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Biomedical subjects

Martin Fisher

Publications and source records attributed to Martin Fisher.

At least 37 records · Page 2Linked to original sources
PubMed2004

ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-A resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other ( approximately 16 degrees ) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S(2)' substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2.

Amino Acid Sequence↗
PubMed2004

Doubts about necessity and concerns about adverse effects: identifying the types of beliefs that are associated with non-adherence to HAART.

This cross-sectional study assessed beliefs about highly active antiretroviral therapy (HAART) and their association with reported adherence to HAART among 109 HIV-positive patients receiving HAART while attending an ambulatory care clinic in Brighton, UK. Patients' beliefs about the necessity for and concerns about HAART and their adherence to it were assessed using validated questionnaires. There was considerable variation in beliefs and reported adherence. A quarter of participants reported low adherence to HAART and this was related to concerns about adverse effects as well as to the way in which each individual balanced concerns against perceptions of necessity. Patients were significantly more likely to report low adherence rates if their concerns were high relative to their perceptions of personal need for HAART. Patients with higher CD4 counts were significantly more likely to hold a view of HAART in which perceptions of necessity were higher relative to their concerns about adverse effects. CD4 was not related to reported adherence. A comparison of most recent viral load results between high and low adherence group identified differences in the predicted direction but these were not statistically significant. These preliminary findings suggest that patients' perceptions of HAART are important determinants of adherence with implications for future research and clinical practice.

Adult↗
PubMed2004

Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine and/or efavirenz.

OBJECTIVE: To assess whether differences in safety profiles between nevirapine (NVP) and efavirenz (EFV), as observed in the 2NN study, translated into differences in 'health related quality of life' (HRQoL). DESIGN: A sub-study of the 2NN study, with antiretroviral-naive patients randomly allocated to NVP (once or twice daily), EFV or NVP+EFV, in addition to stavudine and lamivudine. METHODS: Comparing differences in changes of HRQoL over 48 weeks as measured with the Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire, using analysis of variance. RESULTS: The 2NN study enrolled 1216 patients. No validated questionnaires were available for 244 patients, and 55 patients had no HRQoL data at all, leaving 917 patients eligible for this sub-study. A total of 471 (51%) had HRQoL measurements both at baseline and week 48. The majority (69%) of patients without HRQoL measurements did, however, complete the study. The change in the physical health score (PHS) was 3.9 for NVP, 3.4 for EFV and 2.4 for NVP+EFV (P=0.712). For the mental health score (MHS) these values were 6.1, 7.0 and 3.9, respectively (P=0.098). A baseline plasma HIV-1 RNA concentration (pVL) > or = 100,000 copies/ml and a decline in pVL (per log10) were independently associated with an increase of PHS. An increase of MHS was only associated with pVL decline. Patients experiencing an adverse event during follow-up had a comparable change in PHS but a significantly smaller change in MHS, compared with those without an adverse event. CONCLUSIONS: First-line ART containing NVP and/or EFV leads to an improvement in HRQoL. The gain in HRQoL was similar for NVP and EFV, but slightly lower for the combination of these drugs.

Adult↗
PubMed2003

Purification, crystallization and preliminary crystallographic analysis of phosphoglucose isomerase from the hyperthermophilic archaeon Pyrococcus furiosus.

The glycolytic enzyme phosphoglucose isomerase catalyses the reversible isomerization of glucose 6-phosphate to fructose 6-phosphate. The phosphoglucose isomerase from the hyperthermophilic archaeon Pyrococcus furiosus, which shows no sequence similarity to any known bacterial or eukaryotic phosphoglucose isomerase, has been cloned and overexpressed in Escherichia coli, purified and subsequently crystallized by the hanging-drop method of vapour diffusion using 1.6 M sodium citrate as the precipitant at pH 6.5. Multiple-wavelength anomalous dispersive X-ray data have been collected to a maximum resolution of 1.92 A on a single selenomethionine-incorporated crystal. This crystal belongs to space group C2, with approximate unit-cell parameters a = 84.7, b = 42.4, c = 57.3 A, beta = 120.6 degrees and a monomer in the asymmetric unit.

Crystallization↗
PubMed2003

Joint-working. Worlds apart.

A programme bringing together primary care trust non-executives and local counsellors from the same patch changed participants' perceptions of each other. PCT non-executives and counsellors were convinced of the benefits of joint working, but unsure how to go about it. Knowledge of each other's worlds was initially poor. Annual structured visits between PCTs and local authorities should be encouraged.

Administrative Personnel↗
PubMed2003

Menstrual irregularity in female military cadets: comparison of data utilizing short-term and long-term recall.

STUDY OBJECTIVES: (1) To assess menstrual function in freshman cadets at a structured, rigorous military college utilizing a weekly e-mail questionnaire, (2) to compare these results to longer-term recall results from written questionnaires completed at the start and end of the same year, and (3) to determine if a relationship exists between personality attributes and menstrual regularity in this setting. DESIGN, SETTING, PARTICIPANTS: A questionnaire developed by the investigators about menstrual function was distributed weekly via e-mail and completed satisfactorily by 116 female freshman at the United States Military Academy (USMA), class of 1995. These data were compared to questionnaires completed by this same cohort at the start and end of the year, as well as to personality questionnaires distributed to some of these cadets as part of a larger study. Pearson's chi-square and analysis of variance were performed to determine statistical significance. RESULTS: Weekly e-mail data revealed that only 1.7% of cadets had regular menstrual periods throughout the whole year. The remaining 98.3% were irregular: 10.3% mildly, 35.3% moderately, 30.2% severely, and 22.4% extremely irregular. Only 0.8% of subjects did not menstruate at all during the year. In comparison, on long-term recall data, 90% reported some change in menstrual function, with 48% specifically reporting menstrual irregularity. Those with the greatest irregularity prior to USMA and those who expected greater irregularity at USMA reported the greatest irregularity during the year. Irregularity was associated with coping and with commitment to health on personality questionnaires. CONCLUSIONS: On data collected via weekly e-mail, almost all freshman females at USMA experienced menstrual irregularity. This data, utilizing short-term recall, yielded different, more dramatic results than the data utilizing long-term recall. A link between menstrual irregularity and both coping and commitment suggests that menstrual irregularity may be adaptive in this environment.

Adolescent↗
PubMed2003

The course and outcome of eating disorders in adults and in adolescents: a review.

Over 100 studies have been published in the literature to date on the course and outcome of eating disorders. These have generally shown that approximately 50% of patients do well over time, approximately 30% do reasonably well but continue to have symptoms, and approximately 20% do poorly. In this article, the literature on the course and outcome of eating disorders is reviewed from two perspectives. The first is an analysis of studies in adults, looking in depth at a range of issues (weight, eating behaviors, menstrual function, psychosocial functioning, psychosexual function, mortality, bulimia nervosa, long-term follow-up, comorbidity, and prognostic factors) and reviewing the difficulties inherent to the performance of all eating disorders follow-up studies. The second is an analysis of whether adolescents with eating disorders have a better prognosis than adults, as has been considered in the literature. It is concluded that adolescents do, in fact, have a somewhat better prognosis than adults, with the differences seeming to be greater with a longer duration of follow-up.

Adolescent↗
PubMed2003

Drug resistance genotypes predict response to amprenavir-containing regimens in highly drug-experienced HIV-1-infected patients.

We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.

Adult↗
PubMed2002

A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis.

Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.

AIDS-Related Opportunistic Infections↗
PubMed2002

Long-term follow-up: no effect of therapeutic vaccination with HIV-1 p17/p24:Ty virus-like particles on HIV-1 disease progression.

Long-term effects of therapeutic vaccination of human immunodeficiency virus (HIV)-1-infected subjects with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) on progression to AIDS, death, a CD4 cell count <or=200 cells/mm(3) and CD4 cell count decline were studied in a multicenter cohort study of 56 individuals who participated in a phase II double-blind placebo-controlled trial with p24-VLP in 1993. Using Cox proportional hazard analysis, no difference between vaccine and placebo groups was found in progression to death (adjusted hazard rate (HR): 0.68 (95% CI: 0.05-7.83), AIDS (adjusted HR: 1.07 (95% CI: 0.21-5.36)) and a CD4 cell count <or=200 cells/mm(3) (adjusted HR: 1.00 (95% CI: 0.35-2.87)). Using linear regression with correction for multiple visits within one person, no effect of vaccination on CD4 cell count decline, adjusted for antiretroviral therapy (ART) use, was found (P=0.98). In conclusion, therapeutic vaccination with p24-VLP is not related to slower HIV-1 disease progression.

AIDS Vaccines↗
PubMed2002

Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy.

OBJECTIVE: To assess the risks and benefits of administering highly active antiretroviral therapy (HAART) during the treatment of tuberculosis (TB) in HIV-infected patients. DESIGN AND METHODS: HIV-1 patients presenting to 12 HIV centres in Greater London and south-east England with culture-proven TB were identified from January 1996 to June 1999. Case-notes were reviewed retrospectively. RESULTS: Patients (n = 188) were severely immunocompromised with a median CD4 cell count at TB diagnosis of 90 x 106 cells/l (IQR: 30-180). At presentation, 85% (n = 159) were not taking antiretrovirals. A total of 45% commenced HAART during TB treatment, which was associated with significant reductions in viral load, AIDS-defining illness (ADI) [3.5 versus 24.5%; relative risk (RR) = 0.14] and mortality. Only nine of 91 (10%) patients with a CD4 count > 100 x 106 cells/l at TB diagnosis experienced a further ADI, whereas 18 of 92 (20%) patients with a CD4 count < 100 x 106 cells/l developed this complication. Adverse events (AE) occurred in 99 (54%) of 183 patients, one-third of whom changed or interrupted HIV and/or TB medication. The majority of AE occurred within the first 2 months, with peripheral neuropathy (21%), rash (17%) and gastrointestinal upset (10%) occurring most commonly. CONCLUSIONS: Many physicians delay HAART in patients presenting with TB because of pill burden, drug/drug interactions and toxicity. Although the use of HAART led to significant reductions in viral load, ADI and mortality, co-infected patients commonly experienced AE leading to interruptions in TB/HIV therapy. We therefore recommend starting HAART early for patients with advanced HIV disease (CD4 < 100 x 106 cells/l) and deferring HAART until the continuation phase of TB therapy (i.e. after 2 months) for patients who are clinically stable (CD4 > 100 x 106 cells/l).

Adult↗
PubMed2002

Brief report: two-year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen.

In most studies, people who have not responded virologically to a protease inhibitor (PI)-containing regimen have tended to experience poor virologic responses to subsequent regimens. We describe the 2-year viral load, CD4 count, and clinical outcome of a multidrug regimen used in 60 people who had not responded virologically to a PI-containing regimen. At baseline, median CD4 count was 126/mm(3) (nadir 30/mm(3) ) and median viral load was 320,000 copies/mL. A median of five antiretroviral drugs had previously been used, of which a median of two were PIs. Of these patients, 16% had previously used another nonnucleoside reverse transcriptase inhibitor besides efavirenz. The multidrug regimen (median 5 drugs) started most commonly included efavirenz (100%), at least one PI (92%, usually indinavir/ritonavir), didanosine (78%), and hydroxyurea (74%). At year 2, 5 patients had died and 5 had no measure available. Nine patients developed a new AIDS event and 10 patients were known to have stopped all antiretroviral therapy. Thirty-one patients (52% of the whole group, 72% of those remaining on therapy with viral load value available) had viral load <50 copies/mL. Thus, a substantial proportion of patients who had failed to respond virologically to PI-containing regimens can achieve profound and sustained virologic suppression with a multidrug regimen.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced, HIV-infected individuals: recent data and consensus recommendations.

Recent data from clinical trials investigating the efficacy of enfuvirtide, a fusion inhibitor, in treatment-experienced patients have revealed that the addition of enfuvirtide (ENF) to an active boosted protease inhibitor regimen doubles the rate of virological response. At week 48 of the TORO studies, 55% of patients previously naive to and receiving lopinavir/ritonavir (LPV/r) with ENF achieved a viral load of <400 copies/mL compared with 24% of patients treated with LPV/r alone. At week 24 of the RESIST studies, 70% of previously ENF-naive patients who took both ENF and tipranavir/ritonavir (TPV/r) achieved a >or=1 log10 reduction in viral load compared with 37% of such patients treated with TPV/r alone. Similarly, concomitant use of TMC114/ritonavir (TMC114/r) with ENF, compared with TMC114/r alone, increased the number of patients with <50 copies/mL from 46% to 64% in a combined 24-week analysis from the POWER trials. Data from these trials suggest that combining one agent from a new class with a new agent from a previously exposed class offers a greater chance of achieving full virological control than either type of agent alone. Undetectable viraemia should be the primary objective for treatment-experienced patients requiring a switch in therapy, and the present data support the combination of an active boosted protease inhibitor with an agent from a new class (e.g., ENF) for triple-class-experienced patients.

Antiretroviral Therapy, Highly Active↗
PubMedDate not supplied

Treatment of eating disorders in a division of adolescent medicine.

We present a report on a study of 638 adolescent patients with eating disorders treated at the North Shore University Hospital between 1980 and 1994. Data from the study are presented in this paper, together with a discussion of the implications for treatment in adolescent medicine settings.

Adolescent↗
PubMedDate not supplied

Correlates of low bone density in females with anorexia nervosa.

UNLABELLED: The objectives were to delineate those factors which correlate with low bone density in patients with anorexia nervosa and in turn to predict those at greatest risk for osteopenia. DESIGN: Bone density was evaluated by dual energy x-ray absorptiometry in 28 postmenarchal females with anorexia nervosa who had never received hormonal therapy. Bone density results were correlated with specific historical and physical factors utilizing descriptive statistics, scatter plots, and the Spearman correlation coefficient. RESULTS: Mean age was 18.6 years, mean age at menarche was 12.9 yrs, mean length of illness was 19.8 months and mean duration of amenorrhea was 13.4 months. Mean % ideal body weight was 84% at the time of bone density, 75% at minimum weight and 100% at maximum weight. Mean lumbar spine bone density was -1.69 standard deviations from the norm; mean lateral spine bone density was -1.45 standard deviations from the norm; mean femoral neck of the hip bone density was -1.18 standard deviations from the norm. There was a strong negative correlation between duration of amenorrhea and bone density at the lumbar spine (r = -0.50, p < .01) and a mild correlation at the lateral spine (r = -0.49, p < 0.05) and femoral neck (r = -0.41, p < 0.05). There was also a strong negative correlation between length of illness and bone density at the lumbar spine (r = -0.53, p < 0.01) and lateral spine (r = -0.77, p < 0.0001), and a mild correlation with the femoral neck (r = -0.48, p < 0.05). Scatter plots of lumbar bone density versus duration of amenorrhea, and versus length of illness clearly showed not only that longer duration of amenorrhea and longer length illness correlated to bone loss, but also strikingly that within a short time of being ill and amenorrheic, significant bone loss was seen. Age, and age at menarche correlated mildly with osteopenia at the lateral spine; age correlated mildly with osteopenia at the femoral neck as well. There was a trend for minimum BMI to correlate with osteopenia at the lateral spine. There were no correlations of bone density with % IBW at bone density, minimum % IBW, maximum % IBW, change in % IBW, BMI at the time of the bone density, maximum BMI or change in BMI. CONCLUSIONS: Low bone density, especially in the lumbar spine, correlated with both a longer duration of amenorrhea and longer length of illness, but not with other factors, in our patients with anorexia nervosa. As many of these patients, even those with a short duration of illness and amenorrhea, were osteopenic, it is advisable to continue to perform bone density studies in all patients with anorexia nervosa, on both a clinical and research basis.

Adolescent↗
PubMedDate not supplied

Chronic fatigue syndrome and eating disorders: concurrence or coincidence?

In this report we present four patients who were found to have both an eating disorder and the chronic fatigue syndrome (CFS). Two of the patients presented for evaluation of an eating disorder and also had CFS, while two of the patients presented for evaluation of CFS and also had an eating disorder. In all four patients the eating disorder preceded the CFS. We consider the question of whether the occurrence of these two disorders in the same patients is merely a coincidence; whether an eating disorder can act as a precipitant for CFS, perhaps through the exacerbation of an underlying vascular instability; and whether overlapping etiologies may predispose some adolescents to develop both disorders. We also discuss similarities (including diagnostic dilemmas, cultural influences, psychological correlates, demographic similarities, perceptual biases, and cardiovascular effects) encountered in the management of both of these disorders.

Adolescent↗
PubMedDate not supplied

Cultural factors in orthodox Jewish adolescents treated in a day program for eating disorders.

This study explores the specific role of culture and religion in the development of eating disorders (ED) in Orthodox Jewish female adolescents. We present eight cases admitted to a Day Treatment Program (DTP) for Eating Disorders. Additionally, some preliminary comparisons are examined between Orthodox and all other patients, and also between ultra and modern Orthodox patients. All eight adolescents were transferred from inpatient care, three met program treatment goals, two left prematurely, and three required re-hospitalization. The only significant differences between the Orthodox group and all other patients were on length of stay in the DTP and current use of psychotropic medications. Overall, results suggest that Orthodox patients and all other patients show similar ED presentation and course. However, there are unique cultural and religious circumstances, which require consultation with rabbinic authorities.

Adolescent↗