Exclusion Of Carriers Research Articles

Transfusion of target antigens to preimmunized recipients: a new mechanism in transfusion-related acute lung injury

AbstractTransfusion-related lung injury (TRALI) is a serious side effect of blood transfusion. Exclusion of antibody carriers from the donor pool has significantly decreased the number of cases, but TRALI remains the leading cause of transfusion-related morbidity and mortality in industrialized countries. Here, we show that proteins released from donor cells during processing of blood components are capable of inducing a new type of reverse TRALI when transfused to preimmunized recipients. First, we show that soluble neutrophil surface protein CD177 in complex with proteinase 3 (sCD177/PR3) is not only present in human plasma but also in packed red blood cell (PRBC) supernatant. Filtration or storage enhances the concentration of sCD177/PR3 in PRBCs. Second, we show that sCD177/PR3 specifically binds to PECAM-1 on stimulated (but not on unstimulated) endothelial cells (ECs). Third, we provide evidence that the sCD177/PR3/PECAM-1 complex is functional. In the presence of monoclonal or human antibodies against CD177 or PR3, ECs produce reactive oxygen species and become apoptotic. Albumin flux through an EC monolayer increases significantly whenever antibodies and the cognate antigens are present. Finally, we describe a clinical case in which anti-CD177 present in a transfusion recipient precipitated TRALI after the transfusion of CD177-positive, but not CD177-negative, PRBCs. In conclusion, we introduce a new TRALI mechanism based on the specific binding of transfused, soluble antigens to activated ECs in preimmunized recipients. We suggest that further studies and clinical work-up of TRALI should also include antibody investigation of the recipient.

Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk.

Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson’s disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.

Photoresistors from heteroepitaxial structures n-CdxHg1-xTe with exclusion of charge carriers within the 3–5 µm spectral range

The properties of photoresistors with photosensitive areas of 0.05mm×0.05mm and 0.5mm×0.5mm made of heteroepitaxial structures n-CdxHg1−xTe were investigated within the spectral range of 3–5 µm using indium contacts at a temperature of 80 K. The dependence of the lifetime and concentration of the charge carriers inside the pixels on the bias voltage was determined within a wide range of exposure to background radiation. In photoresistors with a pixel size of 0.05mm×0.05mm, a nonequilibrium mode of operation with the exclusion of minority charge carriers can be realized. The electron concentration in this mode decreases to 1×1013cm−3. Photoresistors made of epitaxial structures n-CdxHg1−xTe (x≈0.305) in exclusion mode at 80 K have a voltage sensitivity of the order of 107V/W and a specific detectivity of approximately 1.3×1012cm⋅Hz1/2/W.

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Animals and Food of Animal Origin as a Potential Source of Salmonellosis: A Review of the Epidemiology, Laboratory Diagnosis, Economic Impact and Public Health Significance

Salmonellosis is an infectious disease of humans and animals caused frequently by two species of Salmonella (Salmonella enterica, and Salmonella bongori). Although primarily an intestinal bacterium, Salmonellae are widespread in the environment and are commonly found in farm effluents, human sewage and in any material that is subjected to fecal contamination. Salmonella cause diarrheal and systemic infections in humans. The infection most commonly results due to the consumption of food originating from animals and the environment. Studies have attributed that the subclinical infection in farm animals may lead to the contamination of meat, eggs, and milk or cause secondary contamination of fruits and vegetables that have been fertilized or irrigated with water containing fecal wastes. Salmonellosis causes significant economic loss in the management of farm animals. This can be attributed to the cost associated with the diagnosis and to treat the disease, the cost of cleaning and disinfection, and the cost of control and prevention. Moreover, emerging antimicrobial resistance can increase morbidity, mortality, and costs associated with disease management. Salmonellosis has both the social and economic consequences that require strong scientific and public health efforts to improve the situation. Because of the financial constraints, serological tests are conducted on a statistically representative sample of the population where the results are not always indicative of active infection in the herd. Enzyme-linked immunosorbent assays are available for some serovars of Salmonella and may be used for serological diagnosis and surveillance, especially in poultry and pigs. Vaccination, herd immunity, and antigenic cross-reactivity may compromise the diagnostic value of serological tests. Many inactivated vaccines are used against salmonellosis and some live vaccines are available commercially. Owing to the low efficacy of inactivated vaccines, oil or aluminum hydroxide adjuvants are used to improve their immunogenic properties. There is no vaccine to prevent salmonellosis in adults, whereas, a vaccine against Salmonella typhi has been developed, which is in use especially in children, but is only 60% effective. Prevention strategies include maintenance of sanitary/hygienic conditions in food processing plants, avoidance of cross-contamination of food, proper refrigeration of food, the supply of Salmonella free feed to animals, a strict inspection of meat originating from animals, detection and exclusion of carriers from food handling, and personal hygiene. Awareness should be created among the public about the risks associated with the consumption of raw meat, unpasteurized milk, smoked fish, un-cleaned vegetables, and contaminated water. This review attempts to highlight the role of farm animals in the transmission of salmonellosis, its epidemiology, laboratory diagnosis, economic impact, and public health significance.

Enhanced Numerical Modeling of HgCdTe Long Wavelength Infrared Radiation High Operating Temperature Non-equilibrium P+\u03bd(\u03c0)N+ Photodiodes

Using our computer programs, numerical simulations of photoelectric and fluctuating phenomena were carried out in diode structures of the CdHgTe mesa in the P+ν(π)N+ configuration operating at 230 K and 300 K. These phenomena were analyzed in structures where additional energy barriers at the absorber boundary were applied. Exclusion and extraction of charge carriers in the absorber area after biasing the structures with reverse voltage reduces their concentration by more than an order of magnitude. Reduction of carrier concentration has a positive effect on the increase of the absorption coefficient due to reduction of the Burstein–Moss effect, increases the resistance and electro-optical gain, and effectively suppresses generation and thermal recombination. It is possible to obtain 70% of quantum efficiency in biased photodiodes. It was shown that a non-equilibrium long-wave photodiode working at room temperature can have a normalized detectivity of over 109 cmHZ1/2W−1 for radiation with 10.6 μm wavelength. The results of our calculations and their analysis are illustrated by numerous figures.

Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

BackgroundEnd-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants.ResultsSix independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10−8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10–9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10–8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis.ConclusionsFindings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

Association of Rare Copy Number Variants With Risk of Depression

The role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear. To examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression. This case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018. CNV carrier status. For the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression. Copy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression. Neurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

Transfusion of Soluble Target Antigens to Pre-Immunized Recipients: A Previously Overlooked Mechanism in Transfusion-Related Acute Lung Injury

Transfusion related lung injury (TRALI) is a leading cause for transfusion related morbidity and mortality in industrialized countries. The majority of cases is induced by antibodies present in donor plasma, and exclusion of antibody carriers from the donor pool has decreased the number of TRALI cases significantly. However, TRALI is still reported. We have identified a new and previously overlooked mechanism in which soluble antigens present in the blood component become the target of pre-existing antibodies present in the recipient.Some of us have recently reported a case of TRALI in a female patient precipitating after the transfusion of 120 mL of leuko-reduced packed red blood cells (PRBC). Immediate serologic work-up revealed no antibody in the donor material; but anti-CD177 was detected in the recipient's blood. The following transfusions with two units of PRBCs from CD177 negative donors were uneventful. CD177 is a glycosylphosphatidylinositol-anchored protein exclusively expressed on neutrophils. Only a small minority of Caucasians (<5%) do not express CD177 and can form antibodies when challenged with CD177 during pregnancy or blood transfusions. CD177 functions as a major surface carrier protein for proteinase-3 (PR3), one key contributor to PECAM-1 dependent neutrophil extravasation.Using a sandwich ELISA, we could demonstrate the presence of soluble CD177 in complex with PR3 (sCD177/PR3) in human plasma. As demonstrated by surface plasmon resonance analysis (SPR), PR3 (KD 4.98e-8 M) and the CD177/PR3 complex (KD 7.39e-9 M) specifically bind to immobilized PECAM-1, whereas CD177 does not interact with PECAM-1. In vitro, TNF-alpha pre-treated endothelial cells were negative with anti-CD177 or anti-PR3 antibodies by flow cytometry, but became positive after incubation with sCD177/PR3. Subsequent stimulation with monoclonal anti-CD177 or anti-PR3 induced the production of reactive oxygen species (ROS) in sCD177/PR3 positive (+EC), but not negative (-EC), endothelial cells. The same results were obtained after incubation with human anti-CD177 IgG (hIgG) isolated from plasma. If pre-treated ECs were incubated with recombinant PR3, only monoclonal anti-PR3, but not anti-CD177 or anti-CD177 hIgG induced ROS production. When experiments were repeated with F(ab)2 fragments, overall effects were still present, but diminished. To study the effects of this interaction on EC barrier integrity, ECs were grown on a transwell system, and pre-treated as outlined above. Monoclonal anti-CD177 or anti-PR3 as well as anti-CD177 hIgG significantly increased the albumin-FITC flux through +EC, but not -EC. In the presence of recombinant PR3 only, anti-PR3, but not anti-CD177, increased the albumin flux. Finally, we could demonstrate that the filtration process of buffy coat-reduced red blood cells by standard blood bank technology enhances the concentration of sCD177/PR3 in the storage solution almost 6-fold.In summary, our data demonstrate the presence of sCD177/PR3 in plasma and PRBC storage solution following filtration. When sCD177/PR3 is transfused, it has the capacity to bind to PECAM-1 on the EC surface of the transfusion recipient. The exposure of sCD177/PR3 positive endothelial cells to antibodies against CD177 or PR3 induces endothelial activation and barrier dysfunction in a partially Fcgamma-receptor dependent mechanism, comparable to the mechanism described for “classical” antibody-dependent TRALI. The relevance of soluble target proteins in transfused blood components has previously been overlooked. Furthermore, we assume that the identified new pathway might also be involved in endothelial dysfunction present in Wegener's granulomatosis. DisclosuresNo relevant conflicts of interest to declare.

An Exome-wide Association Study for Type 2 Diabetes–Attributed End-Stage Kidney Disease in African Americans

IntroductionCompared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs.MethodsExome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals.ResultsA total of 11 suggestive T2D-ESKD associations (P < 1 x 10−4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10−6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals).ConclusionOur findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs.

Polygenic Risk Score Analysis of Alzheimer\u2019s Disease in Cases without APOE4 or APOE2 Alleles

The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer’s disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ∼0.68 and the inclusion of the protective E2 allele increasing this to ∼0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ∼0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.

Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle.

BackgroundBovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium and spinal reflexes remain unaffected. Although the causal mutation has not been identified yet, an indirect genetic test based on six microsatellite markers and consequent exclusion of Weaver carriers from breeding have led to the complete absence of new cases for over two decades. Evaluation of disease status by imputation of 41 diagnostic single nucleotide polymorphisms (SNPs) and a common haplotype published in 2013 identified several suspected carriers in the current breeding population, which suggests a higher frequency of the Weaver allele than anticipated. In order to prevent the reemergence of the disease, this study aimed at mapping the gene that underlies Weaver syndrome and thus at providing the basis for direct genetic testing and monitoring of today’s Braunvieh/Brown Swiss herds.ResultsCombined linkage/linkage disequilibrium mapping on Bos taurus chromosome (BTA) 4 based on Illumina Bovine SNP50 genotypes of 43 Weaver-affected, 31 Weaver carrier and 86 Weaver-free animals resulted in a maximum likelihood ratio test statistic value at position 49,812,384 bp. The confidence interval (0.853 Mb) determined by the 2-LOD drop-off method was contained within a 1.72-Mb segment of extended homozygosity. Exploitation of whole-genome sequence data from two official Weaver carriers and 1145 other bulls that were sequenced in Run4 of the 1000 bull genomes project showed that only a non-synonymous SNP (rs800397662) within the PNPLA8 gene at position 49,878,773 bp was concordant with the Weaver carrier status. Targeted SNP genotyping confirmed this SNP as a candidate causal mutation for Weaver syndrome. Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %.ConclusionsThrough combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-016-0201-5) contains supplementary material, which is available to authorized users.

Origin of Current Blockades in Nanopore Translocation Experiments

We present a detailed investigation of the ionic current in a cylindrical model nanopore in the absence and the presence of a double stranded DNA homopolymer. Our atomistic simulations are capable of reproducing almost exactly the experimental data obtained by Smeets etal., including notably the crossover salt concentration that yields equal current measurements in both situations. We can rule out that the observed current blockade is due to the steric exclusion of charge carriers from the DNA, since for all investigated salt concentrations the charge carrier density is higher when the DNA is present. Calculations using a mean-field electrokinetic model proposed by van Dorp etal. fail quantitatively in predicting this effect. We can relate the shortcomings of the mean-field model to a surface related molecular drag that the ions feel in the presence of the DNA. This drag is independent of the salt concentration and originates from electrostatic, hydrodynamic, and excluded volume interactions.

Patients with low HDL-cholesterol caused by mutations in LCAT have increased arterial stiffness

ObjectiveCarriers of a functional mutation in LCAT, encoding lecithin:cholesterol acyl transferase, are exposed to lifelong low high-density lipoprotein cholesterol (HDL-c) levels. We investigated whether LCAT mutation carriers have increased arterial stiffness as a marker of cardiovascular disease and whether arterial stiffness was associated with carotid wall thickening. MethodsWe assessed 45 carriers of LCAT mutations (mean age ± SD 46 ± 13 yrs) and 45 age-matched controls. Probands referred with established cardiovascular disease were excluded. We measured carotid-fermoral pulse wave velocity (PWV) and carotid artery wall thickening by ultrasound and 3.0 T magnetic resonance imaging. ResultsIn carriers, HDL-c was lower (32 ± 12 vs. 59 ± 16 mg/dl; p < 0.0001) and triglycerides were higher (median 116 [IQR 80–170] vs. 71 [IQR 53–89] mg/dl; p < 0.001) vs. controls. PWV was higher in carriers vs. controls (7.9 ± 2.0 m/s vs. 7.1 ± 1.6 m/s; p < 0.01). This difference retained significance in multivariate analysis including age, sex, mean arterial pressure and body mass index, and after exclusion of carriers and controls with cardiovascular disease. Both in carriers and controls, PWV was correlated with wall thickening of the carotid arteries as assessed by ultrasound (R 0.50, p < 0.001 for carriers and R 0.36, p < 0.04 for controls) and 3.0 T magnetic resonance imaging (R 0.54, p < 0.001 for carriers and R 0.58, p < 0.001 for controls). ConclusionPulse wave velocity is increased in LCAT mutation carriers with low HDL-c and is associated with carotid wall thickening.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case–control study

Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Michael J Fox Foundation and National Institutes of Health.

Evaluation of the BD GeneOhm MRSA and VanR Assays as a Rapid Screening Tool for Detection of Methicillin-ResistantStaphylococcus aureusand Vancomycin-Resistant Enterococci in a Tertiary Hospital in Saudi Arabia

Objectives. The aim of this study was to evaluate the diagnostic performance of BD GeneOhm VanR Assay, a rapid PCR test that detects the presence of vanA and/or vanB genes and the performance of BDGeneOhm MRSA Assay which detects the staphylococcal cassette chromosomemec (SCCmec cassette) carrying the mecA gene and Staphylococcus aureus specific sequence located within the orfX gene. Methods. 300 duplicate rectal swabs collected consecutively were analyzed for the presence of VRE by culture and BD PCR. 2267 duplicate swabs were collected (728 nasal and 1539 groin swabs) and analyzed for the presence of MRSA by culture method and BD PCR. Results. Compared to culture, the BD GeneOhm VanR Assay showed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 91.1%, 23.5%, and 100%, respectively. The BD GeneOhm MRSA Assay revealed sensitivity, specificity, PPV, and NPV of 97.2%, 99.4%, 89.7%, and 99.9%, respectively, for nasal swabs. For groin swabs, it was 100%, 98.7%, 61.5% and 100%, respectively. Conclusion. The BD GeneOhm vanR Assay is a good screening test for rapid exclusion of VRE carriers in hospitals. The BD GeneOhm MRSA Assay represents a reliable screening test. The true strength of the BD GeneOhm Assay for MRSA and VRE is its exceptionally high NPV making the test an ideal tool for rapid exclusion of MRSA and VRE carriers in hospitals. As a consequence, this would dramatically shorten the patient isolation time.

Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children.

To conduct a meta-analysis of randomized, controlled trials of cephalosporin versus penicillin treatment of group A beta-hemolytic streptococcal (GABHS) tonsillopharyngitis in children. Medline, Embase, reference lists, and abstract searches were conducted to identify randomized, controlled trials of cephalosporin versus penicillin treatment of GABHS tonsillopharyngitis in children. Trials were included if they met the following criteria: patients <18 years old, bacteriologic confirmation of GABHS tonsillopharyngitis, random assignment to antibiotic therapy of an orally administered cephalosporin or penicillin for 10 days of treatment, and assessment of bacteriologic outcome using a throat culture after therapy. Primary outcomes of interest were bacteriologic and clinical cure rates. Sensitivity analyses were performed to assess the impact of careful clinical illness descriptions, compliance monitoring, GABHS serotyping, exclusion of GABHS carriers, and timing of the test-of-cure visit. Thirty-five trials involving 7125 patients were included in the meta-analysis. The overall summary odds ratio (OR) for the bacteriologic cure rate significantly favored cephalosporins compared with penicillin (OR: 3.02; 95% confidence interval [CI]: 2.49-3.67, with the individual cephalosporins [cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil, cefixime, ceftibuten, and cefdinir] showing superior bacteriologic cure rates). The overall summary OR for clinical cure rate was 2.33 (95% CI: 1.84-2.97), significantly favoring the same individual cephalosporins. There was a trend for diminishing bacterial cure with penicillin over time, comparing the trials published in the 1970s, 1980s, and 1990s. Sensitivity analyses for bacterial cure significantly favored cephalosporin treatment over penicillin treatment when trials were grouped as double-blind (OR: 2.31; 95% CI: 1.39-3.85), high-quality (OR: 2.50; 95% CI: 1.85-3.36) trials with well-defined clinical status (OR: 2.12; 95% CI: 1.54-2.90), with detailed compliance monitoring (OR: 2.85; 95% CI: 2.33-3.47), with GABHS serotyping (OR: 3.10; 95% CI: 2.42-3.98), with carriers eliminated (OR: 2.51; 95% CI: 1.55-4.08), and with test of cure 3 to 14 days posttreatment (OR: 3.53; 95% CI: 2.75-4.54). Analysis of comparative bacteriologic cure rates for the 3 generations of cephalosporins did not show a difference. This meta-analysis indicates that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis is significantly less if an oral cephalosporin is prescribed, compared with oral penicillin.

Dilated cardiomyopathy in Doberman Pinschers: Survival, Causes of Death and a Pedigree Review in a Related Line

To analyze clinical, electrocardiographic and echocardiographic characteristics, survival, cause of death and possible modes of inheritance of dilated cardiomyopathy (DCM) in Doberman pinschers (DP) and to compare the occurrence and survival with dogs of other breeds. Dogs - Two cohorts of dogs were studied: 1. A consecutive series of 52 dogs of different breeds with DCM were included, 21 were Doberman pinschers and 31 dogs belonged to other breeds: 2. 28 asymptomatic Doberman pinschers, who were screened for DCM. Methods - Medical records of dogs with DCM were reviewed. Physical, electrocardiographic and echocardiographic examinations were performed on asymptomatic Doberman pinschers. Their pedigrees were reviewed. Doberman pinschers survived on average 52 days (range <1-180), while dogs of other breeds survived significantly longer, i.e. 240 days (<1-1230). Survival of Doberman pinschers in congestive heart failure (mean 62, range <1-180) was not different from survival of Doberman pinschers with sudden death (mean 33, range <1-105). High prevalence, short survival time and the clinical course of DCM in Doberman pinschers showed similarities to previous studies. Twenty-one percent of asymptomatic Doberman pinschers had increased left ventricular end-systolic diameter and 14% developed DCM within a year. A line of Doberman pinschers with multiple members affected with DCM was identified by the review of their pedigrees. Exact mode of inheritance could not be established. The prognosis of Doberman pinschers with DCM is poor. Further molecular genetic studies, which would enable detection and exclusion of disease carriers from the breeding, are necessary.

Polymorphisms in the CCR5 promoter region influence disease progression in perinatally human immunodeficiency virus type 1-infected children.

The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression.

Swine dysentery: more unknown than known

Swine dysentery (SD) is an economically important disease. It is caused by the spirochete Serpulina hyodysenteriae. In order to minimize the economic damage of SD, several methods to control this disease are recommended. Whereas hygienic measures and use of antimicrobials are actually practised for prevention, detection and exclusion of carriers of S. hyodysenteriae and vaccination against the desease still needs further attention. The last two methods require reliable and sensitive diagnostic tests and understanding of the pathogenesis of and immune development against SD. At present the detection of all individual carriers of S. hyodysenteriae is not yet assured, since the tests for screening individual animals are not satisfactorily evaluated as far as sensitivity and/or specificity are concerned. Studies on the pathogenesis of SD have been performed to develop a vaccine. Besides hemolysin/cytotoxin production, no other virulence factors have been identified with certainty for S. hyodysenteriae. Recently however, further indications for a role of motility in the pathogenesis of SD have been obtained. In this manuscript we summarize the most relevant recent findings.