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Biomedical subjects

M McLoughlin

Publications and source records attributed to M McLoughlin.

At least 19 recordsLinked to original sources
PubMed2006

Experimental transmission of sleeping disease in one-year-old rainbow trout, Oncorhynchus mykiss (Walbaum), induced by sleeping disease virus.

Sleeping disease (SD) is a serious disease of rainbow trout, Oncorhynchus mykiss, reared in fresh water caused by sleeping disease virus (SDV). In this study a detailed clinical, histological, virological and serological description of the experimental reproduction of SD in 1-year-old rainbow trout exposed to SDV was carried out. Two hundred disease-free fish were intraperitoneally inoculated with a SDV isolate and 100 fish were inoculated with an uninfected cell culture lysate as a negative control. Infected and control fish were randomly removed at days 4, 7, 14, 21, 42 and 70 post-infection. Blood and tissues were collected for virus isolation, histopathological examination and serum neutralization. SDV was detected in serum, kidney and brain of infected fish from 4 to 21 days post-infection (dpi). Characteristic pathological lesions were observed in infected fish as early as 7 dpi. Lesions were first detected in exocrine pancreas and subsequently observed in heart and skeletal muscle. Neutralizing antibodies to SDV were detected in infected fish from 14 to 70 dpi. Infected fish displayed typical signs of SD 1-month pi and the mortality reached 18.7% within 44 days. This study experimentally reproduced all the pathognomonic features of natural outbreaks of SD in 1-year-old rainbow trout.

Alphavirus↗
PubMed2005

A comparative study on attitudes, towards the provision of out-of-hours care, of the spouses of general practitioners participating, or not, in a rural out-of-hours co-op.

Qualitative research has suggested that the stress of general practice, and that of out-of-hours care in particular, has an impact on general practitioners' (GPs') spouses. The effects on the families of practitioners, of the introduction of out-of-hours co-operatives has not been extensively studied. Our objective was to compare, between the spouses of GPs participating or not in a rural co-op, the effects of out-of-hours commitments on personal and family life. The spouses of all 125 GPs in a rural region in Ireland were sent questionnaires; 59 GPs were members of an out-of-hours co-op, 66 were engaged in traditional on-call rotas. Most questions were in statement form, to which participants were required to respond on a five point Likert rating scale. The response rate was 67%. Non-co-op spouses were significantly older than co-op spouses (48.3 years versus 42.6, t(68)=-3.02, p=0.04). 80% of the co-op group favoured a co-op for on-call cover as compared to 46% of the non-co-op group. The majority of respondents from both groups agreed that they dislike when their spouse is on call and that time spent on-call placed a strain on family life and was detrimental to their spouse's health. Spouses of non-co-op general practitioners were more likely to agree that their home life was interrupted by patients telephoning the house (z=-3.06, p=0.002) and by patients calling to the door without a prior appointment (z=2.9, p=0.004). They were also more likely to worry about the safety of their spouse on call (z=-2.07, p=0.038). The general provision of out-of-hours care has a significant impact on the spouses and families of GPs participating, or not, in a rural co-op. Spouses of participants in co-ops had significantly less interruptions to their home life from patients and worried less about the safety of their spouse. The implications of these findings on the recruitment and retention of rural practitioners merits further discussion.

Adult↗
PubMed2001

Temporal lobe-oriented CT scanning and dementia in Down's syndrome.

BACKGROUND: Although individuals with Down's syndrome (DS) are uniquely at risk of developing Alzheimer's disease, the diagnosis of dementia in DS is problematic because of the difficulty in detecting cognitive decline in individuals with pre-existing learning disability. AIM: To determine if dementia in DS is associated with Medial Temporal Lobe (MTL) atrophy as measured by temporal lobe-oriented CT scanning. METHOD: Ten individuals with DS who were experiencing functional decline had CT scans with temporal lobe-oriented views. All individuals were assessed for the presence of dementia according to modified DSM-IIIR criteria. The minimal thickness of the MTL, corrected for age-related atrophy was measured using a computer calipers at the level of the mid-brainstem by a radiologist blind to the dementia diagnosis. RESULTS: All six individuals who met modified DSM-IIIR criteria for dementia showed significant MTL atrophy. CONCLUSIONS: The utility of temporal lobe-oriented CT scanning as an adjunct to the diagnosis of dementia in DS appears promising and warrants further study.

Adult↗
PubMed2001

Comparison of alcohol-dependent patients with and without physiological dependence.

Sociodemographic and clinical characteristics of alcohol-dependent patients with or without physiological dependence (e.g. tolerance to alcohol or withdrawal) were compared. 186 consecutive alcohol-dependent patients hospitalized for alcohol detoxification were assessed. Diagnosis of alcohol dependence, tolerance and withdrawal was determined according to DSM-IV criteria. Assessment also included modalities of alcohol consumption and the Michigan Alcohol Screening Test (MAST). All patients presented alcohol dependence, 124 presented tolerance, 116 alcohol withdrawal and 146 (78.5%) tolerance and/or withdrawal. Patients with physiological dependence were older (51.4 vs. 46.9 years), drank more alcohol each day (20.3 vs. 11.3 drinks/day) and began alcohol consumption more often in the morning (67 vs. 37.5%). MAST scores were significantly higher in patients with physiological dependence (28.8 vs. 24.5), as was the mean corpuscular volume of erythrocytes (108 vs. 83 fl). No difference was found in terms of age, marital status, rate of unemployment, level of education and psychiatric comorbidity between the patients with and without physiological dependence.

Adult↗
PubMed2001

Severe blunt renal trauma: a 7-year retrospective review from a provincial trauma centre.

BACKGROUND: Renal trauma is reported in 3% of trauma patients. The majority (>90%) are due to blunt mechanisms of injury. Minor renal injuries pose few management difficulties and the majority are managed expectantly. More serious injuries are potentially life threatening and have been historically managed by operative intervention with repair of the injured kidney when possible. More recently, there has been a trend towards non-operative management of all solid intra-abdominal organ injury including renal trauma. The purpose of this study was to review a 7-year experience in renal trauma at a provincial trauma centre and to define management practices along with patient and organ outcomes in severe renal injury. METHODS: The BC Trauma Registry was reviewed for all admissions from January 1, 1992 to December 31, 1998 to identify patients with renal injury. Patient charts were reviewed to determine sex, age, mechanism of injury, vitals, imaging, associated injuries, and management and outcomes. Renal injuries were graded according to the American Association for the Surgery of Trauma Grading System. RESULTS: During the study period 16 250 consecutive trauma cases were seen at Vancouver General Hospital. Of these cases, 227 (1.4%) patients sustained renal injuries: blunt in 93.4% and penetrating in 6.6%. Among patients with blunt renal trauma, 18.3% were grade III, IV, or V injuries. In this population, nearly 80% had associated trauma and also 80% had gross hematuria. Management was conservative in 87.5% of grade III and 77.7% of grade IV; however, 90.9% of grade V injuries went immediately to the OR. Nephrectomy rates were: 12.5% (III), 16.6% (IV), and 90.9% (V) with an overall exploration rate of 7.1% for all blunt renal trauma. Blunt renal trauma patients experienced few genitourinary complications. Overall, 3 patients of 40 with grade III, IV or V injuries died due to cardiac arrest in the emergency room. CONCLUSIONS: Blunt renal trauma managed conservatively is associated with few complications in the hemodynamically stable patient. Grade V injuries still result in a nephrectomy rate of 90.9% with hemodynamic instability the indication in 100% of patients.

Adolescent↗
PubMed2000

Biochemical characterization of salmon pancreas disease virus.

Salmon pancreas disease virus (SPDV) has been shown to cause severe economic losses in farmed Atlantic salmon (Salmo salar) and has been reported to occur in Europe, Scandinavia and the United States. This paper describes the biochemical characterization of SPDV in terms of its RNA and protein composition. SPDV was purified by precipitation from infected Chinook salmon embryo (CHSE-214) cell-culture supernatant and sucrose density-gradient centrifugation. Fractions containing virus were identified by an immunodot blot assay using an SPDV-specific MAb. Two major proteins with molecular masses of approximately 55 and 50 kDa, putatively identified as the E1 and E2 alphavirus glycoproteins respectively, were detected when purified virus preparations were analysed by PAGE. Radiolabelling experiments indicated that SPDV infection of CHSE-214 cells did not shut-off host-cell protein synthesis, making attempts to identify virus-specific proteins unsuccessful. However, radioimmunoprecipitation assay (RIPA) experiments showed that two SPDV-specific MAbs reacted with a protein in the 50-55 kDa range. Northern blot hybridization with cloned cDNA probes indicated that infected cells contained RNA species of approximately 11.4 and 4 kb, which correspond to the genomic and subgenomic RNAs specified by SPDV. The results described are consistent with SPDV being characterized as an alphavirus.

Alphavirus↗
PubMed1999

Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase.

DNA double-stranded breaks (dsb) activate surveillance systems that identify DNA damage and either initiate repair or signal cell death. Failure of cells to undergo appropriate death in response to DNA damage leads to misrepair, mutations, and neoplastic transformation. Pathways linking DNA dsb to reproductive or apoptotic death are virtually unknown. Here we report that metabolic incorporation of 125I-labeled 5-iodo-2'deoxyuridine, which produces DNA dsb, signaled de novo ceramide synthesis by post-translational activation of ceramide synthase (CS) and apoptosis. CS activation was obligatory, since fumonisin B1, a fungal pathogen that acts as a specific CS inhibitor, abrogated DNA damage-induced death. X-irradiation yielded similar results. Furthermore, inhibition of apoptosis using the peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone did not affect CS activation, indicating this event is not a consequence of induction of apoptosis. ATM, the gene mutated in ataxia telangiectasia, is a member of the phosphatidylinositol 3-kinase family that constitutes the DNA damage surveillance/repair system. Epstein-Barr virus-immortalized B cell lines from six ataxia telangiectasia patients with different mutations exhibited radiation-induced CS activation, ceramide generation, and apoptosis, whereas three lines from normal patients failed to manifest these responses. Stable transfection of wild type ATM cDNA reversed these events, whereas antisense inactivation of ataxia telangiectasia-mutated gene product in normal B cells conferred the ataxia telangiectasia phenotype. We propose that one of the functions of ataxia telangiectasia-mutated gene product is to constrain activation of CS, thereby regulating DNA damage-induced apoptosis.

Animals↗
PubMed1999

Niemann-Pick human lymphoblasts are resistant to phthalocyanine 4-photodynamic therapy-induced apoptosis.

Stress-induced activation of sphingomyelinase (SMase) leading to generation of ceramide, a lipid mediator, has been associated with apoptosis in several malignant and nonmalignant cell lines. Photodynamic therapy (PDT), with the phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N(CH3)2], is an oxidative stress associated with increased ceramide generation and subsequent induction of apoptosis in various cell types. We assessed the role of SMase in photocytotoxicity. Normal human lymphoblasts accumulated ceramide and underwent apoptosis after Pc 4-PDT. In contrast, Niemann-Pick disease (NPD) lymphoblasts, which are deficient in acid sphingomyelinase (ASMase) activity, failed to respond to Pc 4-PDT with ceramide accumulation and apoptosis, suggesting that ASMase may be a Pc 4-PDT target. NPD lymphoblasts were exposed to exogenous bacterial sphingomyelinase (bSMase) to test whether these defects are reversible. Treatment of NPD cells with bSMase itself led to elevated ceramide formation, which did not translate into induction of apoptosis. However, a combination of Pc 4-PDT + bSMase induced a significant apoptotic response. Thus, the combined treatment of Pc 4-PDT + bSMase, rather than bSMase alone, was required to restore apoptosis in NPD cells. These data support the hypothesis that SMase is a proapoptotic factor determining responsiveness of cells to Pc 4-PDT.

Apoptosis↗
PubMed1998

The benefits of exercise in individuals with traumatic brain injury: a retrospective study.

OBJECTIVE: This study examined the benefits of exercise. DESIGN: A retrospective study. SETTING: A community-based sample. PARTICIPANTS: A sample of 240 individuals with traumatic brain injury (TBI) (64 exercisers and 176 nonexercisers) and 139 individuals without a disability (66 exercisers and 73 nonexercisers). MAIN OUTCOME MEASURES: Scales measuring disability and handicap. RESULTS: It was found that the TBI exercisers were less depressed than nonexercising individuals with TBI, TBI exercisers reported fewer symptoms, and their self-reported health status was better than the nonexercising individuals with TBI. There were no differences between the two groups of individuals with TBI on measures of disability and handicap. CONCLUSIONS: The findings suggest that exercise improves mood and aspects of health status but does affect aspects of disability and handicap.

Adolescent↗
PubMed1998

Aqueous stability of SB 210661: kinetics and primary degradation mechanisms of an N-hydroxyurea-containing 5-lipoxygenase inhibitor.

SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzo furanyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds. Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH > 5 and different degradative pathways at pH < 5. The pathway at pH > 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH < 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.

Benzofurans↗
PubMed1997

Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation.

The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-alpha and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-alpha, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-alpha injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-alpha in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

Adipose Tissue↗
PubMed1996

Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.

Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic response. Conclusive evidence for this paradigm, however, is lacking. In the present study, we used a genetic approach to address this issue directly. We show that lymphoblasts from Niemann-Pick patients, which have an inherited deficiency of acid sphingomyelinase activity, fail to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities are reversible up on restoration of acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Acid sphingomyelinase knockout mice also expressed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice revealed that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are likely distinct and independent. These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis.

Animals↗
PubMed1995

National perspective of acute coronary care in the Republic of Ireland.

OBJECTIVE: To assess the use of acute coronary care facilities in the Republic of Ireland with regard to case mix, patient characteristics, mortality and factors associated with mortality, time intervals to admission, utilisation of thrombolysis, and risk factor profiles. DESIGN: A 1 week prospective census of all hospitals admitting acute coronary cases. These comprised 23 coronary care units (CCU) and 17 combined coronary care/intensive care units (CCU/ICU). Data were collected by standardised methods on each new patient "upon whom a cardiac monitor was placed". RESULTS: Acute coronary heart disease was confirmed in 185 (44.9%) of 412 patients. Of these 109 (26.4%) had a confirmed myocardial infarction and 76 (18.4%) unstable angina. Women were significantly older than men in all groups. Of those with proven acute coronary heart disease, 42.6% were current smokers, 23.1% were aware of having a raised cholesterol concentration, and 42.3% gave a history of prior hypertension. Only 44% were transported by ambulance. Median delay time from the onset of symptoms to admission was 6 h in Dublin and 4 h elsewhere. 34.9% of patients with a confirmed myocardial infarction received thrombolysis. Mortality of patients with myocardial infarction CCU/ICU at 7 days was 10.9 %. CONCLUSIONS: There is potential for considerable improvement in the management of coronary heart disease in the Republic of Ireland through a reduction in delay times to admission to hospital, increased use of thrombolytic treatment, and intensification of advice on primary and secondary risk factors.

Adult↗
PubMed1994

Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.

Recent investigations provided evidence that the sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor alpha (TNF-alpha) in several hematopoietic and nonhematopoietic cells. In this pathway, TNF-receptor interaction initiates sphingomyelin hydrolysis to ceramide by a sphingomyelinase. Ceramide acts as a second messenger stimulating a ceramide-activated serine/threonine protein kinase. The present studies show that ionizing radiation, like TNF, induces rapid sphingomyelin hydrolysis to ceramide and apoptosis in bovine aortic endothelial cells. Elevation of ceramide with exogenous ceramide analogues was sufficient for induction of apoptosis. Protein kinase C activation blocked both radiation-induced sphingomyelin hydrolysis and apoptosis, and apoptosis was restored by ceramide analogues added exogenously. Ionizing radiation acted directly on membrane preparations devoid of nuclei, stimulating sphingomyelin hydrolysis enzymatically through a neutral sphingomyelinase. These studies provide the first conclusive evidence that apoptotic signaling can be generated by interaction of ionizing radiation with cellular membranes and suggest an alternative to the hypothesis that direct DNA damage mediates radiation-induced cell kill.

Animals↗
PubMed1994

Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo.

Apoptosis (programmed cell death) serves as a common mechanism of interphase cell death after radiation exposure in thymic, lymphoid, and hematopoietic cells but has infrequently been documented in other adult mammalian cell types. The present study demonstrates that apoptotic interphase cell death occurs in endothelial cells after exposure to clinically relevant radiation doses and that basic fibroblast growth factor (bFGF) protects endothelial cells against this mode of the lethal effects of radiation. Radiation exposure produced heterologous double-stranded DNA breaks in endothelial cells, but the cells exhibited a similar competence for repair of this damage in the presence or absence of bFGF. However, subsequent to the completion of this repair process, a second process of DNA fragmentation became apparent, which was detected only in the absence of bFGF and was associated with a DNA ladder of oligonucleosomal fragments characteristic of apoptosis. The apoptotic DNA degradation occurred mainly in G0-G1 phase cells and was inhibited by bFGF stimulation. C3H/HeJ mice exposed to lethal doses of whole lung irradiation exhibited similar apoptotic changes in the endothelial cell lining of the pulmonary microvasculature within 6-8 h after radiation exposure. bFGF given i.v. immediately before and after irradiation inhibited the development of apoptosis in these cells and protected mice against the development of lethal radiation pneumonitis. These findings suggest that interphase apoptosis may represent a biologically relevant mechanism of radiation-induced cell kill in nonlymphoid mammalian cells both in vitro and in vivo and that natural protection mechanisms against this effect may be associated with the level of radiation resistance in normal and malignant tissues in vivo.

Animals↗
PubMed1994

Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis.

Basic fibroblast growth factor (bFGF) was found to protect bovine aortic endothelial cells against the lethal effects of ionizing radiation by inhibiting the programmed cell death (apoptosis) induced in these cells by radiation exposure. The involvement of the bFGF receptor tyrosine kinase in this function was demonstrated by abrogation of the radioprotective effect of bFGF by a specific inhibitor of the bFGF receptor tyrosine kinase, the tyrphostin AG213. The downstream signaling after stimulation of the bFGF receptor tyrosine kinase in bovine aortic endothelial cells involved translocation of the alpha isotype of cytoplasmic protein kinase C (PKC) into the membrane and its activation within 30 s after bFGF stimulation. The involvement of PKC in the radioprotective effect conferred by bFGF was suggested by the demonstration that nonspecific PKC activation by short-term exposure (30 min) to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA; 30 ng/ml) mimicked the radioprotective effect of bFGF. Furthermore, treatment of the cells with the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM) abrogated the radioprotective effect of bFGF, as was observed after the depletion of cellular PKC by overnight preincubation with high-dose TPA (200 nM). Agarose gel electrophoresis of DNA extracted from irradiated bovine aortic endothelial cells showed that both TPA (30 ng/ml; 30 min) and bFGF (1 ng/ml) inhibited the apoptotic degradation of DNA induced in these cells by radiation exposure (500 cGy). Both the bFGF- and the TPA-mediated inhibition of apoptosis could be reversed by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM). These data demonstrate the involvement of PKC in the inhibition of radiation-induced apoptosis by bFGF and the rescue of endothelial cells from this mode of radiation-induced cell death.

Animals↗
PubMed1993

Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase.

The wee1 tyrosine kinase and cdc25 tyrosine phosphatase of fission yeast play antagonistic roles in the induction of mitosis through cdc2 regulation. We show here that the human wee1-like tyrosine kinase is a nuclear protein that ensures the completion of DNA replication prior to mitosis in cells expressing otherwise catastrophic levels of cdc2 activators. Paradoxically, wee1-rescued cells display very high levels of mitotic cdc2 kinase activity. We account for this anomaly by our observation that the cdc2 activator, cdc25C, is a cytoplasmic protein that, like cyclin B1, enters the nucleus at the G2/M transition. Thus, cdc2 is likely to be activated in the cytoplasm and requires nuclear localization to initiate both cytoplasmic and nuclear mitotic transformations. The human wee1 kinase appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from this cytoplasmically activated cdc2 kinase.

Amino Acid Sequence↗