Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function.

Background/objectiveYouth with obesity have an altered high-density lipoprotein (HDL) subspecies profile characterized by depletion of large apoE-rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile is reversible and that HDL function would improve with metabolic surgery.MethodsSerum samples from adolescent males with severe obesity mean±s.d. age of 17.4±1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group.ResultsAfter VSG, body mass index decreased by 32% and insulin resistance as estimated by homeostatic model assessment of insulin resistance decreased by 75% (both P<0.01). Large apoE-rich HDL subspecies increased following VSG (P<0.01) and approached that of lean adolescents despite participants with considerable residual obesity. In addition, HDL function improved compared with baseline (cholesterol efflux capacity increased by 12%, HDL lipid peroxidation potential decreased by 30% and HDL anti-oxidative capacity improved by 25%, all P<0.01).ConclusionsMetabolic surgery results in a significant improvement in the quantity of large HDL subspecies and HDL function. Our data suggest metabolic surgery may improve cardiovascular risk in adolescents and young adults

Factor XIIIa-positive dermal dendritic cells and HLA-DR expression in radial versus vertical growth-phase melanomas

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72186/1/j.1600-0560.1998.tb01740.x.pd

Re-evaluation of the diagnosis of porphyria cutanea tarda in Admiral Sir Francis Beaufort

OBJECTIVES: Two biographies of Admiral Francis Beaufort (1774-1857) have stated that, aged 20-25 years, he suffered from porphyria cutanea tarda (PCT) that was 'cured' following severe blood loss during a naval skirmish. We have examined the evidence concerning the nature of his skin disease.  DESIGN: Primary records, most notably Beaufort's correspondence with his family, his journals and his father's diaries were sought out and analysed.  SETTING: This case report is discussed in the context of 18th-century naval medicine and concepts and treatment of skin disease.  RESULTS: The description of his lesions, their age of onset, their progression and response to treatment, particularly topical tar and associated features are quite inconsistent with a diagnosis of PCT. His mother, Mary Waller Beaufort (1739-1821), consulted Dr Robert Darwin in 1803 about a painful skin disease affecting her legs. Detailed description of the lesions and a contemporary diagnosis are not available but possible diagnoses include chronic psoriasis and stasis eczema.  CONCLUSIONS: A more tenable diagnosis is that Francis Beaufort had chronic plaque psoriasis remitted by bed rest and convalescence in the sunny Mediterranean climate with cessation of alcohol consumption and improved nutrition as well as topical and oral medications

Abnormal expression of p27kip1 protein in levator ani muscle of aging women with pelvic floor disorders – a relationship to the cellular differentiation and degeneration

BACKGROUND: Pelvic floor disorders affect almost 50% of aging women. An important role in the pelvic floor support belongs to the levator ani muscle. The p27/kip1 (p27) protein, multifunctional cyclin-dependent kinase inhibitor, shows changing expression in differentiating skeletal muscle cells during development, and relatively high levels of p27 RNA were detected in the normal human skeletal muscles. METHODS: Biopsy samples of levator ani muscle were obtained from 22 symptomatic patients with stress urinary incontinence, pelvic organ prolapse, and overlaps (age range 38–74), and nine asymptomatic women (age 31–49). Cryostat sections were investigated for p27 protein expression and type I (slow twitch) and type II (fast twitch) fibers. RESULTS: All fibers exhibited strong plasma membrane (and nuclear) p27 protein expression. cytoplasmic p27 expression was virtually absent in asymptomatic women. In perimenopausal symptomatic patients (ages 38–55), muscle fibers showed hypertrophy and moderate cytoplasmic p27 staining accompanied by diminution of type II fibers. Older symptomatic patients (ages 57–74) showed cytoplasmic p27 overexpression accompanied by shrinking, cytoplasmic vacuolization and fragmentation of muscle cells. The plasma membrane and cytoplasmic p27 expression was not unique to the muscle cells. Under certain circumstances, it was also detected in other cell types (epithelium of ectocervix and luteal cells). CONCLUSIONS: This is the first report on the unusual (plasma membrane and cytoplasmic) expression of p27 protein in normal and abnormal human striated muscle cells in vivo. Our data indicate that pelvic floor disorders are in perimenopausal patients associated with an appearance of moderate cytoplasmic p27 expression, accompanying hypertrophy and transition of type II into type I fibers. The patients in advanced postmenopause show shrinking and fragmentation of muscle fibers associated with strong cytoplasmic p27 expression

A Genetic Risk Score Combining Ten Psoriasis Risk Loci Improves Disease Prediction

Psoriasis is a chronic, immune-mediated skin disease affecting 2–3% of Caucasians. Recent genetic association studies have identified multiple psoriasis risk loci; however, most of these loci contribute only modestly to disease risk. In this study, we investigated whether a genetic risk score (GRS) combining multiple loci could improve psoriasis prediction. Two approaches were used: a simple risk alleles count (cGRS) and a weighted (wGRS) approach. Ten psoriasis risk SNPs were genotyped in 2815 case-control samples and 858 family samples. We found that the total number of risk alleles in the cases was significantly higher than in controls, mean 13.16 (SD 1.7) versus 12.09 (SD 1.8), p = 4.577×10−40. The wGRS captured considerably more risk than any SNP considered alone, with a psoriasis OR for high-low wGRS quartiles of 10.55 (95% CI 7.63–14.57), p = 2.010×10−65. To compare the discriminatory ability of the GRS models, receiver operating characteristic curves were used to calculate the area under the curve (AUC). The AUC for wGRS was significantly greater than for cGRS (72.0% versus 66.5%, p = 2.13×10−8). Additionally, the AUC for HLA-C alone (rs10484554) was equivalent to the AUC for all nine other risk loci combined (66.2% versus 63.8%, p = 0.18), highlighting the dominance of HLA-C as a risk locus. Logistic regression revealed that the wGRS was significantly associated with two subphenotypes of psoriasis, age of onset (p = 4.91×10−6) and family history (p = 0.020). Using a liability threshold model, we estimated that the 10 risk loci account for only11.6% of the genetic variance in psoriasis. In summary, we found that a GRS combining 10 psoriasis risk loci captured significantly more risk than any individual SNP and was associated with early onset of disease and a positive family history. Notably, only a small fraction of psoriasis heritability is captured by the common risk variants identified to date

S100A6 (Calcyclin) is a prostate basal cell marker absent in prostate cancer and its precursors

S100A6 (Calcyclin) is a calcium-binding protein that has been implicated in a variety of biological functions as well as tumorigenesis. The aim of our study was to investigate the involvement of S100A6 during prostate cancer development and progression. Using immunohistochemistry, the expression of S100A6 was examined in benign (n ¼ 66), premalignant (n ¼ 10), malignant (n ¼ 66) and metastatic prostate (n ¼ 5) tissues arranged in a tissue-microarray or whole sections as well as in prostate cancer cell lines. The S100A6 immunostaining pattern in tissues was compared with that of cytokeratin 5 (a basal cell marker) and 18 (a benign luminal cell marker). In all cases of benign epithelium, intense S100A6 expression was seen in the basal cell layer with absent staining in luminal cells. In all cases of prostatic adenocarcinoma (matched), metastatic lesions and 3/10 high-grade prostatic intraepithelial neoplasia lesions, an absence of S100A6 was seen. Western blotting and RT–PCR analysis of cell lines showed S100A6 expression to be absent in LNCaP, LNCaP-LN3 and LNCaP-Pro5 but present in Du145, PC3, PC-3M and PC-3M-LN4. LNCaP cells treated with 5- Azacytidine, caused re-expression of S100A6 mRNA. Sequencing of bisulphite modified DNA showed CpG methylation within the S100A6 promoter region and exon 1 of LNCaP, LNCaP-LN3 and LNCaP-Pro5 cell lines but not in Du145 cells. Our data suggest that loss of S100A6 protein expression is common in prostate cancer development and may occur at an early stage. The mechanism of loss of expression may involve hypermethylation of CpG sites. The finding of intense S100A6 expression in the basal cells of benign glands but loss of expression in cancer could be useful as a novel diagnostic marker for prostate cancer

Association analysis identifies ZNF750 regulatory variants in psoriasis

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>ZNF750 </it>promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. <it>ZNF750 </it>encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene.</p> <p>Methods</p> <p>We examined whether <it>ZNF750 </it>variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of <it>ZNF750 </it>in 716 Caucasian psoriasis cases and 397 Caucasian controls.</p> <p>Results</p> <p>We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two <it>ZNF750 </it>haplotypes associated with psoriasis (p < 0.05). We also identified an excess of rare promoter and 5'untranslated region (UTR) variants in psoriasis cases compared to controls (p = 0.041), whereas there was no significant difference in the number of rare coding and rare 3' UTR variants. Using a promoter functional assay in stimulated human primary keratinocytes, we showed that four <it>ZNF750 </it>promoter and 5' UTR variants displayed a 35-55% reduction of <it>ZNF750 </it>promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a <it>ZNF750 </it>promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families.</p> <p>Conclusions</p> <p>Two haplotypes of <it>ZNF750 </it>and rare 5' regulatory variants of <it>ZNF750 </it>were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.</p

A review of significant events analysed in general practice: implications for the quality and safety of patient care

<p>Abstract</p> <p>Background</p> <p>Significant event analysis (SEA) is promoted as a team-based approach to enhancing patient safety through reflective learning. Evidence of SEA participation is required for appraisal and contractual purposes in UK general practice. A voluntary educational model in the west of Scotland enables general practitioners (GPs) and doctors-in-training to submit SEA reports for feedback from trained peers. We reviewed reports to identify the range of safety issues analysed, learning needs raised and actions taken by GP teams.</p> <p>Method</p> <p>Content analysis of SEA reports submitted in an 18 month period between 2005 and 2007.</p> <p>Results</p> <p>191 SEA reports were reviewed. 48 described patient harm (25.1%). A further 109 reports (57.1%) outlined circumstances that had the potential to cause patient harm. Individual 'error' was cited as the most common reason for event occurrence (32.5%). Learning opportunities were identified in 182 reports (95.3%) but were often non-specific professional issues not shared with the wider practice team. 154 SEA reports (80.1%) described actions taken to improve practice systems or professional behaviour. However, non-medical staff were less likely to be involved in the changes resulting from event analyses describing patient harm (p < 0.05)</p> <p>Conclusion</p> <p>The study provides some evidence of the potential of SEA to improve healthcare quality and safety. If applied rigorously, GP teams and doctors in training can use the technique to investigate and learn from a wide variety of quality issues including those resulting in patient harm. This leads to reported change but it is unclear if such improvement is sustained.</p

Parental health limitations, caregiving and loneliness among women with widowed parents: longitudinal eveidence from France

We investigate how daughters’ feelings of loneliness are impacted when widowed parents develop health limitations, and when daughters take on personal care tasks in response. Using longitudinal data from daughters of widowed parents drawn from the French Family and Intergenerational Relationships Study (ERFI, 1485 observations nested in 557 daughters), we assess (a) whether health limitations of widowed parents are associated with daughters’ feelings of loneliness regardless of whether or not daughters provide personal care and (b) whether there is an effect of care provision on loneliness that cannot be explained by parental health limitations. Fixed effect regression analyses show that widowed parents’ health limitations were associated with raised feelings of loneliness among their daughters. No significant additional effect of providing personal care to a widowed parent was found. Prior research on the impact of health limitations of older parents on the lives of their adult–children has focused mostly on issues related to informal caregiving. Our findings suggest that more attention to the psychosocial impact of parental health limitations—net of actual caregiving—on adult children’s lives is warranted