Primary dermatological care in general practice

Out of 2,409 clinical cases analysed over an eight-week period, 199 (8.2 per cent) were of a dermatological nature. Atopic eczema, warts, seborrhoeic eczema and acne vulgaris were encountered most frequently. The reaction to a skin clinic in the general practice, with access to liquid nitrogen, electrocautery and histopathology is described. Treatment of patients is summarized. It is suggested that having a practice skin clinic reduces the rate of hospital referrals by two thirds.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Radiochromic film spectroscopy of laser-accelerated proton beams using the FLUKA code and dosimetry traceable to primary standards

A new approach to spectroscopy of laser induced proton beams using radiochromic film (RCF) is presented. This approach allows primary standards of absorbed dose-to-water as used in radiotherapy to be transferred to the calibration of GafChromic HD-810 and EBT in a 29 MeV proton beam from the Birmingham cyclotron. These films were then irradiated in a common stack configuration using the TARANIS Nd:Glass multi-terawatt laser at Queens University Belfast, which can accelerate protons to 10-12 MeV, and a depth-dose curve was measured from a collimated beam. Previous work characterizing the relative effectiveness (RE) of GafChromic film as a function of energy was implemented into Monte Carlo depth-dose curves using FLUKA. A Bragg peak (BP) "library" for proton energies 0-15 MeV was generated, both with and without the RE function. These depth-response curves were iteratively summed in a FORTRAN routine to solve for the measured RCF depth-dose using a simple direct search algorithm. By comparing resultant spectra with both BP libraries, it was found that the effect of including the RE function accounted for an increase in the total number of protons by about 50%. To account for the energy loss due to a 20 mu m aluminum filter in front of the film stack, FLUKA was used to create a matrix containing the energy loss transformations for each individual energy bin. Multiplication by the pseudo-inverse of this matrix resulted in "up-shifting" protons to higher energies. Applying this correction to two laser shots gave further increases in the total number of protons, N of 31% and 56%. Failure to consider the relative response of RCF to lower proton energies and neglecting energy losses in a stack filter foil can potentially lead to significant underestimates of the total number of protons in RCF spectroscopy of the low energy protons produced by laser ablation of thin targets.

Wellbeing, academic buoyancy and educational achievement in primary school students

The study explored the relationship between student wellbeing and academic achievement among 7–11 years old students and whether the relationship was moderated by gender and deprivation. 1081 students in Northern Ireland participated in a crosssectional survey that captured data on academic achievement and a range of wellbeing indicators. Findings suggested the existence of an underlying wellbeing factor, which was positively related to achievement. The relationship was not moderated by gender and/or deprivation. Findings were explored using a model of ‘academic buoyancy’. There was no evidence that suggested efforts to improve achievement that focus on wellbeing should be targeted speci?cally at students in economically deprived areas or be modi?ed in terms of gender.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P <5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P <5 × 10?8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

The changing pattern of adult primary glomerular disease

Published biopsy series have shown geographical and temporal variations in the patterns of primary glomerulonephritis (GN). IgA nephropathy is the most common type of GN in most European studies, but there is evidence suggesting that focal segmental glomerulosclerosis (FSGS) is increasingly common in the USA in all ethnic groups. We report the analysis of 30 years of native renal biopsies and the temporal pattern of primary glomerular disease in a single United Kingdom (UK) region.

Epidermal growth factor and phorbol myristate acetate increase expression of the mRNA for cytosolic phospholipase A2 in glomerular mesangial cells

We have previously shown that phospholipase A2 (PLA2) activity is rapidly activated by epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA) in renal mesangial cells and other cell systems in a manner that suggests a covalent modification of the PLA2 enzyme(s). This PLA2 activity is cytosolic (cPLA2) and is distinct from secretory forms of PLA2, which are also stimulated in mesangial cells in response to cytokines and other agonists. However, longer-term regulation of cPLA2 in renal cells may also occur at the level of gene expression. Cultured rat mesangial cells were used as a model system to test the effects of EGF and PMA on the regulation of cPLA2 gene expression. EGF and PMA both produced sustained increases in cPLA2 mRNA levels, with a parallel increase in enzyme activity over time. Inhibition of protein synthesis by cycloheximide increased basal cPLA2 mRNA accumulation in serum-starved mesangial cells, and the combination of EGF and cycloheximide resulted in super-induction of cPLA2 gene expression compared with EGF alone. Actinomycin D treatment entirely abrogated the effect of EGF on cPLA2 mRNA accumulation. These findings suggest that regulation of cPLA2 is achieved by factors controlling gene transcription and possibly mRNA stability, in addition to previously characterized posttranslational modifications.

The role of p63 in epidermal morphogenesis and neoplasia

The p53 family of transcription factors is made up of p53, p63 and p73, which share significant structural homology. In particular, transcriptional complexity and the expression of multiple protein isoforms are an emergent trait of all family members. p63 is the evolutionarily eldest member of the p53 family and the various isoforms have critical roles in the development of stratifying epithelia. Recent results have uncovered additional splice variants, adding to the complexity of the transcriptional architecture of p63. These observations and the emerging extensive interplay between p63 and p53 in development, proliferation and differentiation underline the importance of considering all isoforms and family members in studies of the function of p53 family members.

Improving clinician self-efficacy does not increase asthma guideline use by primary care clinicians

Objective: The purpose of this study was to show the association between changes in clinician self-efficacy and readiness to change and implementation of an asthma management program (Easy Breathing). Methods: A 36 month randomized, controlled trial was conducted involving 24 pediatric practices (88 clinicians). Randomized clinicians received interventions designed to enhance clinician self-efficacy and readiness to change which were measured at baseline and 3 years. Interventions consisted of an educational toolbox, seminars, teleconferences, mini-fellowships, opinion leader visits, clinician-specific feedback, and pay for performance. The primary outcome was program utilization (number of children enrolled in Easy Breathing/year); secondary outcomes included development of a written treatment plan and severity-appropriate therapy. Results: At baseline, clinicians enrolled 149 ± 147 (mean ± SD) children/clinician/year; 84% of children had a written treatment plan and 77% of plans used severity-appropriate therapy. At baseline, higher self-efficacy scores were associated with greater program utilization (relative rate [RR], 1.34; 95% confidence interval [CI], 1.04-1.72; P =.04) but not treatment plan development (RR, 0.63; 95% CI, 0.29-1.35; P =.23) or anti-inflammatory use (RR, 1.76; 95% CI, 0.92-3.35; P =.09). Intervention clinicians participated in 17 interventions over 36 months. At study end, self-efficacy scores increased in intervention clinicians compared to control clinicians (P =.01) and more clinicians were in an action stage of change (P =.001) but these changes were not associated with changes in primary or secondary outcomes. Conclusions: Self-efficacy scores correlated with program use at baseline and increased in the intervention arm, but these increases were not associated with greater program-related activities. Self-efficacy may be necessary but not sufficient for behavior change. Copyright © 2012 by Academic Pediatric Association.

Effect of preventive primary care outreach on health related quality of life among older adults at risk of functional decline: Randomised controlled trial

Objective: To evaluate the impact of a provider initiated primary care outreach intervention compared with usual care among older adults at risk of functional decline. Design: Randomised controlled trial. Setting: Patients enrolled with 35 family physicians in five primary care networks in Hamilton, Ontario, Canada. Participants Patients: were eligible if they were 75 years of age or older and were not receiving home care services. Of 3166 potentially eligible patients, 2662 (84%) completed the validated postal questionnaire used to determine risk of functional decline. Of 1724 patients who met the risk criteria, 769 (45%) agreed to participate and 719 were randomised. Intervention: The 12 month intervention, provided by experienced home care nurses in 2004-6, consisted of a comprehensive initial assessment using the resident assessment instrument for home care; collaborative care planning with patients, their families, and family physicians; health promotion; and referral to community health and social support services. Main outcome measures: Quality adjusted life years (QALYs), use and costs of health and social services, functional status, self rated health, and mortality. Results: The mean difference in QALYs between intervention and control patients during the study period was not statistically significant (0.017, 95% confidence interval -0.022 to 0.056; P=0.388). The mean difference in overall cost of prescription drugs and services between the intervention and control groups was not statistically significant, (-$C165 (£107; €118; $162), 95% confidence interval -$C16 545 to $C16 214; P=0.984). Changes over 12 months in functional status and self rated health were not significantly different between the intervention and control groups. Ten patients died in each group. Conclusions: The results of this study do not support adoption of this preventive primary care intervention for this target population of high risk older adults. Trial registration: Clinical trials NCT00134836.