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Biomedical subjects

C Kelly

Publications and source records attributed to C Kelly.

At least 55 records · Page 3Linked to original sources
PubMed2001

Thermotolerance protects against endotoxin-mediated microvascular injury.

An early event in endotoxin-induced tissue injury is adhesion and migration of leukocytes through the endothelium. This is a three-stage process, initially low-grade selectin-mediated adhesion, seen as a decrease in rolling velocity, followed by integrin-mediated adhesion and transmigration. Thermotolerance has been shown to reduce tissue injury and mortality induced by endotoxin. The aim of this study was to investigate the effect of thermotolerance on leukocyte-endothelial interactions. Intravital video microscopy was used to examine hemodynamic parameters, leukocyte rolling, adhesion, and migration in rat mesenteric postcapillary venules. Sprague-Dawley rats were randomized into control, lipopolysaccharide (LPS), and thermotolerance + LPS groups. Thermotolerance was induced 18 h prior to administration of LPS by elevating core body temperature to 41 + 0.5 degrees C for 15 min. LPS (055:B5 15 mg/kg) was administered via the jugular vein after baseline recording. Leukocyte rolling velocity and the number of adherent and migrated leukocytes were measured by intravital microscopy at baseline 0 min and 10, 30, 60, and 90 min after LPS administration. Heat shock protein 72 (HSP72) expression in tissues was determined by Western immunoblotting. The results indicated that LPS administration significantly decreased leukocyte rolling velocity during endotoxemia and increased leukocyte adhesion (10.3 +/- 1.67, 13.2 +/- 1.40, and 10.0 +/- 1.57/100 microm) and migration (5.7 +/- 1.02 and 8.3 +/- 1.76/field) at 30, 60, and 90 min after LPS injection (P < 0.01 vs baseline and control group). Thermotolerance maintained leukocyte rolling velocity and significantly reduced leukocyte adhesion (5.7 +/- 0.88 and 4.0 +/- 0.68/100 microm) and migration (2.8 +/- 0.32 and 3.0 +/- 0.68/field) at 30 and 60 min after LPS administration (P < 0.01 and 0.05 vs LPS group). Expression of HSP72 was induced in mesentery, gut, and lung by thermotolerance. This study indicates that thermotolerance attenuated LPS-induced microvascular injury by decreasing leukocyte-endothelial adhesion and migration.

Animals↗
PubMed2001

Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates renal injury in an experimental model of ischemia-reperfusion.

BACKGROUND: Renal dysfunction due to ischemia-reperfusion (IR) injury is a common problem following renovascular surgery or kidney transplantation. There is a lot of emerging evidence that statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have anti-inflammatory properties and exert direct beneficial effects on the vascular endothelium. The aim of this study was to determine if pretreatment with pravastatin would attenuate the acute renal dysfunction that occurs following IR injury in an experimental model. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomized into four groups (n = 7 per group): control, uninephrectomy, IR group, and IR group pretreated with pravastatin (0.4 mg/kg/day for the preceding 5 days). Following a left nephrectomy the IR injury was induced by cross-clamping the right vascular pedicle for 30 min followed by reperfusion for 2 h. In a separate experiment (n = 6 per group) renal function was assessed 12 and 24 h after reperfusion. RESULTS: IR injury causes significant renal dysfunction characterized by oliguria, 0.11 (0.05) ml/h, decreased glomerular filtration rate (GFR), 0.02 (0.01) ml/min; and marked protein leakage, 7.21 (1.3) g/L, 2 h postreperfusion. This renal dysfunction was also evident 12 and 24 h postreperfusion. This was in contrast to values of 0.61 (0.13) ml/h, 0.23 (0.01) ml/min, and 1.67 (0.12) g/L in the uninephrectomy-only group and values of 2 ml/h, 7.3 ml/min, and 0.72 g/L for uninjured time-matched controls. Pretreatment with pravastatin significantly attenuated IR-induced renal injury, improving urine production to 0.62 (0.2) ml/h and GFR to 0.14 (0.02) ml/min and diminishing protein leakage to 3.76 (0.7) g/L at the 2-h time point. This renoprotective effect was also evident 12 and 24 h postreperfusion. This renal protection was associated with an upregulation of constitutive endothelial nitric oxide synthase in the pravastatin-treated group. CONCLUSION: These results show that pravastatin may play a role in modulating renal impairment following aortic or transplantation surgery, allowing earlier recovery from an IR injury.

Animals↗
PubMed2001

The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development.

Vascular endothelial growth factor (VEGF, VEGF-A), a selective mitogen for endothelial cells is a critical factor for vascular development. Two isoforms that differ in the presence of exons 6 and 7, Vegf(165) and Vegf(121), are the dominant forms expressed in zebrafish embryo. Simultaneous overexpression of both isoforms in the embryo results in increased production of flk1, tie1, scl, and gata1 transcripts, indicating a stimulation of both endothelial and hematopoietic lineages. We also demonstrate that vegf can stimulate hematopoiesis in zebrafish by promoting the formation of terminally differentiated red blood cells. Simultaneous overexpression of both isoforms also causes ectopic vasculature and blood cells in many of the injected embryos as well as pericardial edema in later stage embryos. Overexpression of vegf also resulted in earlier onset of flk1, tie1, scl, and gata1 expression in the embryo, indicating a possible role of vegf in stimulating the differentiation of both vascular and hematopoietic lineages. Co-injection of RNAs for both isoforms results in increased expression of three of these markers over and above that observed when either RNA is singly injected and analysis of vegf expression in the notochord mutants no tail and floating head suggests that the notochord patterns the formation of the dorsal aorta by stimulating adjacent somite cells to express vegf, which in turn functions as a signal in dorsal aorta patterning. Finally, studies of vegf expression in cloche mutant indicate that vegf expression is generally independent of cloche function. These results show that in the zebrafish embryo, vegf can not only stimulate endothelial cell differentiation but also hematopoiesis. Moreover, these effects are most dramatic when both vegf isoforms are co-expressed, indicating a synergistic effect of the expression of the two forms of the VEGF protein.

Animals↗
PubMed2001

Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer.

We report on two randomized trials performed in the USA and Europe, which compared methotrexate and nolatrexed as treatment for patients with recurrent head and neck cancer. Eligibility criteria included: histologically confirmed squamous-cell carcinoma, measurable disease, adequate hematological, renal and hepatic functions, failure of a first-line chemotherapy, and informed consent. Methotrexate 40 mg/m2 was weekly given by short infusion, and nolatrexed 725 mg/m2 per day was administered as a five-day continuous infusion, every three weeks. A total of 139 patients (63 in the USA. 76 in Europe) were randomized based on a ratio of 2/1: 93 and 46 received nolatrexed and methotrexate, respectively. Patient characteristics included 115 males and 24 females; median age 60 years. In the nolatrexed arm, the following grade 3-4 toxicities occurred: neutropenia (29.9%) with 3.1% of febrile neutropenia, mucositis (33.3%), and vomiting (10.3%). In the MTX arm, the grade 3-4 toxicities were neutropenia (7.1%) and mucositis (6.9%). There was no difference in activity between the nolatrexed and the methotrexate treatment: 3.3% and 10.8% of objective responses, 1.9 versus 1.5 months of disease-free progression and 3.5 versus 3.7 months of overall survival, respectively. Nolatrexed has demonstrated a similar activity to methotrexate.

Adult↗
PubMed2001

Annexin-V imaging for noninvasive detection of cardiac allograft rejection.

Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.

Adult↗
PubMed2001

Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection.

The role of a nuclear factor kappaB (NF-kappaB) in NMDA receptor-mediated neuroprotection is not known. A candidate sequence from the 5' flanking region of exon 3 of the rat brain-derived neurotrophic factor (BDNF) gene was used to show that exposure of rat cerebellar granule cells to 100 microM NMDA activated a specific DNA binding activity that was blocked by the NMDA receptor antagonist MK-801. Anti-p65 antibody or anti-p50 antibody 'supershifted' the DNA binding activity, suggesting that the DNA-protein complex was composed of p65 and p50 subunits. NMDA receptor-mediated neuroprotection was blocked when cerebellar neurons were transfected with a double-stranded oligonucleotide containing the BDNF gene NF-kappaB sequence. Furthermore, nuclear extracts prepared from neurons treated with NMDA and the double-stranded NF-kappaB oligonucleotide showed reduced DNA binding activity to the target sequence, supporting the idea that NF-kappaB may be involved in the transcriptional activation of the BDNF gene. To address this issue, we quantified the level of exon 3-specific BDNF mRNA. Relative to GAPDH mRNA levels and compared with untreated neurons, NMDA increased exon 3-specific BDNF mRNA twofold. In contrast, pretreatment of neurons with the NF-kappaB target DNA abolished the increase in BDNF mRNA following addition of NMDA. We also determined that BDNF itself induced an NF-kappaB DNA binding activity. Taken together, these data support a mechanism where NF-kappaB plays a critical role in NMDA-mediated neuroprotection.

5' Untranslated Regions↗
PubMed2001

Summer birth and deficit schizophrenia in Nithsdale, Scotland.

Patients with deficit schizophrenia differ from other people with schizophrenia relative to course of illness, treatment response, and neurobiological correlates. An association between deficit schizophrenia and summer birth, in contrast to the winter birth risk factor associated with schizophrenia as a whole, has also been reported. We attempted to replicate the association between summer birth and deficit schizophrenia by using data from a prevalence survey in Nithsdale in southwest Scotland, in which all patients with schizophrenia in Nithsdale were identified and 87% were interviewed directly. Deficit schizophrenia was associated with summer birth, defined as birth in June/July/August (p < .02), June/July (p < .02), or July/August (p < .03). The association with summer birth is consistent with other evidence that patients with deficit schizophrenia have a pathophysiology that differs in some ways from that of other patients with schizophrenia.

Female↗
PubMed2001

What is the prevalence of rheumatic disorders in general medical inpatients?

It has been suggested that rheumatological disorders are underdiagnosed in patients with medical problems and that this might be rectified by incorporating a standard brief screening examination as part of the routine assessment of all patients admitted to hospital with medical conditions. Therefore the GALS screening examination was used to assess the prevalence of rheumatic disease in 100 patients admitted with acute medical problems and in a further 100 in the rehabilitative phase of their disease. The nature of locomotor dysfunction in all patients with a positive result was defined by an independent review and then sensitivity and specificity of the screening test was calculated for rheumatic disease in both populations. The median age of the two populations were 63 and 78 years respectively, with more females in the rehabilitation group. The overall prevalence of a positive screening test was 53% in the acute and 94% in the chronic disease groups, although the false positive rate in the rehabilitation patients was 30% due to factors other than rheumatic disorders limiting locomotor function (mainly orthopaedic and neurological conditions). The diagnosis of a rheumatological disorder was made de novo in a significant minority (10%) of patients and was usually amenable to treatment. The commonest rheumatic disorder was osteoarthritis which accounted for 55% of all rheumatic disease, followed by inflammatory joint disease (16%), and osteoporosis (12%). In addition to osteoporosis, Paget's disease of bone and polymyalgia rheumatica were found more frequently in those patients undergoing rehabilitation than in those admitted with an acute medical problem. A number of clinically important associations between medical and rheumatic disorders were found, such as stroke disease with shoulder capsulitis and heart failure with gout. The sensitivity of the GALS screening test was extremely high (92% and 100%), while its specificity fell in the rehabilitation group from 83% to 17%. None the less, it is felt that this study indicates that the routine use of this test should be considered as part of the assessment of all hospitalised patients with medical problems, whether acute or chronic.

Acute Disease↗
PubMed2001

A randomized trial of lansoprazole, amoxycillin, and clarithromycin versus lansoprazole, bismuth, metronidazole and tetracycline in the retreatment of patients failing initial Helicobacter pylori therapy.

BACKGROUND/AIM: 10-30% of the patients treated for Helicobacter pylori fail to clear the infection after initial therapy. Little is known as to the efficacy of retreatment regimens in these patients. Proton pump inhibitor (PPI) -based triple and quadruple therapies demonstrate efficacies of 80-90% as initial therapy for H. pylori infection, but whether these regimens are as effective when used for retreatment is unknown. The efficacy of a metronidazole-containing regimen in this situation is also unknown. Our aim was to compare the efficacy of a nonmetronidazole-containing PPI-based triple versus a PPI-based quadruple therapy containing metronidazole in patients failing previous H. pylori therapy. METHODS: 48 patients were enrolled in this study at two sites after failure of previous H. pylori therapy as determined by a positive (14)C-urea breath test. Patients were stratified by prior treatment with a metronidazole-containing regimen and were then randomized to either lansoprazole (L) 30 mg twice daily, amoxycillin (A) 1,000 mg twice daily, and clarithromycin (C) 500 mg twice daily for 14 days (LAC) or L 30 mg four times daily, bismuth subsalicylate (B) 2 tablets four times daily, metronidazole (M) 250 mg four times daily and tetracycline (T) 250 mg four times daily for 14 days (LBMT). Side effects and compliance (pill count) were assessed at the completion of therapy. A repeat (14)C-urea breath test was performed 4 or more weeks after completion of therapy, and cure was defined as a negative test result. RESULTS: 48 patients (16 males and 32 females) were enrolled in this study. 20 patients received LAC (18 prior M), and 28 received LBMT (23 prior M). Per protocol and intention-to-treat efficacies were 82% (95% CI 64-100%) and 75% (95% CI 56-94%) for LAC and 80% (96% CI 64-96%) and 71% (95% CI 54-88%) for LBMT (p = 0.85 per protocol and p = 0.78 intention to treat between LAC and LBMT), respectively. The compliance (> or =80% of pills taken) was found to be 89% in both treatment groups. Side effects were noted in 84% for LAC and in 82% for LBMT, but were mild and did not cause discontinuation of therapy. CONCLUSIONS: PPI-based triple and quadruple therapy with both LAC and LBMT are effective in retreating patients failing initial metronidazole-based H. pylori therapies. LAC was not statistically superior to LBMT as a 'retreatment' regimen in this clinical situation, but the small sample size and wide confidence limits do not preclude the possibility of a smaller but significant difference in efficacy between the regimens. To determine whether LAC or LBMT is as effective for retreating patients failing non-metronidazole-containing regimens requires further study.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Oral vitamin C attenuates acute ischaemia-reperfusion injury in skeletal muscle.

Ischaemia-reperfusion injury (IRI) is caused by endothelial and subendothelial damage by neutrophil-derived oxidants. Vitamin C is an antioxidant which attenuates endothelial injury after IRI. Our aim was to evaluate the effect of oral vitamin C in the prevention of IRI in skeletal muscle. We used a model of cross-clamping (3 hours) and reperfusion (1 hour) of the cremaster muscle in rats. Muscle function was assessed electrophysiologically by electrical field stimulation. Infiltration by neutrophils was determined by the activity of tissue myeloperoxidase (MPO) and tissue oedema by the wet-to-dry ratio. Neutrophil respiratory burst activity was measured in control animals and groups pretreated with vitamin C. IRI significantly decreased muscle function and increased muscle neutrophil MPO activity and muscle oedema. Pretreatment with vitamin C preserved muscle function and reduced tissue oedema and neutrophil infiltration. Neutrophil respiratory burst activity was reduced in the group treated with vitamin C compared with the control group. We conclude that pretreatment with oral vitamin C protects against acute muscle IRI, possibly by attenuating neutrophil respiratory burst activity.

Acute Disease↗
PubMed2001

Reasons for patient removals: results of a survey of 1005 GPs in Northern Ireland.

There has been considerable debate on the issue of general practitioners (GPs) removing patients from their lists. The second report of the Health Service Ombudsman addressed this area in some detail and, among other observations, commented on the lack of information available on this subject. This is a report on a questionnaire survey of GPs, aimed at finding out their reasons for removing patients and their feelings about the changes that have been proposed regarding their automatic right to remove patients without giving them a reason.

Attitude of Health Personnel↗
PubMed2001

TGF-beta1 is elevated in breast cancer tissue and regulates nitric oxide production from a number of cellular sources during hypoxia re-oxygenation injury.

Cellular response to treatment is dependent on the metabolic preconditioning of individual cells, which is a reflection of environmental conditions. Within solid tumours there are areas of different oxygen tension, which, we hypothesise, may indicate that cells are exposed to conditions that change continually. Other characteristics of the solid-tumour microenvironment include the production of growth factors, one of which is transforming growth factor (TGF)-beta1. As part of this study, we measured TGF-beta1 and found it raised in the serum of breast cancer patients compared with controls (98.24+/-13.25 vs. 48.87+/-12.14 ng/mL; P < 0.05; n = 7), and in the conditioned medium of breast tumour explant tissue compared with matched normal tissue (21.1+/-5.3 vs. 4.7+/-1.2 ng TGF-beta1/gram of tissue; P < 0.05; n = 11). Nitric oxide (NO) is a cytotoxic molecule produced by a large number of cells and thought to have antimetastatic properties. In order to observe the effect of conditions within breast tumours on NO production, we exposed macrophages, endothelial cells and tumour cells to hypoxia re-oxygenation in vitro, both in the presence and absence of TGF-beta1. Hypoxia stimulated increased NO production in both macrophages (normoxia: 0.34+/-0.04 nmol/L nitrite vs. hypoxia: 1.04+/-0.18 nmol/L nitrite; P < 0.05) and endothelial cells (normoxia: 0.02+/-0.01 nmol/L nitrite vs. hypoxia: 0.21+/-0.07 nmol/L nitrite; P < 0.05). NO production in macrophages, endothelial cells and tumour cells was reduced significantly following hypoxia in the presence of TGF-beta1 in a concentration-dependent manner. These results suggest that, within breast tumours, tumour-derived TGF-beta1 in combination with environmental conditions may result in decreased local NO production, which could have implications for tumour growth.

Breast Neoplasms↗
PubMed2000

Distinct domains of CD98hc regulate integrins and amino acid transport.

CD98 is a cell surface heterodimer formed by the covalent linkage of CD98 heavy chain (CD98hc) with several different light chains to form amino acid transporters. CD98hc also binds specifically to the integrin beta(1A) cytoplasmic domain and regulates integrin function. In this study, we examined the relationship between the ability of CD98hc to stimulate amino acid transport and to affect integrin function. By constructing chimeras with CD98hc and a type II transmembrane protein (CD69), we found that the cytoplasmic and transmembrane domains of CD98hc are required for its effects on integrin function, while the extracellular domain is required for stimulation of isoleucine transport. Consequently, the capacity to promote amino acid transport is not required for CD98hc's effect on integrin function. Furthermore, a mutant of CD98hc that lacks its integrin binding site can still promote increased isoleucine transport. Thus, these two functions of CD98hc are separable and require distinct domains of the protein.

Amino Acids↗
PubMed2000

Tests for homogeneity of the risk ratio in a series of 2x2 tables.

We often apply the risk ratio to measure the strength of a causal relationship between a suspected risk factor and a disease of interest. In this paper we consider testing the homogeneity of risk ratio over a series of 2x2 tables. In addition to the classical weighted least squares (CWLS) test procedure, we consider two test procedures using simple transformations of the CWLS statistic and develop three other asymptotically weighted test procedures. On the basis of Monte Carlo simulation, we conclude that the commonly-used CWLS test procedure is generally conservative, especially when the number of 2x2 tables is large and the mean group size per table is moderate or small. We further find that two of the test procedures discussed here can not only generally outperform the CWLS test procedure, but also perform well in a variety of situations considered in this paper. Finally, we illustrate the use of these testing procedures with an example of six randomized trials that assess the effects of aspirin on the prevention of death in post-myocardial infarction patients.

Aspirin↗
PubMed2000

Depressive symptoms in stable chronic schizophrenia: prevalence and relationship to psychopathology and treatment.

The prevalence and correlates of the depressive syndrome were explored in a population of 120 patients with stable, chronic schizophrenia living in the community. The presence of clinically significant depressive symptoms was defined by a score of 17 or greater on the Beck Depression Inventory. Patients were examined to assess severity of schizophrenic symptoms and medication side-effects. Sixteen of the 120 patients (13.3%) had significant depressive symptoms. Depressive symptoms were significantly correlated with the hostility/suspiciousness (P<0.0001), the positive symptom (P=0.0009) factor of the BPRS and with scores on the Significant Others Scale, a measure of patients' perceived lack of social support (P=0.0004). The association between depression and akathisia approached significance (P=0.007). There was no correlation with demographic variables, alcohol intake, antipsychotic dosage or anticholinergic dosage. Using a scale that rates the subjective aspects of the depressive syndrome, we found no evidence of a relationship between depression and negative symptoms in this population. These results indicate that persistent depressive symptoms in stable patients in the community are related to the degree of persistent positive psychotic symptoms, patient perceptions of social support and, weakly, to the degree of akathisia but not other aspects of antipsychotic treatment.

Adolescent↗
PubMed2000

Analysis of steroids in environmental water samples using solid-phase extraction and ion-trap gas chromatography-mass spectrometry and gas chromatography-tandem mass spectrometry.

This paper describes an improved method for the extraction and determination of three steroids, oestrone, 17beta-oestradiol, and the synthetic contraceptive steroid 17alpha-ethinyloestradiol in aqueous matrices. Samples of wastewater and environmental water were spiked with internal standards, comprising isotopically labelled analogues of the steroids to be determined. The samples were extracted using solid-phase extraction disks and the extracts were then derivatized to form tert.-butyldimethylsilyl derivatives. The derivatised steroids were determined in the final extracts by GC-MS or GC-MS-MS allowing an operational detection limit for each steroid in effluent samples of 1 ng l(-1).

Chromatography, Gas↗