of feelings and problems common to cardiac patients. RESULTS: A large proportion of patients reported experiencing problems in the areas of emotional reactions (70%), physical condition (79%), convalescence (67%) and relating to family and friends (63%). Severe problems were experienced especially in the physical and convalescence areas (43% and 44%, respectively). A greater proportion of patients diagnosed with heart failure experienced problems than those with other diagnoses, and these problems were more severe. Amongst myocardial infarction patients, a greater proportion of females than males reported severe problems in the emotional and physical areas, and patients 65 years and over were more likely than younger patients to report experiencing severe problems with physical condition. CONCLUSIONS: Many cardiac patients are experiencing psychosocial problems 4 months after hospital discharge, especially with physical activities and convalescence. A knowledge of the incidence and nature of these problems may help nurses to assist patients to validate their experiences.

Adaptation, Psychological↗
PubMed2000

Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase.

Exposure of cells to toxic chemical species can result in reduced glutathione (GSH) depletion, generation of free radicals, and/or binding to critical cell determinants. Chemical stress is usually followed by a concerted cellular response aimed at restoring homeostasis, although the precise initial stimulus for the response is unclear. We have focused on one component of this stress response, the up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS) and the preceding molecular events involved in its regulation in an in vivo mouse model. Male CD-1 mice received buthionine sulphoximine (BSO; 7.2 mmol/kg), diethyl maleate (DEM; 4.2 mmol/kg), paracetamol (APAP; 3.5 and 1.0 mmol/kg), or carbon tetrachloride (CCl(4); 1.0 and 0.2 mmol/kg). Biochemical (serum transaminase and hepatic GSH levels) and molecular (c-jun and c-fos messenger RNA [mRNA] levels and activator protein 1 [AP-1] DNA binding activity) parameters were measured, as well as the consequent effects on gamma-GCS levels and activity. All compounds produced GSH depletion, but only the higher doses of APAP and CCl(4) caused liver damage. DEM, APAP, and CCl(4) increased c-jun and c-fos mRNA levels, together with an increase in AP-1 binding; BSO failed to induce AP-1 despite an increase in c-fos. Interestingly, the effects on gamma-GCS varied markedly according to the compound: BSO and DEM increased gamma-GCS enzyme activity, although only DEM, but not BSO, resulted in an increase in gamma-GCS(h) mRNA and protein. In contrast, APAP and CCl(4) both increased gamma-GCS(h) mRNA and protein; however, there was a marked dose-dependent decrease in gamma-GCS activity. These data indicate that the effect of chemical stress on the liver is compound specific and is not merely dependent on depletion of GSH.

Acetaminophen↗
PubMed1999

A collection method and high-sensitivity enzyme immunoassay for sweat pyridinoline and deoxypyridinoline cross-links.

BACKGROUND: Collagen cross-link molecules such as pyridinoline (PYD), deoxypyridinoline (DPD), and N-terminal cross-linked peptides (NTX) have been measured in urine as indices of bone resorption. However, very little is known regarding the excretion of pyridinolines into other biological fluids. We report a collection device, normalizing analyte, and high-sensitivity immunoassay for quantitative analysis of free pyridinoline cross-links in sweat. METHODS: Flame atomic emission and ion-selective electrode techniques were used to measure potassium as a sweat volume marker. The Pyrilinks immunoassay for urine free pyridinolines was optimized to increase sensitivity for measurements in sweat. The precision, accuracy, and detection limit of this assay were characterized. To assess values and variability of sweat pyridinolines in human subjects, a nonocclusive skin patch was used to collect sweat samples from a reference group and from a mixed group experiencing accelerated bone resorption, postmenopausal women and men receiving gonadotropin-releasing hormone for prostate cancer. RESULTS: The immunoassay intra- and interassay variations were </=10% and <16%, respectively, with a detection limit of 309 pmol/L. Linearity upon dilution and analytical recovery ranged from 93% to 109% and 85% to 122%, respectively. Sweat PYD values normalized to potassium output yielded a weekly intraindividual biological variability of 14.7%. The mean increase in the population experiencing increased bone resorption vs the reference group was 36% (P <0.05) for sweat PYD/K vs 23-40% (P <0.05) for urinary PYD/Cr, DPD/Cr, and NTX/Cr. CONCLUSION: We conclude that this new platform sweat collection technology and PYD immunoassay show potential as an indicator of bone resorption.

Amino Acids↗
PubMed1998

Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration.

Type I IFNs, which include IFN-alpha, appear to have complex and broad-ranging actions in the central nervous system (CNS) that may result in protection or injury. To better understand these issues, we generated transgenic mice that produce IFN-alpha1 chronically from astrocytes. These glial fibrillary acidic protein-IFN-alpha transgenic mice developed a progressive inflammatory encephalopathy, with marked calcium mineralization, meninoencephalitis, gliosis, and neurodegeneration. Many features of this murine encephalopathy resembled those found in certain human encephalopathies of unknown etiology; these diseases, exemplified by Aicardi-Goutières syndrome and some viral encephalopathies, show increased intrathecal production of IFN-alpha. Our data suggest that IFN-alpha overproduction may be the primary factor initiating these human diseases. Following intracerebral infection with lymphocytic choriomeningitis virus, glial fibrillary acidic protein-IFN-alpha mice had significantly increased survival rates associated with markedly reduced virus titers and immune pathology in the brain but normal peripheral CTL responses. Therefore, the production of IFN-alpha in the CNS can be a two-edged sword that on the one hand confers protection against a lethal viral infection but on the other causes significant injury to the brain. These transgenic mice provide a novel animal model in which to further evaluate the mechanisms that underlie the diverse actions of type I IFNs in the intact CNS.

Animals↗
PubMed1998

Expression of cytochrome P4502E1 in human liver: assessment by mRNA, genotype and phenotype.

Cytochrome P4502E1 (CYP2E1) is constitutively expressed in human liver and is responsible for the metabolic bioactivation of a wide variety of xenobiotics, including a number of protoxins and procarcinogens. CYP2E1 expression is regulated at several levels including pre-transcriptional, transcriptional and post-transcriptional levels, and any variation in enzyme concentration and hence activity may represent increased risk of toxicity or carcinogenicity. We have investigated variability in the levels of CYP2E1 mRNA, protein and functional activity in a human liver bank, and attempted to relate these parameters to the RsaI restriction fragment length polymorphism in the 5'-flanking region. Variation in CYP2E1 mRNA (18-fold) was greater than the variation seen in CYP2E1 protein (twofold) and functional activity (fourfold) determined using two probe substrates, chlorzoxazone and p-nitrophenol. Although protein and functional activity showed a significant correlation (r = 0.93 and r = 0.83 for chlorzoxazone and p-nitrophenol, respectively), there was no correlation between any of these parameters and mRNA levels. Also, the variation in CYP2E1 activity could not be directly accounted for by the RsaI polymorphism in our samples. In conclusion, our results are consistent with a complex regulation of CYP2E1 and the fact that it is highly conserved in the human population. The absence of a relationship between the RsaI polymorphism and CYP2E1 activity is consistent with other studies performed in Caucasians, but does not exclude an effect of this polymorphism on inducibility of CYP2E1.

Adult↗
PubMed1998

Case of the month: July 1997--diabetic male with transient ischemic attacks.

A 60-year-old diabetic male presented with transient ischemic attacks. Initial neurological examination and head CT were normal. Dysarthria, ataxia, delirium, and lethargy developed. A diagnosis of cryptococcal meningitis was made after lumbar puncture and treatment with intravenous amphotericin B and 5-fluorcytosine was begun. A repeat head CT showed an anterior cerebral artery territory infarct. His condition worsened and he died of associated complications three weeks after admission. The case is used to discuss the association between cryptococcal meningitis and diabetes, transient ischemic attacks, and vasculitis with cerebral infarction.

Cerebral Infarction↗
PubMed1997

Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs.

To define the kinetics and safety of spinally infused recombinant-methionyl human brain-derived neurotrophic factor (r-metHuBDNF), beagle dogs were prepared with lumbar intrathecal catheters passed through the cisternal membrane to the L1-L4 lumbar level. For kinetic studies, r-metHuBDNF was delivered by bolus or infusion through one catheter and lumbar CSF was sampled periodically through a second. As a lumbar bolus, r-metHuBDNF displayed a biphasic clearance with t(1/2)a = 0.7 hr and t(1/2)b = 7. 9 hr. Lumbar to cisternal concentrations after bolus delivery were approximately 60:1. For safety studies, dogs received continuous intrathecal infusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNF at 200 (n = 6), 800 (n = 6), or 2000 (n = 7) microg/day. Control dogs showed no changes. Intrathecally infused r-metHuBDNF produced a dose-dependent increase in muscle tone and decreased coordination. Low-dose r-metHuBDNF was associated with moderate increases in muscle tone after 22-28 days of infusion. No clinically important changes were noted in rectal temperature, arterial pressure, respiration and heart rate, body weight, food consumption, stool or urine output, or change in blood chemistries measured throughout the study. Cisternal CSF protein and glucose sampled at 28 days were not different between dose groups and all cultures were negative. Histopathological examination of the spinal cord typically revealed some degree of chronic inflammation around the catheter, including fibrotic adhesions and focal accumulations of lymphoid and plasma cells, but these effects were not dose dependent. In other dogs receiving r-metHuBDNF (2000 or 4000 microg/day), termination of infusion resulted in significant recovery.

Animals↗
PubMed1997

Changes in the albumin binding of tryptophan during postoperative recovery: a possible link with central fatigue?

Tryptophan is the precursor of the neurotransmitter 5-hydroxytryptamine (5-HT), known to be involved in sleep and fatigue. In the blood, tryptophan binds to albumin, and that which does not, free tryptophan, competes with branched chain amino acids (BCAA) for entry into the brain. The plasma concentrations of albumin, free tryptophan, total tryptophan, and BCAA were measured before and after major surgery in nine elderly and nine coronary artery bypass graft (CABG) patients. In both the elderly and the CABG patients plasma free tryptophan concentrations were increased after surgery, compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased significantly after surgery. Plasma albumin concentrations were decreased significantly after surgery in both the elderly and the CABG patients. Plasma BCAA concentrations were not affected by surgery in either group. The effect of exercising to exhaustion on 5-HT and tryptophan were investigated in Nagase analbuminemic rats (NAR). The intrasynaptosomal concentration of tryptophan, 5-hydroxy-tryptophan, and 5-HT was increased by fatigue after exercise. In addition, running time to exhaustion was shortened in NAR. These data suggest that free tryptophan uptake and 5-HT synthesis were enhanced in the nerve terminal. A decrease in plasma albumin may account for the increase in plasma-free tryptophan levels. An increase in plasma free tryptophan, resulting in an enhanced plasma concentration ratio of free tryptophan/BCAA, may lead to a higher 5-HT concentration in some parts of the brain and, consequently, to central fatigue. It is suggested that provision of BCAA as a dietary supplement may counteract the increase in plasma free tryptophan and thus improve the status of some patients after major surgery.

Aged↗
PubMed1997

Implementation of total quality management after reconfiguration of services on a general hospital unit.

In 1992 the New York State Office of Mental Health issued a statewide plan for mental health services to reduce the number of inpatient beds in state-run facilities from approximately 11,000 to between 6,000 and 8,000 by the year 2000. This reduction resulted in at least a 25 percent increase in psychiatric beds at local general hospitals. In 1992 Albany Medical Center Hospital's department of inpatient psychiatry established an interdisciplinary committee to address changes resulting from the reconfiguration of services to chronic mentally ill persons. The committee established procedures to use the principles of total quality management to respond to problems and to continuously improve the therapeutic milieu. The authors describe how these principles were used to create a patient satisfaction survey, to examine and improve part of the hospital admissions procedure, and to review and revise treatment planning documentation. A concurrent review committee reviews patients' records to ensure accuracy of documentation and quality of care.

Chronic Disease↗
PubMed1996

A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.

BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

Adolescent↗
PubMed1995

Renal transplantation in very young children.

Results of renal transplantation in very young children with end-stage chronic renal failure have been poor compared with those in older children and adults. Consequently small children either may not be treated or may be placed on chronic dialysis programmes. Between 1988 and 1992, six children under the age of 5 years received seven renal transplants at the Royal Children's Hospital, Parkville, Victoria, Australia; five from live donors and two from cadaver donors. All children were treated with peritoneal dialysis before transplantation, and immunosuppressed with a standardized regimen of cyclosporine, azathioprine and prednisolone. An extraperitoneal incision was used, and the donor renal vessels were anastomosed to the lower abdominal aorta and inferior vena cava or the common iliac vein. All children received intensive monitoring and fluid replacement during the peri-operative period. Patient survival was 100%. One cadaver graft failed 1 week after transplantation because of irreversible acute rejection. This child subsequently received a successful second transplant. Two children developed postoperative urinary fistulae which were treated successfully by further operation. Current renal function in all children is excellent. The success of this programme has led us to review our attitude towards renal transplantation in this age group and to advocate live donor renal transplantation as the treatment of choice in very young children with end-stage chronic renal failure whenever possible.

Cadaver↗
PubMed1994

Membranous glomerulonephritis associated with hepatitis C virus infection in an adolescent.

The clinical, laboratory and pathological findings are reported in an adolescent patient with hyper-IgM immunodeficiency syndrome (dysgammaglobulinemia) which was complicated by primary sclerosing cholangitis and membranous glomerulonephritis. Hepatitis C virus (HCV) RNA was detected in serum by the polymerase chain reaction. A possible etiological relationship between hepatitis C virus infection and membranous nephropathy is discussed.

Adolescent↗
PubMed1994

Effects of extradural anaesthesia on interleukin-6 and acute phase response to surgery.

Serum concentrations of the cytokine, interleukin-6 (IL-6), increase after surgical trauma. IL-6 mediates the synthesis of acute phase proteins and stimulates secretion of pituitary hormones. We have examined the time course of circulating IL-6, and cortisol and growth hormone responses in patients undergoing hysterectomy to determine if IL-6 contributes to the early pituitary hormone changes found during surgery. One group (n = 8) received a standardized general anaesthetic while the remaining patients (n = 8) received extradural analgesia to T4-S5 in addition to a similar general anaesthetic. In the general anaesthesia group, there was a significant increase in serum cortisol and growth hormone concentrations before any changes in IL-6 were detected. Furthermore, in the extradural group, in whom these hormonal responses were attenuated, circulating IL-6 concentrations did not differ significantly from the general anaesthesia group. There were no significant differences between the groups in the acute phase response, as measured by circulating concentrations of C-reactive protein and zinc, but the expected effects of extradural block on circulating metabolites and white cell count were demonstrated. We conclude that IL-6 is unlikely to contribute to the initial increases in secretion of pituitary hormones found during surgery, but a later effect of the cytokine on endocrine responses cannot be excluded.

Acute-Phase Proteins↗
PubMed1994

Growth hormone suppression and glutamine flux associated with cardiac surgery.

Pharmacological doses of growth hormone (GH) in humans and rats increase plasma and muscle glutamine values. As major surgery results in a physiological rise in serum GH concentration, we investigated whether this physiological increase in GH altered glutamine metabolism. Eighteen patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive somatostatin, 100 micrograms subcutaneously at induction of anaesthesia and 8 hourly for 48 h, or placebo. Somatostatin effectively blocked the physiological surge of GH following injury but did not affect plasma or muscle glutamine concentrations, which fell significantly in both groups. Plasma glutamine decreased by 31% (P < 0.01) and 28% (P < 0.01) in the control and somatostatin groups respectively. Muscle glutamine was reduced 45% (P < 0.001) in the control group and 50% (P < 0.001) in the somatostatin group. There was no difference in muscle or circulating glutamate, alanine or branched chain amino acid concentrations or in metabolite values between the somatostatin-treated patients and the control group. There was no relationship between the GH response to surgery and glutamine metabolism following major surgery.

Blood Glucose↗