Toll‐like receptors and CD40 modulate each other's expression affecting Leishmania major infection

Toll‐like receptors (TLRs) recognize pathogen‐associated molecular patterns and results in innate immune system activation that results in elicitation of the adaptive immune response. One crucial modulator of the adaptive immune response is CD40. However, whether these molecules influence each other's expression and functions is not known. Therefore, we examined the effects of TLRs on CD40 expression on macrophages, the host cell for the protozoan parasite L eishmania major. While polyinosinic‐polycytidylic acid [poly (I:C)], a TLR‐3 ligand, lipopolysaccharide (LPS), a TLR‐4 ligand, imiquimod, a TLR‐7/8 ligand and cytosine–phosphate–guanosine (CpG), a TLR‐9 ligand, were shown to enhance CD40 expression, CD40 stimulation enhanced only TLR‐9 expression. Therefore, we tested the synergism between CD40 and CpG in anti‐leishmanial immune response. In L eishmania‐infected macrophages, CpG was found to reduce CD40‐induced extracellular stress‐regulated kinase (ERK)1/2 activation; with the exception of interleukin (IL)‐10, these ligands had differential effects on CD40‐induced IL‐1α, IL‐6 and IL‐12 production. CpG significantly enhanced the anti‐leishmanial function of CD40 with differential effects on IL‐4, IL‐10 and interferon (IFN)‐γ production in susceptible BALB/c mice. Thus, we report the first systematic study on CD40–TLR cross‐talk that regulated the experimental L . major infection.     

Chlorotrifluoroethylidenes: an efficient and convenient approach to their synthesis

A convenient one step synthesis of chlorotrifluoroalkyl olefins starting from aldehydes was developed. The stable reagent 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole was prepared from readily available benzothiazole-2-thiol and halothane. This method comprises using stable 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole according to the Julia procedure and presents new opportunities for the synthesis of trifluoroalkylidene derivatives.

A convenient one step synthesis of chlorotrifluoroalkyl olefins starting from aldehydes was developed.     

Role of Pretransplant Echocardiographic Evaluation in Predicting Outcomes Following Liver Transplantation

Maintenance of cardiac function is critical to the survival of patients with end‐stage liver disease after liver transplantation (LT). We sought to determine whether pre‐LT echocardiographic indices of right heart structure and function were independently predictive of morbidity and mortality post‐LT. We retrospectively studied 216 consecutive patients who underwent pre‐LT 2‐dimensional/Doppler echocardiography with subsequent LT from 2007 to 2010. A blinded reader analyzed multiple echocardiographic parameters, including right ventricular structure and function, pulmonary artery systolic pressure (PASP) and the presence and severity of tricuspid regurgitation (TR). On univariate analysis, Model of End‐Stage Liver Disease (MELD) score, PASP, presence of ≥mild TR, post–operative renal replacement therapy (RRT) and spontaneous bacterial peritonitis were found to be significant predictors of adverse outcomes. On multivariate analysis, only ≥mild TR was found to predict both patient mortality (p = 0.0024, HR = 3.91, 95% CI: 1.62–9.44) and graft failure (p = 0.0010, HR = 3.70, 95% CI: 1.70–8.06). PASP and MELD correlated with post‐LT intensive care unit length of stay (LOS) and, along with hemodialysis, were associated with hospital LOS and time on ventilator. In conclusion, pre‐LT echocardiographic assessments of the right heart may be useful in predicting post‐LT morbidity and mortality and guiding the selection of appropriate LT candidates.     

Techniques and outcomes of transcatheter closure of complex atrial septal defects – Single center experience

Objective

To prospectively study the techniques and outcomes of transcatheter closure of complex Atrial septal defects (ASD).

Study design and settings

Prospective single center study with experience in catheter closure of ASD. All patients with complex ASD suitable for device closure.

Objective

Analysis of outcomes of transcatheter closure of complex ASD in JIPMER Hospital over the past 5-year period.

Methods

Complex ASD was predefined and patients satisfying inclusion and exclusion criteria are included. All the patients had meticulous Transesophageal echocardiography (TEE) imaging beforehand. Modifications of the conventional techniques were allowed on a case per case basis according to operator preference. Successfully intervened patients were followed up clinically.

Results

Out of the 75 patients enrolled, 69 patients had successful device closure (success rate 92%) despite challenging anatomy. Fifty-six (74%) patients had ASD ≥25 mm. Fifteen patients (20%) had defect size ≥35 mm and 20 patients (26.6%) had devices implanted with ≥35 mm waist size. Fifty percent of patients had complete absence of aortic rim and 25% had deficient posterior rim. Twenty percent of patients had malaligned septum. Mean follow up period was 3.2 years.

Conclusions

Trans catheter closure is feasible in anatomically complex substrates of Secundum ASD. Careful case selection, scrupulous imaging protocol, and expertise in modified techniques are mandatory for successful outcomes.     

CCL2, CCL3 and CCL4 gene polymorphisms in pulmonary tuberculosis patients of South India

Polymorphisms in chemokine genes are important to determine the host–pathogen interactions which influence the chemokine levels. This study was carried out to find whether various CC chemokine gene polymorphisms, located in the promoter, exon‐2 and intron‐1 regions are associated with susceptibility or resistance to pulmonary tuberculosis (PTB) in south Indian population. The polymorphisms in various CC chemokine genes, MCP‐1 (CCL2) [?2518A/G, 903C/T], MIP‐1α (CCL3) [?2021C/T, +740A/G] and MIP‐1β (CCL4) [?5725A/C] were studied in 295 healthy controls (HCs) and 303 patients with PTB using polymerase chain reaction‐based restriction fragment length polymorphism (PCR‐RFLP). The allele and genotype frequencies of CCL2, CCL3 and CCL4 were not different between HCs and patients with PTB. However, a significantly decreased frequency of CCL2 ?2518GG genotype was observed in male patients with PTB [P value = 0.015, P corrected (Bonferroni correction) Pc = 0.045, odds ratio (OR) 0.43 95% CI (0.21–0.86)], and a significantly increased frequency of the same genotype was observed among female patients with PTB [P value = 0.049, Pc = 0.147, OR 2.28 95% CI (1.00–5.27)]. The results suggest that ?2518GG genotype may be associated with protection in males and susceptibility to PTB in females. Moreover, we also observed differences in the haplotype frequencies of these chemokine genes between HCs and patients with PTB. However, these polymorphisms are not associated with disease independently, probably in combination with other genes, they may be associated with susceptibility or resistance to TB in south Indian population.     

Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology

Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na⁺ and K⁺ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.     

"Triple Trouble" in A Case of Mass Lesion

Bronchogenic carcinoma, the commonest lung tumor occurs more frequently in the elderly with typical symptoms of cough, haemoptysis, weight loss, dyspnoea or chest pain. These symptoms mimic common respiratory infections in en-demic areas like pulmonary tuberculosis. Also, metastasis at presentation itself is common, the favoured sites being liver, contra-lateral lungs, bones, brain, etc., although unusual and rare sites like heart also are known. We herein report a rare association of both carcinoma with active pulmonary tuberculosis in the same lobe associated with intracardiac metastasis. Very few cases have been published describing lung carcinoma with intracardiac metastasis. We hope the documentation of this rare case will shed further light into the subject area and improve clinical education.     

Anomalous left anterior descending artery from pulmonary artery: An extremely rare coronary anomaly

We report a rare coronary artery anomaly–anomalous origin of the left anterior descending artery from the pulmonary artery in a 40-year-old woman. The uniqueness of this case is the absence of any significant morbidity from this condition in adulthood which is in contrast to other reported cases where patients present with myocardial infarction, congestive heart failure, and sometimes death during the early infantile period.¹     

Fine structure of human oogonia in the foetal ovary

Foetal ovarian tissue is now being cultured or frozen, to generate oocytes for assisted reproduction, an emerging technology. This study examines the ultrastructure of oogonia at 13-15 weeks of gestation, which could be used as a control for culture and freezing of foetal ovaries. Oogonia are largely located in the ovarian cortex, whilst primordial germ cells (PGC) and somatic follicle cells compose the surface epithelium. Oogonia and PGC have large vesicular nuclei with clear cytoplasm, compared to dense follicle cells, which have polymorphic nuclei. Follicle cells intermingle with oogonia and establish close contacts - beginning of folliculogenesis. Nuclei of oogonia contain one to three highly reticulated nucleoli, reflecting high levels of RNA synthesis at the onset of growth. Rough endoplasmic reticulum (RER) form stacks of cisternae associated with numerous ribosomes. Prominent organelles in the ooplasm are elongated mitochondria with dense matrices and tubular cristate presenting a multilocular appearance. Typical Golgi complexes, dense bodies and clear vacuoles are present and microfilaments are located beneath the plasma membrane. The most remarkable feature of oogonia is that they have typical juxtanuclear centrioles (diplosomes) with dense pericentriolar material, which nucleate microtubules, characteristic of functional centrosomes organizing the cytoskeleton. The mature oocyte has no centrioles, since the maternal centrosome is inactivated or reduced, while the paternal is dominant. Centrioles are most likely involved in mitosis of oogonia.