Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs.

BACKGROUND: Genetic correlations between complex traits suggest that pleiotropic variants contribute to trait variation. Genome-wide association studies (GWAS) aim to uncover the genetic underpinnings of traits. Multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS enable detecting variants associated with multiple phenotypes. In this study, we used array-derived genotypes and phenotypes for 24 reproduction, production, and conformation traits to explore differences between the two methods and used imputed sequence variant genotypes to fine-map six quantitative trait loci (QTL). RESULTS: We considered genotypes at 44,733 SNPs for 5,753 pigs from the Swiss Large White breed that had deregressed breeding values for 24 traits. Single-trait association analyses revealed eleven QTL that affected 15 traits. Multi-trait association testing and the meta-analysis of the single-trait GWAS revealed between 3 and 6 QTL, respectively, in three groups of traits. The multi-trait methods revealed three loci that were not detected in the single-trait GWAS. Four QTL that were identified in the single-trait GWAS, remained undetected in the multi-trait analyses. To pinpoint candidate causal variants for the QTL, we imputed the array-derived genotypes to the sequence level using a sequenced reference panel consisting of 421 pigs. This approach provided genotypes at 16 million imputed sequence variants with a mean accuracy of imputation of 0.94. The fine-mapping of six QTL with imputed sequence variant genotypes revealed four previously proposed causal mutations among the top variants. CONCLUSIONS: Our findings in a medium-size cohort of pigs suggest that multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS provide very similar results. Although multi-trait association methods provide a useful overview of pleiotropic loci segregating in mapping populations, the investigation of single-trait association studies is still advised, as multi-trait methods may miss QTL that are uncovered in single-trait GWAS.

Characterisation and comparison of immune response mechanisms in an indigenous and a commercial pig breed after classical swine fever vaccination.

The live attenuated classical swine fever (CSF) vaccine has been successfully used to prevent and control CSF outbreaks for 6 decades. However, the immune response mechanisms against the vaccine remain poorly understood. Moreover, very few reports exist regarding the breed differences in the response to CSF vaccine. In this study, we generated the peripheral blood mononuclear cell transcriptomes of indigenous Ghurrah and commercial Landrace pig breeds, before and 7 days after CSF vaccination. Subsequently, between and within-breed differential gene expression analyses were carried out. Results revealed large differences in pre-vaccination peripheral blood mononuclear cell transcriptome profiles of the two breeds, which were homogenised 7 days after vaccination. Before vaccination, gene set enrichment analysis showed that pathways related to antigen sensing and innate immune response were enriched in Ghurrah, while pathways related to adaptive immunity were enriched in Landrace. Ghurrah exhibited greater immunomodulation compared to Landrace following the vaccination. In Ghurrah, cell-cycle processes and T-cell response pathways were upregulated after vaccination. However, no pathways were upregulated in Landrace after vaccination. Pathways related to inflammation were downregulated in both the breeds after vaccination. Key regulators of inflammation such as IL1A, IL1B, NFKBIA and TNF genes were strongly downregulated in both the breeds after vaccination. Overall, our results have elucidated the mechanisms of host immune response against CSF vaccination in two distinct breeds and revealed common key genes instrumental in the global immune response to the vaccine.

Who and how in the regulation of mitochondrial cristae shape and function.

Mitochondrial adaptation to different physiological conditions highly relies on the regulation of mitochondrial ultrastructure, particularly at the level of cristae compartment. Cristae represent the membrane hub where most of the respiratory complexes embed to account for OXPHOS and energy production in the form of adenosine triphosphate (ATP). Changes in cristae number and shape define the respiratory capacity as well as cell viability. The identification of key regulators of cristae morphology and the understanding of their contribution to the mitochondrial ultrastructure and function have become an strategic goal to understand mitochondrial disorders and to exploit as therapeutic targets. This review summarizes the known regulators of cristae ultrastructure and discusses their contribution and implications for mitochondrial dysfunction.

A systematic review of left unilateral electroconvulsive therapy.

OBJECTIVE: To systematically review the published clinical trials, case series, and case reports on left unilateral (LUL) electrode placement for clinical electroconvulsive therapy (ECT). METHOD: PubMed, Ovid Medline, and the Cochrane Library were searched for articles concerning LUL ECT. Number of patients, efficacy, and cognitive outcomes were extracted from the papers that met our inclusion criteria. RESULTS: A total of 52 articles were included in this review, consisting of 33 clinical trials, seven case series, and 12 case reports. CONCLUSION: Overall, the efficacy of LUL electrode placement for the treatment of depression and psychosis is similar to that of right unilateral (RUL) and bilateral (BL) electrode placements. Patients receiving LUL ECT tend to experience more verbal memory impairment than patients receiving RUL ECT, but less verbal impairment than patients receiving BL ECT. In contrast, patients receiving LUL ECT tended to experience the least visual and nonverbal memory impairment, compared to patients receiving RUL or BL ECT.

Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure.

The optimal timing of pregnancy after kidney transplantation remains uncertain. We determined the risk of allograft failure among women who became pregnant within the first 3 posttransplant years. Among 21 814 women aged 15-45 years who received a first kidney-only transplant between 1990 and 2010 captured in the United States Renal Data System, n = 729 pregnancies were identified using Medicare claims. The probability of allograft failure from any cause including death (ACGL) at 1, 3, and 5 years after pregnancy was 9.6%, 25.9%, and 36.6%. In multivariate analyses, pregnancy in the first posttransplant year was associated with an increased risk of ACGL (hazard ratio [HR]: 1.18; 95% confidence interval [CI] 1.00, 1.40) and death censored graft loss (DCGL) (HR:1.25; 95% CI 1.04, 1.50), while pregnancy in the second posttransplant year was associated with an increased risk of DCGL (HR: 1.26; 95% CI 1.06, 1.50). Pregnancy in the third posttransplant year was not associated with an increased risk of ACGL or DCGL. These findings demonstrate a higher incidence of allograft failure after pregnancy than previously reported and that the increased risk of allograft failure extends to pregnancies in the second posttransplant year.

Decontamination of heavy metal laden sewage sludge with simultaneous solids reduction using thermophilic sulfur and ferrous oxidizing species.

A possibility of using simultaneous sewage sludge digestion and metal leaching (SSDML) process at the thermophilic temperature to remove heavy metals and suspended solids from sewage sludge is explored in this study. Though thermophilic sludge digestion efficiently produces a stable sludge, its inability to remove heavy metals requires it to be used in tandem with another process like bioleaching for metal reduction. Previously, different temperature optima were known for the heterotrophs (thermophilic) responsible for the sludge digestion and the autotrophs involved in bioleaching (mesophilic), because of which the metal concentration was brought down separately in a different reactor. In our study, SSDML process was carried out at 50 °C (thermophilic) by using ferrous sulfate (batch-1) and sulfur (batch-2) as the energy source in two reactors. The concentration of volatile suspended solids reduced by >40% in both batches, while that of heavy metals zinc, copper, chromium, cadmium and nickel decreased by >50% in both batch-1 and batch-2. Lead got leached out only in batch-1. Using 16S rRNA gene-based PCR-denaturing gradient gel electrophoresis analysis, Alicyclobacillus tolerans was found to be the microorganism responsible for lowering the pH in both the reactors at thermophilic temperature. The indicator organism count was also below the maximum permissible limit making sludge suitable for agricultural use. Our results indicate that SSDML at thermophilic temperature can be effectively used for reduction of heavy metals and suspended solids from sewage sludge.

Getting England to be more physically active: are the Public Health Responsibility Deal's physical activity pledges the answer?

BACKGROUND: The Public Health Responsibility Deal (RD) in England is a public-private partnership involving voluntary pledges between government, industry, and other organisations to improve public health by addressing alcohol, food, health at work, and physical activity. This paper analyses the RD physical activity (PA) pledges in terms of the evidence of their potential effectiveness, and the likelihood that they have motivated actions among organisations that would not otherwise have taken place. METHODS: We systematically reviewed evidence of the effectiveness of interventions proposed in four PA pledges of the RD, namely, those on physical activity in the community; physical activity guidelines; active travel; and physical activity in the workplace. We then analysed publically available data on RD signatory organisations' plans and progress towards achieving the physical activity pledges, and assessed the extent to which activities among organisations could be attributed to the RD. RESULTS: Where combined with environmental approaches, interventions such as mass media campaigns to communicate the benefits of physical activity, active travel in children and adults, and workplace-related interventions could in principle be effective, if fully implemented. However, most activities proposed by each PA pledge involved providing information or enabling choice, which has limited effectiveness. Moreover, it was difficult to establish the extent of implementation of pledges within organisations, given that progress reports were mostly unavailable, and, where provided, it was difficult to ascertain their relevance to the RD pledges. Finally, 15 % of interventions listed in organisations' delivery plans were judged to be the result of participation in the RD, meaning that most actions taken by organisations were likely already under way, regardless of the RD. CONCLUSIONS: Irrespective of the nature of a public health policy to encourage physical activity, targets need to be evidence-based, well-defined, measurable and encourage organisations to go beyond business as usual. RD physical activity targets do not adequately fulfill these criteria.

SWI/SNF chromatin remodeling enzymes in melanocyte differentiation and melanoma.

Epidermal melanocytes are pigment-producing cells derived from the neural crest that protects skin from the damaging effects of solar radiation. Malignant melanoma, a highly aggressive cancer, arises from melanocytes. SWI/SNF enzymes are multiprotein complexes that remodel chromatin structure and have extensive roles in cellular differentiation. Components of the complex have been found to be mutated or lost in several human cancers. This review focuses on studies that implicate SWI/SNF enzymes in melanocyte differentiation and in melanoma.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Congenital paediatric atlantoaxial dislocation: clinico-radiological profile and surgical outcome.

INTRODUCTION: Congenital atlantoaxial dislocation (AAD) is the most common bony abnormality affecting the craniovertebral junction. The paediatric population has specific problems like preoperative diagnostic difficulties, precise neurological examination, radiological diagnosis, surgical problems including physical fitness to tolerate surgery (including problems of anaesthesia), technical difficulties in surgery and problems related to immobilization. MATERIAL AND METHODS: A total of 229 consecutive paediatric (≤18 years) patients of AAD visited our centre from the period of January 1997 to August 2011. Twenty-nine cases were excluded from the study as these cases were diagnosed as CVJ tuberculosis, 31 cases were excluded as they were traumatic and the remaining 169 cases were retrospectively analysed. These patients were operated by a single experienced surgeon (the senior author) at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. The preoperative and the postoperative clinical evaluation of the patient was done by the Kumar and Kalra myelopathic scoring system. The score was recorded in the preoperative period, at the time of discharge, at 3 months follow-up and at 6 months follow-up. RESULTS: Ninety-four were males and 75 were females. The age range was 4 to 18 years with mean age 9.96±3.78 years. The follow-up ranged from 3 to 120 months with mean follow-up being 39.03±13.38 months. One hundred five cases were of fixed/irreducible AAD, and 64 were cases of mobile/reducible AAD. Majority of these cases presented with features of pyramidal tract involvement, and 108 cases had compromised pulmonary function test. One hundred thirty-seven cases had improved outcome, and 18 cases were in the same grade in the postoperative period with only 14 cases either deteriorated or died. CONCLUSIONS: Congenital paediatric AAD are a different subset of abnormalities and have a satisfactory outcome. Preoperative evaluation must also include identification of various syndromes associated with paediatric AAD and respiratory reserve. Cormack-Lehane grade can be helpful in selecting borderline cases for postoperative need of tracheostomy. Majority of the cases have a good outcome, and therefore, surgery should be offered even in severe grade.

Deterministic characterization of phase noise in biomolecular oscillators.

On top of the many external perturbations, cellular oscillators also face intrinsic perturbations due the randomness of chemical kinetics. Biomolecular oscillators, distinct in their parameter sets or distinct in their architecture, show different resilience with respect to such intrinsic perturbations. Assessing this resilience can be done by ensemble stochastic simulations. These are computationally costly and do not permit further insights into the mechanistic cause of the observed resilience. For reaction systems operating at a steady state, the linear noise approximation (LNA) can be used to determine the effect of molecular noise. Here we show that methods based on LNA fail for oscillatory systems and we propose an alternative ansatz. It yields an asymptotic expression for the phase diffusion coefficient of stochastic oscillators. Moreover, it allows us to single out the noise contribution of every reaction in an oscillatory system. We test the approach on the one-loop model of the Drosophila circadian clock. Our results are consistent with those obtained through stochastic simulations with a gain in computational efficiency of about three orders of magnitude.

Measures of Neural Similarity.

One fundamental question is what makes two brain states similar. For example, what makes the activity in visual cortex elicited from viewing a robin similar to a sparrow? One common assumption in fMRI analysis is that neural similarity is described by Pearson correlation. However, there are a host of other possibilities, including Minkowski and Mahalanobis measures, with each differing in its mathematical, theoretical, and neural computational assumptions. Moreover, the operable measures may vary across brain regions and tasks. Here, we evaluated which of several competing similarity measures best captured neural similarity. Our technique uses a decoding approach to assess the information present in a brain region, and the similarity measures that best correspond to the classifier's confusion matrix are preferred. Across two published fMRI datasets, we found the preferred neural similarity measures were common across brain regions but differed across tasks. Moreover, Pearson correlation was consistently surpassed by alternatives.

Thermal conductivity of leaf compost used in biofilters: an experimental and theoretical investigation.

Thermal conductivity is an important property that governs the behaviour of leaf compost biofilters used in treating gaseous pollutants. Measurements were carried out for the thermal conductivity (K) of 44 samples of leaf compost, covering wide ranges of the volume fractions of water (xi(w)), solids (xi(s)) and air (xi(a)), at 20 degrees C using an unsteady state thermal probe. The results indicated that the compost thermal conductivity increased with an increase in xi(w), with a decrease in xi(a), and with an increase in the degree of saturation (defined as the volumetric fraction of water in the total void space). The predictions from the Woodside-Messmer quadratic parallel (QP) model for the thermal conductivity of leaf compost were higher than the experimental values. A simple linear relationship was developed between the thermal conductivity and the degree of saturation, which provided a satisfactory correlation for the data measured in this study as well as those reported recently for sandy and clay loams.

Circulating T helper 1 (Th1) cell- and Th2 cell-associated cytokines in Indian patients with visceral leishmaniasis.

Sera from 61 Indian patients with visceral leishmaniasis caused by infection with Leishmania donovani were tested for the presence of T helper 1 (Th1) cell-(interferon-gamma [IFN-gamma]) and Th2 cell-associated cytokines (interleukin-4 [IL-4] and IL-10). The IFN-gamma activity was detected in 53%. IL-4 in 84%, and IL-10 in 56% of patient samples. Sera from 10 healthy Indian controls showed detectable IFN-gamma in 90%. IL-4 in 10%, and IL-10 in 20%; corresponding percentages for sera from eight healthy American controls were 100%, 12%, and 0%, respectively. Quantitative data for the 61 patients compared with the 10 Indian controls indicated comparable mean levels of IFN-gamma, but three- and 13-fold increases in IL-10 and IL-4, respectively. Undetectable IFN-gamma activity, observed in 47% of patients, was associated with the presence IL-4 alone or in combination with IL-10 but not with IL-10 alone. In patients who had failed prior therapy (n = 29) compared with previously untreated patients (n = 32). IFN-gamma levels were 67% lower and IL-4 levels were two-fold higher, IL-10 activity was comparable. These results using peripheral blood support the presence of a suppressive Th2 cell-associated immune response in symptomatic Indian kala-azar and point to a possible role for IL-4.

Role of fatty infiltration during malaria in rhesus monkey.

P. cynomolgi B-rhesus monkey model of malarial infection has been used to study lipid infiltration in host tissues in early (exoerythrocytic) and late (chronic) stages of malaria infection. Histochemically we could demonstrate significant infiltration of neutral & total lipids in liver during the exoerythrocytic stage and in liver and kidney in the erythrocytic stage. The parasite used in the study closely resembles the human parasite P. vivax. It has a defined prepatent period, can be cyclically passaged with ease and non fatal in nature.

Jail inmates and HIV care: provision of antiretroviral therapy and Pneumocystis carinii pneumonia prophylaxis.

The objective of this study was to examine prescription and acceptance of antiretroviral therapy (ART) and Pneumocystis carinii pneumonia (PCP) prophylaxis in jail and at release. A retrospective cross sectional design was used, by record review, of 77 inmates receiving HIV-related care in the San Francisco City and County Jail and released to the community in 1997. Average CD4 cell count was 335/microl. Fifteen had undectable HIV RNA, and average viral load was 19,826 copies/ml. Fifty-eight per cent were put on ART in jail. Lower CD4 cell count was associated with ART (P=0.017). All inmates with CD4 cell counts less than 200/microl received PCP prophylaxis. According to 1996 guidelines, 72% of those eligible for ART were on therapy. Of 24 inmates released on ART, 71% followed medical advice and picked up medication at release. HIV care in the San Francisco Jail met high standards and exceeded levels reported in other populations.

Cytopathology and AgNOR counts in fine-needle aspiration cytology smears of thyroid lesions.

The object of the present work is to study the cytomorphological features and the value of silver colloidal staining method in distinguishing the non-neoplastic, benign, and malignant neoplasm in fine-needle aspiration cytology (FNAC) smears of thyroid nodules. One hundred forty histologically confirmed aspirated samples of thyroid lesions were studied and classified cytologically. These smears were stained for AgNOR counts. The number and location of AgNOR dots as well as clusters in nuclei were studied by two different observers independently. Lower AgNOR counts were recorded in cases of thyroiditis (1.375 +/- 0.414), whereas follicular carcinoma had a higher number of AgNOR counts (5.04 +/- 0.52). The clusters of AgNOR dots were centrally located in colloid goitre, but no cluster arrangement was observed in cases of carcinomas. Increased nuclear size, nucleoli, and chromocentres were helpful in the diagnosis of follicular carcinoma. AgNOR counting cannot be reliably used on an individual case basis to differentiate adenoma from carcinoma. Therefore, AgNOR study in thyroid lesions can be used as an additional diagnostic method with cytomorphological features to differentiate benign and malignant follicular neoplasms.

Polymerase chain reaction vs. conventional diagnosis in fine needle aspirates of tuberculous lymph nodes.

OBJECTIVE: To compare four conventional methods of diagnosing tuberculous lymphadenophathy (TL)--namely fine needle aspiration cytology (FNAC), Zeihl-Neelsen staining of smears for acid-fast bacilli (AFB), culture for Mycobacterium tuberculosis (MTB) and lymph node biopsies--with the polymerase chain reaction (PCR) in order to assess the practicability and advantage of its use in routine diagnosis in a developing country. STUDY DESIGN: Fine needle aspirates from 142 consecutive patients presenting with lymphadenopathy (mainly cervical) without any known systemic involvement underwent cytomorphologic diagnosis, AFB smears, culture for MTB, confirmatory biopsy and PCR for MTB. The aspirates from cases other than TL served as controls for PCR. RESULTS: Correct diagnosis of tuberculosis could be made in 94.87% of cases by a combination of the four methods. PCR was done in 52 cases, 39 confirmed TL and 13 controls. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value of PCR were 94.44%, 38.23%, 44.73% and 92.85%, respectively, when culture alone was considered the gold standard. However, specificity (38.23-92.30%) and PPV (44.73-97.36%) of PCR increased remarkably when response to treatment was taken as the final arbiter. CONCLUSION: The four conventional tests were found to be the methods of choice for the diagnosis of TL in developing countries. PCR should be reserved for problem cases.

Adenosine-induced ventricular fibrillation.

The use of adenosine has been suggested as a diagnostic tool in the evaluation of wide ORS complex tachycardia. However, adenosine shortens the antegrade refractoriness of accessory atrioventricular connections and may cause acceleration of the ventricular rate during atrial fibrillation. We observed ventricular fibrillation in 2 patients who presented to the emergency department with pre-excited atrial fibrillation and were given 12 mg of adenosine.