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A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).

While annual influenza vaccination of healthcare workers (HCWs) is recommended, uptake is often suboptimal. We sought to evaluate influenza vaccination uptake by HCWs in Victorian public healthcare facilities, where non-mandatory programs are used. All participating facilities completed an annual survey (2014–2019) recording HCW influenza vaccination status. Uptake in high-risk departments (emergency and intensive care units) was evaluated for the 2019 season. The proportion of vaccinated HCWs increased annually, from 72.2% (2014) to 87.7% (2019), with pre-set targets generally achieved. In 2019, 110,324 HCWs in 107 facilities were vaccinated (87.7%). Of those without documented vaccination, 7591 (6.0%) declined and 7906 (6.3%) had unknown status. Uptake was higher in high-risk departments (91.4%). Increasing annual influenza vaccination uptake by HCWs in Victorian public healthcare facilities has been achieved in the context of performance monitoring targets. Small proportions declined or had unknown status. Future policies should focus on these HCWs.

The human renin gene (REN) is a good candidate in studies aimed at unravelling the genetic basis of essential hypertension and stroke. We previously established that both a BglI and an MboI dimorphisms (located respectively in the first and ninth introns of the REN gene) were associated with essential hypertension in a population of hyperlipidaemic US subjects. In this association (retrospective case-control) study, we investigated the haplotype distribution of alleles defined by the combination of REN BglI and MboI dimorphic sites in 329 hyperlipidaemic US Caucasian subjects referred to UCSF Medical Center (140 hypertensives, 141 normotensives, and 48 hypertensive patients who had suffered a stroke). A statistically significant association was found between alleles determined by both (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) haplotypes and clinical diagnosis of EHT (combined odds ratios, OR = 3.35, corrected P < 10(-7)). Haplotypes (-,+) and (+,+) were also found to be associated with clinical diagnosis of stroke (OR = 4.31, P < 10(-7)). These associations do not occur through the effects of classical risk factors related to lipid, lipoprotein and apolipoprotein levels. We conclude that variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with REN (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) alleles could play a role in contributing to increased individual's genetic susceptibility to EHT and to stroke. Journal of Human Hypertension(2001) 15, 49-55

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between- and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt1/2) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2. P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt1/2 (mean difference in PCt1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisinin-resistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.

The metabolism of apolipoproteins B-48 and B-100 (apo B-48 and B-100) in large triglyceride-rich lipoproteins (300 to 1500 angstrom in diameter) has been compared in three normal subjects and two subjects with genetically determined deficiency of lipoprotein lipase. The triglyceride-rich lipoproteins were obtained from a lipoprotein lipase-deficient donor 4 hr after a fat-rich meal in order to obtain chylomicrons (containing apo B-48) and very low density lipoproteins (VLDL) (containing apo B-100), whose properties had not been modified by the action of this enzyme. The triglyceride-rich lipoproteins were labeled with125I and injected intravenously into recipients who had fasted overnight. In normal recipients, most of the apo B-48 was removed from the blood within 15 min, and most of the apo B-100 was removed within 30 min. In the lipoprotein lipase-deficient recipients, most of the injected apo B-100 remained in the blood for more than 8 hr; removal of apo B-48 was only slightly more rapid. In all subjects, only trace amounts of either protein were found in lipoproteins more dense than 1.006 g/ml. The results indicate that (i) the removal of the apo B of both chylomicrons and large VLDL from the blood is dependent upon the hydrolysis of their component triglycerides by lipoprotein lipase, and (ii) little or no apo B-48 of chylomicrons or apo B-100 of large VLDL is converted appreciably to low density lipoproteins (LDL). Our results suggest that the reported variability of the conversion of VLDL to LDL may be related to the size and composition of the particles secreted from the liver. The rapid production of remnant particles that are removed efficiently by the liver may minimize the opportunity for further reactions leading to the formation of LDL.

We studied the effect of the bile acid sequestrant colestipol, alone and in combination with clofibrate or niacin, in patients with heterozygous familial hypercholesterolemia who were given a diet low in cholesterol and saturated fat. With colestipol alone, mean cholesterol levels in serum decreased 16 to 25 per cent. The addition of clofibrate produced a total mean decrement of only 28 per cent. In contrast, serum cholesterol levels fell 45 per cent when colestipol was combined with niacin. Low-density-lipoprotein (LDL) cholesterol decreased 55 per cent with colestipol and niacin, whereas highdensity-lipoprotein (HDL) cholesterol increased. Mean LDL cholesterol was lower in patients given this regimen than in matched normal controls eating an unrestricted diet. Tendinous xanthomas, measured by quantitative xeroradiography, were significantly reduced (P<0.01), indicating that this regimen mobilized cholesterol from tissue pools with slow turnover. Colestipol plus niacin promises to be useful in the treatment of patients at high risk from elevated levels of LDL. (N Engl J Med. 1981; 304:251–8.) HYPERLIPIDEMIA, especially elevated levels of low-density lipoprotein (LDL), has consistently been identified as a major risk factor in coronary heart disease. 1 In persons with familial hypercholesterolemia, an autosomal-dominant disorder in which levels of LDL are two to three times normal 2 and high-affinity receptors for LDL on cell membranes are deficient, the risk of coronary disease is five times that in the normolipidemic population. 3 4 5 Clinical characteristics that discriminate heterozygous familial hypercholesterolemia from other states with elevated levels of LDL include high levels of serum cholesterol (300 to 500 mg per deciliter or 7.75 to 13.0 mmol per liter), relative resistance to . . .

Regulator of G protein signaling 9-2 (RGS9-2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight.

HM74 (GPR109B) and the highly homologous gene, HM74A (GPR109A) code for Gi‐G protein‐coupled orphan receptors that recently have been discovered to be involved in the metabolic effects of niacin. The B vitamin niacin is an important agent used in the treatment of dyslipidemias, but its use is limited by side effects. The novel role of the adjacent HM74 and HM74A genes in the metabolism of niacin may provide new targets for drug development. Human genetic variations in HM74 and HM74A have been reported but have not been studied in detail. These variations may play a role in the response to agents targeting receptors coded by these genes. Here we show that many of the nonsynonymous SNPs listed in public databases for HM74 and HM74A are artifacts resulting from extensive homology between these two genes. This may be representative of a neglected phenomenon in reporting sequences of highly homologous genes. We provide primer sequences that permit selective amplification of the complete coding regions of HM74 and HM74A. Using these primers, we show that subsequent sequencing of HM74 and HM74A reveals a novel and unique variation in the HM74A gene. Haplotype analysis suggests four SNPs can define the five major haplotypes that lie within a single haplotype block encompassing these two genes. Hum Mutat 25:18–21, 2005. © 2004 Wiley‐Liss, Inc.

This paper examines the interaction between social welfare policies and the \"population problem\" in Latin America. It demonstrates that social security programs, by reinforcing highly unequal patterns of stratification, have had a largely negative effect on population issues in the region. Social security policy in turn is analyzed as a particular political adaptation to the realities of dependent capitalist development. As a result, the population problem in Latin America is viewed less as a product of mindless demographic forces than as a politically induced reality stemming from the accumulated impact and negative consequences of a variety of consciously formulated public policies.