Biomedical subjects
R Baker
Publications and source records attributed to R Baker.
Kidney dysfunction: a safety update on adefovir (preveon).
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Evaluation of a primary care counselling service in Dorset.
BACKGROUND: Research into the effectiveness of counselling in primary care is rare. This study attempts to provide a thorough evaluation of the effects of a new counselling service introduced throughout Dorset. AIM: To evaluate the impact of counselling on client symptomatology, self-esteem, and quality of life. The effect of counselling on drug prescribing, referrals to other mental health professionals, and client and general practitioner (GP) satisfaction were also assessed. METHOD: All new clients referred for counselling were asked to complete and return questionnaires before and after counselling. A total of 385 clients took part in the study. The first and second assessments were compared statistically. Clients were ascribed a psychiatric diagnosis using a simplified version of DSM-IIIR (Diagnostic and Statistical Manual of the American Psychiatric Association). GPs' views of the service were determined using a specially designed questionnaire. Drug data were obtained from the Prescription Pricing Authority and referral statistics from Dorset HealthCare National Health Service (NHS) Trust. RESULTS: The number of psychiatric symptoms and their severity were significantly reduced by counselling. There were no significant differences in the prescription of anxiolytic/hypnotic and anti-depressant medication between matched practices with and without counsellors. The presence of a counsellor did not affect the rate of referral to other mental health professionals. Clients and GPs valued the service highly. CONCLUSIONS: The Psychology Managed Counselling Service is an effective method of running a counselling service and is well received by both clients and GPs. Counselled clients improved significantly on several measures.
A survey of audit activity in general practice.
BACKGROUND: Since 1991, all general practices have been encouraged to undertake clinical audit. Audit groups report that participation is high, and some local surveys have been undertaken, but no detailed national survey has been reported. AIM: To determine audit activities in general practices and the perceptions of general practitioners (GPs) regarding the future of clinical audit in primary care. METHOD: A questionnaire on audit activities was sent to 707 practices from 18 medical audit advisory group areas. The audit groups had been ranked by annual funding from 1992 to 1995. Six groups were selected at random from the top, middle, and lowest thirds of this rank order. RESULTS: A total of 428 (60.5%) usable responses were received. Overall, 346 (85%) responders reported 125.7 audits from the previous year with a median of three audits per practice. There was no correlation between the number of audits reported and the funding per GP for the medical audit advisory group. Of 997 audits described in detail, changes were reported as 'not needed' in 220 (22%), 'not made' in 142 (14%), 'made' in 439 (44%), and 'made and remeasured' in 196 (20%). Thus, 635 (64%) audits were reported to have led to changes. Some 853 (81%) of the topics identified were on clinical care. Responders made 242 (42%) positive comments on the future of clinical audit in primary care, and 152 (26%) negative views were recorded. CONCLUSION: The level of audit activity in general practice is reasonably high, and most of the audits result in change. The number of audits per practice seems to be independent of the level of funding that the medical audit advisory group has received. Although there is room for improvement in the levels of effective audit activity in general practice, continued support by the professionally led audit groups could enable all practices to undertake effective audit that leads to improvement in patient care.
c-fos and c-jun mRNA expression in activated cord and adult lymphocytes: an analysis by Northern hybridization.
BACKGROUND AND OBJECTIVES: To further analyze the neonatal immune response to an antigenic challenge such as blood transfusion, c-fos and c-jun mRNA expression were analyzed in twelve in-vitro-stimulated normal cord blood and ten in-vitro-stimulated normal adult peripheral blood lymphocyte samples. MATERIALS AND METHODS: Lymphocyte samples were stimulated by either the mitogen phytohemagglutinin (PHA) or the monoclonal antibody alphaCD3. Proliferation rate and Northern blot hybridization were employed. RESULTS: Cord lymphocytes revealed a greater proliferation rate with PHA and alphaCD3 than adult lymphocytes (p = 0.0081 and 0.0023, respectively). In addition, Northern blot analysis of cord and adult samples revealed similar maximal increases in c-fos (99+/-15 and 126+/-11%, p = 0.0126) and c-jun (123+/-9 and 185+/-38%, p = 0.0291) mRNA expression, respectively, as early as 15 min post-alphaCD3 stimulation. Adult lymphocytes showed an equivalent increase in mRNA expression of c-fos and c-jun (140+/-25 and 155+/-31%) at 30 min post-PHA stimulation, while cord lymphocyte maximum c-fos and c-jun expression (82+/-6 and 142+/-12%) occurred at 15 min post-PHA stimulation (c-fos, p = 0.0354; c-jun, p = 0.0112). CONCLUSION: Although cord lymphocyte proliferation rates were significantly greater than those of adult lymphocytes following stimulation, lymphocyte activation, as analyzed by c-fos and c-jun mRNA expression, appears similar in both cord and adult samples. We conclude that cord lymphocyte activation exhibits an adult-type profile.
Learners' experience of continuing medical education events: a qualitative study of GP principals in Dorset.
BACKGROUND: General practitioners' (GPs') attendance at continuing medical education (CME) events has increased since the introduction of the Post Graduate Educational Allowance (PGEA) in 1990. However, few studies have examined doctors' perceptions about their continuing education, and explored their views in depth. AIM: To investigate general practitioners' experience of CME events, what personal impact they had, and how the GPs perceived the influence of CME in their professional practice and patient care. METHOD: A qualitative study, with in-depth semi-structured interviews, of a purposive sample of 25 general practitioners in Dorset was conducted. Content analysis was used to identify major themes from the transcripts. RESULTS: GPs perceived CME events as beneficial. Confidence levels rose, and the events provided a break from practice that refreshed and relaxed, thus indirectly benefiting patients. The opportunities provided by formal events for informal learning and exchange of ideas, with both peers in general practice and consultant colleagues, were highly valued. The relevance of the subject to general practice, and the appropriateness of the educational format, were considered of paramount importance. Few responders identified major changes in their practice as a result of formal CME events, and information was seldom disseminated among practice colleagues. CONCLUSION: The results of this study challenge GP educators to provide CME that is relevant, to recognize the value of peer contact, and to facilitate the incorporation of new information into practice.
The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.
Effect of plasma protein binding on in vivo activity and brain penetration of glycine/NMDA receptor antagonists.
A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4-hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. Relative binding to the major plasma protein, albumin, was measured in two different ways: by a radioligand binding experiment or using an HPLC assay, for a wide structural range of glycine/NMDA site ligands. These measures of plasma protein binding correlate well (r = 0.84), and the HPLC assay has been used extensively to quantify plasma protein binding. For the 4-hydroxyquinolone series, binding to plasma protein correlates (r = 0.92) with log P (octanol/pH 7.4 buffer) over a range of log P values from 0 to 5. The anticonvulsant activity increases with in vitro affinity, but the slope of a plot of pED50 versus pIC50 is low (0.40); taking plasma protein binding into account in this plot increases the slope to 0.60. This shows that binding to albumin in plasma reduces the amount of compound free to diffuse across the blood-brain barrier. Further evidence comes from three other experiments: (a) Direct measurements of brain/blood ratios for three compounds (2, 16, 26) show the ratio decreases with increasing log R. (b) Warfarin, which competes for albumin binding sites dose-dependently, decreased the ED50 of 26 for protection against seizures induced by NMDLA. (c) Direct measurements of brain penetration using an in situ brain perfusion model in rat to measure the amount of drug crossing the blood-brain barrier showed that compounds 2, 26, and 32 penetrate the brain well in the absence of plasma protein, but this is greatly reduced when the drug is delivered in plasma. In the 4-hydroxyquinolones glycine site binding affinity increases with lipophilicity of the 3-substituent up to a maximum at a log P around 3, then does not improve further. When combined with increasing protein binding, this gives a parabolic relationship between predicted in vivo activity and log P, with a maximum log P value of 2.39. Finally, the plasma protein binding studies have been extended to other series of glycine site antagonists, and its is shown that for a given log P these have similar protein binding to the 4-hydroxyquinolones, except for compounds that are not acidic. The results have implications for the design of novel glycine site antagonists, and it is suggested that it is necessary to either keep log P low or pKa high to obtain good central nervous system activity.
Identification of residues in the class II-associated Ii peptide (CLIP) region of invariant chain that affect efficiency of MHC class II-mediated antigen presentation in an allele-dependent manner.
Invariant chain (Ii) associates with class II MHC molecules and is crucial for Ag presentation by class II molecules. A general explanation for how invariant chain (Ii) associates with polymorphic MHC class II molecules has been suggested by the crystallographic structure of CLIP (class II-associated Ii peptide) complexed with an HLA class II molecule, HLA-DR3. We show here that methionine residues at positions 93 and 99 in Ii are important in MHC class II-mediated Ag presentation, but function in an allele-dependent manner. Introduction of a Met-->Ala mutation at position 99 in Ii (M99AIi) impaired presentation of peptides derived from exogenous proteins by I-Ad and I-Au class II molecules. Mutating Met-->Ala in Ii at position 93 (M93AIi) abrogated presentation by I-Au molecules, but not by I-Ad. Impaired Ag presentation was associated with conformationally altered expression of I-A molecules on the surface of cells expressing mutated Ii. Cell surface CLIP staining and immunoprecipitation studies showed that both I-Ad and I-Au molecules were associated with an increased abundance of Ii peptides, CLIP, in cells expressing mutated Ii. These results show that methionine 93 and methionine 99 play an important physiologic role in Ii association with class II molecules by regulating release of CLIP from class II in the endocytic compartments to allow binding of cognate peptides.
Careers in academic medicine. It's surprising that any juniors consider careers in academic medicine.
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4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor.
5-(4-Chlorophenyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 (hD4) receptor ligand with moderate affinity (61 nM) and 4-fold selectivity over human D2 (hD2) receptors. Four separate parts of the molecule have been examined systematically to explore structure-activity relationships with respect to hD4 affinity and selectivity over other dopamine receptors. It was found that the 4-chlorophenyl group attached to the pyrazole is optimal, as is the 4-substituted piperidine. The lipophilic group on the basic nitrogen is more amenable to change, with the optimal group found to be a phenethyl. The aromatic heterocyle can be altered to a number of different groups, with isoxazoles and pyrimidines showing improved affinities. This heterocycle can also be advantageously alkylated, improving the selectivity of the compounds over D2 receptors. It is hypothesized that the conformation around the bond joining the aromatic heterocycle to the piperidine is important for D4 affinity, based on crystal structures of isoxazoles (29 and 30) and on a conformationally constrained compound (28). Putting all the favorable changes together led to the discovery that 5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)iso xazole (36) is a nanomolar antagonist at human dopamine D4 receptors with > 500-fold selectivity over hD2 and > 200-fold selectivity over hD3. Compound 36 is an antagonist of hD4 receptors with good oral bioavailability of 38%, a half life of 2 h, and brain levels 10-fold higher than plasma levels.
Crisis, ethics, and the American Medical Association 1847 and 1997.
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Series on the quality of health care.
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4-substituted-3-phenylquinolin-2(1H)-ones: acidic and nonacidic glycine site N-methyl-D-aspartate antagonists with in vivo activity.
4-Substituted-3-phenylquinolin-2(1H)-ones have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA (N-methyl-D-aspartate) receptor and in vivo for anticonvulsant activity in the DBA/2 strain of mouse in an audiogenic seizure model. 4-Amino-3-phenylquinolin-2(1H)-one (3) is 40-fold lower in binding affinity but only 4-fold weaker as an anticonvulsant than the acidic 4-hydroxy compound 1. Methylsulfonylation at the 4-position of 3 gives an acidic compound (6, pKa = 6.0) where affinity is fully restored but in vivo potency is significantly reduced (Table 1). Methylation at the 4-position of 1 to give 18 results in the abolition of measurable affinity, but the attachment of neutral hydrogen bond-accepting groups to the methyl group of 18 produces compounds with comparable in vitro and in vivo activity to 1 (e.g., 23 and 28, Table 2). Replacement of the 4-hydroxy group of 1 with an ethyl group abolishes activity (42), but again, incorporation of neutral hydrogen bond acceptors to the terminal carbon atom restores affinity (e.g., 36, 39, and 40, Table 3). Replacement of the 4-hydroxy group of the high-affinity compound 2 with an amino group produces a compound with 200-fold reduced affinity (43; IC50 = 0.42 microM, Table 4) which is nevertheless still 10-fold higher in affinity than 3. The results in this paper indicate that anionic functionality is not an absolute requirement for good affinity at the glycine/NMDA site and provide compelling evidence for the existence of a ligand/receptor hydrogen bond interaction between an acceptor attached to the 4-position of the ligand and a hydrogen bond donor attached to the receptor.
Reliability and validity of a new measure of patient satisfaction with out of hours primary medical care in the United Kingdom: development of a patient questionnaire.
OBJECTIVE: To develop a reliable, valid measure of patient satisfaction with out of hours care suitable for large scale service evaluation. DESIGN: Focus group meetings and semistructured interviews with patients to identify issues of importance to patients and possible questionnaire items; interviews and two pilot studies to test and identify new questionnaire items; modification or removal of items to eliminate ambiguity and reduce non-response and skewed responses; questionnaire survey of out of hours care. SETTING: Greater Manchester and Leicester. SUBJECTS: 11 general practice patients participated in the focus groups and 28 in the semistructured interviews; 41 in the preliminary interviews; 41 and 378 in the postal pilots; and 1466 in the survey of out of hours care. RESULTS: A 32 item questionnaire was developed. Component analysis indicated seven scales (satisfaction with communication and management, doctor's attitude, continuity of care, delay until visit, access to out of hours care, initial contact person, telephone advice) related to overall satisfaction and containing issues identified as important to patients. Levels of reliability were satisfactory, Cronbach's alpha correlation coefficient exceeding 0.60 for all scales. CONCLUSION: A reliable, valid measure of patient satisfaction has been developed, suitable for large scale evaluation of out of hours care.
Assay for toxic chemicals using bacteria.
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Metastatic malignant mesothelioma presenting as colonic polyps.
A 66-year-old male engineer diagnosed with malignant pleural mesothelioma 4 years previously had thoracotomy, radiotherapy, and chemotherapy. He was followed regularly with chest computed tomography (CT) scan and had been asymptomatic. During one of his physical examinations, routine sigmoidoscopy showed incidental colonic polyps which were biopsied. Subsequently, recurrence of pleural mesothelioma and peritoneal involvement by mesothelioma was documented. Two of the polyps showed metastatic malignant mesothelioma in the lamina propia which strongly resembled adenocarcinoma histologically causing difficulty in making definitive diagnosis. Review of the literature disclosed no previously documented similar occurrence. This case shows the importance of clinical history and ancillary laboratory procedures such as immunohistochemistry and electron microscopy to avoid diagnostic pitfalls.
Characterization of Purkinje cells in the goldfish cerebellum during eye movement and adaptive modification of the vestibulo-ocular reflex.
The discharge characteristics of Purkinje cells were analyzed in the goldfish cerebellum during eye movement and adaptation of the vestibulo-ocular reflex (VOR). Purkinje cells, identified by the simultaneous recording of complex and simple spikes, were recorded in the cerebellar area where electrical microstimulation elicited ipsiversive horizontal eye movements. Simple spikes of Purkinje cells displayed signals related to head and/or eye velocity as determined independently during either VOR suppression or optokinetic stimulation, respectively. Head velocity-only Purkinje cells (12%) increased their firing rate in relationship to ipsilateral head movements. Two types of eye velocity-only Purkinje cells (28%) were found that responded either in phase with ipsi- (16%) or contralateral (12%) eye movement, respectively. Purkinje cells combining both eye and head velocity (60%) were classified into two groups according to their preferred direction for eye movement. Eye velocity signals either added to (18%) or subtracted from (42%) head velocity during all visuo-vestibular interactions. Short term adaptive changes of the VOR were induced by oscillating goldfish in a moving visual surround that modified the ratio of eye to head velocity (gain) from a level of 1.0 (16 degrees/s) towards gains ranging from 2.5 (40 degrees/s) to -1.0 (-16 degrees/s). Simple spike modulation of individual Purkinje cells was shown to correlate well with VOR performance throughout adaptation irrespective of training direction. Purkinje cell behavior always equaled the algebraic summation of eye and head velocity signal sensitivity. Causality of signal generation was addressed by measuring Purkinje cell responses to both eye and head velocity separately throughout the time course of VOR adaptation. The sensitivity of each type of Purkinje cell was found to be independent of the VOR gain state. We therefore conclude that the changes responsible for short term VOR plasticity do not occur in the cerebellum. These observations suggest that Purkinje cells integrate corollary head and eye velocity signals to continuously adjust the set point of brainstem VOR interneurons that embrace the substantive site for adaptive plasticity.