Biomedical subjects
Publications and source records attributed to D M Walker.
A retirement crisis looms in the United States due to a number of recent and emerging trends that affect government retirement programs, employer- and union-sponsored retirement benefits and personal savings arrangements. The crisis can be averted, but only with well-thought-out action on a number of issues, particularly Social Security and Medicare reform.
OBJECTIVE: To determine the attitudes, knowledge and practices of family medicine residents relating to the pharmaceutical industry and to assess the effectiveness of existing guidelines on appropriate interactions with the pharmaceutical industry. DESIGN: Survey by mailed questionnaire. SETTING: Ontario. PARTICIPANTS: All 262 second-year family medicine residents in Ontario (seven centres); 226 (86.3%) responded. RESULTS: Fifty-two (23.0%) of the residents who responded stated that they had read the CMA policy statement on appropriate interactions between physicians and the pharmaceutical industry. A total of 124 (54.9%) stated that they would attend a private dinner paid for by a pharmaceutical representative; the proportion was not significantly reduced among those who had read the CMA guidelines, which prohibit the acceptance of personal gifts. In all, 186 (82.3%) reported that they would like the opportunity to interact with pharmaceutical representatives in an educational setting, even though several programs now discourage these interactions. Approximately three quarters (172/226 [76.1%]) of the residents indicated that they plan to see pharmaceutical representatives in their future practice. Residents at Centre 2 were significantly more critical of the pharmaceutical industry than those from the other centres. Overall, being aware of, and familiar with, departmental policy or CMA policy on interactions with the pharmaceutical industry did not affect the residents' attitudes or intended future practices. CONCLUSION: The presence of guidelines concerning physicians' interactions with the pharmaceutical industry does not appear to have a significant impact on family medicine residents in Ontario.
Oral submucous fibrosis (OSF) affects an estimated 2.5 million people, mostly in the Indian subcontinent. Limitation of oral opening resulting in difficulty in eating is the main presenting feature. Although nutritional deficiencies and immunological processes may play a part in the pathogenesis, the available epidemiological evidence indicates that chewing betel quid (containing areca nut, tobacco, slaked lime or other species) is an important risk factor for OSF. Genetically determined susceptibility could explain why only a small fraction of those using betel quid develop the disease. In OSF there is an incidence of oral cancer of 7.6 per cent for a median 10-year follow-up period. Risk markers for malignant transformation in OSF include epithelial dysplasia, silver binding nucleolar organizer region counts, and sister-chromatid exchange frequencies; p53 tumour suppressor gene mutations may be involved in these potentially malignant changes.
The incidence of squamous cell carcinoma in patients with oral submucous fibrosis (OSF) exceeds 7 per cent. The proliferative cell nuclear antigen (PCNA) is a convenient marker of epithelial cell proliferation and p53 tumour suppressor gene mutations or deletions are frequent in oral cancer. The present study estimated the basal epithelial cell growth fraction using a standard immunohistological method for the detection of nuclear PCNA from 20 Nepalese patients with OSF as 31.8 per cent compared with 7.6 per cent for oral mucosa from 43 normal subjects (p < 0.001) and 39.4 per cent for 44 patients with oral cancer. The PCNA growth fraction correlated significantly with that derived by Ki-67 labelling. There was no correlation between the growth fraction and the severity of epithelial dysplasia found is OSF. Abnormal expression of p53 protein identified by immunohistochemistry with a panel of antibodies was found in 70 per cent of the OSF specimens, and 21 per cent of mucosal specimens from subjects with clinically normal mouths. PCNA-positive cells and p53 expression were restricted to the basal epithelial layer in OSF. The unexpected finding of p53 protein in clinically healthy mucosa was confined to subjects aged over 40 years who smoked tobacco, a known risk factor for oral cancer. There was no association between p53 expression and epithelial atypia scores in OSF. It is concluded that the proportion of actively cycling epithelial cells is increased in OSF and that p53 tumour suppressor gene mutations or deletions may be prevalent. Confirmation by molecular biology techniques of this genetic damage is now needed.
OBJECTIVE: To describe the variability of reproductive life, from menarche to menopause, in the Geneva female population. DESIGN: Women's Health Survey, 1992-1993. SETTING: Mobile epidemiology unit of a University Hospital. SUBJECTS: One thousand and thirty-two women aged 30 to 74 years, resident in Geneva, Switzerland. MAIN OUTCOME MEASURE: Menstrual and reproductive history. RESULTS: A 'typical' woman of Geneva has her menarche at 13 years, regular 28 day cycles with 5 days of menstrual flow. She is 26 years old when she first gives birth and has her last baby (which is typically the second) at age 31. She has 37 years of potential fecundity and a natural menopause at age 50. In addition, 11% of the women have tried to be pregnant during two years without success, 67% have ever used oral contraceptives, 20% had a first birth at age 30 or more and 23% were nulliparous. Younger women reported earlier ages at menarche. Women with lower education tended to be a younger age at the birth of her first child. CONCLUSIONS: In this first study of the reproductive characteristics of women in Geneva, nulliparity and a late first birth appeared unusually frequent, especially when compared with American or Chinese women. The observed distributions of reproductive history are compatible with the very high incidence rate of breast cancer in the Geneva population.
The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His16-Leu17-Asp18-Ile19-Ile20-Trp21) to the development of potent antagonists at both receptor subtypes (ETA and ETB). In particular, it has been shown that Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ETB receptor selective ligands and the pharmacological differences that exist between species ETB receptors with respect to their affinity for C-terminal hexapeptide antagonists.
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OBJECTIVES: To examine the possible occupational hazard of infection with human herpes viruses among dental personnel. METHODS: Sera from 81 preclinical dental students, 53 clinical dental students and 103 qualified dental surgeons were tested for antibodies to herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus type 6 (HHV-6). The same number of control subjects, matched individually for age (+/- 1 year), sex and social class, was also examined. Antibodies were detected by ELISA for HSV-1, latex agglutination for CMV, indirect immunofluorescence with P3HR1 cells for EBV and indirect immunofluorescence with infected JJhan cells for HHV-6. Each participant also completed a questionnaire to permit correlation of demographic data and risk factors with serological results. RESULTS: No significant difference in seroprevalence was detected between any of the dental groups and their respective controls. There was a significantly higher prevalence of antibodies to EBV among clinical students (P = 0.02) and qualified dentists (P = 0.0003) than among preclinical students. These significant increases were not mirrored in the three corresponding control groups. CONCLUSION: The results suggest a possible occupational risk of infection with EBV in dentists. There was no evidence for a significant risk of occupational infection with HSV-1, CMV or HHV-6.
Studies in isolated superfused rabbit papillary muscles indicate that preconditioning (PC) is not confined to arterially perfused myocardium. In the present study PC of isolated human right atrial trabeculae was investigated avoiding the problems of invasive experimentation in patients. Atrial trabeculae were suspended in an organ bath, superfused with Tyrode's solution and field stimulated at 1 Hz. After stabilization, muscles were randomly allocated to five groups (n = 8 per group). Control (C) muscles had no additional treatment. PC was induced by 3 min rapid pacing at 3 Hz with hypoxic substrate-free buffer, followed by reoxygenation with substrate for 12 min. In two additional groups 8-p-sulfophenyltheophylline (SPT) was added to the superfusate either during stabilization in controls (C+SPT) or during preconditioning (PC+SPT). In the final group, R-phenyl-isopropyl adenosine (R-PIA) was added to the superfusate for 5 min to see whether or not this could substitute for preconditioning. All muscles were then exposed to 90 min hypoxia with no substrate and pacing at 3 Hz, followed by 120 min reoxygenation at 1 Hz. Recovery of developed tension was significantly improved by PC 46.5 +/- 2.4% v 24.6 +/- 2.3% in controls) and this protective effect was blocked by the addition of SPT without adversely affecting controls (recovery in PC+SPT, 25.8 +/- 4.1% and C+SPT, 22.7 +/- 2.9%). R-PIA protected the muscles to a similar extent as PC (43.8 +/- 1.9%). These data provide evidence for the involvement of adenosine in preconditioning in human myocardium.
The leukocyte adhesion molecule L-selectin mediates binding to lymph node high endothelial venules (HEV) and contributes to leukocyte rolling on endothelium at sites of inflammation. Previously, it was shown that truncation of the L-selectin cytoplasmic tail by 11 amino acids abolished binding to lymph node HEV and leukocyte rolling in vivo, but the molecular basis for that observation was not determined. This study examined potential interactions between L-selectin and cytoskeletal proteins. We found that the cytoplasmic domain of L-selectin interacts directly with the cytoplasmic actin-binding protein alpha-actinin and forms a complex with vinculin and possibly talin. Solid phase binding assays using the full-length L-selectin cytoplasmic domain bound to microtiter wells demonstrated direct, specific, and saturable binding of purified alpha-actinin to L-selectin (Kd = 550 nM), but no direct binding of purified talin or vinculin. Interestingly, talin potentiated binding of alpha-actinin to the L-selectin cytoplasmic domain peptide despite the fact that direct binding of talin to L-selectin could not be measured. Vinculin binding to the L-selectin cytoplasmic domain peptide was detectable only in the presence of alpha-actinin. L-selectin coprecipitated with a complex of cytoskeletal proteins including alpha-actinin and vinculin from cells transfected with L-selectin, consistent with the possibility that alpha-actinin binds directly to L-selectin and that vinculin associates by binding to alpha-actinin in vivo to link actin filaments to the L-selectin cytoplasmic domain. In contrast, a deletion mutant of L-selectin lacking the COOH-terminal 11 amino acids of the cytoplasmic domain failed to coprecipitate with alpha-actinin or vinculin. Surprisingly, this mutant L-selectin localized normally to the microvillar projections on the cell surface. These data suggest that the COOH-terminal 11 amino acids of the L-selectin cytoplasmic domain are required for mediating interactions with the actin cytoskeleton via a complex of alpha-actinin and vinculin, but that this portion of the cytoplasmic domain is not necessary for proper localization of L-selectin on the cell surface. Correct L-selectin receptor positioning is therefore insufficient for leukocyte adhesion mediated by L-selectin, suggesting that this adhesion may also require direct interactions with the cytoskeleton.
We describe the pharmacological characteristics of PD 156707 (sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5- trimethoxy-benzyl)-but-2-enoate), a potent, orally active, nonpeptide antagonist of the endothelin A (ETA) receptor subtype. PD 156707 was designed on the basis of a compound identified by screening the Parke-Davis chemical library. PD 156707 is highly selective for the ETA receptor (ETAR) and inhibits the binding of [125I]-ET-1 to cloned human ETAR and ETBR with Ki values of 0.17 and 133.8 nM, respectively. PD 156707 antagonizes ET-1-stimulated phosphoinositide hydrolysis in Ltk- cells expressing cloned human ETAR with an IC50 value of 2.4 nM. PD 156707 inhibits vasoconstriction in isolated blood vessels mediated by ETAR (rabbit femoral artery) and ETBR (rabbit pulmonary artery) with pA2 values of 7.5 and 4.7, respectively. PD 156707 administered orally to rats blocked subsequent ETAR-mediated pressor responses in vivo but had no effect on ETBR-mediated dilator responses. As a potent and orally active ETA-selective antagonist, PD 156707 will be useful in defining the physiological and pathological roles of ETAR.
The development of nonpeptide, low molecular weight antagonists with high potency, oral activity, and selectivity is an important objective to adequately define the potential role of endothelin (ET) and its isopeptides in human diseases. This report describes the structure-activity relationships, ETA/ETB selectivity, and pharmacokinetics of the PD 155080 and PD 156707 series of orally active nonpeptide ET receptor-selective antagonists. Modification of the substituents around the butenolide ring has led to compounds with differing selectivity for human ETA and ETB receptors. Thus, compounds with increased lipophilicity at R2 show increased ETB affinity and a more balanced ETA/ETB profile. For example, the 4-O-n-pentyl analogue of PD 156707 is a potent competitive inhibitor of [125I]ET-1 and [125I]ET-3 binding to human cloned ETA and ETB receptors, with IC50s of 0.8 nM and 44 nM, respectively. Pharmacokinetic properties can also be significantly influenced by structural modifications at the R2 group. The pharmacokinetics of PD 155719, PD 155080, and PD 156707 were compared in male Wistar rats after a 15 mg/kg intravenous or oral gavage dose (three animals per dose). Plasma concentrations were determined by a specific HPLC assay. Oral bioavailability ranged from less than 5% for PD 155719 to 41% for PD 156707 and 87% for PD 155080.
Preconditioning has only been demonstrated in arterially perfused myocardium. Our aim was to develop a model of preconditioning in isolated, superfused, isometrically contracting rabbit right ventricular papillary muscle. This would eventually allow us to evaluate isolated human muscles. Papillary muscles were suspended in an organ bath, superfused with oxygenated Tyrode solution, and field stimulated at 1 Hz. Muscles were assigned either to control or to preconditioning groups. Preconditioning was induced with 3 min of rapid pacing (3 Hz) with substrate-free hypoxic buffer and was followed by 15 min of reoxygenation with substrate. Subsequently, both groups were exposed to 45 min of substrate-free hypoxia followed by 120 min of reoxygenation with substrate. Preconditioning protected the myocardium with better recovery of developed force (50.6 +/- 6.7 vs. 27.4 +/- 4.2% of baseline developed force, P < 0.01). This effect could be blocked by 8-(p-sulfophenyl)theophylline (SPT) given during preconditioning at a dose that did not increase hypoxic damage in controls (percent developed force compared to baseline: preconditioned muscles + SPT = 30.9 +/- 2.8% and control muscles + SPT = 27.1 +/- 2.3%). In addition, pretreatment with (-)N6(2-phenylisopropyl)adenosine similarly protected the myocardium (49.5 +/- 5.5% recovery, P < 0.01). We conclude that isolated superfused muscles can be preconditioned. This preconditioning does not depend on coronary flow and involves activation of adenosine receptors.
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Over a 6-month period, all patients admitted to the Royal United Hospital, Bath, with acute ischaemic heart disease were prospectively followed for the period of their hospital stay. Strict admission and discharge criteria were defined for the Coronary Care Unit (CCU), so that groups of patients could be identified in which the treatment was not ideal. The mortality in the groups of patients who were admitted to the CCU without delay and for an appropriate length of time was 5.1% (18/355). It was significantly higher overall in the groups of patients who were either not admitted (14.3%, 4/28) or whose admission was delayed (17.4%, 4/23). The results underline the importance of the provision of adequate coronary care facilities.
Thirty-five patients suffering from minor recurrent aphthous ulceration (RAU) entered a single-phase double-blind clinical trial of treatment with topical prostaglandin E2 (PGE2). The PGE2 was applied as a gel at a dose of 0.3 mg twice daily for 10 days. The vehicle alone acted as control. Patients were examined on days 1, 3, 5, 7 and 10 and also maintained daily diary cards. Of the 33 patients (94%) who completed the study, 18 had been allocated the active PGE2 and 15 the placebo. The two volunteers who failed to complete were excluded on technical grounds related to the strict study design and did not withdraw on the basis of adverse reactions to the trial preparation. Patients using the active PGE2 gel experienced significantly fewer new lesions than those on placebo (P < 0.05) over the 10-day trial period. There were no significant differences between the PGE2 and placebo gels in terms of speed of healing or pain relief of established aphthous ulcers. Prostaglandin E2 may, therefore, have useful prophylactic activity in RAU.
OBJECTIVE: Rapid pacing has been shown to precondition the dog heart against ischaemic dysrhythmia. The aim of this study was to determine whether rapid pacing could also limit infarct size. METHODS: Rabbits (n = 5) were rapidly paced via the left atrium at 420-480 beats.min-1. Five min of rapid pacing and 10 min of recovery in sinus rhythm were followed by 45 min of regional ischaemia and 120 min of reperfusion. Control rabbits (n = 9) were treated identically without prior rapid pacing. Infarct size was determined in both groups using tetrazolium and expressed as a percentage of the area at risk demarcated by fluorescent microspheres. In a separate series of experiments, rapidly paced Langendorff perfused rabbit hearts (n = 9) were used to determine coronary flow under perfusion conditions designed to simulate the in vivo situation during rapid pacing. RESULTS: Rapid pacing caused a fall in systolic pressure from 91.4(SEM 4.5) to 47.0(5.9) mm Hg (p < 0.01) and diastolic pressure from 67.2(2.9) to 23.6(3.2) mm Hg (p < 0.01). Both recovered within 30 s of cessation of pacing. During rapid pacing the action potential duration shortened from 192(13) to 128(5) ms (p = 0.01) and developed electrical alternans (n = 4). Following rapid pacing the ECG showed either ST depression or T wave inversion (n = 4). Despite these profound changes, rapid pacing did not reduce infarct size v control [52.7(4.6)% v 60.8(9.1)% of the area at risk, respectively]. The in vitro experiments estimated that rapid pacing would result in a reduction in coronary flow to 44% of that in sinus rhythm without a significant rise in lactate efflux. CONCLUSIONS: In our model, pretreatment with rapid pacing fails to reduce infarct size. The most likely reason for this is that rapid pacing at a rate of 480 beats.min-1 does not cause myocardial ischaemia of sufficient severity to trigger the preconditioning response.
OBJECTIVE: Heat stress, with the expression of heat stress proteins, has been shown to protect the rabbit heart in vitro against global ischaemia/reperfusion injury, though no benefit is apparent in an in vivo rabbit model of infarct size. The aim of this study was therefore to investigate this discrepancy and to discover whether heating itself has any effect which could negate the protection derived from myocardial stress protein synthesis. METHODS: (1) To ascertain whether heat stress could limit infarct size in the absence of blood, isolated buffer perfused hearts, with or without prior heat stress, were subjected to 45 min of regional ischaemia and 120 min reperfusion, and the resulting infarct size was expressed as a percentage of the risk area (I/R%). (2) The observations were repeated in an isolated blood perfused heart model in which a support rabbit (heat stressed or control) was used to perfuse the isolated heart. RESULTS: In the buffer perfused heart, prior heat stress reduced I/R from 70.8(SEM 4.4)%, n = 10, in controls to 51.5(5.7)%, n = 12 (p < 0.05). In hearts perfused by support rabbits, prior heat stress reduced I/R [from 34.7(3.7)%, n = 16, to 23.5(3.3)%, n = 15 (p < 0.05)] only when the perfusing rabbit was a control (not heat stressed). If the perfusing rabbit had been heated, I/R was greater in both heat stressed and control hearts [51.9(7.0)% and 44.9(3.3)%, p < 0.05 v control support rabbit]. CONCLUSIONS: Heat stress limits infarct size in this rabbit model. However it appears to have additional adverse effects, probably on the blood, which may override any benefit associated with myocardial stress protein synthesis.