MOS-SF-36 in evaluating health-related quality of life in alcohol-dependent patients.

Health-related quality of life (HRQoL) was evaluated in a sample of alcohol-dependent patients with the 36-item Medical Outcome Study Short-Form Health Survey (MOS-SF-36). The instrument was administered to 147 patients (77% males), aged 26-78, with a DSM-III-R diagnosis of alcohol dependence. The Hamilton Depression Scale (HDS), the Severity of Alcohol Dependence Questionnaire (SADQ), and the Addiction Severity Index (ASI) were also administered to the first 100 patients included in the study. The reliability and validity of the MOS-SF-36 were evaluated. Test-retest intraclass coefficients for a 10-day interval were in the range .65 to .79, whereas the Cronbach alpha coefficient indicated good internal consistency (range .70 to .89). Compared to scores observed in the general population, MOS-SF-36 scores for alcohol-dependent patients were relatively low (indicating worse perception of HRQoL), especially in the psychological and role dimensions (range 52/100 to 55/100), but were closer to populational values in the physical and functional dimensions (range 61/100 to 75/100)). The highest correlation between MOS-SF-36 dimensions and HDS was found in the MOS-SF-36 "mental health" dimension (r=-.56, p < .001); this dimension was also correlated highly with the psychiatric dimension of the ASI (r=-.73, p < .001). The eight dimensions of the MOS-SF-36 were 21% to 127% lower in patients with HDS greater than or equal to 16 (major depression) compared to those with HDS less than or equal to 7 (absence of depression). The MOS-SF-36 dimensions were 10% to 141% lower in patients with high "ASI alcohol" scores, indicating worse HRQoL profiles with a higher severity of alcohol dependence. The MOS-SF-36 presents good criteria for reliability and validity in alcohol-dependent patients. The results suggested that alcohol-dependent patients perceived their problems more as psychological than physical. The severity of alcohol dependence and depression seemed to influence the perception of HRQoL negatively.

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene.

Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid 46;-oxidation.

Statin-associated myasthenia gravis: report of 4 cases and review of the literature.

A few recent individual case reports have suggested that a myasthenic syndrome may be associated with statin treatment, but this association is not well described. We report 4 patients who developed symptoms of myasthenia gravis within 2 weeks of starting treatment with a statin drug. In 1 case the drug appears to have exacerbated underlying myasthenic weakness, whereas in the other 3 cases, de novo antibody formation appears to be most likely. In each case, some degree of recovery followed discontinuation of the statin medication.

Phytochrome interacting factors 4 and 5 control seedling growth in changing light conditions by directly controlling auxin signaling.

Plant growth is strongly influenced by the presence of neighbors that compete for light resources. In response to vegetational shading shade-intolerant plants such as Arabidopsis display a suite of developmental responses known as the shade-avoidance syndrome (SAS). The phytochrome B (phyB) photoreceptor is the major light sensor to mediate this adaptive response. Control of the SAS occurs in part with phyB, which controls protein abundance of phytochrome-interacting factors 4 and 5 (PIF4 and PIF5) directly. The shade-avoidance response also requires rapid biosynthesis of auxin and its transport to promote elongation growth. The identification of genome-wide PIF5-binding sites during shade avoidance revealed that this bHLH transcription factor regulates the expression of a subset of previously identified SAS genes. Moreover our study suggests that PIF4 and PIF5 regulate elongation growth by controlling directly the expression of genes that code for auxin biosynthesis and auxin signaling components.

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Cultured primary fetal cells from one organ donation could possibly meet the exigent and stringent technical aspects for development of therapeutic products. These cell types have fewer technological limitations for cellular proliferation capacity (simple culture conditions) and maintenance of differentiated phenotype, and they also have low probability for transmission of communicable diseases. Master and Working Cell Banks (MCB, WCB) can be obtained from one fetal organ donation, permitting multiple tissues (skin, bone, cartilage, muscle and intervertebral disc) to be processed in short periods of time with identical methods to assure a stringent tracing of the processes for the production of standardized therapeutic agents. Clinical use of biologics from embryo and fetal tissues is relatively new and current legislation and ethics have some differences between countries to date. In addition, specific cell delivery systems for each tissue type can be adapted to the clinical application. Since it is the intention that banked primary fetal cells enhance the prospective treatment of hundreds of thousands of patients with only one organ donation, it is imperative to show consistency, traceability and safety of the processes including donor tissue selection, cell banking, cell testing and growth of cells in out-scaling for the preparation of bio-engineered products for clinical application.

The SPONASTRIME dysplasia: familial short-limb dwarfism with saddle nose, spinal alterations and metaphyseal striation. Report of 4 siblings.

We report clinical, anthropometric and radiological findings in 4 siblings with a new type of skeletal dysplasia. 4 normally intelligent girls exhibit dwarfism between -3.4 and -4.6 standard deviations with accentuated shortening of the lower limbs, moderate deformity of the vertebral bodies, mildly striated metaphyses, saddle nose, frontal bossing, and relatively large head. The family pedigree suggests autosomal recessive inheritance. We propose the designation of SPONASTRIME dysplasia, derived from spondylar and nasal alterations with striation of the metaphyses.

Activation of HTLV-I transcription in the presence of Tax is independent of the acetylation of CREB-2 (ATF-4).

We have previously demonstrated that the bZIP transcription factor CREB-2, also called ATF-4, trans-activates, in association with the viral protein Tax, the human T-cell leukemia virus type I (HTLV-I) promoter. In this study, we have examined whether CREB-2 acetylation affects transcriptional activation mediated by Tax. We present evidence that CREB-2 is acetylated in vitro and in vivo. CREB-2 is acetylated in two regions: the basic domain of the bZIP (from amino acid residue 270 to 300) and the short basic domain (from 342 to 351) located downstream from the bZIP. We also demonstrate that CREB-2 is acetylated by p300/CBP but not by p/CAF. Moreover, replacement of lysine by arginine in the basic domains decreases the trans-activating capacity of CREB-2. However, in the presence of Tax, the HTLV-I transcription remains fully activated by these CREB-2 mutants. Although we cannot totally exclude that the mutations could also affect CREB-2 structure and activity independent of acetylation, our results suggest that activation of the viral promoter in the presence of Tax is independent of the CREB-2 acetylation.