A rare image of post-CTRT iatrogenic tracheoesophageal fistula

A tracheoesophageal fistula may occur due to direct extension of tumour tissue in the trachea and oesophagus, pressure necrosis by a tracheostomy tube in apposition to a nasogastric tube, or tracheoesophageal injury due to other sorts of instrumentation. Bevacizumab is known to cause post-chemotherapy tracheoesophageal fistulae. We present barium swallow x-rays of a female with squamous cell carcinoma of the middle third of the oesophagus; she was being treated weekly with a 6-week regimen of concurrent chemoradiotherapy (CTRT). The x-rays show the formation of a tracheoesophageal fistula at the mid-oesophagus with dye traversing in both directions. It is likely that the tracheoesophageal fistula was formed by trauma due to food matter on a friable sloughed off post-CTRT oesophageal mass. In the majority of cases, these fistulae do not form during chemoradiotherapy, but manifest about six months later. However, in the case presented herein, the fistula was formed in the immediate post-radiation phase.     

Efficacy of a new model for delivering integrated TB and HIV services for people living with HIV/AIDS in Delhi – case for a paradigm shift in national HIV/TB cross-referral strategy

Under National TB/HIV framework, all TB patients are referred by Revised National Tuberculosis Programme (RNTCP) service providers to Integrated Counseling and Testing Centers (ICTCs) for voluntary counseling and testing (C&T) and ICTC “TB-suspects” are referred to RNTCP facilities for TB diagnosis and treatment. HIV–TB coinfected patients are then referred to Anti Retroviral Treatment (ART) center for initiation of ART between two weeks and two months of initiating TB treatment. During the third phase of National AIDS Control Programme (NACP-III, April 2007–April 2012), 30749/130503 (23.6%) TB/HIV cross-referrals were lost to follow up (LTFU) and there was missed opportunity for 940/1884 (49.9%) HIV–TB coinfected patients for initiation of ART during TB treatment. This motivated Delhi State AIDS Control Society (DSACS) and State TB Cell (STC) to revise existing cross-referral strategy. The new strategy was launched in May 2012, wherein HIV–TB coinfected and HIV-positive “TB-suspects” were referred to nearest ART center for HIV care and investigations of TB at Chest Clinic/Designated Microscopy Centre (DMC) located within the same hospital instead of referral to area RNTCP facility. Outcome of the strategy was evaluated in March 2013. The new HIV–TB cross-referral strategy in Delhi has shown advantage over national strategy: first, improved retention of coinfected clients in HIV care; second, ensured timely initiation of TB-treatment and ART; and third, significantly improved survival of HIV–TB coinfected patients.     

Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function

Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article.     

Genomic donor cassette sharing during VLRA and VLRC assembly in jawless vertebrates

Lampreys possess two T-like lymphocyte lineages that express either variable lymphocyte receptor (VLR) A or VLRC antigen receptors. VLRA⁺ and VLRC⁺ lymphocytes share many similarities with the two principal T-cell lineages of jawed vertebrates expressing the αβ and γδ T-cell receptors (TCRs). During the assembly of VLR genes, several types of genomic cassettes are inserted, in step-wise fashion, into incomplete germ-line genes to generate the mature forms of antigen receptor genes. Unexpectedly, the structurally variable components of VLRA and VLRC receptors often possess partially identical sequences; this phenomenon of module sharing between these two VLR isotypes occurs in both lampreys and hagfishes. By contrast, VLRA and VLRC molecules typically do not share their building blocks with the structurally analogous VLRB receptors that are expressed by B-like lymphocytes. Our studies reveal that VLRA and VLRC germ-line genes are situated in close proximity to each other in the lamprey genome and indicate the interspersed arrangement of isotype-specific and shared genomic donor cassettes; these features may facilitate the shared cassette use. The genomic structure of the VLRA/VLRC locus in lampreys is reminiscent of the interspersed nature of the TCRA/TCRD locus in jawed vertebrates that also allows the sharing of some variable gene segments during the recombinatorial assembly of TCR genes.The only two extant taxa of jawless vertebrates (agnatha), lampreys and hagfishes, occupy a unique position in chordate phylogeny and thus are a focal point for studies in comparative immunology. Although jawless vertebrates were shown to reject skin allografts and to produce serum agglutinins to mammalian red blood cells and bacteria (1, 2), the cellular and molecular bases for these adaptive responses remained elusive until the recent identification of their alternative adaptive immune system (3). In contrast to the antigen receptors of jawed vertebrates, whose structural framework is the Ig-domain, the basic building block of agnathan antigen receptors is the leucine-rich repeat (LRR) (4–6). In analogy to the situation in jawed vertebrates, mature genes of so-called variable lymphocyte receptors (VLRs) are combinatorially assembled from different types of genomic donor LRR cassettes; their sequences are inserted into incomplete germ-line VLR genes (4–6). A gene conversion-like process is postulated to underlie the VLR gene assembly (7, 8), through the activity of orthologs of mammalian activation-induced cytidine deaminase (AID), termed cytidine deaminases 1 and 2 (CDA1 and CDA2) (7, 9). As is the case for T-cell receptors (TCRs) and B-cell receptors (BCRs) of jawed vertebrates, combinatorial VLR assembly generates vast repertoires of diverse anticipatory receptors (4–6).Three VLR genes, VLRA, VLRB and VLRC, have been identified in lampreys and hagfishes (3, 9–12). The three VLR isotypes are differentially expressed by three distinct populations of lymphocytes in lampreys (9, 13). The two types of T-like cells of lamprey, VLRA⁺ and VLRC⁺ lymphocytes, are generated in the thymoid, a lymphoepithelial tissue equivalent to the thymus (13–15); this situation is analogous to the development in the thymus of the two distinct αβ and γδ T-cell lineages in jawed vertebrates. The VLRB⁺ cells appear to be generated in hematopoietic tissues outside of the thymoid (14), much like B cells in jawed vertebrates. These findings suggest that these basic pathways of lymphocyte differentiation already existed in a common ancestor of jawed and jawless vertebrates (4–6, 16).The close developmental relationship of the two principal lineages of T lymphocytes in jawed vertebrates is reflected in the unique genomic organization of the TCR genes that encode the four chains of the two different heterodimeric αβ and γδ TCRs (17). Here, we examine the sequence diversity and genomic organization of VLRA and VLRC receptor genes to gain insight into their functional and evolutionary relationship.     

Reclassification of predictions for uncovering subgroup specific improvement

Risk prediction models play an important role in prevention and treatment of several diseases. Models that are in clinical use are often refined and improved. In many instances, the most efficient way to improve a successful model is to identify subgroups for which there is a specific biological rationale for improvement and tailor the improved model to individuals in these subgroups, an approach especially in line with personalized medicine. At present, we lack statistical tools to evaluate improvements targeted to specific subgroups. Here, we propose simple tools to fill this gap. First, we extend a recently proposed measure, the Integrated Discrimination Improvement, using a linear model with covariates representing the subgroups. Next, we develop graphical and numerical tools that compare reclassification of two models, focusing only on those subjects for whom the two models reclassify differently. We apply these approaches to BRCAPRO, a genetic risk prediction model for breast and ovarian cancer, using data from MD Anderson Cancer Center. We also conduct a simulation study to investigate properties of the new reclassification measure and compare it with currently used measures. Our results show that the proposed tools can successfully uncover subgroup specific model improvements. Copyright © 2013 John Wiley & Sons, Ltd.     

14-Deoxyandrographolide alleviates ethanol-induced hepatosteatosis through stimulation of AMP-activated protein kinase activity in rats

Andrographis paniculata (AP) is a traditional medicinal plant of Ayurveda. It grows widely in Asia and is prescribed in the treatment of liver diseases. Here we have investigated the beneficial role of 14-deoxyandrographolide (14-DAG), a bioactive diterpenoid from AP, against alcoholic steatosis in rats. 14-DAG was extracted from aerial parts (leaves and stems) of AP. Rats were fed with ethanol for 8 weeks. Animals were treated with 14-DAG during the last 4 weeks of ethanol treatment. In vitro studies were undertaken in a human hepatocellular liver carcinoma cell line culture. Hepatosteatosis was assessed from histopathological studies of liver sections. Acetyl-CoA, malonyl-CoA, and triglyceride contents were determined using commercially available kits. Fatty acid synthesis was evaluated from incorporation of 1-¹⁴C acetate. Regulation of fatty acid oxidation and lipogenesis were monitored with immunoblotting and immunoprecipitation studies. Ethanol exposure led to hepatotoxicity, as evident from the marked enhancement in the levels of AST and ALT. The values decreased almost to control levels in response to 14-DAG treatment. Results showed that ethanol feeding induced deactivation of AMP-activated protein kinase (AMPK) that led to enhanced lipid synthesis and decreased fatty acid oxidation, culminating in hepatic fat accumulation. Treatment with 14-DAG activated AMPK through induction of cyclic AMP-protein kinase A pathway. Activation of AMPK was followed by down-regulation of sterol regulatory element binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, leading to suppression of lipogenesis. This was associated with up-regulation of sirtuin 1 and depletion of malonyl-CoA, in favor of increased fatty acid oxidation. 14-DAG controlled ethanol-induced hepatosteatosis by interfering with dysregulation of lipid metabolism. In conclusion, our results indicated that 14-DAG was capable of preventing the development of fatty liver through AMPK-mediated regulation of lipid metabolism. This finding supported the hepatoprotective role of 14-DAG, which might serve as a therapeutic option to alleviate hepatosteatosis in chronic alcoholism.     

Singapore Neonatal Resuscitation Guidelines 2021

Neonatal resuscitation is a coordinated, team-based series of timed sequential steps that focuses on a transitional physiology to improve perinatal and neonatal outcomes. The practice of neonatal resuscitation has evolved over time and continues to be shaped by emerging evidence as well as key opinions. We present the revised Neonatal Resuscitation Guidelines for Singapore 2021. The recommendations from the International Liaison Committee on Resuscitation Neonatal Task Force Consensus on Science and Treatment Recommendations (2020) and guidelines from the American Heart Association and European Resuscitation Council were compared with existing guidelines. The recommendations of the Neonatal Subgroup of the Singapore Resuscitation and First Aid Council were derived after the work group discussed and appraised the current available evidence and their applicability to local clinical practice.     

Clinical profile,multimodal imaging,and treatment response in macular serpiginous choroiditis

Purpose:To describe the clinical profile, multimodal imaging, and treatment response in macular serpiginous choroiditis (MSC).Methods:Clinical records of 16 eyes (14 patients) with MSC presenting to a tertiary eye care institute between 2015 and 2019 were analyzed retrospectively.Results:Mean age of 14 patients presenting with MSC was 33 ± 13 yrs with 64% males and 36% females. Mean visual acuity of the eyes with MSC at presentation was 0.43 ± 0.46 (logMAR) improving to 0.16 ± 0.28 (logMAR) at final visit. Thirteen eyes (81.3%) had active lesion at presentation. Mantoux test was positive in seven patients (50%) and QuantiFERON TB gold test positive in 10 patients (71%). HRCT chest showed latent tuberculosis in seven patients (50%). All patients underwent multimodal imaging. All patients received oral steroids as treatment therapy; 11 patients also received immunosuppressives, nine patients received additional anti-tubercular therapy (ATT). Mean duration of follow-up for the patients was 18 ± 10 months. A total of eight (50%) eyes had recurrence of lesions after an average duration of 14 ± 14 (3-36) months and were restarted on the treatment as per the requirement. At final follow-up, all eyes showed a good response to treatment and had healed lesions. Comparing the final BCVA to the initial BCVA, 38% (n = 6) showed improvement, 56% (n = 9) remained stable, and 6% (n = 1) eyes worsened at the final follow-up.Conclusion:Clinical profile and presentation of MSC is similar to that of CSC, and combination treatment with intravenous methyl prednisolone (IVMP), steroids, immunosuppressives, and ATT can salvage vision. A high suspicion of associated tuberculosis in endemic regions should be kept in mind.