Biomedical subjects
J Walsh
Publications and source records attributed to J Walsh.
Symptomatic Schistosoma mansoni infection as an immune restoration phenomenon in a patient receiving antiretroviral therapy.
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Renal injury: similarities and differences in male and female rats with the metabolic syndrome.
The metabolic syndrome is complicated by nephropathy in humans and rats, and males are more affected than females. We hypothesized that female rats had reduced expression of glomerular oxidized low-density lipoprotein (oxLDL) receptor 1 (LOX-1), attendant glomerular oxidant injury, and renal inflammation. Three groups, obese males (OM), obese females (OF), and lean males (LM) of first-generation (F(1)) hybrid rats derived from the Zucker fatty diabetic (ZDF) strain and the spontaneous hypertensive heart failure rat (SHHF/Gmi-fa) were studied from 6 to 41 weeks of age. OM had severe renal oxidant injury and renal failure. Their glomeruli expressed the LOX-1, and exhibited heavier accumulation of the lipid peroxide 4-hydroxynonenal (4-HNE). OM had compromised mitochondrial enzyme function, more renal fibrosis, and vascular leakage. Younger LM, OM, and OF ZS (ZDF/SHHF F(1) hybrid rat) rats, studied from 6 to 16 weeks of age, showed that unutilized renal lipids were comparable in OM and OF, although young OM had worse nephropathy and inflammation. In conclusion, glomerular LOX-1 expression is coupled to deposits of 4-HNE and glomerulosclerosis in OM. We presume that LOX-1 enhances glomerular uptake of oxidized lipids and renal inflammation, causing greater oxidant stress and severe glomerulosclerosis. In OF, renal protection from lipid oxidants appears to be conferred by blunted glomerular LOX-1 expression and renal inflammation.
The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia.
Post-mortem studies conducted over the past 15 years suggest that apoptosis could play a role in the pathophysiology of bipolar disorder (BD) and, to a lesser degree, schizophrenia (SZ). To test this hypothesis, we have performed a post hoc analysis of an extant gene expression profiling database obtained from the hippocampus using a novel methodology with improved sensitivity. Consistent with the working hypothesis, BDs showed a marked upregulation of 19 out of 44 apoptosis genes; however, contrary to the hypothesis, the SZ group showed a downregulation of genes associated with apoptotic injury and death. These changes in the regulation of apoptosis genes were validated using quantitative RT-PCR. Additionally, antioxidant genes showed a marked downregulation in BDs, suggesting that accumulation of free radicals might occur in the setting of a previously reported decrease of the electron transport chain in this disorder. Overall, the changes seen in BDs and SZs do not appear to be related to exposure to either neuroleptics or mood stabilizers. We conclude that fundamental differences in the genetic regulation of apoptosis and antioxidant genes may help discriminate between the pathophysiology of BD and SZ and potentially point to new treatment strategies that are specific for each disorder.
Mapping of hippocampal gene clusters regulated by the amygdala to nonlinkage sites for schizophrenia.
A recent study using a 'partial' rodent model of schizophrenia has employed amygdalar activation to induce reported changes in the expression of hippocampal genes associated with metabolic and signaling pathways in response to amygdalar activation. The amygdalo-hippocampal pathway plays a central role in the regulation of the stress response and emotional learning. In the current study, we have performed a chromosome mapping analysis to determine whether genes showing changes in response to environmental stress may form clusters and, if so, whether they might show a topographical association with linkage sites for schizophrenia. When the hippocampal genes showing changes in expression were topographically mapped on specific rat chromosomes, significant clustering was observed on chromosomes 1, 4 and 8, although chromosome 1 showed the largest amount of clustering. When these same rodent genes were mapped to human chromosomes, most of the genes found on chromosome 1 in rat mapped to chromosome 11 in human. The vast majority of the genes showing changes in regulation were excluded from known linkage sites for schizophrenia. Based on these findings, we postulate that environmental factors may contribute to the endophenotype for schizophrenia through the activation and/or deactivation of specific genetic clusters, ones that do not appear to be directly associated with susceptibility genes for this disorder.
Outcome of clinical pregnancies after ovulation induction using metformin.
The objective of this study was to review the first 50 clinical pregnancies of women with polycystic ovarian syndrome (PCOS) who had ovulation induced either with metformin alone, or in combination with clomifene. The study was confined to women with PCOS attending our infertility service. A register of clinical pregnancies was maintained of women who conceived after metformin therapy. The metformin was continued throughout the first trimester. The outcome of pregnancy was determined by individual chart review. Of the 50 women, 21 conceived with a combination of clomifene and metformin, and 29 with metformin alone. Seven women had a first trimester loss and 43 had a live birth. There were no perinatal deaths, no neonatal seizures and no congenital malformations. There were also no multiple pregnancies. The overall caesarean rate was 37%, and none of the babies had an Apgar score less than 7, at 5 min. This study found no evidence of any adverse clinical effects when metformin is continued in the first trimester of women with PCOS following ovulation induction. There was also no evidence of an increase in the rate of miscarriage or multiple pregnancy.
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006).
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A prospective cohort study of health outcomes following whiplash associated disorders in an Australian population.
OBJECTIVE: To define health outcomes of whiplash associated disorders (WAD) at three months, six months, and two years after injury and to examine predictors of these outcomes. DESIGN: Prospective cohort study. SETTING: New South Wales, Australia. SUBJECTS: People with compensable motor crash injuries who reported whiplash as one of their injuries. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Functional Rating Index (FRI), Short Form 36 (SF-36) at three months, six months, and two years after injury, ascertained by telephone interview. RESULTS: At three months, 33.6% of the cohort was recovered (as defined by FRI<or=25), increasing marginally at six months (38.9% recovered), but more significantly at two years (51.7% recovered, p = 0.001). The mean physical component score of the SF-36 improved at each time point (p = 0.002), while the mean mental component score did not (p = 0.59). Predictors of recovery at two years (as defined by global perceived effect) included a lower FRI index at baseline (p = 0.001) and closure of the claim at two years (p = 0.02). CONCLUSION: Whiplash injury had a large effect on the health of this Australian cohort of whiplash sufferers, with only 50% of the cohort recovered at two years. Physical measures of health appear to improve over time, whereas mental measures of health did not. Despite this, this cohort is largely able to participate in activities and work at two years. Prevention of chronic disability may lie with concentration of resources to those who score highly on the FRI at baseline. In addition, chronic psychological ill health may be prevented by directing treatment to those with poor scores on sensitive measures of psychological ill health at baseline.
Envenoming bites by kraits: the biological basis of treatment-resistant neuromuscular paralysis.
Beta-bungarotoxin, a neurotoxic phospholipase A2 is a major fraction of the venom of kraits. The toxin was inoculated into one hind limb of young adult rats. The inoculated hind limb was paralysed within 3 h, and remained paralysed for 2 days. The paralysis was associated with the loss of synaptic vesicles from motor nerve terminal boutons, a decline in immunoreactivity of synaptophysin, SNAP-25 and syntaxin, a loss of muscle mass and the upregulation of NaV(1.5) mRNA and protein. Between 3 and 6 h after the inoculation of toxin, some nerve terminal boutons exhibited clear signs of degeneration. Others appeared to be in the process of withdrawing from the synaptic cleft and some boutons were fully enwrapped in terminal Schwann cell processes. By 12 h all muscle fibres were denervated. Re-innervation began at 3 days with the appearance of regenerating nerve terminals, a return of neuromuscular function in some muscles and a progressive increase in the immunoreactivity of synaptophysin, SNAP-25 and syntaxin. Full recovery occurred at 7 days. The data were compared with recently published clinical data on envenoming bites by kraits and by extrapolation we suggest that the acute, reversible denervation caused by beta-bungarotoxin is a credible explanation for the clinically important, profound treatment-resistant neuromuscular paralysis seen in human subjects bitten by these animals.
Determinants of HAART discontinuation among injection drug users.
The objective of this study was to identify psychosocial determinants of, and self-reported reasons for, HAART discontinuation among HIV-positive injection drug users (IDUs). We examined correlates between sociodemographic characteristics, drug use and risk behaviors, outcome expectations, adherence self-efficacy, social support and HAART discontinuation among 160 HIV-positive participants in the Vancouver Injection Drug Users' Study (VIDUS). Logistic regression was used to identify the factors independently associated with discontinuation of HAART. Seventy-one (44%) study participants discontinued HAART during the study period. Factors independently associated with discontinuation of HAART included recent incarceration (OR = 4.84, p = 0.022), negative outcome expectations (OR = 1.41, p = 0.001), adherence efficacy expectations (OR = 0.70, p = 0.003) and self-regulatory efficacy (OR = 0.86, p = 0.050). The most frequently cited reasons provided for discontinuing HAART were being in jail (44%) and medication side effects (41%). The results of this study suggest that psychological constructs derived from self-efficacy theory are highly germane to the understanding of HAART discontinuation behavior and interventions that may change it. Incarceration may result in interruptions in HAART among IDUs, and programmatic changes may be needed to promote optimal retention on HAART among incarcerated HIV-infected IDUs.
Symptomatic hypocalcaemia and renal impairment associated with bisphosphonate treatment in patients with multiple myeloma.
We report three cases of severe hypocalcaemia associated with i.v. bisphosphonate treatment in patients with multiple myeloma. All patients had symptomatic hypocalcaemia, including a tonic-clonic seizure and tachyarrhythmia in one case. Two cases were associated with the development of acute renal failure, whereas the third patient had pre-existing renal impairment. We recommend that bisphosphonates be used with caution in patients with myeloma and renal impairment, that vitamin D deficiency be corrected prior to treatment (to reduce the risk of hypocalcaemia) and that serum calcium and renal function be monitored during treatment.
A novel Shigella dysenteriae serovar isolated in Canada.
The etiological agent most commonly associated with bacillary dysentery is Shigella. As part of its mandate, the Bacteriology and Enteric Disease Program of Health Canada identifies and serotypes unusual isolates of Shigella received from provincial laboratories of public health. In this report, six unusual isolates from three provinces were analyzed biochemically and serologically using slide and tube agglutinations and molecularly using standard pulsed-filed gel electrophoresis (PFGE), PCR, and PCR-restriction fragment length polymorphism (RFLP) techniques. All six isolates were identical. PFGE analysis grouped these strains; biochemically, they were mannitol negative and consistent with the profile of Shigella. Serologically, these strains produced weak reactions in Shigella dysenteriae serovars 4 and 16 and Escherichia coli O159 and O173 antisera. Molecular serotyping by PCR-RFLP of the rfb gene produced an S. dysenteriae serovar 2/E. coli O112ac pattern. They were positive by PCR for ipaH and ial enteroinvasive genes but negative for all other genes tested. Antiserum was prepared from one of the isolates and tested against Shigella and E. coli reference strains as well as the other isolates. The antiserum reacted with the five remaining isolates and showed cross-reactivity with S. dysenteriae serovars 1, 4, and 16; Shigella flexneri type 3; and E. coli O118, O159, O168, O172, and O173 antigens. Absorbing the sera with E. coli O159 and S. dysenteriae serovar 4 antigen removed all cross-reactions and only slightly reduced the homologous titer. Based on biochemical, molecular, and complete serological analysis, we propose that these six isolates represent a new provisional serovar of S. dysenteriae, type strain BEDP 02-5104.
Cystic lung lesions as an immune reconstitution inflammatory syndrome (IRIS) in HIV-TB co-infection?
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Head lice in children--a modern pandemic.
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Beta-bungarotoxin-induced depletion of synaptic vesicles at the mammalian neuromuscular junction.
The neurotoxic phospholipase A(2), beta-bungarotoxin, caused the failure of the mechanical response of the indirectly stimulated rat diaphragm. Exposure to beta-bungarotoxin had no effect on the response of the muscle to direct stimulation. Resting membrane potentials of muscle fibres exposed to the toxin were similar to control values, and the binding of FITC-labelled alpha-bungarotoxin to nAChR at the neuromuscular junction was unchanged. Motor nerve terminal boutons at a third of cell junctions were destroyed by exposure to beta-bungarotoxin leaving only a synaptic gutter filled with Schwann cell processes and debris. At other junctions, some or all boutons survived exposure to the toxin. Synaptic vesicle density in surviving terminal boutons was reduced by 80% and synaptophysin immunoreactivity by >60% in preparations exposed to beta-bungarotoxin, but syntaxin and SNAP-25 immunoreactivity was largely unchanged. Terminal bouton area was also unchanged. The depletion of synaptic vesicles was completely prevented by prior exposure to botulinum toxin C and significantly reduced by prior exposure to conotoxin omega-MVIIC. The data suggest that synaptic vesicle depletion is caused primarily by a toxin-induced entry of Ca(2+) into motor nerve terminals via voltage gated Ca(2+) channels and an enhanced exocytosis via the formation of t- and v-SNARE complexes.
Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus.
A "partial" rodent model for schizophrenia has been used to characterize the regulation of hippocampal genes in response to amygdalar activation. At 96 h after the administration of picrotoxin into the basolateral nucleus, we have observed an increase in the expression of genes associated with 18 different monoamine (ie adrenergic alpha 1, alpha 2 and beta 2, serotonergic 5HT5b and 5HT6, dopamine D4 and muscarinic m1, m2 and m3) and peptide (CCK A and B, angiotensin 1A, mu and kappa opiate, FSH, TSH, LH, GNRH, and neuropeptide Y) G-protein coupled receptors (GPCRs). These latter receptors are associated with three different G protein signaling pathways (Gq, Gs, and Gi) in which significant changes in gene expression were also noted for adenylate cyclase (AC4), phosphodiesterase (PDE4D), protein kinase A (PKA), and protein kinase C (PKC). Quantitative RT-PCR was used to validate the results and demonstrated that there were predictable increases of three GPCRs selected for this analysis, including the dopamine D4, alpha 1b, and CCK-B receptors. Eight out of the nine monoamine receptors showing these changes have moderate to high affinity for the atypical antipsychotic, clozapine. Taken together, these results suggest that amygdalar activation may play a role in the pathophysiology and treatment of psychosis by regulating the activity of multiple GPCR and metabolic pathways in hippocampal cells.
Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation.
BACKGROUND: Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. METHODS: For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). RESULTS: Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung. CONCLUSIONS: These data suggest that limiting inducible NO synthase-generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.
Superior mesenteric artery syndrome in an HIV positive patient.
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