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Introduction: Since early 2020 the whole world has been challenged by the SARS-CoV-2 virus (COVID-19), its successive variants and the associated pandemic caused. We have previously shown that for people living with type 2 diabetes (T2DM), the risk of being admitted to hospital or dying following a COVID-19 infection progressively decreased through the first months of 2021. In this subsequent analysis we have examined how the UK COVID-19 vaccination programme impacted differentially on COVID-19 outcomes in people with T1DM or T2DM compared to appropriate controls. Methods: T1DM and T2DM affected individuals were compared with their matched controls on 3:1 ratio basis. A 28-day hospital admission or mortality was used as the binary outcome variable with diabetes status and vaccination for COVID-19 as the main exposure variables. Results: A higher proportion of T1DM individuals vs their controls was found to be vaccinated at the point of their first recorded positive COVID-19 test when compared to T2DM individuals vs their controls. Regarding the 28-day hospital admission rate, there was a greater and increasing protective effect of subsequent vaccination dosage (one, two or three) in mitigating the effects of COVID-19 infection versus no vaccination in T1DM than in T2DM individuals when compared with matched controls. Similar effects were observed in T2DM for death. Across both diabetes and non-diabetes individuals, those at greater socio-economic disadvantage were more likely to test positive for COVID-19 in the early phase of the pandemic. For T2DM individuals socio-economic disadvantage was associated with a greater likelihood of hospital admission and death, independent of vaccination status. Age and male sex were also independently associated with 28-day hospital admission in T2DM and to 28-day mortality, independent of vaccination status. African ethnicity was also an additional factor for hospital admission in people with T2DM. Conclusion: A beneficial effect of COVID-19 vaccination was seen in mitigating the harmful effects of COVID-19 infection; this was manifest in reduced hospital admission rate in T1DM individuals with a lesser effect in T2DM when compared with matched controls, regarding both hospital admission and mortality. Socio-economic disadvantage influenced likelihood of COVID-19 confirmed infection and the likelihood of hospital admission/death independent of the number of vaccinations given in T2DM.

Background The short synacthen test (SST) is the most commonly performed investigation to assess adrenal function. Appropriate criteria for when an SST is performed are subject to debate. We investigated how random serum cortisol levels relate to SST response. Methods We examined random cortisol measurements taken between 04.40–23.55 p.m. results of SST baseline and 30-/60-min cortisol performed over 12 months (225 SSTs) at Salford Royal Hospital. Serum cortisol was measured on the Siemens Centaur Analyser. A 30–60-min cortisol concentration of ≥450 nmol/L defined a pass; 350–449 nmol/L defined borderline. Results Patients only proceeded to SST if random cortisol was

The water buffalo (Bubalus bubalis) is well adapted in most regions of the eastern part of Uttar Pradesh, India. Despite its socio-economic importance, little is known about the prevalence of ectop...

INTRODUCTION: Research is ongoing to increase our understanding of how much a previous diagnosis of type 2 diabetes mellitus (T2DM) affects someone's risk of becoming seriously unwell following a COVID-19 infection. In this study we set out to determine the relative likelihood of death following COVID-19 infection in people with T2DM when compared to those without T2DM. This was conducted as an urban population study and based in the UK.METHODS: Analysis of electronic health record data was performed relating to people living in the Greater Manchester conurbation (population 2.82 million) who had a recorded diagnosis of T2DM and subsequent COVID-19 confirmed infection. Each individual with T2DM (n = 13,807) was matched with three COVID-19-infected non-diabetes controls (n = 39,583). Data were extracted from the Greater Manchester Care Record (GMCR) database for the period 1 January 2020 to 30 June 2021. Social disadvantage was assessed through Townsend scores. Death rates were compared in people with T2DM to their respective non-diabetes controls; potential predictive factors influencing the relative likelihood of admission were ascertained using univariable and multivariable logistic regression.RESULTS: For individuals with T2DM, their mortality rate after a COVID-19 positive test was 7.7% vs 6.0% in matched controls; the relative risk (RR) of death was 1.28. From univariate analysis performed within the group of individuals with T2DM, the likelihood of death following a COVID-19 recorded infection was lower in people taking metformin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 (GLP-1) agonist. Estimated glomerular filtration rate (eGFR) and hypertension were associated with increased mortality and had odds ratios of 0.96 (95% confidence interval 0.96-0.97) and 1.92 (95% confidence interval 1.68-2.20), respectively. Likelihood of death following a COVID-19 infection was also higher in those people with a diagnosis of chronic obstructive pulmonary disease (COPD) or severe enduring mental illness but not with asthma, and in people taking aspirin/clopidogrel/insulin. Smoking in people with T2DM significantly increased mortality rate (odds ratio of 1.46; 95% confidence interval 1.29-1.65). In a combined analysis of patients with T2DM and controls, multiple regression modelling indicated that the factors independently relating to a higher likelihood of death (accounting for 26% of variance) were T2DM, age, male gender and social deprivation (higher Townsend score).CONCLUSION: Following confirmed infection with COVID-19 a number of factors are associated with mortality in individuals with T2DM. Prescription of metformin, SGLT2is or GLP-1 agonists and non-smoking status appeared to be associated with a reduced the risk of death for people with T2DM. Age, male sex and social disadvantage are associated with an increased risk of death.

During the last few years, gene editing has emerged as a powerful tool for the therapeutic correction of monogenic diseases. CRISPR/Cas9 applied to hematopoietic stem and progenitor cells (HSPCs) has shown great promise in proof-of-principle preclinical studies to treat haematological disorders, and clinical trials using these tools are now underway. Nonetheless, there remain important challenges that need to be addressed, such as the efficiency of targeting primitive, long-term repopulating HSPCs and expand them in vitro for clinical purposes. Here we have tested the effect exerted by different culture media compositions on the ability of HSPCs to proliferate and undergo homology directed repair-mediated knock-in of a reporter gene, while preserving their stemness features during ex-vivo culture. We tested different combinations of compounds and demonstrated that by supplementing the culture media with inhibitors of histone deacetylases, and/or by fine-tuning its cytokine composition it is possible to achieve high levels of gene targeting in long-term repopulating HSPCs both in vitro and in vivo, with a beneficial balance between preservation of stemness and cell expansion, thus allowing to obtain a significant amount of edited, primitive HSPCs compared to established, state-of-the-art culture conditions. Overall, the implantation of this optimized ex vivo HSPC culture protocol will improve the efficacy, feasibility and applicability of gene editing and will likely provide one step further to unlock the full therapeutic potential of such powerful technology.

Neurodegenerative disorders are one of the most terrible consequences of aging and damage due to unbalanced biochemical reactions occur in the body. Numbers of research has been conducted to digout the reason and possible therapeutic strategies against the neurodegenerative damage and many more are on the way to be studied. There are many commercial drugs available in the market to cure neurodegenerative disorders but with many side effects. Therefore, researchers are searching for key therapies with minimum side effects. Many phytochemicals attract the researchers due to promising therapeutic effects and least side effects. Nigella sativa is one among many herbal plants. The chemical constituents of the plants are also studied against many diseases like inflammatory, bacterial/fungal disease, oxidative stress, and neurodegenerative disorders. In this chapter, the authors have focused the therapeutic role of N. sativa and its chemicals against neurodegenerative disorders.

INTRODUCTION: Since early 2020 the whole world has been challenged by the SARS-CoV-2 virus and the associated global pandemic (Covid-19). People with diabetes are particularly at high risk of becoming seriously unwell after contracting this virus.METHODS: This population-based study included people living in the Greater Manchester conurbation who had a recorded diagnosis of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and subsequent Covid-19 infection. Each individual with T1DM (n = 862) or T2DM (n = 13,225) was matched with three Covid-19-infected non-diabetes controls.RESULTS: For individuals with T1DM, hospital admission rate in the first 28 days after a positive Covid-19 test was 10% vs 4.7% in age/gender-matched controls [relative risk (RR) 2.1]. For individuals with T2DM, hospital admission rate after a positive Covid-19 test was 16.3% vs 11.6% in age/gender-matched controls (RR 1.4). The average Townsend score was higher in T2DM (1.8) vs matched controls (0.4), with a higher proportion of people with T2DM observed in the top two quintiles of greatest disadvantage (p CONCLUSION: In a UK population we have confirmed a significantly higher likelihood of admission in people with diabetes following Covid-19 infection. A number of factors mediate that increased likelihood of hospital admission. For T2DM, the majority of factors related to increased admission rate are common to the general population but more prevalent in T2DM. There was a protective effect of metformin in people with T2DM.

The current data shows the beginning and advancement into the "present" heredity of Mycobacterium tuberculosis complex infections of circa 74,500 BCE. The concern is as to how MtbC can maintain itself, as it is a significant opponent of humankind. Two new epidemiological models were built, adapted for body size and moreover coinfections for diverse MtbC pedigrees, to respond to just this question. In order to address this issue. Our current research was conducted at DHQ Mirpur AJK from March 2020 to February 2021. We gave a larger figure The lesser occurrence in this sex, better Paleolithic welfare status in relation to males, was attributed to women with superior resilience. The well-being state of the Paleolithic is better than of the Neolithic and the "present" genetic is more dispersed compared to the "old" than to the "old." Our results reveal that the 'present' heritage has a tremendous influence that leads to the conclusion of the clusters. A remarkable growth in the population must be overcome (x20 times in 100 years). Population and the safety afforded by "outdated" genealogy of former illnesses. Our findings also propose a major portion of the women's MtbC blockage. That knowledge leads us to reassess the boundaries of developed population in the Paleolithic period and unravel the notion of human female antagonism to TB to comprehend both the persistence of MtbC as well as population durability. Keywords: Paleolithic Tuberculosis (Tb), Population Increase, Female Resistance.

Aim: In order to describe the system, it is necessary to classify and quantify the risk factors for post-discharge entanglement that occur within 30 days of 21 inpatient general medical procedure system gatherings. Design: Retrospective survey of associates. Methods: A number of 557,520 older adults enrolled in one of the 21 meetings on the methodology of general surgical practices in hospital settings. Our current research was conducted at DHQ Mirpur AJK from May 2019 to April 2020. Main result measures: post-discharge complexity, reoperation and death. Results: Of the 551,510 patients (mean age, 56.7 years), 17.9 percent reported discomfort; 41.5 percent had Parkinson's disease. Of the PD-related pain, 77.2% occurred within 14 days of PD. Proctectomy (14.5 per cent), enteric fistula repair (13.7 per cent) and pancreatic procedures (11.4 per cent) had the highest PD pain percentage. Chest fixation, obesity and ventral hernia procedures have the highest PD quantum coherence rates (79.8 percent, 68.5 percent and 65.6 percent, separately). In both procedures, site problems, toxicity and thromboembolic events were usually common. The likelihood of complications of PD rose with hospitalization (13.6% versus 7.3% without hospitalization; P 0.002). In contrast, patients without complications of Parkinson's disease had a higher rate of re-operation (5.7% vs. 18.8%, individually; P.001) and disappearance (3.1% vs. 7.8%, individually; P.002) within 30 days after medical intervention; those with Parkinson's disease preceded by hospitalization had the highest rate of re-operation (34.8%) and disappearance (25.8%) (all P.002). After the change, PD discomfort was related to system type, American Society of Anesthesiologists class above 3, and steroid use. Conclusion: Difficulty ratios vary by technique, are typically closely related to the location and are related to mortality. Meticulous, explicit release-tolerant methodology just as rapid patient growth could enhance PD outcomes. Keywords: Outpatient treatment Complications, Reoperation and Deaths, General Surgery.

Dysregulated sensing of self–nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self–nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation., Excessive innate cell responses in WASp-null cells depend on activation of the cGAS/STING pathway.

The important aspect of light environment is to provide time-of-day and time-of-year information to the endogenous machinery that measures time. In a 24 h day there are conspicuous alterations in light intensity and spectrum. VIBGYOR is the visible portion of spectrum covering the light wavelength range from 380-760 nm. Each wavelength can activate the select class of photoreceptors, and hence a specific colour is experienced. Photoreceptors have opsin-based molecules that can trap light and thus play a key role in the perception of light and dark signals of the day. Eyes are the main photoreceptive structure but non-mammalian vertebrates such as birds have both retinal (eyes) and extra-retinal (e.g. lateral eyes, pineal, parapineal organs and deep brain photoreceptors) structures for photoreception. These opsin-based molecules found in different regions of the eyes and brain are sensitive to different wavelengths of light, hence play an important role in regulating the circadian and seasonal rhyt...

Cardiovascular disease is the leading cause of death worldwide, despite the growing advances that have been made in the development of therapeutics. Almost all aspects of the pathogenesis underlying a cardiac injury are critically influenced by the inflammatory response. Over the past two decades, researchers have shown that the myocardium triggers an intense innate immune response that activates various immune effectors including the pattern recognition receptors.

Kala pathar (Paraphenylene Diamine) is one of the hair dying substance and is commonly used in developing countries like Pakistan. The cases of its exposure accidentally as well as for suicidal intent are commonly seen in emergency departments with wide range of clinical spectrum. Objective: To determine the frequency of different complications seen in cases with kala pathar poisoning. Methods: This cross sectional study was done at Services Hospital, Lahore and THQ Kotmomim from the period of July 2018 to December 2018. The patients with age 12-60 years having suspected history of PPD exposure were taken. The data regarding the type, duration and intent of exposure was taken along with the other demographics. They were then underwent extensive investigation to look for various complications. Results: In this study there were 60 cases, comprising 22 (36.67%) males and 38 (63.33%) females with mean age 25.42±7.42 years. Out of 60 cases, 54 (90%) were unmarried and 56 (93.33%) had oral ingestion in contrast to 04 (6.67%), trans-dermal intoxication. All those cases that had trans-dermal intoxication had the accidental exposure while out of 56 cases that had oral intake 54 (90%) had it with suicidal intent. Dysphagia was seen in 44 (73.33%) cases, followed by hyperkalemia (53.33%) and then maxillofacial edema (40%). There was almost equal distribution of acute renal failure and arrhythmia while acute hepatitis was seen in only 8 (13.33%) of cases. Conclusion: Kala pathar intoxication is common in female gender, younger age groups and unmarried population. Its toxicity is also common with oral intake. Dysphagia and hyperkalemia are the most common complications of this. Key words: kala pathar intoxication, PPD, ARF.

Correlation between midnight and post dexamethasone salivary cortisone and cortisol and post dexamethasone serum cortisol concentrations in patients with unilateral and bilateral adrenal incidentalomas Background: The commonest functional abnormality in adrenal incidentalomas (AI) is autonomous cortisol secretion. Most guidelines recommend a 1 mg overnight dexamethasone suppression test (ONDST) as a screening test for this abnormality. This requires either a short stay or attendance to hospital as well as the inconvenience of venepuncture. Aim: To investigate the utility of using salivary samples in an ONDST by correlating post dexamethasone salivary cortisol (SaC) and cortisone (SaCn) and midnight salivary cortisol (MSaC) and cortisone (MSaCn) concentrations with post dexamethasone cortisol (SC). Methods: Using linear regression analysis we correlated post SC with SaC and SaCn and with MSaC and MSaCn. Results: We examined the results of 57 patients with unilateral or bilateral adrenal incidentalomas who underwent a 1 mg dexamethasone suppression test on our unit. The SC range

Background: The most common functional abnormality in adrenal incidentalomas (AI) is autonomous cortisol secretion. Most guidelines recommend a 1 mg overnight dexamethasone suppression test (ONDST) as a screening test for this abnormality. There is some evidence that simultaneous measurement of post dexamethasone serum dexamethasone (SD) with serum cortisol (SC) improves the accuracy of the ONDST. We have therefore been routinely measuring SD in our unit to ensure adequate concentrations when interpreting the results of this test. Aim: To measure the correlation between SD and SC concentrations and SD with the decrement in serum cortisol levels from baseline (9 am the day before the test) to the post dexamethasone level (DSC) in the ONDST. Method: We examined the results of 57 patients with unilateral or bilateral adrenal incidentalomas who underwent a 1 mg ONDST on our unit. Using linear regression analysis, we correlated SC and SD concentrations and serum SD concentration with the DSC. We also examined whether lower levels of SD were associated with adequate suppression of SC following ONDST. Results: SD levels range 16, median 7.656 nmol/L. SC range

Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of the viral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded by the host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1 IN degradation, we performed a targeted RNAi screen using a library of siRNAs against all components of the ubiquitin-conjugation machinery using high-content microscopy. Here we report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNA formation, while those overexpressing the factor display opposite effects. Knock down of TRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of IN serine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation., HIV-1 integration into host DNA is mediated by the viral integrase (IN). Here, using siRNA screen and high-content microscopy, the authors identify the host E3 RING ligase TRIM33 to affect IN stability and show that TRIM33 prevents viral integration by triggering IN proteasome-mediated degradation.

Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy., Highlights • Laser light reduces tumor progression while increasing metabolism of cultured cells • Laser-treated tumors contain mature vessels and less pro-angiogenic macrophages • Tumors treated by photobiomodulation are surrounded by lymphocytes and dendritic cells • Laser light promotes secretion of type I interferons in vitro and in vivo Laser therapy, also named photobiomodulation, is recommended to heal mucositis induced by oncological treatments, raising concerns on its safe use in cancer patients. Ottaviani et al. showed that laser light inhibits tumor progression, induces tumor vessel normalization and stimulates the immune system to produce type I interferons, proving the safety and extending the use of laser-based therapies to cancer.

Serine protease inhibitors (serpins) family have a complex mechanism of inhibition that requires a large scale conformational change. Antithrombin (AT), a member of serpin superfamily serves as a key regulator of the blood coagulation cascade, deficiency of which leads to thrombosis. In recent years, a handful of studies have identified small compounds that retard serpin polymerization but abrogated the normal activity. Here, we screened small molecules to find potential leads that can reduce AT polymer formation. We identified simple sugar molecules that successfully blocked polymer formation without a significant loss of normal activity of AT under specific buffer and temperature conditions. Of these, trehalose proved to be most promising as it showed a marked decrease in the bead like polymeric structures of AT shown by electron microscopic analysis. A circular dichroism (CD) analysis indicated alteration in the secondary structure profile and an increased thermal stability of AT in the presence of trehalose. Guanidine hydrochloride (GdnHCl)-based unfolding studies of AT show the formation of a different intermediate in the presence of trehalose. A time-dependent fluorescence study using 1,1′-bi(4-anilino)naphthalene-5,5′-disulfonic acid (Bis-ANS) shows that trehalose affects the initial conformational change step in transition from native to polymer state through its binding to exposed hydrophobic residues on AT thus making AT less polymerogenic. In conclusion, trehalose holds promise by acting as an initial scaffold that can be modified to design similar compounds with polymer retarding propensity.

Endogenous proteins that promote vascular endothelial cell based inhibition of angiogenesis are an attractive option for antitumor therapy. Inactive cleaved and latent conformations of antithrombin (AT) are antiangiogenic, but not its native form which is an inhibitor of proteases involved in blood coagulation. Unlike native, the cleaved and latent conformations are reactive center loop inserted conformations which binds heparin with very low affinity. We use a sulfoxy modified AT to assess the role of reactive center loop insertion and heparin affinity in antiangiogenic function. Chorioallantoic membrane assay (CAM) shows that antiangiogenic activity of latent and oxidized AT are better than thalidomide, a potent antiangiogenic drug. Wound healing experiments suggest that latent and oxidized conformations can influence endothelial cell migration. Latent and cleaved conformations of AT shows an increase in α-helical content in the presence of unfractionated heparin, but not the oxidized AT. Unlike the loop inserted polymer, cleaved and latent conformations, oxidized AT has factor Xa inhibitory activity indicating that loop insertion is not necessary for antiangiogenic role. The results of our study establish that active conformation of AT can become antiangiogenic while maintaining its anticoagulant activity possibly through chelation of low affinity heparin in the vicinity of endothelial cell.

Endogenous angiogenesis inhibitor that specifically decreases tumor cell proliferation can be used to treat cancer since angiogenesis is required at every step of tumor progression and metastasis. Endothelial cells are the main target for the antiangiogenic therapy because they are non-transformed and easily accessible to angiogenic inhibitors. Antithrombin functions as a principal plasma protein inhibitor of blood coagulation proteinases and belongs to the family of serine protease inhibitors (serpins) which have common mechanism of inhibition. Antithrombin acquires a potent antiangiogenic activity upon conversion of the native molecule to cleaved or latent conformation. Cleaved and latent preparations of bovine and human plasma derived antithrombin inhibits capillary endothelial cell proliferation and the growth of human SK-NAS neuroblastoma and Lewis lung carcinoma tumors in mice but not the native antithrombin's. The native form of antithrombin binds with high affinity to vascular heparan sulfate proteoglycans containing a specific pentasaccharide sequence and it is this cofactor interaction that activates antithrombin to maximal rate of thrombin inhibition. Upon inhibitory complex formation with target proteinases the antithrombin undergoes stressed to relaxed transformation and lose their high affinity for pentasacchride. Low affinity relaxed conformation with reduced heparin binding like cleaved and latent are antiangiogenic but native high affinity heparin binding stressed conformation is not, indicating the critical importance of heparin affinity in antithrombin antiangiogenic function. Based on evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with heparin like molecule in matrix, the possibility of antiangiogenic antithrombin to interfere with endothelial cell growth and angiogenesis through heparin mediated mechanism deserves serious consideration and investigation. It is also possible that cleaved and latent conformations with reduced affinity for heparins can also induce conformational change in the antithrombin which can open an epitope on the antithrombin surface for appropriate interactions on the endothelial surface for better antiangiogenic activity. This review illustrates the potential of antithrombin and other serpin family members as endogenous antiangiogenic proteins.

Background: The incidence of Tuberculosis (TB) in renal transplant recipients in Pakistan is 15%. Following findings of our randomized controlled trial 1 showing an overwhelming benefit of Isoniazid (INH) prophylaxis, from June 2009 every transplant recipient receives INH for one year post transplant in our unit. Aims and objectives: To find out incidence, risk factors and complications of tuberculosis in renal transplant recipients receiving INH prophylaxis. Methods: We reviewed the records of all renal transplant recipients on INH prophylaxis from June 2009 to December 2011, followed up till June 2015. We noted details of transplantation and immunosuppression, Tuberculosis including occurrence after transplantation, site, methods of diagnosis, treatment, drugs side effects and other complications, and outcome. Results: Out of 910 recipients, 91% completed one year of INH. Forty six (5%) developed TB, incidence higher in later than 2 years post transplantation than earlier. Majority were pulmonary (48%); most were diagnosed on cultures. Out of 14 positive cultures, only one (7%) was INH resistant. Out of 46 patients with TB, majority (84%) were cured, 6 (13%) died while one suffered graft failure. Incidence of hepatotoxicity was 1.42%. Conclusion: INH prophylaxis is effective in preventing TB in post renal transplant recipients. Late development of TB still remains a challenge. 1 Use of isoniazid chemoprophylaxis in renal transplant recipients. Rubina Naqvi et al. Nephrol. Dial. Transplant. (2010) 25 (2): 634-637.

Serpin constitute about 10% of blood protein and are associated with mutations that results in aberrant intermolecular linkages which leads to polymer formation. Studies with short peptides have shown promise in depolymerization of serpins however a reactive center loop based peptide also makes the serpin inactive. A chemical chaperone based approach is a better option in terms of maintaining activity and retarding polymerization but not much is known about its binding and mechanism. Specific target for chemical chaperones and its effectiveness across many serpin is not known. We did an analysis of serpin cavity using CASTp and show that cavities are distributed throughout the molecule where the largest cavities are generally present in areas of major conformational change like shutter region, helix D and helix F. An analysis of different conformational states of serpins showed that this large cavity undergoes increase in size in latent and cleaved states as compared to native state. We targeted serpins with a variety of carbohydrate, methylamine and amino acid based chemical chaperones and selected those that have highest binding energy across different serpins to assess their ability to bind large cavities. The results show that carbohydrate based chemical chaperone like sorbitol, sucrose, arabitol and trehalose and amino acid based chaperones like dopamine, phenylalanine, arginine and glutamic acid are the most effective in binding serpins. Most of these chemical chaperone interacted with residues in the shutter region and the helix D arm at the C-terminal which are part of the largest cavities. We selected the carbohydrate based chemical chaperone with best binding energies and did experimental study under the condition that induce polymerization and show that indeed they were able to retard polymer formation with moderate effect on inhibition rates. However a fluorometric study with native antithrombin showed that chemical chaperone may effect the conformation of the proteins. Our study shows that chemical chaperones have the best binding affinities for the cavities around shutter region and helix D and that a cavity targeting based approach seems to be a better option for retarding polymerization in serpins, but a thorough analysis of its effect on folding, inhibition and cofactor binding is required.

The serpins (serineproteinaseinhibitors) are structurally similar but functionally diverse proteins that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. Serpins play absolutely critical role in the control of proteases involved in the inflammatory, complement, coagulation and fibrinolytic pathways and are associated with many conformational diseases. Serpin's native state is a metastable state which transforms to a more stable state during its inhibitory mechanism. Serpin in the native form is in the stressed (S) conformation that undergoes a transition to a relaxed (R) conformation for the protease inhibition. During this transition the region called as reactive center loop which interacts with target proteases, inserts itself into the center ofβ-sheet A to form an extra strand. Serpin is delicately balanced to perform its function with many critical residues involved in maintaining metastability. However due to its typical mechanism of inhibition, naturally occurring serpin variants produces conformational instability that allows insertion of RCL of one molecule into theβ-sheet A of another to form a loop-sheet linkage leading to its polymerization and aggregation. Thus understanding the molecular basis and amino acid involved in serpin polymerization mechanism is critical to devising strategies for its cure.

Background Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. Objective Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. Methods We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo . By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. Results Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. Conclusions These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.