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Biomedical subjects

M Bond

Publications and source records attributed to M Bond.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regulation of PKA binding to AKAPs in the heart: alterations in human heart failure.

BACKGROUND: cAMP-dependent protein kinase (PKA) regulates a broad range of cellular responses in the cardiac myocyte. Downstream regulation of the PKA pathway is mediated by a class of scaffolding proteins called A-kinase anchoring proteins (AKAPs), which sequester PKA to specific subcellular locations through binding to its regulatory subunit (R). However, the effect of RII autophosphorylation on AKAP binding and the degree of RII autophosphorylation in failing and nonfailing human hearts remains unknown. METHODS AND RESULTS: We investigated AKAP-RII binding by overlay analysis and surface plasmon resonance spectroscopy and measured RII autophosphorylation in human hearts by backphosphorylation. Binding of Ht31 peptide (representing the RII-binding region of AKAPs) to cardiac RII was increased approximately 145% (P<0.01) for autophosphorylated RII relative to unphosphorylated control. By surface plasmon resonance, RII autophosphorylation significantly increased binding affinity to Ht31 by approximately 200% (P<0.01). Baseline PKA-dependent phosphorylation of RII was significantly decreased approximately 30% (P<0.05) in human hearts with dilated cardiomyopathy compared with nonfailing controls. CONCLUSIONS: These results suggest that AKAP binding of PKA in the heart is regulated by RII autophosphorylation. Therefore AKAP targeting of PKA may be reduced in patients with end-stage heart failure. This mechanism may be responsible for the decreased cAMP-dependent phosphorylation of proteins in dilated cardiomyopathy that we and others have previously observed.

A Kinase Anchor Proteins↗
PubMed2000

Evaluation of outreach clinics held by specialists in general practice in England.

OBJECTIVES: To measure the processes of care, health benefits and costs of outreach clinics held by hospital specialists in primary care settings. DESIGN: The study was designed as a case-referent (comparative) study in which the features of 19 outreach clinics (cases) were compared with matched outpatient clinics (controls). The measuring instruments were self administered questionnaires. Patients were followed up at six months to reassess health status. The specialties included in the study were cardiology, ENT, general medicine, general surgery, gynaecology and rheumatology. SETTING: Specialist outreach clinics in general practice in England, with matched outpatient clinic controls. SUBJECTS: Consecutive patient attenders in the outreach and outpatient clinics, their specialists, the outreach patients' general practitioners, practice managers and trust accountants. Patients' response rate at baseline: 78% (1420). MAIN OUTCOME MEASURES: Patient satisfaction, doctors' attitudes, processes and health outcomes, costs. RESULTS: Outreach patients were more satisfied with the processes of their care than outpatients, their access to specialist care was better than that for outpatients and they were more likely to be discharged. Doctors reported that the main advantages of the outreach clinic were improved patient access to specialists and convenience for patients, in comparison with outpatients, and most GPs and specialists felt the outreach clinic was "worthwhile". At six month follow up, the health status of the outreach sample had significantly improved more than that of the outpatients on all eight sub-scales of the HSQ-12, but this was probably because of their better starting point at baseline. The impact of outreach on health outcomes was small. The NHS costs of outreach were significantly higher than outpatients. An increase in outreach clinic size would reduce cost per patient, but would lead to the loss of most of the clinics' benefits. CONCLUSIONS: While the process of care was of higher quality in outreach than in outpatients, and the efficiency of care was also greater in the latter, the effect on patients' health outcomes was small. Responsiveness to patients' views and preferences is an essential component of good quality service provision. However, the greater cost of outreach raises the issue of whether improvements in the quality and efficiency of health care, without a substantial impact on health outcomes, is money well spent in a publicly funded health service. On the other hand, the real costs of outreach in comparison with outpatients clinics can probably only be truly estimated in a longitudinal study with a resource based costing model derived from documented patient attendances and treatment costs over time in relation to longer term outcome (for example, at a two year end point).

Ambulatory Care Facilities↗
PubMed2000

Investigation of the increased incidence of gonorrhoea diagnosed in genitourinary medicine clinics in England, 1994-6.

OBJECTIVES: To determine important risk factors associated with cases of gonorrhoea in England, and whether any particular risk groups were associated with the substantial rise in numbers of cases seen between 1994 and 1996. DESIGN: Two retrospective cross sectional surveys. SETTING: 70 randomly selected genitourinary medicine (GUM) clinics in England. SUBJECTS: 10% of all gonorrhoea patients attending GUM clinics in England in 1994 (847 patients) and 1996 (1146 patients). MAIN OUTCOME MEASURES: For risk factors in 1996 (study 1), unadjusted rates per 100,000 population aged 14-70 and relative rates (RR) with 95% confidence intervals (CIs). For the change in risk factors between 1994 and 1996 (study 2), adjusted odds ratios (ORs) with 95% CIs, derived from logistic regression analyses of data on patients in 1996, with patients in 1994 as the comparison group. RESULTS: The incidence of gonorrhoea in 1996 was higher in homosexual males (812 per 100,000; RR = 30.2, CI = 25.2 to 36.0) compared with heterosexual males (27 per 100,000); in black Caribbeans (467 per 100,000; 21.4, 17.9 to 25.5) and black Africans (235 per 100,000; 10.8, 7.5 to 15.5) compared with white people (22 per 100,000); and in previous GUM clinic attenders (433 per 100,000; 37.93, 35.46 to 40.56) compared with those who had not attended previously (11 per 100,000). However, most patients were either white or heterosexual. Heterosexual patients in 1996 were significantly more likely to have reduced sensitivity to penicillin (2.55, 1.20 to 5.41) than those in 1994. Male homo/bisexual patients in 1996 were significantly more likely to be from the north west (3.77, 1.45 to 9.80) and to have either reduced sensitivity (2.63, 1.03 to 6.73) or complete resistance (1.98, 1.03 to 3.78) to penicillin, compared with those in 1994. CONCLUSIONS: Homo/bisexual men and the black Caribbean population in England experience a disproportionate burden of gonococcal infections, however, the bulk of diagnoses are in white heterosexuals. No single risk group was associated with the rise in numbers of cases between 1994 and 1996. Resistance to penicillin is widespread and has increased in homo/bisexual men, and it is possible that a rise in treatment failures has, to some extent, enhanced transmission of gonorrhoea and contributed to the rise in numbers of diagnoses in this group.

Adolescent↗
PubMed1999

Cyclic AMP-dependent protein kinase binding to A-kinase anchoring proteins in living cells by fluorescence resonance energy transfer of green fluorescent protein fusion proteins.

A-kinase anchoring proteins tether cAMP-dependent protein kinase (PKA) to specific subcellular locations. The purpose of this study was to use fluorescence resonance energy transfer to monitor binding events in living cells between the type II regulatory subunit of PKA (RII) and the RII-binding domain of the human thyroid RII anchoring protein (Ht31), a peptide containing the PKA-binding domain of an A-kinase anchoring protein. RII was linked to enhanced yellow fluorescent protein (EYFP), Ht31 was linked to enhanced cyan fluorescent protein (ECFP), and these constructs were coexpressed in Chinese hamster ovary cells. Upon excitation of the donor fluorophore, Ht31.ECFP, an increase in emission of the acceptor fluorophore, RII.EYFP, and a decrease in emission from Ht31.ECFP were observed. The emission ratio (acceptor/donor) was increased 2-fold (p < 0.05) in cells expressing Ht31.ECFP and RII.EYFP compared with cells expressing Ht31P.ECFP, the inactive form of Ht31, and RII.EYFP. These results provide the first in vivo demonstration of RII/Ht31 interaction in living cells and confirm previous in vitro findings of RII/Ht31 binding. Using surface plasmon resonance, we also showed that the green fluorescent protein tags did not significantly alter the binding of Ht31 to RII. Thus, fluorescence resonance energy transfer can be used to directly monitor protein-protein interactions of the PKA signaling pathway in living cells.

A Kinase Anchor Proteins↗
PubMed1999

Nuclear factor kappaB activity is essential for matrix metalloproteinase-1 and -3 upregulation in rabbit dermal fibroblasts.

Expression of matrix metalloproteinases (MMPs)-1 and -3 in fibroblasts is upregulated by pro-inflammatory cytokines and growth factors during proliferative inflammatory processes, including wound healing and rheumatoid arthritis. The Activator Protein-1 (AP-1) transcription factor is essential but, we show here, not sufficient for upregulation because platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which strongly activate AP-1, poorly induce MMP-1 and -3. Interleukin-1alpha, which activates nuclear factor-kappaB (NF-kappaB), synergistically upregulates MMP-1 and -3 expression in the presence of bFGF or PDGF. Adenovirus mediated overexpression of IkappaBalpha, the inhibitor of NF-kappaB, completely suppresses MMP-1 and -3 protein and mRNA expression. Hence, we show for the first time that (NF-kappaB) activity is also essential for MMP-1 and -3 upregulation.

Adenoviridae↗
PubMed1999

Protein kinase A (PKA)-dependent troponin-I phosphorylation and PKA regulatory subunits are decreased in human dilated cardiomyopathy.

BACKGROUND: Most studies indicate that failing human hearts have greater baseline myofibrillar Ca2+ sensitivity of tension development than nonfailing hearts. Phosphorylation of cardiac troponin I (TnI) by cAMP-dependent protein kinase (PKA) decreases the affinity of the troponin complex for Ca2+, thus altering the Ca2+ sensitivity of force production. We tested the hypothesis that PKA-dependent TnI phosphorylation is altered in the failing human heart and investigated changes in PKA regulatory subunits as a potential mechanism. METHODS AND RESULTS: Using in vitro back-phosphorylation with [gamma-32P]ATP, we demonstrated a significant (P<0.05) approximately 25% reduction in baseline PKA-dependent TnI phosphorylation in human hearts with dilated cardiomyopathy (DCM) compared with nonfailing (NF) human hearts. There was no significant difference in cAMP content or maximal PKA activity between DCM and NF hearts, but expression of the regulatory subunits of PKA-I (RI) and PKA-II (RII) was significantly decreased in DCM versus NF hearts (RI by approximately 40%, P<0.05; RII by approximately 30%, P<0.01). CONCLUSIONS: PKA activity is regulated at the substrate level through interactions of PKA regulatory subunits with A-kinase anchoring proteins. The reduced baseline PKA-dependent phosphorylation of TnI in DCM may be due to decreased expression of RI and RII and consequently reduced anchoring of PKA holoenzyme. These findings provide new evidence of deficiencies in downstream regulation of the beta-adrenergic pathway in the failing human heart and may account for increased baseline myofibrillar Ca2+ sensitivity.

Adult↗
PubMed1999

Computer assisted outcomes research in orthopedics: total joint replacement.

Long-term studies are needed to determine clinically relevant outcomes within the practice of orthopedic surgery. Historically, the patient's subjective feelings of quality of life have been largely ignored. However, there has been a strong movement toward measuring perceived quality of life through such instruments as the SF-36. In a large database from an orthopedic practice results are presented. First, computerized data entry using touch screen technology is not only cost effective but user friendly. Second, patients undergoing hip or knee arthroplasty surgeries make statistically significant improvements in seven of the eight domains of the SF-36 in the first 3 months after surgery. Additional statistically significant improvements over the next 6 to 12 months are also seen. The data are presented here in detail to demonstrate the benefits of a patient outcomes program, to enhance the understanding and use of outcomes data and to encourage further work in outcomes measurement in orthopedics.

Activities of Daily Living↗
PubMed1999

Can memory requirements account for species' differences in invisible displacement tasks?

We tested the hypothesis that poor performance on the Piagetian invisible displacement task is related to increased memory requirements. Rhesus monkeys and orangutans received 3 types of problems (invisible, visible, and no transfer problems) each containing a number of steps equivalent to that of standard invisible displacements. If failure to solve invisible displacements was due to increased memory requirements, then the primates should perform at chance level on all 3 problems. However, rhesus monkeys solved visible and no transfer problems, but not invisible transfer problems. Half of the orangutans solved all 3 transfer problems, although their performance on invisible transfer problems was lower than that on the other problems. A subsequent cuing phase led to improved performance, and a few monkeys solved invisible transfer problems.

Animals↗
PubMed1999

Towards understanding women's decisions to cease HRT.

Drawing upon an exploratory study into women's decisions to stop hormone replacement therapy, this paper discusses the patterns of information seeking and exchange between a convenience sample of 16 white European women and their doctors. Cessation was associated with confused and confusing diagnostic, prescribing and monitoring practices in a context of uncertainty about changing bodily states and the merits of medication. Enhanced openness to dialogue at critical points could enlighten health workers about why individual women stop treatment and enable women more easily to make informed decisions about continuing to take hormone replacement therapy.

Adult↗
PubMed1999

Short Form 36 (SF-36) Health Survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey.

BACKGROUND: Population norms for the attributes included in measurement scales are required to provide a standard with which scores from other study populations can be compared. This study aimed to obtain population norms for the Short Form 36 (SF-36) Health Survey Questionnaire, derived from a random sample of the population in Britain who were interviewed at home, and to make comparisons with other commonly used norms. METHODS: The method was a face-to-face interview survey of a random sample of 2056 adults living at home in Britain (response rate 78 per cent). Comparisons of the SF-36 scores derived from this sample were made with the Health Survey for England and the Oxford Healthy Life Survey. RESULTS: Controlling for age and sex, many of mean scores on the SF-36 dimensions differed between the three datasets. The British interview sample had better total means for Physical Functioning, Social Functioning, Mental Health, Energy/Vitality, and General Health Perceptions. The Health (interview) Survey for England had the lowest (worst) total mean scores for Physical Functioning, Social Functioning, Role Limitations (physical), Bodily Pain, and Health Perceptions. The postal sample in central England had the lowest (worst) total mean scores for Role Limitations (emotional), Mental Health and Energy/Vitality. CONCLUSION: Responses obtained from interview methods may suffer more from social desirability bias (resulting in inflated SF-36 scores) than postal surveys. Differences in SF-36 means between surveys are also likely to reflect question order and contextual effects of the questionnaires. This indicates the importance of providing mode-specific population norms for the various methods of questionnaire administration.

Adolescent↗
PubMed1999

Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice.

To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.

Alleles↗
PubMed1999

A one-year survey of gonococcal infection seen in the genitourinary medicine department of a London district general hospital.

The results of a one-year clinical, epidemiological and microbiological survey of gonococcal infection presenting to the Patrick Clements Clinic (PCC), a London district general hospital (DGH) genitourinary medicine (GUM) clinic, are presented. Clinical and epidemiological patient data were collected by a combination of questionnaire and retrospective case-note review. Microscopy performance within the PCC, outcome of treatment, return for tests of cure and efficacy of contact tracing were assessed. Isolates were tested for susceptibility to penicillin, tetracycline and ciprofloxacin. The study showed the PCC continues to diagnose and treat over 200 cases of gonorrhoea per year. High level resistance to penicillin, tetracycline and ciprofloxacin was documented among the year's isolates and antibiotic resistance was linked to acquisition of gonorrhoea overseas. Despite interviewing 183 patients concerning health advice and contact tracing issues, only 55% of new episodes re-attended for a first test of cure. In addition, only 29% of reported sexual contacts attended GUM clinics for investigation and treatment.

Adolescent↗
PubMed1999

Langerhans' cell histiocytosis: paediatric head and neck study.

OBJECTIVE: This study presents the experience of the Montreal Children's Hospital (MCH) with Langerhans' cell histiocytosis (LCH) and reviews the new advances in diagnosis and therapy of this disorder. DESIGN: Retrospective study of 20 patients seen between July 1986 and July 1997 diagnosed with LCH. METHODS: All of the 20 charts were examined for variables including age, sex, area involved, treatment modalities, and complications. RESULT: Sixty-five percent of patients presented with localized lesions and 35% with multisystem involvement. The most common involved area was the skull, and 57% of skull lesions involved frontal bone. The temporal bone was involved in 25% of cases. The most common ear symptom was otorrhea. CONCLUSION: Langerhans' cell histiocytosis is a rare paediatric disorder. Head and neck involvement occurs frequently in both localized and multisystem disease. The prognosis is highly dependent on the age and number of systems involved.

Adolescent↗
PubMed1999

Sequential consequences of therapists' interventions.

Using sequential analysis, the authors examined how therapists' actions related to the verbal disclosure and defensive patterns that followed therapists' interventions within a single therapy hour for 20 patients. At the same time, a new measure, the Psychodynamic Intervention Rating Scale (PIRS), was tested for reliability and construct validity. Results indicated that therapists fit their styles of intervention to patients' levels of distress and functioning. Within the session, patient's emotional elaboration was followed by therapist's defense interpretation, followed by more patient emotional elaboration. Patient elaboration of significance was followed by more transference interpretation, followed by more patient elaboration of significance. Noninterpretive interventions were followed by patient's disclosure of facts, not emotion. Both interpretive intervention process sequences and therapist's use of support predicted posttreatment symptom reduction. The PIRS was shown to have satisfactory reliability and construct validity.

Depressive Disorder↗
PubMed1998

Changes in magnesium content and subcellular distribution during retinoic acid-induced differentiation of HL60 cells.

Magnesium (Mg) is required for cellular proliferation; however, the differences in subcellular regulation of Mg between proliferating and differentiated cells has not been determined. We used electron probe microanalysis (EPMA) to investigate the subcellular distribution of Mg in HL60 cells (a promyelocytic leukemia cell line) before and after retinoic acid (RA)-induced differentiation. Most intracellular Mg is bound to ATP and the Mg-ATP complex regulates several metabolic enzymes. We also compared alterations in Mg content following differentiation with the changes in ATP and ADP levels. Using atomic absorption spectrophotometry, we observed a significant decrease (-20%) in cellular Mg content in RA-differentiated HL60 cells. To investigate which intracellular compartments were involved in these changes, we analyzed subcellular elemental composition in freeze-dried cryosections of rapidly frozen undifferentiated and differentiated HL60 cells by EPMA. Following differentiation of HL60 cells, we observed an 18% decrease in Mg content in both the cytoplasm (regions of the cell excluding mitochondria and nuclei) and mitochondria. There was also a significant (40%) decrease in cytoplasmic Ca content after RA-induced differentiation. Nuclear Mg concentration was not significantly different between differentiated and undifferentiated HL60 cells, although differentiation was accompanied by a 30% decrease in the nuclear K/Na ratio. After differentiation, cellular ATP and ADP content decreased by 31 and 40%, respectively. We conclude that during exit from the cell cycle, Mg redistributes within cells and that the decrease in cytoplasmic and mitochondrial Mg is accompanied by a decrease in ATP and ADP content.

Adenosine Diphosphate↗
PubMed1998

Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B.

Matrix metalloproteinase (MMPs) enzymes are implicated in matrix remodelling during proliferative inflammatory processes including wound healing. We report here synergistic upregulation of MMP-9 protein and mRNA by platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in combination with interleukin-1alpha (IL-1alpha) or tumour necrosis factor-alpha (TNF-alpha) in primary rabbit and human dermal fibroblasts. The synergistic interaction between growth factors and cytokines implies that basement membrane remodelling is maximal physiologically when both are present together. The signalling pathways mediating this synergistic regulation are not understood, although analysis of the MMP-9 promoter has identified an essential proximal AP-1 element and an upstream nuclear factor kappa-B (NF-kappaB) site. Using electromobility shift assays, binding to the AP-1 site was only slightly increased by growth factors and cytokines. NF-kappaB binding was rapidly induced by IL-1alpha or TNF-alpha but was neither induced nor potentiated by bFGF or PDGF. Neither AP-1 nor NF-kappaB was therefore sufficient on its own for synergistic regulation. Using a recently developed adenovirus that overexpresses the inhibitory subunit, IkappaB alpha, we demonstrated an absolute requirement for NF-kappaB in upregulation of MMP-9. Activation of NF-kappaB binding by inflammatory cytokines was therefore necessary but not sufficient for synergistic upregulation of MMP-9.

Animals↗