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The glycans on the plasma membrane of cells manifest as the glycocalyx, which serves as an information-rich frontier that is directly in contact with its immediate milieu. The glycoconjugates (GCs) that adorn most of the mammalian cells are also abundant in gametes, especially the spermatozoa where they perform unique reproduction-specific functions e.g., inter-cellular recognition and communication. This study aimed to implicate the sperm glycosylation pattern as one of the factors responsible for low conception rates observed in buffalo bulls. We hypothesized that a differential abundance of glycans exists on the spermatozoa from bulls of contrasting fertilizing abilities endowing them with differential immune evasion abilities. Therefore, we investigated the role of glycan abundance in the phagocytosis and NETosis rates exhibited by female neutrophils (PMNs) upon exposure to such spermatozoa. Our results indicated that the spermatozoa from high fertile (HF) bulls possessed a higher abundance of O-linked glycans e.g., galactosyl (β-1,3)N-acetylgalactosamine and N-linked glycans like [GlcNAc]1-3, N-acetylglucosamine than the low fertile (LF) bull spermatozoa. This differential glycomic endowment appeared to affect the spermiophagy and NETosis rates exhibited by the female neutrophil cells (PMNs). The mean percentage of phagocytizing PMNs was significantly different ( P < 0.0001) for HF and LF bulls, 28.44 and 59.59%, respectively. Furthermore, any introduced perturbations in the inherent sperm glycan arrangements promoted phagocytosis by PMNs. For example, after in vitro capacitation the mean phagocytosis rate (MPR) rate in spermatozoa from HF bulls significantly increased to 66.49% ( P < 0.01). Likewise, the MPR increased to 70.63% ( p < 0.01) after O-glycosidase & α2-3,6,8,9 Neuraminidase A treatment of spermatozoa from HF bulls. Moreover, the percentage of PMNs forming neutrophil extracellular traps (NETs) was significantly higher, 41.47% when exposed to spermatozoa from LF bulls vis-à-vis the spermatozoa from HF bulls, 15.46% ( P < 0.0001). This is a pioneer report specifically demonstrating the role of O-linked glycans in the immune responses mounted against spermatozoa. Nevertheless, further studies are warranted to provide the measures to diagnose the sub-fertile phenotype thus preventing the losses incurred by incorrect selection of morphologically normal sperm in the AI/IVF reproduction techniques., (Copyright © 2020 Batra, Dagar, Nayak, Kumaresan, Kumar and Datta.)

Background: The treatment of high-risk neuroblastoma continues to present a formidable challenge to pediatric oncology. Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors can inhibit MYCN expression and suppress MYCN-amplified neuroblastoma in vivo. Furthermore, alterations within RAS-MAPK (mitogen-activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS-MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET/MEK inhibition utilizing I-BET726 or I-BET762 and trametinib in high-risk neuroblastoma., Procedure: Utilizing a panel of genomically annotated neuroblastoma cell line models, we investigated the in vitro effects of combined BET/MEK inhibition on cell proliferation and apoptosis. Furthermore, we evaluated the effects of combined inhibition in neuroblastoma xenograft models., Results: Combined BET and MEK inhibition demonstrated synergistic effects on the growth and survival of a large panel of neuroblastoma cell lines through augmentation of apoptosis. A combination therapy slowed tumor growth in a non-MYCN-amplified, NRAS-mutated neuroblastoma xenograft model, but had no efficacy in an MYCN-amplified model harboring a loss-of-function mutation in NF1., Conclusions: Combinatorial BET and MEK inhibition was synergistic in the vast majority of neuroblastoma cell lines in the in vitro setting but showed limited antitumor activity in vivo. Collectively, these data do not support clinical development of this combination in high-risk neuroblastoma., (© 2020 Wiley Periodicals, Inc.)

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, 131 I-metaiodobenzylguanidine, is ineffective at targeting micrometastases because of the low-linear-energy-transfer (LET) properties of high-energy β-particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted near DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in preclinical models of high-risk neuroblastoma. Methods: We used a radiolabled poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor called 125 I-KX1 to deliver Auger radiation to PARP-1, a chromatin-binding enzyme overexpressed in neuroblastoma. The in vitro cytotoxicity of 125 I-KX1 was assessed in 19 neuroblastoma cell lines, followed by in-depth pharmacologic analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize 125 I-KX1-induced DNA damage. Finally, in vitro and in vivo microdosimetry was modeled from experimentally derived pharmacologic variables. Results: 125 I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double-strand DNA breaks. On the basis of subcellular dosimetry, 125 I-KX1 was approximately twice as effective as 131 I-KX1, whereas cytoplasmic 125 I-metaiodobenzylguanidine demonstrated low biological effectiveness. Despite the ability to deliver a focused radiation dose to the cell nuclei, 125 I-KX1 remained less effective than its α-emitting analog 211 At-MM4 and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells and has the potential to be used in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1-targeted Auger emitter, calling for further investigation into targeted Auger therapy., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Renal biopsy is an important investigation to make the diagnosis of an underlying glomerular or tubular disease, and is commonly done by trained pediatricians. In this review, we discuss the procedure and also detail important points in interpretation of renal biopsy in children.

FDG PET/CT was performed for staging in a 15-year-old adolescent girl with cholangiocarcinoma, which showed only mild activity in the tumor but more impressive FDG activity in right femoral fibrous cortical defect without any other hypermetabolic lesions elsewhere. Pathological examination of the resected cholangiocarcinoma revealed significant neuroendocrine differentiation, which lead to subsequent Ga-DOTATATE PET/CT study. Unexpectedly, the same femoral fibrous cortical defect also had increased Ga-DOTATATE activity.

In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the phosphorylation of Jak2 (Tyr1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the G2/M phase and modulated cell cycle regulatory proteins (cyclin B1, p21, p34 cdc2 and pcdk1). Moreover, VERU-111 treatment induced apoptosis and modulated the expression of Bid, Bcl-xl, Survivin, Bax, Bcl2 and cleavage in PARP. In functional assays, VERU-111 markedly reduced the migratory and invasive potential of cervical cancer cells via modulations of MMPs. VERU-111 treatment also showed significant (P < 0.05) inhibition of orthotopic xenograft tumor growth in athymic nude mice. Taken together, our results demonstrate the potent anti-cancer efficacy of VERU-111 in experimental cervical cancer models.Thus, VERU-111 can be explored as a promising therapeutic agent for the treatment of cervical cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cardiovascular disease is the leading cause of death in India. Previously it was thought to be a disease of the elderly but now an epidemiological transition is being seen with increasing incidence in the very young adults as well. Such patterns are not well studied in the South East Asian population., Objective: To study the epidemiological profile of very young (≤35 years) adults presenting with an acute myocardial infarction (AMI) in comparison with an older cohort., Methodology: The present study included all patients presenting with AMI to the emergency or to the out-patient department of the G B Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi between January 2014 and October 2015. A total of 102 subjects ≤35 years with AMI comprised the study subjects (cases) and were compared with 104 subjects >35 years old with AMI (Controls)., Results & Conclusion: Most of the very young AMI patients presented with an anterior wall ST segment elevation myocardial infarction, a stable hemodynamic profile, single vessel disease and better left ventricular ejection fraction as compared with controls. Most of the patients were from urban and semi-urban areas, middle and lower middle socioeconomic status and were smokers but lacked other traditional risk factors., (Copyright © 2020 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

ST-segment elevation myocardial infarction (STEMI) is associated with increased mortality and morbidity. Although remarkable progress has been made in the management of STEMI in high-income countries, contemporary data to evaluate processes and outcomes of STEMI care in India is limited. The North Indian ST-segment elevation myocardial infarction (NORIN STEMI) registry is a prospective cohort study based at government funded and largely free of cost tertiary medical centers in New Delhi, India. These hospitals serve a large proportion of the patients with lower socioeconomic status presenting from multiple states in India, as many centers in these states lack adequate specialized cardiovascular care. The study has been approved by the Institutional Review Boards of each institution and informed consent has been obtained from study participants. The NORIN STEMI registry aims to provide important insights regarding contemporary risk factors profiles, practice patterns, and prognosis in patients with STEMI in an underserved population in North India. These findings may identify opportunities to improve the outcomes of patients with STEMI in India., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: The buffalo, despite its superior milk-producing ability, suffers from reproductive limitations that constrain its lifetime productivity. Male sub-fertility, manifested as low conception rates (CRs), is a major concern in buffaloes. The epididymal sperm surface-binding proteins which participate in the sperm surface remodelling (SSR) events affect the survival and performance of the spermatozoa in the female reproductive tract (FRT). A mutation in an epididymal secreted protein, beta-defensin 126 (DEFB-126/BD-126), a class-A beta-defensin (CA-BD), resulted in decreased CRs in human cohorts across the globe. To better understand the role of CA-BDs in buffalo reproduction, this study aimed to identify the BD genes for characterization of the selection pressure(s) acting on them, and to identify the most abundant CA-BD transcript in the buffalo male reproductive tract (MRT) for predicting its reproductive functional significance., Results: Despite the low protein sequence homology with their orthologs, the CA-BDs have maintained the molecular framework and the structural core vital to their biological functions. Their coding-sequences in ruminants revealed evidence of pervasive purifying and episodic diversifying selection pressures. The buffalo CA-BD genes were expressed in the major reproductive and non-reproductive tissues exhibiting spatial variations. The Buffalo BD-129 (BuBD-129) was the most abundant and the longest CA-BD in the distal-MRT segments and was predicted to be heavily O-glycosylated., Conclusions: The maintenance of the structural core, despite the sequence divergence, indicated the conservation of the molecular functions of the CA-BDs. The expression of the buffalo CA-BDs in both the distal-MRT segments and non-reproductive tissues indicate the retention the primordial microbicidal activity, which was also predicted by in silico sequence analyses. However, the observed spatial variations in their expression across the MRT hint at their region-specific roles. Their comparison across mammalian species revealed a pattern in which the various CA-BDs appeared to follow dissimilar evolutionary paths. This pattern appears to maintain only the highly efficacious CA-BD alleles and diversify their functional repertoire in the ruminants. Our preliminary results and analyses indicated that BuBD-129 could be the functional ortholog of the primate DEFB-126. Further studies are warranted to assess its molecular functions to elucidate its role in immunity, reproduction and fertility.

Metal/ferroelectric/metal capacitors were fabricated using ferroelectric thin films of Pb 0.95 La 0.05 Zr 0.54 Ti 0.46 O₃. Pb 0.95 La 0.05 Zr 0.54 Ti 0.46 O₃ films were deposited on Pt/Si substrate using chemical solution deposition method and Au metal electrodes were vacuum deposited on top of these films using a shadow mask. Electrical properties of these capacitors measured in two different electrode configurations, coplanar (Au/PLZT/Au) and interplanar (Au/PLZT/Pt) showed different behavior. For coplanar electrode configuration, higher values of polarization and photovoltaic parameters were obtained under illumination. The studies suggest that both the polarization-induced electric field and interface electric field increase for coplanar configuration, which enhance the transport of photogenerated charge carriers. Electrical poling further improves the photovoltaic parameters of the capacitors, with higher values obtained from the coplanar electrode configuration. Thus, for ferroelectric based photovoltaics devices, coplanar electrode configuration combined with poling enhances the photovoltaic parameters.

Pulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

Alternative radiolabeled, targeted agents are being investigated for children with relapsed neuroblastoma (NB) who do not respond to I-metaiodobenzylguanidine (MIBG) therapy. (DOTA-Tyr)-octreotate targets somatostatin receptors (SSTRs), particularly SSTR2, which are expressed on NB cells. We investigated SSTR2 expression in NB tumors (36 high-risk [HR]; 33 non-HR patients) and correlated SSTR2 levels with clinical features, norepinephrine transporter (NET) expression, and MIBG avidity. SSTR2 and NET immunohistochemistry scores (0 to 3) were calculated on biopsies using digital image analysis based on staining intensity and distribution. Clinical data were correlated with SSTR2 expression. Median SSTR2 score for 69 patients was 1.31 (0.26 to 2.55). Non-HR NB was associated with a higher SSTR2 score (P=0.032). The SSTR2 expression did not correlate with age, International Neuroblastoma Staging System (INSS) stage, MYCN amplification and histology. Higher SSTR2 scores were observed in MIBG-avid versus MIBG-nonavid NB. SSTR2 score was not significantly associated with NET score (r=-0.062, P=0.62). Twenty-six patients who relapsed or progressed had a median SSTR2 score of 1.33 (0.26 to 2.55). Patients with NB including relapsed or progressive disease showed SSTR2 expression at diagnosis, suggesting they could be candidates for radiolabeled-DOTA-conjugated peptide imaging or therapy.

Pelvic fracture associated urethral injury (PFUI) is a sequel of blunt pelvic trauma. The published rate of urethral injury varies from 5-25% in different series. Management includes options from primary realignment to delayed anastomotic urethroplasty. Anastomotic urethroplasty include an elaborated progressive perineal approach and combined transpubic approach. Though the treatment and approach is well accepted across the globe, controversies do exist. Through this section we would debate the literature regarding some controversial issues in management of PFUI. The aim of this article was to evaluate and elucidate upon the controversies that surround the PFUI repair in this era.The following controversial and pertinent issues with respect to the repair of such injuries were reviewed: Primary realignment versus delayed repair of PFUI, Necessity of inferior pubectomy, Predictability of inferior wedge pubectomy, Spatulation of distal bulbar and proximal urethral ends, Nomenclature of bulbar urethra. This study and evaluation comes from a tertiary high-volume center of reconstructive urology. Apart from our own center's experience the literature was reviewed for evidence synthesis and framing an opinion. Each of the above principles and surgical steps regarding management of pelvic fracture urethral injury was dealt with sequentially and evidence based literature reviewed. Only data from high volume urethroplasty centers and peer reviewed articles which made significant contribution were considered. The data was analyzed and conclusion drawn. On evidence collection there was sparse and scattered evidence in favour of early realignment even after technical advancement. Delayed anastomotic urethroplasty with progressive perineal approach is recommended. Inferior wedge pubectomy cannot be predicted based upon current conventional imaging.The injury and urethral distraction has a wide spectrum and with the fallibility of imaging, inferior pubectomy is a necessary steps under relevant settings to gain access to the posterior urethra. There are multitude of ways to spatulate urethra at either end although literature does not provide a superior way. Spatulation of distal urethra dorsally and leaving the proximal sphincter active urethra unspatulated is be the best scientifically. There is a need to reclassify the bulbar urethra to the penoscrotal junction to avoid under mobilization of bulbar urethra during the repair. There is no conclusive article addressing the controversial issues highlighted in this article. Adequate mobilization of bulbar urethra should be done till penoscrotal junction. Inferior pubectomy as a technique cannot be predicted and its utility cannot be underestimated. The spatulation of urethra can be done in multiple ways. Current anatomical definition of bulbar urethra is erroneous to imply urethra only in the bulb but with respect to surgery it should be extended till the penoscrotal junction.

Background: Incidence rate of acute myocardial infarction (MI) has increased in younger population over the years. The young patients have a different risk profile, presentation, and prognosis than the elderly. Hence, it is essential to understand the risk factors in young patients for proper treatment., Methods: Apolipoprotein E (ApoE) polymorphism and biochemicals such as total cholesterol, serum triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein(a), insulin, interleukin-6, homocysteine, fibrinogen, and highly sensitive C-reactive protein were investigated in very young MI (yMI patients; age ≤ 35 years; n = 125), in old MI (oMI patients; age >35 and < 80 years; n = 111), and healthy controls (age ≤35 years; n = 103)., Results: HDL-C was significantly lower in yMI patients than in controls (p = 2.63E-04) and oMI patients (p = 1.29E-05). ApoA1 was also lowest in yMI patients, but significant only in comparison to controls (p = 2.62E.04). The yMI group had the highest ratios of total cholesterol:HDL-C (p = 0.027 in yMI patients versus controls and p = 0.018 in yMI patients versus oMI patients), LDL-C:HDL-C (p = 0.002 in yMI patients versus controls and p = 0.005 in yMI patients versus oMI patients), and ApoB:ApoA1 (p = 8.75E-05 in yMI patients versus controls and p > 0.05 in yMI patients versus oMI patients). No significant pattern of ApoE polymorphisms was observed., Conclusion: The lower level of HDL-C and ApoA1 and higher ratios of total cholesterol:HDL-C, LDL-C:HDL-C, and ApoB:ApoA1 are risk factors for MI in young patients., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Diffusion dialysis, acid retardation and nanofiltration plants were acquired from Europe and demonstrated in several Indian metal finishing companies over a three year period. These companies are primarily small and medium enterprises (SMEs). Free acid recovery rate from spent pickling baths using diffusion dialysis and retardation was in the range of 78-86% and 30-70% respectively. With nanofiltration, 80% recovery rate of rinse water was obtained. The demonstrations created awareness among the metal finishing companies to reuse resources (acid/water) from the effluent streams. However, lack of efficient oil separators, reliable chemical analysis and trained personnel as well as high investment cost limit the application of these technologies. Local manufacturing, plant customization and centralized treatment are likely to encourage the uptake of such technologies in the Indian metal finishing sector., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Germinal vesicle breakdown (GVBD) is the first milestone that an oocyte needs to achieve toward completing the maturation and gaining potential to fertilize. Significantly lower in vitro embryo production rate in buffaloes can be attributed to heterogeneity of GVBD occurrence among oocytes obtained from abattoir derived ovaries. Evidence from our earlier work had suggested that different qualities of buffalo oocytes differ significantly in their timing of GVBD. Besides, these oocytes also differ in terms of volume of Akt phosphorylation, which initiates the process of GVBD. With objective of synchronizing the oocytes for GVBD, immature buffalo oocytes were subjected to a two-step culture protocol, initially in the presence of GVBD inhibitors and subsequently, in vitro maturation (IVM) with added SC79 (activates Akt). Expression of developmentally important genes was assessed along with embryo development rate and blastocyst health to interpret the consequences. Oocytes subjected to a short GVBD inhibition period of 6 h followed by IVM with SC79 resulted in improved cleavage and blastocyst rates. Resultant blastocysts also possessed higher ICM: TE ratio. Further, GVBD inhibited oocytes displayed a sustained cytoplasmic maturation status in terms of reorganization of cortical granules (CGs), mitochondrial membrane potential, and glutathione levels during the period of inhibition. We conclude that a temporary GVBD arrest of buffalo oocytes and modulation of Akt improves the in vitro embryo development rate as well as quality of resultant embryos. Besides, our meiotic arrest protocol does not affect the cytoplasmic maturation. J. Cell. Biochem. 119: 278-289, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Prior studies suggest that neuroblastomas that do not accumulate metaiodobenzylguanidine (MIBG) on diagnostic imaging (MIBG non-avid) may have more favorable features compared with MIBG avid tumors. We compared clinical features, biologic features, and clinical outcomes between patients with MIBG nonavid and MIBG avid neuroblastoma., Procedure: Patients had metastatic high- or intermediate-risk neuroblastoma and were treated on Children's Oncology Group protocols A3973 or A3961. Comparisons of clinical and biologic features according to MIBG avidity were made with chi-squared or Fisher exact tests. Event-free (EFS) and overall (OS) survival compared using log-rank tests and modeled using Cox models., Results: Thirty of 343 patients (8.7%) had MIBG nonavid disease. Patients with nonavid tumors were less likely to have adrenal primary tumors (34.5 vs. 57.2%; P = 0.019), bone metastases (36.7 vs. 61.7%; P = 0.008), or positive urine catecholamines (66.7 vs. 91.0%; P < 0.001) compared with patients with MIBG avid tumors. Nonavid tumors were more likely to be MYCN amplified (53.8 vs. 32.6%; P = 0.030) and had lower norepinephrine transporter expression. Patients with MIBG nonavid disease had a 5-year EFS of 50.0% compared with 38.7% for patients with MIBG avid disease (P = 0.028). On multivariate testing in high-risk patients, MIBG avidity was the sole adverse prognostic factor for EFS identified (hazard ratio 1.77; 95% confidence interval 1.04-2.99; P = 0.034)., Conclusions: Patients with MIBG nonavid neuroblastoma have lower rates of adrenal primary tumors, bone metastasis, and catecholamine secretion. Despite being more likely to have MYCN-amplified tumors, these patients have superior outcomes compared with patients with MIBG avid disease., (© 2017 Wiley Periodicals, Inc.)

This work investigates the value added utilization of two sugar-distillery wastes: (i) melanoidins, which are complex Maillard reaction products in molasses distillery wastewater, and (ii) unburnt carbon in sugarcane bagasse ash. Activated unburnt carbon (AUC), prepared by deashing and steam activation, had properties comparable to commercial activated carbon (CAC). Both carbons are suitable for melanoidins adsorption followed by desorption using 25% pyridine solution. For AUC, the equilibrium adsorption data is well described by Langmuir isotherm up to 35 °C while Freundlich model fits better at higher temperature. Adsorption using CAC followed Freundlich isotherm at all temperatures. Both carbons followed pseudo second order kinetics and displayed endothermic physisorption. Recovery of melanoidins from AUC (78%) was close to that observed with CAC (80%)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Cervical cancer is the most common cancer in Indian women. Infection with a high-risk human papillomavirus (HR-HPV) is the greatest risk factor for developing cervical cancer. The genetic and epigenetic changes in the tumor suppressor p16 gene is play an important role in the development of cervical cancer., Objective: To evaluate the expression and promoter methylation of p16 gene in HR-HPV infected squamous cell carcinoma of the uterine cervix., Methods: To find out p16INK4a expression and methylation status 105 squamous cell carcinoma of the uterine cervix were investigated by using immunohistochemistry and Methylation Specific PCR techniques., Results: HPV16/18 was amplified in 83.8% cases of the cervix. 80% of them were positive for HPV type 16, while only 3.8% were positive for HPV type 18. Promoter CpG island hypermethylation of p16 gene was detected in 20.9% tissue samples of cervical carcinoma. Of these hypermethylated samples 90.9% cases showed nil/very low p16INK4a expression (P= 0.001). Overexpression of p16INK4a was observed in 73.3% cases of HR-HPV infected squamous cell carcinoma of the cervix., Conclusion: An association between p16 methylation, expression, and HR-HPV infection suggested the compliance of HPV infection and aberration of p16 gene have a synergic effect on initiation and progression of cervical carcinoma.

Introduction: Kimura's disease (KD) is an allergic inflammatory disorder of unknown etiology endemic in Orientals. Kimura's disease was first mentioned by Kimm and Szeto in China in 1937. Kimura's disease is commonly encountered in Asia and is mostly reported in Japan, China, Singapore and Honkong. However, only a few cases have been reported in the Indian subcontinent., Case Report: A case of Kimura's disease in a young male managed by surgery is reported in addition to a literature review., Conclusion: Diagnosis is made on the basis of histopathological analysis, clinical presentation, and laboratory investigations. Long term follow-up is required as Kimura's disease is prone for recurrence.

Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies. Results: Sensitivity to binimetinib and ribociclib was inversely related ( r = -0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs. Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR ., (©2016 American Association for Cancer Research.)

OBJECTIVE There is increasing interest in neuromodulation for addiction. Methamphetamine abuse is a global health epidemic with no proven treatment. The objective of this study was to examine the effects of intermittent nucleus accumbens shell (AcbSh) deep brain stimulation (DBS) on operant methamphetamine intake and on methamphetamine seeking when stimulation is delivered in an environment different from that of drug use. METHODS Eighteen rats were implanted with intravenous (IV) catheters and bilateral AcbSh electrodes and subsequently underwent daily sessions in 2-lever (active/methamphetamine and inactive/no reward) operant chambers to establish IV methamphetamine self-administration. After stable responding was achieved, 3 hours of DBS or sham treatment was administered (sham: 0 µA, n = 8; active: 200 µA, n = 10) in a separate nondrug environment prior to the daily operant sessions for 5 consecutive days. Immediately following each DBS/sham treatment, rats were placed in the operant chambers to examine the effects of remote stimulation on methamphetamine intake. After the 5 days of therapy were finished, rats reestablished a posttreatment baseline, followed by extinction training, abstinence, and 1 day of relapse testing to assess methamphetamine-seeking behavior. RESULTS There was a decrease in total methamphetamine intake in rats receiving active DBS versus sham on Days 1 (42%) and 2 (44%). Methamphetamine administration returned to baseline levels following the cessation of DBS therapy. Compared with baseline drug responding, methamphetamine seeking was reduced (57%) in the DBS group but not in the sham group. CONCLUSIONS It is feasible to deliver noncontinuous DBS outside of the drug use environment with a resultant decrease in IV methamphetamine intake and seeking. The AcbSh is a neuroanatomical substrate for psychostimulant reinforcement and may be a target for intermittent neuromodulatory therapies that could be administered during brief periods of sobriety.

Background: Neuroblastoma is a pediatric malignancy, and most tumor cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. Meta-iodobenzylguanidine (MIBG) is a NET-specific ligand used as a highly specific imaging agent and targeted radiotherapeutic. Patients with neuroblastoma frequently require sedation during targeted radiotherapy. Dexmedetomidine has been increasingly used to achieve efficacious sedation. There are theoretical concerns that this highly selective alpha-2 adrenergic receptor agonist may interfere with active uptake of MIBG through the NET transporter. In this study, we analyzed the impact of [125-iodine]-labeled MIBG ([ 125 I]MIBG) uptake in the presence of dexmedetomidine in human neuroblastoma-derived cellular models., Procedure: Carrier-free [ 125 I]MIBG was synthesized using UltraTrace® resin (Molecular Insight Pharmaceuticals, Inc., Tarrytown, NY) through radioiododestannylation from a tin precursor bound by a solid-state polymer. NET (SLC6A2) protein expression was determined in human neuroblastoma cell lines (BE2C, SKNSH and IMR5). [ 125 I]MIBG internalization studies were performed using [ 125 I]MIBG alone or in combination with either desipramine or dexmedetomidine. Dexmedetomidine and desipramine competitive inhibition studies were performed and concentration at 50% maximal inhibition was calculated. Finally, NET inhibitor dissociation studies were performed in which after pre-incubation with either desipramine or dexmedetomidine, cells were washed and [ 125 I]MIBG was added., Results: We show dose-dependent inhibition of [ 125 I]MIBG uptake by dexmedetomidine, but at several logs lower potency than the known NET inhibitor desipramine. A review of pediatric dexmedetomidine pharmacokinetic data shows that the concentrations achieved in the serum are much lower than those required to block MIBG uptake., Conclusion: We conclude that dexmedetomidine will not interfere with therapeutic [ 131 I]MIBG efficacy., (© 2016 Wiley Periodicals, Inc.)

Introduction: Complex penile strictures are usually repaired using a two-stage urethroplasty. Buccal mucosal graft (BMG) placed in the first stage can have a significant contraction rate, which may require a subsequent revision surgery. We describe a composite two-stage penile urethroplasty using BMG for patients of complex penile strictures who have some salvageable urethral plate., Methods: Within a multi-institutional cohort, 82 patients underwent a two-stage urethroplasty for complex stricture of the penile urethra. Of these 42 patients who underwent our composite two-stage penile urethroplasty using BMG implanted at the second-stage were included. Patients with genital lichen sclerosus or incomplete clinical records were excluded from this study. The primary outcome of the study was to evaluate stricture-free success rate., Results: Of total 42, 4 patients were lost to follow-up. 42% of stricture etiology was failed hypospadias repair. Mean stricture length was 4.5 cm (range 3-8 cm). Seventeen (44.7%) patients had undergone the previous urethroplasty. At a median follow-up of 44 months, of 38 patients, 34 (89.5%) were successful, and 4 (10.5%) had a recurrence. No patient required revision surgery before the second-stage and required redo buccal graft harvesting for subsequent urethroplasty., Conclusions: The composite two-stage technique in repairing complex penile urethral strictures is a valid and reproducible surgical treatment for complex penile stricture and it may reduce the rate of contraction of the transplanted BMG., Competing Interests: Conflicts of interest: There are no conflicts of interest.

Intracranial tuberculoma is an uncommon presentation of tuberculosis, and its occurrence in an intraventricular location is very rare. It is usually confused with glioma, parasitic cyst, and craniopharyngioma. Few case reports exist in the literature on this entity. We report a case of tuberculoma at the foramen of Monro in a 7-year-old child and review the literature in terms of diagnostic dilemma., (© 2016 S. Karger AG, Basel.)

Rice (Oryza sativa L.) is the most important cereal crop and a major staple food for majority of the human populations worldwide. Rice crop is sensitive to salinity. In spite of large number of studies on salinity tolerance of rice, our knowledge on the overall effect of salinity on rice seedling growth is limited. Improvement in salt tolerance of crop plants remains indescribable, largely due to the fact that salinity is a complex trait which affects almost every aspect of the physiology, biochemistry and genomics of plants. The present investigation was conducted to establish the relationship between various morphological, physiological traits and stress indices. A set of 131 rice accessions was evaluated in two levels namely, non-stress (EC ~ 1.2 dS/m) and saline stress (EC ~ 10 dS/m) in hydroponics at seedling stage. Root length and shoot lengths were reduced by 52 and 50%, respectively in saline stress compared to non-stress conditions. There was a significant correlation between various morphological and physiological parameters in non-saline in addition to saline stress as well as non-stress. The effect of the increased Na+ concentration in the medium is detrimental to root length and shoot length as observed by reduction in root length and a concomitant reduction in shoot length. Increased concentration of Na+ led to augmented Na+/K+ ratio with increased stress in the medium and decreased expression of traits. A significant positive correlation (r=0.60) was noticed between stress tolerance index (STI) of root and shoot length. The stress susceptibility index (SSI) for root length was expressed significant positive correlation with SSI for shoot length (r=0.43). SSI for K+ content was registered significant negative correlation with STI for Na+ content (r=-0.43). The three accessions namely, IC 545004, IC 545486 and IC 545215 were found to be the best performers adjudged on the morphological and physiological criteria in saline stress situation. These three rice accessions could be used as a donor parent or for genotypic studies in future breeding programs.

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with (131)I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after (131)I-MIBG have not been defined. This is a multi-institutional retrospective review of patients with neuroblastoma treated with (131)I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to (131)I-MIBG. A competing risk regression was used to identify potential risk factors for SMN. The analytical cohort included 644 patients treated with (131)I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4-13.0%) and 14.3% (95% CI, 8.3-23.9%) at 5 and 10 years from first (131)I-MIBG, respectively. No increase in SMN risk was found with increased number of (131)I-MIBG treatments or higher cumulative activity per kilogram of (131)I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first (131)I-MIBG, bone disease, disease status at time of first (131)I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1-0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma. The cumulative risk of SMN after (131)I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A 77-year-old man with chronic obstructive lung disease who was on steroids, presented to the hospital after a fall with subacute headaches and ataxia. During the patient's hospital course, his clinical condition deteriorated with myoclonic jerks, fevers and severe encephalopathy. An extensive workup, including EEG, brain MRI and lumbar puncture, revealed possible Creutzfeldt-Jakob disease. Unfortunately, the patient failed to improve and died 12 days after admission. A brain-only autopsy revealed he had acute histoplasma meningitis with patchy superficial cerebritis., (2016 BMJ Publishing Group Ltd.)

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people. There is a need for novel, effective and practical treatment strategies that are validated in animal models. Neuromodulation, including deep brain stimulation (DBS) therapy, refers to the use of electricity to influence pathological neuronal activity and has shown promise for psychiatric disorders, including drug dependence. DBS in clinical practice involves the continuous delivery of stimulation into brain structures using an implantable pacemaker-like system that is programmed externally by a physician to alleviate symptoms. This treatment will be limited in methamphetamine users due to challenging psychosocial situations. Electrical treatments that can be delivered intermittently, non-invasively and remotely from the drug-use setting will be more realistic. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence. Methamphetamine dependence is rapidly developed in rodents using an operant paradigm of intravenous (IV) self-administration that incorporates a period of extended access to drug and demonstrates both escalation of use and high motivation to obtain drug.

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) -metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities., (© 2015 Wiley Periodicals, Inc.)

Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m(2) ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m(2) , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM., (© 2015 John Wiley & Sons Ltd.)

We present a case of bilateral lesions in a 50-year-old man, which were on first impression mistaken for and initially treated as bilateral cellulitis. We propose that bilateral cellulitis, as opposed to unilateral, is rare and that other aetiologies should be considered in evaluating a patient with bilateral lesions. The differential diagnosis includes stasis-dermatitis, lipodermatosclerosis, lymphoedema and vascular lesions such as Kaposi sarcoma, as was identified in this case. Early consultation with dermatology and biopsy in unclear cases mitigates the unnecessary use of prolonged antibiotics, antibiotic resistance and Clostridium difficile infections. HIV testing is an essential screening test in all adults who present with non-specific viral symptoms and rash., (2015 BMJ Publishing Group Ltd.)

Objective: To compare the efficacy of a Neurofacilitation of Developmental Reaction (NFDR) approach with that of a Conventional approach in the modulation of tone in children with neurodevelopmental delay., Methods: Experimental control design. A total of 30 spastic children ranging in age from 4 to 7 years with neurodevelopmental delay were included. Baseline evaluations of muscle tone and gross motor functional performance abilities were performed. The children were allocated into two intervention groups of 15 subjects each. In groups A and B, the NFDR and conventional approaches were applied, respectively, for 3 months and were followed by subsequent re-evaluations., Results: Between group analyses were performed using independent t test for tone and primitive reflex intensity and a Mann-Whitney U test for gross motor functional ability. For the within-group analyses, paired t tests were used for tone and primitive reflex intensity, and a Wilcoxon signed-rank test was used for gross motor functional ability., Conclusion: The NFDR approach/technique prepares the muscle to undergo tonal modulation and thereby enhances motor development and improves the motor functional performance abilities of the children with neurodevelopmental delay., Competing Interests: Conflicts of Interest None.

Introduction: Pelvic lymphadenectomy during radical prostatectomy (RP) improves staging and may provide a therapeutic benefit. However, there is no clear consensus on the selection criteria for subjecting patients to this additional procedure. With a growing adoption of robot assisted radical prostatectomy (RARP) in India, it has become imperative to study the incidence and predictive factors for lymph node involvement in our patients., Materials and Methods: From February 2010 to February 2014, 452 RARP procedures were performed at our institution. A total of 100 consecutive patients from July 2011 to August 2012 were additionally subjected to a robotic extended pelvic lymphadenectomy (EPLND). Lymph node positivity rates and lymph node density were analyzed on the basis of preoperative prostate specific antigen (PSA), Gleason score, clinical stage, D'Amico risk category and magnetic resonance imaging (MRI) findings. Multivariate analysis was performed to ascertain factors associated with lymph node positivity in our cohort., Results: The mean age of the patients was 65.5 (47-77) years and the body mass index was 26.3 (16.3-38.7) kg/m(2). The mean console time for EPLND was 45 (32-68) min. A median of 17 (two to 40) lymph nodes were retrieved. Seventeen patients (17%) had positive lymph nodes (median of 1, range 1-6). Median lymph node density in these patients was 10%. When stratified by PSA, Gleason score, clinical stage, D'Amico risk category and features of locally advanced disease on MRI, a trend towards increasing incidence of lymph node positivity was observed, with an increase in adverse factors. However, on multivariate analysis, clinical stage > T2a was the only significant factor impacting lymph node positivity in our cohort., Conclusions: A significant proportion of men undergoing RARP in India have positive lymph nodes on EPLND. While other variables may also have a potential impact, a higher clinical stage predisposes to an increased incidence of lymph node metastases.

Background: Healthcare workers (HCWs) are at high risk for hepatitis B virus (HBV) infection. The aim of the study was to evaluate HBV immunization status and anti-HBs titer among HCWs., Methods: AntiHBs titer was prospectively examined in all vaccinated of the 464 HCWs enrolled. A comparison was done between two groups who had received vaccination within or beyond 5 years (Group A >5 years, Group B <5 years) and also between those who received a booster dose, Group I (<1 year) and Group II (>1 year)., Results: 49.6% HCWs were vaccinated, 46.1% were unvaccinated, and 4.3% were partially vaccinated. Among HCWs, doctors had the highest vaccination rate of 92.5%, followed by medical students (62.4%), nursing staff (41.6%), technical staff (24.2%), administrative staff (12.1%), nursing students (8.5%), and grade IV/laundry staff (0%). Of the vaccinated HCWs, 30% had anti-HBs titer <10 mIU/mL, 10.8% between 10-100 mIU/mL, and 59.2% >100 mIU/mL. Mean anti-HBs titer between groups A and B was 334.8 and 649.2 mIU/mL, respectively (P<0.05); mean anti-HBs titer between groups I and II was 1742.7 and 629.2 mIU, respectively (P<0.002)., Conclusion: A significant proportion of HCWs is unvaccinated. A fair proportion of fully vaccinated HCWs can have low titers to protect them against HBV infection. Measuring anti-HBs titer, administering a booster dose, and offering general screening for HBs antigen should be made compulsory for HCWs.

Purpose: Currently, most high-grade glioma patients undergo a 1.5T brain magnetic resonance (MR) for radiation treatment planning. We hypothesized that 3T MR imaging (MRI) scanning is superior to 1.5T due to higher signal-to-noise ratio (SNR), and thus will result in more accurate quantification of tumor volumes. The purpose of this prospective study was to determine differences in radiation planning volumes for high-grade gliomas when scanned on 3T MR versus 1.5T MR., Methods and Materials: In this prospective controlled trial, 23 patients with high-grade gliomas underwent brain MRI scanning in both 1.5T and 3T field strengths within a 24-hour period; no steroids or treatment changes were made in-between scans. After 3 investigators contoured the T2 fast low-angle inversion recovery (FLAIR) abnormality (gross tumor volumes or [GTV]) for all patients, clinical target volume (CTV) and planning treatment volumes (PTV) were defined. Calculations by an independent investigator included volumes, standard deviations, SNRs, and contrast-to-noise ratios (CNRs); statistical analysis was performed on raw data., Results: Planning treatment volume ratios (3T:1.5T) for each investigator were 0.95 ± 0.12 (range, 0.64-1.10), 0.98 ± 0.10 (range, 0.64-1.16), and 0.99 ± 0.06 (range, 0.86-1.13). By paired 2-tailed t test, these volumes were not statistically different (P = .051), although there is a trend to 3T producing smaller volumes than 1.5T. Dice similarity coefficients were 0.90 ± 0.05, 0.90 ± 0.06, and 0.91 ± 0.05 for the investigators., Conclusions: Planning target volumes for high-grade gliomas were similar at 3T and 1.5T MR using our standard imaging protocols. However, in some patients, the 3T MR may reveal substantially smaller tumor volume due to inferior conspicuity of the lesion. These findings imply that while overall the radiation target volumes are comparable, there are differences in CNR and SNR that lead to differences in individual patients. The 1.5T may be better for gaining conspicuity of the tumor., (Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)