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Biomedical subjects

M Fisher

Publications and source records attributed to M Fisher.

At least 19 recordsLinked to original sources

Oral antidiabetic agents as cardiovascular drugs.

The increased risk of cardiovascular disease associated with type 2 diabetes is well documented. Lesser degrees of abnormal glucose metabolism including impaired fasting glycaemia and impaired glucose tolerance are also associated with increased cardiovascular risk. Studies showing improved cardiovascular outcomes with oral antidiabetic agents are limited, with the UKPDS demonstrating improved macrovascular outcomes only in a subgroup of obese patients with type 2 diabetes treated with metformin, and the heavily criticized STOP NIDDM trial showing a reduction in the number of cardiovascular events with the alpha glucosidase inhibitor acarbose. In recent years there has been an increase in the number of oral antidiabetic drugs available to treat the hyperglycaemia of diabetes. Some of these drugs have complex metabolic properties, additional to their antihyperglycaemic effect, improving endothelial function and markers of atherogenesis, with the potential to reduce cardiovascular morbidity and mortality, as supported by the recently published results of the PROACTIVE study. The results of further long-term cardiovascular outcome studies with these newer agents are awaited.

Blood Glucose↗

Perspectives on neuroprotective stroke therapy.

After years of setbacks, the perspective of neuroprotective stroke therapy has revived in light of recent study results. We outline in this review how a neuroprotective candidate drug should be developed, beginning with a thorough preclinical evaluation according to the STAIR (Stroke Therapy Academic Industry Roundtable) criteria. Assessing the safety of the candidate drug in the relatively straightforward Phase IIA would be the first step into clinical development. While advancing into Phase IIB, the implementation of a responder analysis, the use of a surrogate biomarker as well as the use of Bayesian methodology should be considered to increase the likelihood of seeing any therapeutic sign. Clinical development in Phase III should consider that previously used dichotomized endpoints appropriate for evaluation of thrombolytic drugs are likely to be insufficient for assessing efficacy of neuroprotective drugs. Detection of a clinically relevant shift in the outcome measure appears to be a more relevant approach for the type of drug that achieves a reduction and not a reverse of the ischaemic lesion.

Animals↗

Ixodes frontalis and avian tick-related syndrome in the United Kingdom.

OBJECTIVES: This study aimed to characterise tick species responsible for avian tick infestations in the UK, to analyse various risk factors for tick-related syndrome in tick-infested birds and to test samples for the presence of certain tick-transmitted pathogens. METHODS: Ticks, blood, splenic tissue and tick attachment site tissue from birds with attached ticks were requested from veterinarians and wildlife sanctuaries around the UK. Ticks were identified according to standard keys, and samples were analysed via DNA PCR test for Borrelia burgdorferi sensu lato, Babesia species, Bartonella species and Ehrlichia species. RESULTS: Ixodes frontalis was the most commonly identified tick, and an association of adult female I frontalis with tick-related syndrome in birds was demonstrated. Tick infestation was markedly seasonal. I frontalis was found on 32 species of birds. DNA PCR testing was uniformly negative. Of the birds known to have been treated, 75 per cent (nine of 12) survived. CLINICAL SIGNIFICANCE: Tick-related syndrome is a poorly understood syndrome, with sporadic distribution, both geographically and seasonally. This study confirms I frontalis as the most common cause of this syndrome in the UK and identifies some features of the tick life cycle in this country. The benefit of treatment in affected birds is highlighted. Risk factors for tick-related syndrome are examined and preventive strategies discussed.

Animals↗

Refocusing health promotion for syphilis prevention: results of a case-control study of men who have sex with men on England's south coast.

BACKGROUND: Prevention interventions have had little impact on syphilis outbreaks among men who have sex with men (MSM) and diagnosis rates continue to rise rapidly. Detailed studies of the determinants of syphilis transmission are needed to inform new prevention interventions. OBJECTIVE: To investigate factors associated with recent syphilis diagnosis and recommend strategies for improved prevention interventions. METHODS: A case-control study of MSM attending genitourinary medicine (GUM) and HIV outpatient clinics. Cases were MSM testing positive for early syphilis, based on either laboratory or microscopy results, with those testing negative being controls. All participants completed the same anonymous questionnaire covering demographics, lifestyle, sexual behaviour, and sexual partnerships. RESULTS: 50 cases and 108 controls returned questionnaires. Syphilis diagnosis was significantly associated with sexually transmitted infection history, recent recreational drug use, receptive anal sex practices, but not insertive ones, higher numbers of oral sex partners, but not specific oral sex practices. Overall, there were no differences between HIV positive and HIV negative/untested men in reporting of sexual behaviours or partnership combinations. The use of public sex settings (backrooms, saunas, "cruising grounds," etc) was reported by 68% of all participants and not significantly associated with syphilis diagnosis. CONCLUSIONS: Many key behavioural and partnership risk factors for syphilis are also risk behaviours for HIV transmission and point to the need for integrated strategies that tackle the two infections together. Simplified procedures for syphilis screening should be available in GUM clinical settings, along with targeted community outreach prevention interventions.

Adult↗

Experimental stroke: ischaemic lesion volume and oedema formation differ among rat strains (a comparison between Wistar and Sprague-Dawley rats using MRI).

Investigating focal cerebral ischaemia requires animal models that are relevant to human stroke. This study was designed to evaluate the influence of early reperfusion and choice of rat strains on infarct volume and oedema formation. Thirty-six Wistar and Sprague-Dawley rats were subjected to temporary middle cerebral artery occlusion (MCAO) for 90 min (groups I and II) or to permanent MCAO (groups III and IV) using the suture technique. Ischaemic lesion volume and oedema formation were quantified 24 h after MCAO using 7T-magnetic resonance imaging (MRI). Impact of rat strains: Reperfusion led to significant larger ischaemic lesion volumes in Wistar rats as compared to Sprague-Dawley rats (P<0.0005). Oedema formation was similar in both rat strains. Permanent MCAO led to significantly larger ischaemic lesion volumes in Sprague-Dawley rats (P<0.05). Oedema formation, however, was significantly more accentuated in Wistar rats (P<0.005). Impact of reperfusion: Reperfusion did not cause any changes in ischaemic lesion volume in Wistar rats. Oedema formation, however, was significantly reduced (P<0.0005). In Sprague-Dawley rats, reperfusion caused a significant reduction of ischaemic lesion volume (P<0.00005), but did not modify oedema formation. These findings emphasize the critical importance of rat strain differences in experimental stroke research.

Animals↗

Mycobacterial immune reconstitution inflammatory syndrome in HIV-1 infection after antiretroviral therapy is associated with deregulated specific T-cell responses: beneficial effect of IL-2 and GM-CSF immunotherapy.

BACKGROUND: With the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported. IRIS usually occurs in individuals with a rapidly rising CD4 T-cell count or percentage upon initiation of ART, who develop a deregulated immune response to infection with or without reactivation of opportunistic organisms. Here, we evaluated rises in absolute CD4 T-cells, and specific CD4 T-cell responses in 4 HIV-1+ individuals presenting with mycobacterial associated IRIS who received in conjunction with ART, IL-2 plus GM-CSF immunotherapy. METHODS: We assessed CD4 T-cell counts, HIV-1 RNA loads, phenotype for naïve and activation markers, and in vitro proliferative responses. Results were compared with those observed in 11 matched, successfully treated asymptomatic clinical progressors (CP) with no evidence of opportunistic infections, and uninfected controls. RESULTS: Median CD4 T-cell counts in IRIS patients rose from 22 cells/microl before initiation of ART, to 70 cells/microl after 8 months of therapy (median 6.5 fold increase). This coincided with IRIS diagnosis, lower levels of naïve CD4 T-cells, increased expression of immune activation markers, and weak CD4 T-cell responses. In contrast, CP had a median CD4 T-cell counts of 76 cells/microl at baseline, which rose to 249 cells/microl 6 months post ART, when strong T-cell responses were seen in > 80% of patients. Higher levels of expression of immune activation markers were seen in IRIS patients compared to CP and UC (IRIS > CP > UC). Immunotherapy with IL-2 and GM-CSF paralleled clinical recovery. CONCLUSION: These data suggest that mycobacterial IRIS is associated with inadequate immune reconstitution rather than vigorous specific T-cell responses, and concomitant administration of IL-2 and GM-CSF immunotherapy with effective ART may correct/augment T-cell immunity in such setting resulting in clinical benefit.

Journal Article↗

Candida albicans: the estrogen target for vaginal colonization.

BACKGROUND: Estradiol (E(2)) stimulates colonization of the vagina by Candida albicans. Although this yeast expresses an estrogen-binding protein (EBP), the cellular target for estrogenic modulation of this infection is unresolved. Findings support direct E(2)-induced C. albicans growth as well as indirect effects via E(2)-induced changes in the vaginal epithelium. Our primary goal was to pursue the issue of direct versus indirect estrogen action on vaginal candidiasis using diethylstilbestrol (DES), an efficacious mammalian estrogen receptor agonist, which exhibits no detectable affinity for the EBP of C. albicans. METHODS: We used both in vitro and in vivo experimentation with an EBP-positive strain of C. albicans isolated from the human vagina. Ligand-binding studies were performed with steroidal and nonsteroidal estrogens and anti-estrogens using the soluble EBP from both the yeast and the rat uterus. Mature ovariectomized rats were treated with either E(2) or DES for 7 days before and after C. albicans inoculation into the vaginas. Subsequent estrogen-sensitive colonization was quantified based on cultures of vaginal homogenates on Sabouraud dextrose (SD) agar pour plates. RESULTS: We confirmed that our isolate of C. albicans contained a high-affinity EBP, with no detectable affinity for DES. Vaginal colonization by C. albicans was 8.6-fold greater in response to in vivo treatment with E(2) than with the comparable dose regimen of DES. CONCLUSIONS: The mechanism for estrogen-sensitive vaginal colonization by C. albicans includes a functional ligand-EBP interaction within the yeast.

Animals↗

Sensitivity and specificity of electrodiagnostic criteria for CIDP using ROC curves: comparison to patients with diabetic and MGUS associated neuropathies.

INTRODUCTION: Electrodiagnostic testing plays a key role in the characterization of neuropathies. To this end, sets of electrodiagnostic criteria have been proposed to define chronic inflammatory demyelinating polyneuropathy (CIDP). These criteria sets differ because of the number of data points within the sets, the number of required abnormal measures within a criterion, and the cutoff value of each measure. OBJECTIVE: To evaluate the sensitivity and specificity of the published criteria for defining CIDP in comparison to diabetic polyneuropathy (DMPN) and monoclonal gammopathy of undetermined significance associated neuropathies (MGUS-PN). DESIGN/METHODS: Electrodiagnostic studies of 21 patients with biopsy proven CIDP, 35 patients with MGUS-PN, and 82 patients with DMPN were analyzed. Data were compared against 4 different published criteria sets. Receiver operator characteristic (ROC) curves were used to determine the ideal threshold values for individual electrodiagnostic parameters. RESULTS/CONCLUSION: None of the currently published criteria sets could adequately separate CIDP from DMPN and MGUS-PN. Analysis of our data using ROC curves shows that the best discrimination was achieved using the following criteria: (1) FWL>145%ULN in one nerve or 110%ULN in two nerves in separate nerve roots. (2) Motor CV<90%LLN in four nerves with at least one nerve <70%LLN. Furthermore, proximal-to-distal amplitude ratio alone is not adequate to define conduction block. Although electrodiagnostic studies are important for evaluating CIDP, these studies by themselves cannot be used to define this neuropathy.

Adult↗

A randomized controlled trial of the value of phenotypic testing in addition to genotypic testing for HIV drug resistance: evaluation of resistance assays (ERA) trial investigators.

OBJECTIVES: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options. DESIGN: Multicenter randomized trial. METHODS: Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months. RESULTS: Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%). CONCLUSION: The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.

Acquired Immunodeficiency Syndrome↗

Nanometal surface energy transfer in optical rulers, breaking the FRET barrier.

Optical-based distance measurements are essential for tracking biomolecular conformational changes, drug discovery, and cell biology. Traditional Forster resonance energy transfer (FRET) is efficient for separation distances up to 100 A. We report the first successful application of a dipole-surface type energy transfer from a molecular dipole to a nanometal surface that more than doubles the traditional Forster range (220 A) and follows a 1/R(4) distance dependence. We appended a 1.4 nm Au cluster to the 5' end of one DNA strand as the energy acceptor and a fluorescein (FAM) to the 5' end of the complementary strand as the energy donor. Analysis of the energy transfer on DNA lengths (15, 20, 30, 60bp), complemented by protein-induced DNA bending, provides the basis for fully mapping the extent of this dipole surface type mechanism over its entire usable range (50-250 A). Further, protein function is fully compatible with these nanometal-DNA constructs. Significantly extending the range of optical based methods in molecular rulers is an important leap forward for biophysics.

Base Sequence↗

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

Aged↗

Patients' perception of information about HAART: impact on treatment decisions.

The aim of this study was to profile patients' satisfaction with information they have received about HAART in relation to treatment uptake. As part of a prospective investigation into uptake and adherence to HAART, 115 participants, comprising predominantly gay men, completed validated questionnaires investigating their satisfaction with information relating to practical aspects and potential problems of HAART, perceptions of information from different sources and beliefs about HAART, following a clinically recommended treatment offer. There was a wide range of total satisfaction scores indicating variation in patients' information requirements. Those who declined HAART were less satisfied with the information they had received than those who accepted the treatment recommendation (p < 0.05). Lower levels of satisfaction were associated with stronger concerns about the potential adverse effects of HAART (p < 0.05). Furthermore, concerns about HAART were related to uptake of HAART with those declining treatment being significantly more concerned about potential adverse effects than those who accepted the treatment offer (p < 0.001). The most helpful sources of information were specialist HIV staff: hospital consultants, pharmacists and nurses, as well as other people with HIV. This study improves our understanding of how information about HAART is perceived by people faced with treatment decisions. It emphasizes the importance of providing information tailored to meet the needs of individual patients and address their specific concerns, in order to support informed decision making.

Adult↗

Community based syphilis screening: feasibility, acceptability, and effectiveness in case finding.

OBJECTIVES: To investigate the feasibility and acceptability of implementing community based syphilis screening using different sample collection techniques, and its effectiveness in screening at-risk populations and identifying new syphilis cases. METHODS: Two phases of syphilis screening were conducted in venues frequented by men who have sex with men (MSM). Phase 1 used venepuncture and phase 2 a validated saliva test. Evaluation used quantitative data from testers, venues and the local genitourinary medicine (GUM) clinic, and qualitative data from venue and programme staff. RESULTS: 1090 MSM were tested over 7 weeks. 62% of testers had not attended a GUM clinic in the past year. 64% of testers reported > or = 2 sexual contacts in the past 90 days and 11% reported > or = 10. Similar diagnosis rates were recorded for phase 1 (1.4%) and phase 2 (1.8%). There was greater uptake of testing with the saliva test in saunas during phase 2. CONCLUSIONS: Syphilis screening in gay venues is feasible and acceptable to at-risk MSM, and reaches a group not routinely accessing GUM services. The low case detection for syphilis suggest this approach, while unlikely to contain outbreaks, may be more useful if combined with screening for other sexually transmitted infections and effective health promotion strategies.

Adult↗

Normoglycaemia in acute renal failure--a difficult diagnosis of diabetes.

We report diagnostic difficulties in a case of diabetes mellitus presenting as acute on chronic renal failure with normoglycaemia. A renal biopsy indicated diabetic nephropathy; she developed hyperglycaemia following the institution of haemodialysis. It is important to remember that diabetic patients may have normal blood glucose concentrations in renal failure. In a patient with undiagnosed diabetes mellitus presenting with acute on chronic renal failure, choice of diagnostic biochemical test for diabetes may be difficult.

Acute Kidney Injury↗

Screening, diagnosis and management of early syphilis in genitourinary medicine clinics in the UK.

New diagnoses of syphilis in the UK increased eight-fold between 1997 and 2002. This study, conducted in 2002, demonstrated that 31% of clinics were not confident of their expertise to obtain an adequate specimen for dark ground microscopy (DGM), and 35% were not confident of their expertise to detect treponemes on DGM. In all, 64% of clinics had observed adherence problems in HIV-positive patients treated with parenteral regimens, as against 42% with oral regimens. Also, 51% of clinics waited more than a week for the results of initial serological tests for syphilis, and 88% of clinics waited more than a week for confirmatory test results. Other concerns include the failure to perform syphilis serology consistently whenever HIV-positive patients were at risk, and the widespread use of doxycycline as a therapy for syphilis in HIV-positive patients despite concerns that this is not known to be fully treponemicidal in cerebrospinal fluid.

Anti-Bacterial Agents↗

Effects of a 12-month physical activity counselling intervention on glycaemic control and on the status of cardiovascular risk factors in people with Type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effectiveness of physical activity counselling in promoting physical activity in people with Type 2 diabetes and to evaluate resultant physiological and biochemical effects. METHODS: A total of 70 inactive people with Type 2 diabetes were given standard exercise information and randomised to receive physical activity counselling (n=35, experimental) or not (n=35, control). Physical activity consultations were delivered at baseline and after 6 months, with follow-up phone calls after 1, 3, 6 and 9 months. Changes from baseline after 6 and 12 months were assessed for physical activity (7-day recall and accelerometer), for physiological characteristics (body mass index and blood pressure) and for biochemical variables (HbA(1)c, lipid profile, fibrinogen, tissue plasminogen activator and microalbuminuria). RESULTS: Significant differences between groups were recorded for physical activity after 6 and 12 months (p<0.01). The experimental group had increased levels of physical activity from baseline to 6 months (p<0.01), with no decrease from 6 to 12 months (p>0.05). In the control group, accelerometer counts per week decreased from baseline to 12 months (p=0.03). Between-group differences (p<0.05) were recorded for the change in HbA(1)c (experimental: 0.26% decrease; control: 0.15% increase), for systolic blood pressure (experimental: 7.7 mm Hg decrease; control: 5.6 mm Hg increase) and for fibrinogen (experimental: 0.28 mmol/l decrease; control: 1.43 mmol/l increase) from baseline to 6 months, and for total cholesterol (experimental: 0.33 mmol/l decrease; control: 0.04 mmol/l increase) from baseline to 12 months (p<0.05). No significant differences were recorded in other measured variables. CONCLUSIONS/INTERPRETATIONS: Physical activity counselling was effective in promoting physical activity in people with Type 2 diabetes. The counselling improved glycaemic control as well as the status of cardiovascular risk factors in these patients.

Blood Pressure↗

Outcome of patients with HIV-related germ cell tumours: a case-control study.

Testicular germ cell tumour (GCT) is not an AIDS-defining illness despite an increased incidence in men with HIV infection. We performed a matched case-control study comparing outcomes in HIV-positive men and the general population with GCT, using three age and stage matched controls for each case. There was no difference in the 5-year GCT-free survival between cases and controls. However, overall survival was significantly decreased in the cases (log rank P=0.03). HIV was responsible for 70% of this mortality. The relapse-free survival for stage I patients treated with orchidectomy and surveillance was not affected by HIV status (log rank P=0.68). There was no difference in disease free survival in patients with metastatic disease (log rank P=0.78). The overall survival has not improved since the introduction of highly active antiretroviral therapy (log rank P=0.4). Thus, HIV-related GCT is not more aggressive than GCT in the general population.

Adult↗