SARS-CoV-2 Epitopes Are Recognized by a Public and Diverse Repertoire of Human T Cell Receptors.

Understanding the hallmarks of the immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed antibody and T cell reactivity in convalescent COVID-19 patients and healthy donors sampled both prior to and during the pandemic. Healthy donors examined during the pandemic exhibited increased numbers of SARS-CoV-2-specific T cells, but no humoral response. Their probable exposure to the virus resulted in either asymptomatic infection without antibody secretion or activation of preexisting immunity. In convalescent patients, we observed a public and diverse T cell response to SARS-CoV-2 epitopes, revealing T cell receptor (TCR) motifs with germline-encoded features. Bulk CD4+ and CD8+ T cell responses to the spike protein were mediated by groups of homologous TCRs, some of them shared across multiple donors. Overall, our results demonstrate that the T cell response to SARS-CoV-2, including the identified set of TCRs, can serve as a useful biomarker for surveying antiviral immunity.

Pregnancy outcomes in women with Budd-Chiari syndrome or portal vein thrombosis - a multicentre retrospective cohort study.

OBJECTIVE: To evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. DESIGN AND SETTING: Multicentre retrospective cohort study between 2008 and 2021. POPULATION: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis. METHODS AND MAIN OUTCOME MEASURES: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. RESULTS: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of the 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 were at term (79% of live births and 60% of pregnancies). No maternal deaths were observed; one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. CONCLUSIONS: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Individualised, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population. TWEETABLE ABSTRACT: Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy.

A rare missense variant in RCL1 segregates with depression in extended families.

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, ßT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, ßT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population.

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Enhanced liver fibrosis test in patients with psoriasis, psoriatic arthritis and rheumatoid arthritis: a cross-sectional comparison with procollagen-3 N-terminal peptide (P3NP).

BACKGROUND: The enhanced liver fibrosis (ELF) test has been introduced to screen, diagnose and/or monitor liver conditions in large groups of patients with liver diseases. It has not been used in inflammatory skin or joint diseases. OBJECTIVES: To evaluate the distribution of the ELF test, apply existing cut-offs for hepatic patients and healthy controls, and compare it with the procollagen-3 N-terminal peptide (P3NP) test in patients with psoriasis (PSO), psoriatic arthritis (PsA) and rheumatoid arthritis (RA), and controls. METHODS: In total, 531 patients were included. Demographic, lifestyle and disease-specific data were collected. ELF and P3NP tests were performed. RESULTS: Prevalence of an increased ELF score (> 11) and P3NP was highest in patients with RA (7·7% and 6·1%, respectively) followed by patients with PSO (1·7% and 5·2%, respectively) and PsA (0·7% and 1·3%, respectively). Mean ± SD ELF scores for PSO, PsA and RA were, respectively, 9·09 ± 0·86, 8·96 ± 0·76 and 9·55 ± 1·04. All subgroups with moderate-to-severe disease severity had higher (> 9·8) ELF scores (PSO 27·0% vs. 18·3%; PsA 19·2% vs. 12%; RA 45·8% vs. 30·5%) and P3NP values. Distribution of the ELF score was smaller than the P3NP value [mean ± SD: 9·15 ± 0·92 (range 6·53-13·05) vs. 8·37 ± 4·30 (range 0·53-63·88)]. CONCLUSIONS: ELF score and P3NP are elevated in PSO, PsA and RA. ELF may be superior to P3NP alone, but further research should be done to validate the ELF test in determining susceptibility for developing liver fibrosis in PSO, PsA and RA.

Primary versus secondary immune thrombocytopenia in adults; a comparative analysis of clinical and laboratory attributes in newly diagnosed patients in Southern Pakistan.

BACKGROUND: Immune thrombocytopenic purpura (ITP) is a hemorrhagic diathesis, characterized by platelets destruction alongside impaired production. Patients from Asian regions often exhibit distinctive characteristics in comparison to the western patients. We accomplished this study to evaluate the prevalence of primary versus secondary ITP along with the comparative analysis between them. The secondary objective was to determine the etiological spectrum of secondary ITP. METHODS: We illustrate the results of a large cohort of newly diagnosed adults ITP from southern Pakistan. The study extended from January 2009-December 2013. Complete blood counts, HbsAg, Anti-HCV, ANA, stool for Helicobacterpylori were done on all. HIV, TSH, anti-dsDNA, RA factor, APLA and direct coombs test were evaluated in cases where indicated. RESULTS: A total of 417 patients were included with a mean age of 40.95±14.82 years. Primarily disease was observed in the 3rd decade of life. Male to female ratio was 1:1.5. Mean platelets count was 46.21±27.45x109/l. At diagnosis 43.16% (n=180) patients had hemorrhagic manifestations whilst 56.8% (n=237) were asymptomatic. None of the patient presented with visceral, retropharyngeal or intracranial bleed. The prevalence of secondary ITP was substantially higher (64.8%) as compared to primary ITP (35.2%). Secondary ITP was predominantly seen in HCV reactive patients (24.4%) followed by helicobacter-pylori infection (11%). Nevertheless 16.4% patients had underlying autoimmune disorders. Providentially no study subject was found to be HIV reactive. CONCLUSIONS: Our study revealed predominance of secondary ITP. However bleeding manifestations and degree of thrombocytopenia were high in primary-ITP. Infectious etiology followed by autoimmune disorders is mainly implicated for secondary ITP in our setting.

LRIG1 expression during homeostasis and skin wound healing in mice.

Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 belong to the family of proteins known to be expressed in skin. Ablation of LRIG1 in mice results in epidermal hyperplasia and its aberrant expression levels have been reported in pathological conditions such as psoriasis, thus evident of an indispensible role of LRIG1 in maintaining epidermal homeostasis. In order to gain insight into the homeostatic expression of LRIG1 and in various stages of cutaneous wound healing, LRIG1 expression was immunohistochemically analyzed in full thickness skin wounds in mice. The full thickness skin wounds were established on the dorsal back of Balb/c mice (n=6). LRIG1 expression at various post wounding days (1, 2, 3, 6 and 14) was determined through Immunohistochemical analysis (IHC) of the murine skin sections. The injury caused a sharp decline in LRIG1 expression in the basal epidermal cells and appendages surrounding the wound which correlates with the re-epithelialization phase of healing. LRIG1 expression remained down regulated during most of the wound healing stages. LRIG1+ cells were found to re-populate the neo-epidermis on day 14, suggesting an important homeostatic role of LRIG1 in skin.

Analysis of different HCV NS4B domains for the development of global consensus sequence.

The non-structural 4B (NS4B) protein of hepatitis C virus (HCV) is a hydrophobic protein implicated recently in the formation of membranous web, a platform for the formation of replication complex and thus is potential target for antivirals. The CLC main workbench was used to generate genotype-specific consensus sequence, global consensus sequence and a representative phylogenetic tree from non-structural 4 B (NS4B) protein sequences of seven different HCV genotypes reported from all over the world. The C-terminal domain (CTD) of NS4B protein especially the residues involved in interaction with ER membrane were found to be highly conserved. Other residues found to be highly conserved across all HCV genotypes included; 5 aromatic residues of N-terminal domain (NTD) (F49, W50, W55, F57, and Y63), 3 hydrophobic leucine residues (L237, L240, L245), and 2 positively charged residues of CTD (R248 and H250), dimerization motif of transmembrane domain 3 (TMD3) (G143YGAG147) and its surrounding residues (F118 and F155) and TMD1 Ser/Thr cluster residues (T87, S88 and T95) involved in the hydrogen (H) bond interactions. In short, amino acids of NTD, TMD and CTD domains involved in the membrane association/anchoring of NS4B and formation of membranous web are highly conserved and can serve as potential targets for antivirals and peptide vaccines. These conserved residues formed the basis for the development of five short peptides proposed to serve as potential therapeutic target. The phylogenetic analysis was particularly interesting for NS4B sequences of 3a Pakistani isolates. The high degree of variability prevented the clustering of Pakistani isolates with other sequences in phylogenetic tree, revealing geographical disparity.

Exchange rate asymmetry and its impact on bilateral trade: Evidence from BCIM-EC countries using N-ARDL approach.

The novelty of this study is to examine the asymmetric effect of the exchange rate on bilateral export and import between Bangladesh and its three trading partners in the Bangladesh-China-India-Myanmar Economic Corridor using nonlinear ARDL models from 1973 to 2022. After controlling income and structural breaks, the empirical findings confirm the asymmetric effects of exchange rates on the short-run and long-run export and import demand functions of Bangladesh. Furthermore, the impacts of the appreciation and depreciation of the Bangladeshi currency are heterogeneous for these three trading partners. For instance, the depreciation of the Bangladeshi currency increases exports to China and India while it decreases exports to Myanmar in the short run. However, the depreciation increases exports to India and Myanmar, and the appreciation also increases exports to China and India in the long-run. On the contrary, depreciation increases imports from China and Myanmar in the short-run, while it decreases imports from Myanmar in the long run. Only appreciation has significant negative effects on China and India. As a robustness measure, we exclude the COVID-19 period. However, it does not substantially change our main findings.

Genetic differentiation in Pyrenophora teres f. teres populations from Syria and Tunisia as assessed by AFLP markers.

UNLABELLED: To investigate the level of genetic differentiation and diversity among Pyrenophora teres isolate populations originating from different agro-ecological areas of Syria and Tunisia and to determine the potential of AFLP profiling in genotyping Pyrenophora teres f. teres. In this study, AFLP markers have been employed to identify patterns of population structure in 20 Pyrenophora teres f. teres populations from Syria and Tunisia. Ninety-four isolates were studied by the use of a protocol that involved stringent PCR amplification of fragments derived from digestion of genomic DNA with restriction enzymes EcoRI and MesI. Based on 401 amplified polymorphic DNA markers (AFLP), variance analyses indicated that most of the variation was partitioned within rather than between populations. Genotypic diversity (GD) was high for populations from Rihane, local landraces and different agro-ecological zones (GD = 0·75-0·86). There was high genetic differentiation among pathogen populations from different host populations in Syria (Gst  = 0·31, ht = 0·190) and Tunisia (Gst  = 0·39, ht = 0·263), which may be partly explained by the low gene flow around the areas sampled. A phenetic tree revealed three groups with high bootstrap values (55, 68, 76) and reflected the grouping of isolates based on host, or agro-ecological areas. AFLP profiling is an effective method for typing the genetically diverse pathogen Pyrenophora teres f. teres. SIGNIFICANCE AND IMPACT OF THE STUDY: The study represents a comparative analysis of the genetic diversity in P. teres isolates from two countries spanning two continents and also shows that several distinct P. teres genotypes may be found in a given environment. The implications of these findings for Pyrenophora teres f. teres evolutionary potential and net blotch-resistance breeding in Syria and Tunisia were also discussed.

Rapidly Progressive Portal Cavernoma Cholangiopathy in a Patient With Infeasible Decompressive Shunt Surgery.

We present a 27-year-old man with a 2-year history of extrahepatic portal vein obstruction and selective immunoglobulin A deficiency, referred for acute cholangitis from portal cavernoma cholangiopathy (PCC). Because recurrent cholangitis rapidly led to liver failure, orthotopic liver transplantation (OLT) was successfully performed. To date, this is one of the few cases of patients with symptomatic PCC who required OLT and the first case who had a successful 6-year follow-up. Thus, OLT can be used for symptomatic PCC associated with nonshuntable anatomy, ineffective biliary drainage, and progressive liver damage. Selective immunoglobulin A deficiency may play a role in recurrent cholangitis.

Does air pollution increase child mortality? Evidence from 58 developing countries.

This study aims to investigate the effects of air quality on child mortality in developing countries. We consider annual data covering the period from 2010 to 2016 of 58 countries and estimate the empirical models using recently developed panel quantile regression with the method of moments (MM-QR). It is found that outdoor air quality (measured by the concentration of PM2.5 in the air) has a positive and significant effect on total child mortality, post-neonatal mortality, and under-five child mortality. However, its effect on neonatal mortality is not statistically significant at lower quantiles. Furthermore, Household air pollution (HAP) also has a positive and significant effect on total child mortality, neonatal mortality, and under-five child mortality. The effect of HAP on post-neonatal mortality is not significant in most cases. Overall, the adverse effect of HAP is larger than the PM2.5. For instance, a 1% increase of PM2.5 concentration in the outdoor causes 0.231% total child mortality due to respiratory diseases at [Formula: see text], while a 1% increase of HAP causes 0.532% total child mortality at the same quantile. In many cases, the coefficients of PM2.5 and HAP increase at the higher quantiles, supporting asymmetric effects of pollutants on child mortality. However, per capita income, access to basic drinking water and sanitation facilities, and domestic and external health expenditures significantly reduce child mortality. On the contrary, open defecation increases mortality. Consequently, policymakers should take adequate measures to improve indoor and outdoor air quality to combat child mortality due to respiratory diseases in developing countries. They should also take initiatives to enhance per capita income, basic drinking water, and sanitation facilities, domestic and external health expenditures, and public awareness against open defecation.

Novel curcumin derivatives as P-glycoprotein inhibitors: Molecular modeling, synthesis and sensitization of multidrug resistant cells to doxorubicin.

The MDR1/P-glycoprotein (Pgp)/ABCB1 multidrug transporter is being investigated as a druggable target for antitumor therapy for decades. The natural product curcumin is known to provide an efficient scaffold for compounds capable of blocking Pgp mediated efflux and sensitization of multidrug resistant (MDR) cells to the Pgp transported drug doxorubicin (Dox). We performed molecular dynamics simulations and docking of curcumin derivatives into the Pgp model. Based on these calculations, a series of pyrazolocurcumin derivatives with predicted metabolic stability and/or improved binding affinity were proposed for synthesis and evaluation of MDR reversal potency against Dox selected K562/4 subline, a derivative of K562 human chronic myelogenous leukemia cell line. Compounds 16 and 19 which are both dimethylcurcumin pyrazole derivatives bearing an N-p-phenylcarboxylic amide substitution, were the most potent Pgp blockers as determined by intracellular Dox accumulation. Furthermore, at non-toxic submicromolar concentrations 16 and 19 dramatically sensitized K562/4 cells to Dox. Together with good water solubility of 16 and 19, these results indicate that the new pyrazolo derivatives of curcumin are a promising scaffold for development of clinically applicable Pgp antagonists.

First Report of Chickpea Wilt Caused by Clonostachys rhizophaga in Syria.

In 2007 and 2008, disease symptoms were observed on four cultivars of chickpea (Cicer arietinum L.), including two of the most popular cultivars grown in Syria (Ghab 3 and Ghab 4), in a replicated on-farm trial conducted in the fertile Al Ghab Plains. Affected plants exhibited chlorosis of the foliage, vascular discoloration, and death. In both years, plant mortality reached 100% in plots of cvs. ICC 12004, Ghab 3, and Ghab 4, but only 60% in plots of cv. ILC 97-706. Five monosporic isolates obtained from surface-disinfested stems and roots were identified morphologically. All micromorphological characteristics indicated that the isolated fungi fit the description of Clonostachys rhizophaga Schroers (1). Wilting of chickpea was widespread in the area, and fungal isolations from a random sample of diseased plants in neighboring farmers' fields revealed the presence of C. rhizophaga. In culture, isolates formed dimorphic, Verticillium-like (primary) or penicillate (secondary) conidiophores and ovoidal to elongate, slightly curved or asymmetrical, 5 to 9 µm long and 2.5 to 3.5 µm wide conidia showing a slightly laterally displaced hilum. The identification of the five isolates as C. rhizophaga was supported by sequencing approximately 600 bp of the ß-tubulin gene (tub2). Two representative sequences have been deposited under GenBank, Accession No. FJ593882 for strain CBS 124507 and No. FJ593883 for CBS 124511. Both were 100% similar to the sequence of C. rhizophaga strain CBS 361.77 (GenBank Accession No. AF358158) but differed by a deletion of 2 nucleotides relative to the ex-type strain of C. rhizophaga, CBS 202.37 (GenBank Accession No. AF358156). Two methods were used to inoculate plants and complete Koch's postulates. Method 1 used a 10-mm-diameter mycelial plug to inoculate healthy 3-day-old seedlings grown on 40 ml of Hoagland nutrient agar medium in a glass tube (one seedling per tube). The plug was placed mycelial-side down on the surface of the medium, and the fungus subsequently colonized the medium and penetrated the plant roots. Method 2 involved mixing autoclaved seed that had been colonized by each isolate with sterilized soil (1:12 vol/vol) prior to transplanting healthy seedlings into the soil mix. Thirty plants of each cultivar were tested per isolate per method, and controls received sterile agar plugs or autoclaved chickpea seed only. Irrespective of inoculation method, all five isolates caused wilt and plant death of all cultivars within 15 days (method 1) or 2 months (method 2) postinoculation. Symptoms were similar to those originally observed in the field and controls remained healthy. C. rhizophaga was recovered from all affected plants. To our knowledge, this is the first report of C. rhizophaga as a pathogen of chickpea. In an earlier report, C. rhizophaga (as Verticillium rhizophagum Tehon & Jacobs, nom. invalid.) was identified as the causal agent of a disastrous disease of Ulmus americana in Ohio (2). C. rhizophaga has been reported from Chile, Ecuador, the United States, and Switzerland (1). References: (1) H.-J. Schroers. Stud. Mycol. 46:85, 2001. (2) L.-R. Tehon and H. L. Jacobs. Bull. Davey Tree Expert Company, Kent, OH. 6:3, 1936.

Fulminant Liver Failure due to Hepatitis B Reactivation During Treatment With Tocilizumab.

Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor that is frequently used for the treatment of refractory rheumatoid arthritis. Since patients with hepatitis B virus (HBV) infection were excluded from pivotal trials, the risk of HBV reactivation with this novel drug class remains uncertain. We present the first case of tocilizumab-associated HBV reactivation resulting in fulminant hepatic failure and a need for liver transplant. Our findings underscore the need for prophylactic antiviral therapy in patients being treated with novel immunosuppressive agents.

Dialysis outcomes in Colombia (DOC) study: a comparison of patient survival on peritoneal dialysis vs hemodialysis in Colombia.

The goal of the Dialysis Outcomes in Colombia (DOC) study was to compare the survival of patients on hemodialysis (HD) vs peritoneal dialysis (PD) in a network of renal units in Colombia. The DOC study examined a historical cohort of incident patients starting dialysis therapy between 1 January 2001 and 1 December 2003 and followed until 1 December 2005, measuring demographic, socioeconomic, and clinical variables. Only patients older than 18 years were included. As-treated and intention-to-treat statistical analyses were performed using the Kaplan-Meier method and Cox proportional hazard model. There were 1094 eligible patients in total and 923 were actually enrolled: 47.3% started HD therapy and 52.7% started PD therapy. Of the patients studied, 751 (81.3%) remained in their initial therapy until the end of the follow-up period, death, or censorship. Age, sex, weight, height, body mass index, creatinine, calcium, and Subjective Global Assessment (SGA) variables did not show statistically significant differences between the two treatment groups. Diabetes, socioeconomic level, educational level, phosphorus, Charlson Co-morbidity Index, and cardiovascular history did show a difference, and were less favorable for patients on PD. Residual renal function was greater for PD patients. Also, there were differences in the median survival time between groups: 27.2 months for PD vs 23.1 months for HD (P=0.001) by the intention-to-treat approach; and 24.5 months for PD vs 16.7 months for HD (P<0.001) by the as-treated approach. When performing univariate Cox analyses using the intention-to-treat approach, associations were with age > or =65 years (hazard ratio (HR)=2.21; confidence interval (CI) 95% (1.77-2.755); P<0.001); history of cardiovascular disease (HR=1.96; CI 95% (1.58-2.90); P<0.001); diabetes (HR=2.34; CI 95% (1.88-2.90); P<0.001); and SGA (mild or moderate-severe malnutrition) (HR=1.47; CI 95% (1.17-1.79); P=0.001); but no association was found with gender (HR=1.03, CI 95% 0.83-1.27; P=0.786). Similar results were found with the as-treated approach, with additional associations found with Charlson Index (0-2) (HR=0.29; Cl 95% (0.22-0.38); P<0.001); Charlson Index (3-4) (HR=0.61; Cl 95% (0.48-0.79); P<0.001); and SGA (mild-severe malnutrition) (HR=1.43; Cl 95% (1.15-1.77); P<0.001). Similarly, the multivariate Cox model was run with the variables that had shown association in previous analyses, and it was found that the variables explaining the survival of patients with end-stage renal disease in our study were age, SGA, Charlson Comorbidity Index 5 and above, diabetes, healthcare regimes I and II, and socioeconomic level 2. The results of Cox proportional risk model in both the as-treated and intention-to-treat analyses showed that there were no statistically significant differences in survival of PD and HD patients: intention-to-treat HD/PD (HR 1.127; CI 95%: 0.855-1.484) and as-treated HD/PD (HR 1.231; CI 95%: 0.976-1.553). In this historical cohort of incident patients, there was a trend, although not statistically significant, for a higher (12.7%) adjusted mortality risk associated with HD when compared to PD, even though the PD patients were poorer, were more likely to be diabetic, and had higher co-morbidity scores than the HD patients. The variables that most influenced survival were age, diabetes, comorbidity, healthcare regime, socioeconomic level, nutrition, and education.

Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells.

CD58 is expressed on the surface of antigen-presenting cells, including B-cells, and provides co-stimulation to regulatory T-cells (Treg) through CD2 receptor binding. Tregs appear to be essential suppressors of tissue-specific autoimmune responses. Thereby, CD58 plays protective role in multiple sclerosis (MS) and CD58 was identified among several loci associated with MS susceptibility. Minor (C) variant of the single-nucleotide polymorphism (SNP) rs1335532 is associated with lower MS risk according to genome-wide association studies (GWAS) and its presence correlates with higher CD58 mRNA levels in MS patients. We found that genomic region containing rs1335532 has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. Using bioinformatics and pull-down assay we found that the protective (C) rs1335532 allele created functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway. Both in B-lymphoblastoid cell lines and in primary B-cells, as well as in a monocytic cell line, activation of Wnt signaling resulted in an increased CD58 promoter activity in the presence of the protective but not the risk allele of rs1335532, whereas ASCL2 knockdown abrogated this effect. In summary, our results suggest that ASCL2 mediates the protective function of rs1335532 minor (C) allele in MS.

Solubility analysis of buspirone hydrochloride polymorphs: measurements and prediction.

In this paper, the solubility of two polymorphs of buspirone hydrochloride (BUS-HCl) in isopropanol, water and mixture of these two solvents has been investigated. The solubility of BUS-HCl Form 2 in water and isopropanol is higher than BUS-HCl Form 1. According to thermodynamic properties and Burger and Ramberger polymorphic rules (Bernstein, 2002), BUS-HCl Forms 1 and 2 are enantiotropes (Sheikhzadeh et al., 2007). Using the solubility data, transformation analysis has been done and the results confirm these two polymorphs are enantiotropes and Form 1 converts to Form 2 at 95 degrees C. The UNIQUAC binary adjustable parameters have been found and based on these parameters, the solubility of these molecules has been predicted and compared with the experimental solubility. The solubility prediction has been performed by using different UNIFAC equations for binary and ternary systems. The UNIQUAC and original UNIFAC showed better prediction capability. Different general solubility equations (GSE) have been used for estimation of solubility which works based on partial charge, hydrogen bond factors and partition coefficients.

Response surface analysis of solution-mediated polymorphic transformation of buspirone hydrochloride.

Buspirone hydrochloride has several polymorphs including Form 1 and Form 2. The solution-mediated transformation of Form 2 to Form 1 has been studied in this research. The interconversion of two polymorphs can occur in the salt formation step which is the last step for producing this drug. In addition, the effect of co-solvent and rate of addition of acid to the solution were investigated on the extent of interconversion of Form 2 to Form 1. It has been found that pH, co-solvent ratio and amount of solvent have more influence on polymorphic interconversion. A factorial design approach was used to carry out a response surface analysis to identify the more important factors affecting the interconversion of polymorphs and find the optimum experimental conditions for the production of the desired polymorph. Quantitative characterization of the product was done by XRPD, FT-IR, SEM, DSC and TSI-PSD.