'He just gave up': an exploratory study into the perspectives of paid carers on supporting older people living in care homes with depression, self-harm, and suicide ideation and behaviours

This study explored the concept of ‘giving up’ from the perspective of care staff working in care homes, and their everyday communication and hidden knowledge concerning what they think about this taboo topic and the context it reflects. Moving to a care home is a major transition where cumulative losses can pose risks to mental health in later life. If not recognised, this vulnerability can lead to depression which extends to suicide ideation and behaviours in the form of self-harm and self-neglect. Care homes are a significant place of care until death, yet a discourse of silence means that self-harm and suicide is under-reported or not attended to with specialist expertise. The layperson’s concept of an older person ‘giving up’ on life is hardly discussed in the literature. This co-produced qualitative study used an inductive approach to explore this phenomenon through focus groups with 33 care staff across four care homes in South-East England. Findings paint a complex picture, highlighting tensions in providing the right support and creating spaces to respond to such challenging situations. ‘Giving up’ requires skilled detailed assessment to respond to risks alongside improved training and support for paid carers, to achieve a more holistic strategy which capitalises on significant relationships within a wider context

A point mutation affecting an SP1 binding site in the promoter of ferrochelatase gene impairs gene transcription and causes erythropoietic protoporphyria

Objective. Clinical manifestation of erythropoietic protoporphyria (EPP) results from coinheritance of a mutated allele and a wild-type low-expressed allele of the ferrochelatase (FECH) gene. Currently, up to 90 different mutations affecting the coding region or splicing junctions of the FECH gene have been identified. Despite the high molecular heterogeneity, no functional mutations have been previously reported in the promoter region. The weaker allele expression has been controversially associated to the presence of different intragenic polymorphisms. Methods. We applied a two-step screening strategy using denaturing gradient gel electrophoresis followed by direct sequencing in order to rapidly identify FECH gene mutations in Italian EPP patients. We identified two unrelated subjects showing a normal FECH coding region but a single G>C base substitution at position -250 in the FECH promoter and the -251G, IVS1-23T, and IVS3-48C polymorphisms in trans to the substitution. To investigate the effect of the -250G>C mutation on protein binding to the FECH promoter, we conducted electro mobility shift assay (EMSA) and supershift analysis. To determine its effect on the transcriptional activity, K562 and Jurkat cell lines were transiently transfected. Results. EMSA showed that the -250G>C mutation results in the loss of an SP1 binding site, and transient transfection assays demonstrated that such mutation strongly impairs promoter activity. Moreover, we showed that the -251A>G polymorphism, although unable to affect SP1 binding, displays a significant reduction in the transcriptional activity of the promoter. Conclusion. This is the first report of a mutation in the FECH promoter affecting binding of a transcription factor and causing EPP phenotype

Thalidomide in the treatment of chronic hepatitis C unresponsive to alfa-interferon and ribavirin

Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor (alpha) and costimulatory effect on human CD8+ T cells. We investigated the efficacy and safety of a 24-wk course of thalidomide at a dosage of 200 mg/day in eight patients with HCV chronic hepatitis nonresponders to interferon (alpha) plus ribavirin. We observed a significant mean decrease of serum aminotransferases and (gamma)-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-(alpha)in vitro production in mononuclear cells decreased with thalidomide in all the subjects (p= 0.028). Perforin- and granzyme-specific mRNA expression increased under thalidomide without statistical significance. A positive correlation between biochemical and immunological parameters was observed with higher increase of granzyme and perforin values in patients showing reduction of aminotransferases. Finally upregulation of T-helper 1 cytokine expression as mean interferon (gamma)/IL-10 ratio was evidenced. Thalidomide was well tolerated. In conclusion, thalidomide was able to reduce liver enzymes in six out of eight patients with chronic hepatitis C and to reduce tumor necrosis factor (alpha) production, representing a promising new approach for the treatment of HCV infection. (copyright) 2006 by Am. Coll. of Gastroenterology Published by Blackwell Publishing

Vpr and HIV-1 disease progression : R77Q mutation is associated with long-term control of HIV-1 infection in different groups of patients

Vpr (viral protein R) is a 96 amino acid sol. protein that is expressed late during viral replication. Recent studies have focused on the role of a mutation at position 77 that might be assocd. with the condition of long-term non-progression, but data are still controversial. Fifteen long-term non-progressors (LTNP), 19 therapy-naive HIV-1-infected patients with progressive disease (Pr), 23 HIV-1-infected patients receiving sub-optimal therapy with dual nucleoside [nucleoside reverse transcriptase inhibitor (NRTI)] therapy but efficiently controlling viral replication (STP) and 19 antiretroviral therapy multi-experienced patients with actively replicating virus (MEP) were analyzed. HIV-RNA was extd. from plasma samples, the Vpr region was amplified, cloned and sequenced. The Pol gene was amplified, directly sequenced and analyzed using Sequence Navigator software. A significantly higher prevalence of the R77Q mutation was evidenced both in LTNP (86.7%) and STP (73.9%) in comparison with Pr (42.1%) and MEP (42.1%), (P= 0.007). Comparing groups of patients with progressive disease (Pr + MEP) and groups with non-progressive disease (LTNP + STP) the probability of harboring the R77Q mutation was significantly higher in non-progressors (odds ratio, 5.16; P= 0.001). Our results support the hypothesis of the assocn. of R77Q mutation in the Vpr gene with delayed progression of HIV-1 disease. R77Q does not seem to be linked to a particular viral strain but might be assocd. with immunol. selection. The R77Q mutation might reduce CD4+ T-cell depletion possibly affecting T-cell survival in vivo by altering the pro-apoptotic activity of Vpr. [on SciFinder (R)

Genetic polymorphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy

Objective and design: The present study aims at evaluating the influence of geneticpolymorphisms on antiretroviral therapy (ART)-associated lipodystrophy. We includedin the study 255 ICoNA. patients and we assessed the distribution of Fas 670 AGpolymorphism, ApoC3 455 CT and 482 CT polymorphisms, C161T silent substitutionin the PPAR g gene, the Adrenergic b3 Receptor (ARb3) codon 64 TC variant, andtwo polymorphisms in the Adrenergic b2 Receptor (ARb2) codon 16 AG and codon 27CG. Crude rates of lipoatrophy and fat accumulation and adjusted relative rates werecalculated using Poisson regression.Results: In a multivariate model after adjusting for gender, HIV exposure, age, currentviral load, hepatitis C virus (HCV) serology, nucleoside reverse-transcriptase inhibitor(NRTI) pair/\u2018third drugs\u2019 currently used, months of pre-highly active antiretroviraltherapy (HAART) exposures to NRTI, the following genotypes resulted protectiveagainst lipoatrophy: ApoC3 455 CC genotype [adjusted relative risks (ARR) 0.2,95% confidence interval (CI) 0.046\u20130.91 vs CT/TT, P\ubc0.037], ARb3 codon 64 TTgenotype (ARR 0.39, 95% CI 0.14\u20131.06 vs TC/CC, P\ubc0.066), and Fas 670 GGgenotype (ARR 0.51, 95% CI 0.26\u20131.01 vs AG/AA, P\ubc0.053). With regard to fataccumulation, in the multivariate model, the ARb2 codon 27 CC genotype resultedprotective (ARR 0.21, 95% CI 0.08\u20130.51 vs CG/GG, P\ubc0.0006), whereas the ARb2codon 16 AA genotype resulted associated with higher risk (ARR 3.72, 95% CI 1.58\u20138.76 vs AG/GG, P\ubc0.0026).Conclusion: Our study suggests that genetic polymorphisms of genes involved inapoptosis and adipocyte metabolism are significantly related to ART associated lipodystrophy.Particularly, we evidenced a role for ApoC3 455 in lipoatrophy and for thetwo variants of ARb2 in fat accumulation

Single-Nucleotide Polymorphism-Defined Class I and Class III Major Histocompatibility Complex Genetic Subregions Contribute to Natural Long-term Nonprogression in HIV Infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in 654 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype