Pattern of missing probes in rifampicin resistant TB by Xpert MTB/RIF assay at a tertiary care centre in Mumbai

Setting

Department of Microbiology.

Aldosterone,inactive matrix gla-protein,and large artery stiffness in hypertension

Vascular calcification leads to increased large artery stiffness. Matrix gla-protein (MGP) is a vitamin K–dependent protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized β = 0.50, P < .001), which was independent of potential confounders (β = 0.37, P < .001). Levels of dp-ucMGP were significantly associated with CF-PWV (β = 0.30; P < .001), which persisted after adjustment for potential confounders (β = 0.25; P = .004). Plasma aldosterone was also significantly associated with CF-PWV (standardized β = 0.21; P = .035). However, in a model that included aldosterone and dp-ucMGP, only the latter was associated with CF-PWV. Mediation analyses demonstrated a significant dp-ucMGP–mediated effect of aldosterone on CF-PWV, without a significant direct (dp-ucMGP independent) effect. Our study demonstrates a novel independent association between high aldosterone levels and dp-ucMGP, suggesting that aldosterone may influence the MGP pathway. This relationship appears to underlie the previously documented relationship between aldosterone and increased arterial stiffness.     

Inotuzumab ozogamicin in relapsed B‐cell acute lymphoblastic leukemia

Despite an improved understanding of disease biology and the use of multi‐agent chemotherapy, the long‐term survival of adults with B‐cell acute lymphoblastic leukemia (B‐ALL) ranges from 35% to 50%. Management of patients with relapsed B‐ALL, a group characterized by dismal outcomes, poses a clinical challenge. To address this unmet need, novel therapeutics are being investigated in the setting of relapsed B‐ALL with encouraging results. CD22 is an important B‐cell antigen expressed in 80‐90% of B‐ALL cases. CD22 undergoes constitutive endocytosis with antibody ligation, making it an attractive biologic target for immunoconjugates. Inotuzumab ozogamicin (IO), a CD22‐targeted antibody‐drug conjugate demonstrated impressive single agent activity even among heavily pretreated relapsed B‐ALL patients. A recent randomized phase III clinical trial demonstrates superiority of IO over standard of care chemotherapy as first‐ or second‐line salvage therapy for relapsed B‐ALL. In this review, we summarize the preclinical and clinical data available to date using IO in relapsed B‐ALL.     

Interplay between electrical activity and bone morphogenetic protein signaling regulates spinal neuron differentiation

A gradient of bone morphogenetic proteins (BMPs) along the dorsoventral axis of the spinal cord is necessary for the specification of dorsal neurons. Concurrently, a gradient of calcium-mediated electrical activity is present in the developing spinal cord but in an opposing ventrodorsal direction. Whether BMPs and electrical activity interact in embryonic spinal neurons remains unknown. We show that BMP decreases electrical activity by enhancing p38 MAPK-mediated negative modulation of voltage-gated sodium channels. In turn, electrical activity affects the phosphorylation status and nuclear level of activated Smads, the canonical components of BMP signaling. This interaction between calcium spike activity and BMP signaling regulates the specification of the dorsal commissural spinal neuron phenotype. The present study identifies an unexpected interplay between BMPs and electrical activity that is critical for decoding the morphogen gradient during spinal neuron differentiation.     

Methotrexate treatment provokes apoptosis of proliferating keratinocyte in psoriasis patients

Psoriasis is a chronic inflammatory skin disease characterized by hyper proliferation of keratinocytes. Recent data show that the epidermis thickening in psoriasis may be related to imbalance of homeostasis caused by abnormal apoptotic process. Maintenance of keratinocyte apoptotic process is very important in psoriasis. Methotrexate (MTX) has been used for many years to restore the normal skin in psoriasis condition. However, the exact mechanism of MTX in psoriasis condition is poorly understood. The aim of this study was to examine the role of MTX on keratinocyte apoptosis pathway in psoriasis patients. A total of 58 psoriasis vulgaris patients were recruited for this study. Nonlesional skin biopsies served as control. Skin biopsies of psoriatic patients were collected and analyzed for cytosolic, mitochondria and total cytochrome c by ELISA. Expression of caspase-9, NFκBp65, pAkt1 by western blot, real-time PCR and immunohistochemical analysis of c-FLIP protein was analyzed in nonlesional and lesional skin biopsies before (day 0) and after (at the end of 6 and 12 weeks) MTX treatment. After MTX treatment, a significant increase in cytochrome c was observed when compared with before MTX treatment in psoriasis patients (p < 0.001). Protein and gene expression of cleaved caspase-9 were significantly increased after MTX treatment, whereas the expression of Bcl-xL, c-FLIP, NFκBp65, pAkt1 significantly downregulated after MTX treatment. In conclusion, these results showed that intrinsic apoptotic pathway induced by MTX eventually adds the beneficial therapeutic role of MTX in psoriasis by controlling the acanthosis.     

A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies

The initial treatment of lupus nephritis is usually based on a renal biopsy. Subsequent disease flares, however, are often treated without the benefit of kidney pathology because repeat biopsies are infrequent. A noninvasive, real-time method to assess renal pathology would be useful to adjust treatment and improve outcome. To develop such a method we collected urine samples at or close to the time of 64 biopsies from 61 patients with lupus nephritis to identify potential biomarkers of tubulointerstitial inflammation and correlated these to biopsy parameters scored by a renal pathologist using a semiquantitative scale. Linear discriminant analysis was used to weight variables and derive composite biomarkers that identified the level of tubulointerstitial inflammation based on urine concentrations of monocyte chemotactic protein-1, hepcidin (a marker of active lupus), and liver fatty acid-binding protein. The discriminant function that described the most accurate composite biomarkers included urine monocyte chemotactic protein-1 and serum creatinine as the independent variables. This composite had sensitivity, specificity, positive predictive value, and negative predictive value of 100, 81, 67, and 100%, respectively. Only 14% of the biopsies were misclassified. Thus, specific renal pathologic lesions can be modeled by composite biomarkers to noninvasively follow and adjust the treatment of lupus nephritis reflecting renal injury.     

Relationship of Electro-mechanical Remodeling to Survival Rates after Cardiac Resynchronization Therapy

Cardiac resynchronization therapy, when added to optimal medical therapy, increases longevity in symptomatic congestive heart failure patients with left ventricular ejection fractions (LVEF) ≤0.35 and QRS durations >120 ms. Cardiac resynchronization therapy is also associated with electrical and mechanical reverse remodeling. We examined whether reverse remodeling predicts increased survival rates in non-trial settings.Recipients of cardiac resynchronization therapy and defibrillators (n=112; 78 men; mean age, 69 ± 11 yr) underwent repeat echocardiography and electrocardiography at least 90 days after device implantation. Forty patients had mechanical responses of at least 0.05 improvement in absolute LVEF; 56 had electrical responses (any narrowing of biventricular-paced QRS duration compared with the electrocardiogram immediately after therapy). During a mean follow-up period of 3.1 ± 1.7 years, 55 patients died. The average death rate per 100 person-years was lower among mechanical responders than nonresponders (9.2% vs 23.9%; P=0.009); the unadjusted hazard ratio was 0.39 (95% confidence interval [CI], 0.19–0.79).In a multivariate model adjusted for age, sex, baseline LVEF, and QRS duration, mechanical responders had 60% better survival than nonresponders (hazard ratio=0.40; 95% CI, 0.21–0.79; P=0.008). No difference in survival was observed in electrical response. In our association of absolute change in LVEF over the observed range with death (using restricted cubic splines), we observed a linear relationship with survival.In patients given cardiac resynchronization therapy, mechanical but not electrical remodeling was associated with better survival rates, suggesting that mechanical remodeling underlies this therapy''s mechanism of conferring a survival benefit.Key words: Cardiac resynchronization therapy/methods, combined modality therapy, heart conduction system/physiopathology, heart failure/mortality/physiopathology/therapy, predictive value of tests, survival analysis, ventricular dysfunction, left/mortality/prevention & control/therapy, ventricular remodelingIn selected heart-failure patients, cardiac resynchronization therapy (CRT) improves exercise tolerance, maximal oxygen consumption, and quality of life, and reduces the risks of repeat hospitalization for heart failure or death.^1,2 Lower left ventricular ejection fraction (LVEF) is a predictor of cardiac events independently of QRS duration or electrical evidence of dyssynchrony.^3,4 Secondary data analyses from clinical trials yielded better clinical outcomes in the context of reverse mechanical remodeling.^5,6 In addition, electrical dyssynchrony—commonly observed in patients with left ventricular (LV) dysfunction⁷—is a predictor of LV systolic dysfunction.^8,9 Data from clinical practice are sparse in regard to associations of reverse mechanical and electrical remodeling with improved survival rates. In this study, we examined the association between electromechanical reverse remodeling and survival rates in a tertiary-care hospital.     

The role of Tenonplasty in the management of limbal and scleral ischemia due to acute ocular chemical burns

Of the various manifestations of ocular chemical burns (OCBs), ischemia of the limbus and the peri-limbal sclera indicates poor prognosis and in severe cases threaten the integrity of the globe. Tenonplasty is a surgical procedure which involves advancing the Tenon’s capsule over the ischemic areas to provide a vascular supply and to enable migration of the conjunctival epithelium. This review aims to provide an overview of the diagnosis of limbal ischemia and its management with Tenonplasty. A literature review was conducted using the keywords “Tenonplasty,” “Tenon’s capsule,” “ocular chemical injury,” “ocular thermal injury,” “Tenon advancement,” “scleral ischemia,” and “limbal ischemia,” and outcomes were studied from seven selected articles. In addition to clinical evaluation, in vivo imaging techniques such as anterior segment optical coherence tomography angiography can provide an objective method of measuring and monitoring the ischemia and re-perfusion of the peri-limbal vasculature. Tenonplasty can be performed in eyes with acute OCBs with scleral or limbal ischemia by dissecting the Tenon’s layer from the orbit and securing it to the limbus. The indications, mechanism of action, peri-operative considerations, surgical technique, and post-operative care of Tenonplasty are discussed in detail. The average time for post-operative re-epithelization ranges from 1 to 6 months with the formation of a symblepharon being the most common complication. In conclusion, Tenonplasty is a globe-salvaging procedure in cases with severe limbal and scleral ischemia because of OCBs and has good anatomical outcomes priming the globe for subsequent re-constructive and vision-restoring surgeries.