Association of nuclear matrix proteins with granular and threaded nuclear bodies in cell lines undergoing apoptosis.

The granules which appear in the nucleolar area in apoptotic HL-60 cells after camptothecin administration (Zweyer et al., Exp. Cell Res. 221,27-40, 1995) were detected also in several other cell lines induced to undergo apoptosis by different stimuli, such as MOLT-4 treated with staurosporine, K-562 incubated with actinomycin D, P-815 exposed to temperature causing heat shock, Jurkat cells treated with EGTA, U-937 growing in the presence of cycloheximide and tumor necrosis factor-alpha, and HeLa cells treated with etoposide. Using immunoelectron microscopy techniques, we demonstrate that, besides the already described nuclear matrix proteins p125 and p160, these granules contain other nucleoskeletal polypeptides such as proliferating cell nuclear antigen, a component of ribonucleoprotein particles, a 105-kDa constituent of nuclear spliceosomes, and the 240-kDa nuclear mitotic apparatus-associated protein referred to as NuMA. Moreover, we also found in the granules SAF-A/hn-RNP-U and SATB1 proteins, two polypeptides that have been reported to bind scaffold-associated regions DNA sequences in vitro, thus mediating the formation of looped DNA structures in vivo. Fibrillarin and coilin are not present in these granules or the PML protein. Thus, the granules seen during the apoptotic process apparently are different from coiled bodies or other types of nuclear bodies. Furthermore, these granules do not contain chromatin components such as histones and DNA. Last, Western blotting analysis revealed that nuclear matrix proteins present in the granules are not proteolytically degraded except for the NuMA polypeptide. We propose that these granules might represent aggregates of nuclear matrix proteins forming during the apoptotic process. Moreover, since the granules are present in several cell lines undergoing apoptosis, they could be considered a previously unrecognized morphological hallmark of the apoptotic process.

Patent foramen ovale and obstructive sleep apnoea: from pathophysiology to diagnosis of a potentially dangerous association.

Patent foramen ovale and obstructive sleep apnoea are frequently encountered in the general population. Owing to their prevalence, they may coexist fortuitously; however, the prevalence of patent foramen ovale seems to be higher in patients with obstructive sleep apnoea. We have reviewed the epidemiological data, pathophysiology, and the diagnostic and therapeutic options for both patent foramen ovale and obstructive sleep apnoea. We focus on the interesting pathophysiological links that could explain a potential association between both pathologies and their implications, especially on the risk of stroke.

An Overview of the association between schizotypy and dopamine

Schizotypy refers to a constellation of personality traits that are believed to mirror the subclinical expression of schizophrenia in the general population. Evidence from pharmacological studies indicates that dopamine is involved in the aetiology of schizophrenia. Based on the assumption of a continuum between schizophrenia and schizotypy, researchers have begun investigating the association between dopamine and schizotypy using a wide range of methods. In this article, we review published studies on this association from the following areas of work: (1) Experimental investigations of the interactive effects of dopaminergic challenges and schizotypy on cognition, motor control and behaviour, (2) dopaminergically supported cognitive functions, (3) studies of associations between schizotypy and polymorphisms in genes involved in dopaminergic neurotransmission, and (4) molecular imaging studies of the association between schizotypy and markers of the dopamine system. Together, data from these lines of evidence suggest that dopamine is important to the expression and experience of schizotypy and associated behavioural biases. An important observation is that the experimental designs, methods, and manipulations used in this research are highly heterogeneous. Future studies are required to replicate individual observations, to enlighten the link between dopamine and different schizotypy dimensions (positive, negative, cognitive disorganisation), and to guide the search for solid dopamine-sensitive behavioural markers. Such studies are important in order to clarify inconsistencies between studies. More work is also needed to identify differences between dopaminergic alterations in schizotypy compared to the dysfunctions observed in schizophrenia.

Increasing prevalence of obesity in the Seychelles and association with socioeconomic status

Objective: We assessed the 15-year trends in the distribution of body mass index (BMI) categories in the Seychelles (Indian Ocean, African Region) and the relationship with sex, age and socio-economic status (SES). Methods: We conducted three population-based examination surveys in 1989 (n=1,081; participation rate: 86.4%), in 1994 (n=1,067; 87.0%), and in 2004 (n=1,255; 80.2%). Occupation was categorized as "laborer", "intermediate" or "professional". Results are adjusted to the population of 2002. Results: Between 1989 and 2004, mean BMI increased markedly in all sex and age categories (overall: ∼0.15 kg/m2/calendar year). The prevalence of overweight and obesity combined ("excess weight", BMI ≥25 kg/m2) increased from 29% to 52% in men and from 50% to 67% in women. The prevalence of obesity (BMI ≥30 kg/m2) increased from 4% to 15% in men and from 23% to 34% in women. Mean BMI - respectively the prevalence of excess weight- was lower in laborers than professionals in men but higher in laborers that professionals in women and this pattern was similar in the three surveys. Odds ratios for excess weight in professionals vs. laborers were 2.10 (95% CI: 1.94-2.17) in men and 0.51 (0.48-0.53) in women, adjusting for calendar year and participants' age and smoking habits. Conclusion: The prevalence of overweight/obesity increased markedly during a 15- year period. Similar increase of BMI over time in all age and sex categories suggests common environment obesogenic factors. The association between SES and excess weight was in opposite directions in men and women. The study emphasizes the need for prevention measures in all sex, age and SES groups, and suggests that they should be tailored according to sex and SES categories.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Cis association of Ly49A with MHC class I restricts natural killer cell inhibition.

Natural killer (NK) cell function is negatively regulated by inhibitory receptors interacting with major histocompatibility complex class I molecules expressed on target cells. Here we show that the inhibitory Ly49A NK cell receptor not only binds to its H-2D(d) ligand expressed on potential target cells (in trans) but also is constitutively associated with H-2D(d) in cis (on the same cell). Cis association and trans interaction occur through the same binding site. Consequently, cis association restricts the number of Ly49A receptors available for binding of H-2D(d) on target cells and reduces NK cell inhibition through Ly49A. By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction allows optimal discrimination of normal and abnormal host cells.

No consistent association between processes-of-care and health-related quality of life among patients with diabetes : a missing link?

PURPOSE: Health-related quality of life (HRQoL) is considered a representative outcome in the evaluation of chronic disease management initiatives emphasizing patient-centered care. We evaluated the association between receipt of processes-of-care (PoC) for diabetes and HRQoL. METHODS: This cross-sectional study used self-reported data from non-institutionalized adults with diabetes in a Swiss canton. Outcomes were the physical/mental composites of the short form health survey 12 (SF-12) physical composite score, mental composite score (PCS, MCS) and the Audit of Diabetes-Dependent Quality of Life (ADDQoL). Main exposure variables were receipt of six PoC for diabetes in the past 12 months, and the Patient Assessment of Chronic Illness Care (PACIC) score. We performed linear regressions to examine the association between PoC, PACIC and the three composites of HRQoL. RESULTS: Mean age of the 519 patients was 64.5 years (SD 11.3); 60% were male, 87% reported type 2 or undetermined diabetes and 48% had diabetes for over 10 years. Mean HRQoL scores were SF-12 PCS: 43.4 (SD 10.5), SF-12 MCS: 47.0 (SD 11.2) and ADDQoL: -1.6 (SD 1.6). In adjusted models including all six PoC simultaneously, receipt of influenza vaccine was associated with lower ADDQoL (β=-0.4, p≤0.01) and foot examination was negatively associated with SF-12 PCS (β=-1.8, p≤0.05). There was no association or trend towards a negative association when these PoC were reported as combined measures. PACIC score was associated only with the SF-12 MCS (β=1.6, p≤0.05). CONCLUSIONS: PoC for diabetes did not show a consistent association with HRQoL in a cross-sectional analysis. This may represent an effect lag time between time of process received and health-related quality of life. Further research is needed to study this complex phenomenon.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Housewife or working mum--each to her own? The relevance of societal factors in the association between social roles and alcohol use among mothers in 16 industrialized countries.

Aims To investigate whether differences in gender-income equity at country level explain national differences in the links between alcohol use, and the combination of motherhood and paid labour. Design Cross-sectional data in 16 established market economies participating in the Gender, Alcohol and Culture: An International Study (GenACIS) study. Setting Population surveys. Participants A total of 12 454 mothers (aged 25-49 years). Measurements Alcohol use was assessed as the quantity per drinking day. Paid labour, having a partner, gender-income ratio at country level and the interaction between individual and country characteristics were regressed on alcohol consumed per drinking day using multi-level modelling. Findings Mothers with a partner who were in paid labour reported consuming more alcohol on drinking days than partnered housewives. In countries with high gender-income equity, mothers with a partner who were in paid labour drank less alcohol per occasion, while alcohol use was higher among working partnered mothers living in countries with lower income equity. Conclusion In countries which facilitate working mothers, daily alcohol use decreases as female social roles increase; in contrast, in countries where there are fewer incentives for mothers to remain in work, the protective effect of being a working mother (with partner) on alcohol use is weaker. These data suggest that a country's investment in measures to improve the compatibility of motherhood and paid labour may reduce women's alcohol use.

Association with {beta}-COP regulates the trafficking of the newly synthesized Na,K-ATPase.

Plasma membrane expression of the Na,K-ATPase requires assembly of its α- and β-subunits. Using a novel labeling technique to identify Na,K-ATPase partner proteins, we detected an interaction between the Na,K-ATPase α-subunit and the coat protein, β-COP, a component of the COP-I complex. When expressed in the absence of the Na,K-ATPase β-subunit, the Na,K-ATPase α-subunit interacts with β-COP, is retained in the endoplasmic reticulum, and is targeted for degradation. In the presence of the Na,K-ATPase β-subunit, the α-subunit does not interact with β-COP and traffics to the plasma membrane. Pulse-chase experiments demonstrate that in cells expressing both the Na,K-ATPase α- and β-subunits, newly synthesized α-subunit associates with β-COP immediately after its synthesis but that this interaction does not constitute an obligate intermediate in the assembly of the α- and β-subunits to form the pump holoenzyme. The interaction with β-COP was reduced by mutating a dibasic motif at Lys(54) in the Na,K-ATPase α-subunit. This mutant α-subunit is not retained in the endoplasmic reticulum and reaches the plasma membrane, even in the absence of Na,K-ATPase β-subunit expression. Although the Lys(54) α-subunit reaches the cell surface without need for β-subunit assembly, it is only functional as an ion-transporting ATPase in the presence of the β-subunit.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.

BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.¦METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.¦RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.¦CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Nutrition parentérale compé- mentaire de la nutrition entérale aux soins intensifs: une association logique [Supplemental parenteral nutrition for intensive care patients: a logical combination with enteral nutrition]

Undernutrition is a widespread problem in the intensive care and is associated with a worse clinical outcome. Enteral nutrition is the recommended nutritional support in ICU patients. However, enteral nutrition is frequently insufficient to cover protein-energy needs. The initiation of supplemental parenteral nutrition, when enteral nutrition is insufficient, could optimize the nutritional therapy. Such a combination could allow reducing morbidity, length of stay and recovery, as well as improving quality of life and health care costs. Prospective studies are currently underway to test this hypothesis.

Complete bilateral facial cleft (Tessier 4) with corneal staphyloma: a rare association.

The oro-ocular cleft no. 4 according to the Tessier classification is one of the rarest facial cleft, and to this day, few cases have been reported in the literature. We describe the case of a 9-month-old girl with a complete bilateral facial cleft. On the right cornea protruded a hard lesion, a corneal staphyloma. We describe the 3 primary surgical steps used to restore the possibility of satisfactory feeding, to promote language acquisition, and to protect vision in the nonaffected eye. The psychological and social aspects of severe facial deformities in developing countries are also tackled.

Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.