Biomedical subjects
R Palmer
Publications and source records attributed to R Palmer.
Profile of neurocognitive impairments associated with female in-patients with anorexia nervosa.
BACKGROUND: Although many studies have reported impairments of neurocognitive performance in patients with anorexia nervosa (AN), these have involved a wide range of assessment methods and some findings are inconsistent. METHOD: Twenty-five female in-patients with a DSM-IV diagnosis of AN, identified from three units specializing in the treatment of eating disorders, volunteered for the study. Twenty-five non-clinical control subjects were recruited, matched for age, gender and estimated IQ. Subjects were assessed with a range of computer-administered neurocognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has been validated in many studies of neuropsychiatric disorders. RESULTS: The patient group showed significant but moderate impairments (i.e. less than one standard deviation below the mean performance of the control group) on tests of spatial recognition memory, a planning task and rapid visual information processing, while a subgroup of patients (n = 14) showed greater degrees of impairments on at least one of these tests. The degrees of impairments did not correlate with body mass index (BMI). No impairments were observed on tests of spatial span, pattern recognition memory, spatial working memory, matching-to-sample, paired associates learning and set-shifting. CONCLUSIONS: The findings, in relation to a mean BMI of 15.3, are compatible with, in general, subtle impairments in neurocognition in AN. However, in those patients with relatively severe degrees of impairments, these may have adverse effects on complex tasks of social and occupational functioning. Further research is needed on the nature of relevant causal mechanisms, including the effects of potentially confounding variables.
The immune responses to human and microbial heat shock proteins in periodontal disease with and without coronary heart disease.
The human 60 kDa and microbial 65 kDa heat shock proteins (HSP) have been implicated in the pathogenesis of chronic periodontitis (P) and coronary heart disease (CHD). We have studied four male non-smoking cohorts of 81 subjects, matched for age. Group (a) consisted of a healthy group with minimal gingivitis (n = 18), group (b) were patients with P (n = 23), group (c) patients with CHD and minimal gingivitis (n = 20) and group (d) patients with CHD and P (n = 20). T cells separated from peripheral blood were found to be primed to both microbial HSP65 and human HSP60 but significant CD4, human leucocyte antigen (HLA) class II-restricted proliferative responses were found only with the human HSP60 in patients with P (P < 0.001) and CHD without (P < 0.001) or with (P < 0.00001) periodontitis. Dose-dependent inhibition of T cell proliferative responses was carried out to determine the receptors involved in recognition of HSP60 and HSP65. Monoclonal antibodies to CD14 showed inhibition of T cell proliferation stimulated by both HSP60 and HSP65, consistent with the role of CD14 as a receptor for these HSPs in P and CHD. The toll-like receptor 2 (TLR-) and TLR-4 were then studied and these showed that TLR-4 was recognized by microbial HSP65, whereas TLR-2 was recognised by human HSP60 in both P and CHD. However, a dissociation was found in the HSP60 and TLR4 interaction, as TLR4 appeared to have been recognized by HSP60 in P but not in CHD. The results suggest an autoimmune or cross-reactive CD4(+) class II-restricted T cell response to the human HSP60 in P and CHD. Further studies are required to determine if there is a common epitope within HSP60 that stimulates T cell proliferation in P and CHD.
A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis.
OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.
Variations in health status within and between socioeconomic strata.
OBJECTIVES: To analyse the variability in health status within as well as between socioeconomic groups. What is the range of individual variability in the health effects of socioeconomic status? Is the adverse effect of lower socioeconomic status uniform across the entire distribution of health status? DESIGN: Nationally representative telephone survey of the US population in 1996. SETTING: 60 US metropolitan and rural areas. PARTICIPANTS: 47 076 adult respondents to the community tracking study. MAIN OUTCOME MEASURES: Self rated physical and mental health status, measured by the Short Form-12 instrument. RESULTS: There is considerable variability in self rated health within socioeconomic strata and that variability increases in a step-wise fashion at each lower stratum of income. Most of the increased variability is accounted for by changes in the middle and lower (10th, 25th, and 50th centiles) rather than the upper (75th and 90th) portions of the distribution. A resilient subgroup of lower socioeconomic status people seems to maintain excellent self rated health throughout life, while a more vulnerable lower socioeconomic status group experiences rapid deterioration in health status as people reach middle age. CONCLUSIONS: Within the population level social structuring of health there are differences in individual resilience and vulnerability that are amenable to further exploration and potential modification.
Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders.
In the rich, developed parts of the world there has been a steady and simultaneous increase in at least three groups of disease: (1) allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohn's disease and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and multiple sclerosis). Because the medical world is so compartmentalised it was some time before the connection between these increases was noticed and understood. There is now evidence that the simultaneous increase in these diseases of immunodysregulation is at least partly attributable to malfunction of regulatory T cells (Treg). This paper provides an overview of relevant work in each of these fields of medicine (though with emphasis on the allergic disorders), and concludes that the increasing failure of Treg is a consequence of diminished exposure to certain micro-organisms that are "old friends", because of their continuous presence throughout mammalian evolution. These organisms, which include saprophytic mycobacteria, helminths and lactobacilli, are recognised by the innate immune system as harmless, and as adjuvants for Treg induction. Polymorphisms of components of the innate immune system such as TLR2 and NOD2 appear to define subsets of the population that will develop immunoregulatory disorders when living in the modern environment. A further role of the "old friends" and of the Treg that they induce might be to maintain the levels of regulatory IL-10 secreting macrophages and antigen-presenting cells, which are depleted in asthma and Crohn's disease. These concepts are leading to novel therapies based on harmless organisms or their components. Phase I/II clinical trials have yielded some statistically significant results, and phase II trials are in progress.
Infectivity of microsporidia spores stored in water at environmental temperatures.
To determine how long waterborne spores of Encephalitozoon cuniculi, E. hellem, and E. intestinalis could survive at environmental temperatures, culture-derived spores were stored in water at 10, 15, 20, 25, and 30 C and tested for infectivity in monolayer cultures of Madin Darby bovine kidney (MDBK) cells. At 10 C, spores of E. intestinalis were still infective after 12 mo, whereas those of E. hellem and E. cuniculi were infective for 9 and 3 mo, respectively. At 15 C, spores of the same species remained infective for 10, 6, and 2 mo, and at 20 C, for 7, 5, and 1 mo, respectively. At 25 C, spores of E. intestinalis and E. hellem were infective for 3 mo, but those of E. cuniculi were infective for only 3 wk. At 30 C, the former 2 species were infective for 3 wk and 1 mo, respectively, and the latter species for only 1 wk. These findings indicate that spores of different species of Encephalitozoon differ in their longevity and temperature tolerance, but at temperatures from 10 to 30 C, all 3 have the potential to remain infective in the environment long enough to become widely dispersed.
The use of multidisciplinary assessment and scientific measurement in advanced juvenile idiopathic arthritis can categorise gait deviations to guide treatment.
BACKGROUND: It is difficult to identify the range of gait deviations associated with juvenile idiopathic arthritis (JIA) using simple clinical observations. AIMS: To use objective gait analysis to accurately describe biomechanical gait abnormalities in JIA and to search for common patterns, which may subsequently serve as a basis for therapeutic intervention. METHODS: Children with persistent polyarticular arthritis and symmetrical joint involvement were referred to the Gait Analysis Laboratory and independently assessed by a multidisciplinary team. Gait analysis was performed using an in-house Visual Vector System and the Novel PEDAR in-shoe plantar pressure measurement system. Clinical groupings were based on the extent of joint restriction: minimal (group A), and moderate-severe (with supinatory foot deformity (group B), or with pronatory foot deformity (group C)). Gait analysis enabled classification of each subject into one of four gait patterns: either near normal (pattern I) or one of three adaptive patterns defined by the predominant abnormality--lower limb pain (pattern II), lower limb deformity (pattern III), or a combination of pain and deformity of the lower limb (pattern IV). RESULTS: Of the 15 subjects assessed as part of this study, seven were placed into clinical group A, six into group B, and two into group C. All the subjects with gait patterns I and II were found in clinical group A. Both subjects from clinical group C exhibited gait pattern III. All subjects from clinical group B and the remainder from group A exhibited a mixture of gait patterns III and IV. CONCLUSION: Despite the initial clinical observations it was not always possible to predict the resultant gait pattern. Scientific gait analysis allowed a clear distinction to be made between primary and secondary gait deviations, and accurate targeting of physiotherapy and orthotic interventions to suit each individual. Prospective quantitative analysis in a larger sample is under way to support the clinical effectiveness of these findings.
Effects of gamma radiation on viability of Encephalitozoon spores.
Spores of Encephalitozoon cuniculi, E. hellem, and E. intestinalis harvested from cultured mammalian cells were suspended in deionized water, exposed to gamma irradiation at doses of 0-3.0 kGy, and then tested for infectivity by inoculating spores into monolayer cultures of Madin-Darby bovine kidney cells. The cultures were examined for developing microsporidia 4 days later. As the dosage level of radiation increased, corresponding decreases were observed in the number of developing microsporidia for all 3 species. For E. cuniculi and E. intestinalis, 100% inhibition of development was observed after exposure to 1.5 and 2.0 kGy, respectively. Although development of E. hellem was greatly inhibited (97.6% inhibition) after exposure to 3.0 kGy, complete inhibition was not obtained. These findings provide a baseline for investigating the dose levels required to render food products safe when kept under varying temperature, moisture, and other storage conditions.
Doctors in management. Career view mirror.
A survey of doctors and managers found agreement that management training should be given at various stages of a doctor's career. Managers felt strongly that doctors should receive management training in groups with other staff. Doctors believed clinical budgets should be under doctors' control, but managers were opposed to this. The results suggested that a 'them and us' culture persists between managers and doctors in the NHS.
Failure of treatment for chronic Mycobacterium abscessus meningitis despite adequate clarithromycin levels in cerebrospinal fluid.
We report a case of posttraumatic meningitis due to Mycobacterium abscessus, treated initially with oral clarithromycin and intravenous amikacin plus intrathecal amikacin. Despite cerebrospinal fluid (CSF) levels of clarithromycin and amikacin in excess of their in vitro minimum inhibitory concentrations for the organism, the CSF cultures remained continuously positive for M. abscessus. To our knowledge, this is the first documented case of M. abscessus meningitis and the first report of measured CSF levels of clarithromycin in a patient with meningitis, showing that even therapeutic CSF levels of clarithromycin and amikacin might not be successful in eradicating M. abscessus meningitis.
New roles for the Snp1 and Exo84 proteins in yeast pre-mRNA splicing.
The mammalian 70K protein, a component of the U1 small nuclear ribonucleoprotein involved in pre-mRNA splicing, interacts with a number of proteins important for regulating constitutive and alternative splicing. Similar proteins that interact with the yeast homolog of the 70K protein, Snp1p, have yet to be identified. We used the two-hybrid system to find four U1-Snp1 associating (Usa) proteins. Two of these proteins physically associate with Snp1p as assayed by coimmunoprecipitation. One is Prp8p, a known, essential spliceosomal component. This interaction suggests some novel functions for Snp1p and the U1 small nuclear ribonucleoprotein late in spliceosome development. The other, Exo84p, is a conserved subunit of the exocyst, an eight-protein complex functioning in secretion. We show here that Exo84p is also involved in pre-mRNA splicing. A temperature-sensitive exo84 mutation caused increased ratios of pre-mRNA to mRNA for the Rpl30 and actin transcripts in cells incubated at the non-permissive temperature. The mutation also led to a defect in splicing and prespliceosome formation in vitro; an indication that Exo84p has a direct role in splicing. The results elucidate a surprising link between splicing and secretion.
A functional interaction with CBP contributes to transcriptional activation by the Wilms tumor suppressor WT1.
The Wilms tumor gene WT1 encodes a zinc finger transcription factor that is required for normal kidney development. WT1 was identified as a transcriptional repressor, based on its suppression of promoter reporters, but analysis of native transcripts using high density microarrays has uncovered transcriptional activation, rather than repression, of potential target genes. We report here that WT1 binds to the transcriptional coactivator CBP, leading to synergistic activation of a physiologically relevant promoter. The physical interaction between WT1 and CBP is evident in vitro and in vivo, and the two proteins are co-immunoprecipitated from embryonic rat kidney cells. The WT1-CBP association requires the first two zinc fingers of WT1 and the adenovirus 5 E1A-binding domain of CBP. Overexpression of this domain of CBP is sufficient to inhibit WT1-mediated transcriptional activation of a promoter reporter, as is co-transfection of E1A. Retrovirally driven expression of either the CBP fragment or of E1A in human hematopoietic cells suppresses the induction by WT1 of its endogenous target gene, p21(Cip1). These observations support a model of WT1 as a transcriptional activator of genes required for cellular differentiation.
A cytotoxicity assay for the detection and differentiation of two families of shellfish toxins.
There is an urgent need for an alternative to the mouse bioassay for the detection of algal toxins in shellfish on both analytical and animal welfare grounds. Several alternative methodologies have been described, but have not gained widespread acceptance to date, because each assay measures only one or a small number of related phycotoxins out of the increasing range that needs to be detected. A simple cytotoxicity assay using either the HepG2 or ECV-304 cell lines is described with two end-point measurements, which can detect and distinguish between two unrelated classes of phycotoxins. Morphological examination following 3h exposure to the sample enables the detection of the diarrhetic shellfish poisons, including okadaic acid and related toxins. Viability testing using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), following 24h exposure of the same cells to the sample, reveals a second class of toxin, which is most probably the newly-described toxin, azaspiracid. This assay should play an important role in shellfish monitoring in the future.
Measurement of the setting and thermal expansion of dental investments used for the superplastic forming of dental implant superstructures.
OBJECTIVES: The study examined the setting and thermal expansions of seven dental casting investments intended for use in the superplastic forming (SPF) of Ti6A14V for dental implant superstructures. The total expansion is compared with the coefficient of thermal expansion of the alloy. METHODS: The unrestricted setting expansion of the investment was measured at room temperature using a lined brass trough and dial gauge. The thermal expansion was measured at a heating rate of 5 degrees C/min up to 900 degrees C. The thermal expansion of Ti6A14V was measured at a heating rate of 15 degrees C/min. RESULTS: The Selevest investment had a small shrinkage on setting. The largest setting expansions were observed with Rema Exakt and Fujivest. Selevest DM and Fujivest had the greatest thermal expansions. Rema Exakt had the greatest overall expansion. The total expansion of Rematitan most closely matched the thermal expansion of Ti6A14V when the manufacturer's recommended special liquid to water ratio for crowns and bridges was used. SIGNIFICANCE: SPF is a novel technique which is being applied to the manufacture of dental prostheses. As dental casting investments are used to make the dies used for SPF the dimensional changes associated with these materials should be matched to the dimensional changes of the Ti6A14V alloy used in order to achieve a passive fit. This study has identified Rematitan as an investment whose total expansion may enable an accurately fitting SPF implant superstructure to be made.
Objective threshold selection procedure (OTS) for segmentation of scanning laser confocal microscope images.
The determination of volumes and interface areas from confocal laser scanning microscopy (CLSM) images requires the identification of component objects by segmentation. An automated method for the determination of segmentation thresholds for CLSM imaging of biofilms was developed. The procedure, named objective threshold selection (OTS), is a three-dimensional development of the approach introduced by the popular robust automatic threshold selection (RATS) method. OTS is based on the statistical properties of local gray-values and gradients in the image. By characterizing the dependence between a volumetric feature and the intensity threshold used for image segmentation, the former can be determined with an arbitrary confidence level, with no need for user intervention. The identification of an objective segmentation procedure renders the possibility for the full automation of volume and interfacial area measurement. Images from two distinct biofilm systems, acquired using different experimental techniques and instrumental setups were segmented by OTS to determine biofilm volume and interfacial area. The reliability of measurements for each case was analyzed to identify optimal procedure for image acquisition. The automated OTS method was shown to reproduce values obtained manually by an experienced operator.
An introduction to geriatrics for first-year medical students.
OBJECTIVE: To prepare medical students to better serve their older patients while raising awareness of geriatrics as a career choice. DESIGN: To determine the impact of a new educational program, attitudinal assessments were administered to the group before and after participation in the program and to a comparison group of nonintervention students. SETTING: University of Texas Health Science Center, San Antonio. PARTICIPANTS: Two hundred and three first-year medical students. MEASUREMENTS: Student response on a scale of one to six regarding four constructs: attitudes and beliefs about providing medical care for older people, knowledge and beliefs about aging, interest in pursuing clinical geriatrics, and interest in pursuing aging research. RESULTS: Four factors were consistently formed in the analysis process: beliefs about physical decline; comfort with older people; beliefs about career opportunities; and interest in geriatric research. The intervention group made significant gains in two areas: comfort with older people and understanding of physical decline in aging. Two new factors emerged in post-test data. CONCLUSIONS: The impact of the program was mixed. Although awareness of geriatrics and comfort with older people was increased, there was little change in career aspirations. Students in the program increased their awareness of physical decline in old age, setting the stage for teaching them about the physician's role with regard to function, and learned that geriatrics is a low-status specialty.
Treatment of elderly patients with nabumetone or diclofenac: gastrointestinal safety profile.
GOALS: To evaluate the efficacy and gastrointestinal safety of nabumetone and diclofenac in the treatment of elderly patients with osteoarthritis, participating in a 3-month efficacy trial. BACKGROUND: Elderly patients have an elevated risk for developing gastrointestinal complications with chronic use of nonsteroidal anti-inflammatory drugs. STUDY: This was a randomized, double-blind, parallel-group, multicenter study with a 3-to 14-day placebo washout period and a 12-week active treatment phase. Patients 65 years or older with moderate-to-severe osteoarthritis of the knee or hip were randomized to receive 1,000 to 2,000 mg/d of nabumetone or 100 to 150 mg/d of diclofenac. The primary efficacy parameters were the percent of patients improved using a Patients' and Physicians' Global Assessment at endpoint. Gastrointestinal safety was assessed by the incidence of gastrointestinal symptoms and adverse events. RESULTS: Three hundred thirty-five patients (mean age = 72 years) with active osteoarthritis were enrolled. There were no statistically significant differences between the two treatment groups in any of the primary efficacy variables. However, differences between the groups were apparent in the frequency of adverse gastrointestinal events. Two patients in the diclofenac group had evidence of gastrointestinal bleeding and/or ulcer compared with none in the nabumetone group. In addition, significantly more (p < 0.05) patients (4%) receiving diclofenac had alanine transaminase values more than twice the upper limit of normal at endpoint compared with patients receiving nabumetone (0%). CONCLUSIONS: Nabumetone was as effective as diclofenac in the treatment of elderly patients with moderate-to-severe osteoarthritis. However, the gastrointestinal safety profile of nabumetone was superior to that of diclofenac with respect to elevation of liver enzymes.