Overexpression of the type 1 adenylyl cyclase in the forebrain leads to deficits of behavioral inhibition

The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1+ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1+ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1+ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition

Genetic disruption of the core circadian clock impairs hippocampus-dependent memory

Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1−/− mice, which are arrhythmic under constant conditions, were examined for hippocampus-dependent memory, LTP at the Schaffer-collateral synapse, and signal transduction activity in the hippocampus. Bmal1−/− mice exhibit impaired contextual fear and spatial memory. Furthermore, LTP in hippocampal slices from Bmal1−/− mice is also significantly decreased relative to that from wild-type mice. Activation of Erk1,2 MAP kinase (MAPK) during training for contextual fear memory and diurnal oscillation of MAPK activity and cAMP in the hippocampus is also lost in Bmal1−/− mice, suggesting that the memory defects are due to reduction of the memory consolidation pathway in the hippocampus. We conclude that critical signaling events in the hippocampus required for memory depend on BMAL1

DEVELOPMENT AND EVALUATION OF FREEZING RESISTANT INTRAVENOUS FLUID

Objectives: Hemorrhagic or hypovolemic shocks accounts for a large portion of civilian and military trauma deaths due to life-threatening blood loss which requires intravenous fluid infusion to prevent essential deficiencies of fluids. However, at low temperature (-150C) fluid bottles freeze out and can not be used in emergency. In view of that, objective of the present work is to develop a freezing resistant intravenous formulation (FRIV) and its in vivo safety and efficacy evaluation. Methods: FRIV formulations were developed using standardized ringer lactate (RL) formulation protocol, in which varying concentrations of ethanol and glycerol were added to induce desired physiochemical properties. Efficacy of FRIV was evaluated in terms of survival percentage of hemorrhagic animal models (Swiss albino strain mice). Acute toxicity studies were carried out through an infusion at dose levels (0, 20 and 40 ml/Kg b. wt.). Results: In vitro data showed that optimized FRIV (F-10) takes more time (360 ± 21 min) for freezing and less time in thawing (50 ± 4.50 min) in comparison to control which takes (110 ± 15 min) in freezing and (80 ± 7.25 min) in thawing. Formulations were found to be stable and sterile up to six months. In vivo efficacy data showed ≥ 75% survival in animals infused with FRIV as compared to control group in hemorrhagic animal models and no treatment related toxic effects of optimized formulation in terms of hematological, serum biochemistry and histopathological analysis. Conclusion: Pre-clinical safety and efficacy data of the present study indicated that developed FRIV formulation could be used for fluid recovery during the hemorrhagic shocks conditions in the combat scenario

FORMULATION AND CHARACTERIZATION OF METFORMIN HYDROCHLORIDE SUSTAINED RELEASE MATRIX TABLET CONTAINING CASSIA TORA MUCILAGE

All the present investigation an attempt has been made to study the formulation and evaluation of matrix tablet of Metformin HCL using natural mucilage of Cassia tora as a release retardant. The matrix tablet was formulated using different drug polymer ratio. The developed formulation of tablet was evaluated for pre-compression and post–compression method. The result of the pre-compression parameter like Bulk density, tapped density, Carr’s index and Hausner’s ratio were found to be with the limits indicating good flow properties of the granules. Swelling index reveals that with increasing mucilage concentration there is increased swelling showing 61% for F-2 at the end of 5 h whereas for F-3 it was around 89.9 % respectively. In- vitro drug release for F3 formulation was found to be 75% at the end of 10 h. With increases in mucilage concentration the drug release from the matrix tablet got retarded. In- vitro, drug release data obtained were fitted to various release model excess the possible mechanism of the drug release. The results of all these parameters are tabulated and depicted graphically in the result and discussion section. IR spectral studies revealed that the drug, polymer and excipients used were compatible.  Drug release profile of all formulation was plotted in different kinetics. The calculated regression coefficients showed a higher r2 value with higuchi equation (r2= 0.958). Hence the release data of the Tablet obeyed higuchi model and release the drug diffusion. Keywords: Cassia tora, mucilage, granules, drug release, polymerÂ

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC

Non-adenine based purines accelerate wound healing

Wound healing is a complex sequence of cellular and molecular processes that involves multiple cell types and biochemical mediators. Several growth factors have been identified that regulate tissue repair, including the neurotrophin nerve growth factor (NGF). As non-adenine based purines (NABPs) are known to promote cell proliferation and the release of growth factors, we investigated whether NABPs had an effect on wound healing. Full-thickness, excisional wound healing in healthy BALB/c mice was significantly accelerated by daily topical application of NABPs such as guanosine (50% closure by days 2.5′.8). Co-treatment of wounds with guanosine plus anti-NGF reversed the guanosine-promoted acceleration of wound healing, indicating that this effect of guanosine is mediated, at least in part, by NGF. Selective inhibitors of the NGF-inducible serine/threonine protein kinase (protein kinase N), such as 6-methylmercaptopurine riboside abolished the acceleration of wound healing caused by guanosine, confirming that activation of this enzyme is required for this effect of guanosine. Treatment of genetically diabetic BKS.Cg-m+/+lepr db mice, which display impaired wound healing, with guanosine led to accelerated healing of skin wounds (25% closure by days 2.8′.0). These results provide further confirmation that the NABP-mediated acceleration of cutaneous wound healing is mediated via an NGF-dependent mechanism. Thus, NABPs may offer an alternative and viable approach for the treatment of wounds in a clinical setting

A Review New Thread Based Wormhole Attack Prevention Mechanism in MANET

ABSTRACT: In this Paper a In wireless networks, security has become the prime factor of concern. The mobility of the nodes, in these so called Mobile Ad hoc Networks (MANETS), furthermore leads to a situation where it is very difficult to establish secure data transmission. Since the use of mobile equipments such as cellular phones or laptops is tremendously increasing and because of limited physical security, vulnerability to attacks, including an attack known as the wormhole attack, has become a challenging work. The wormhole attack is very powerful and preventing the attack has proven to be very difficult [3]. A strategic placement of the wormhole can result in a significant breakdown in communication across a wireless network. This addresses the aforementioned gap by providing a proper definition and categorization of wormhole attacks against MANET by introducing a new cooperative, clock synchronized technique based on Reference Broadcast System (RBS), and discussits effect on network performance. To improve network scalability and throughput, we propose the concept of thread for each and every node of MANET. So that our proposed scheme has three mechanisms namely, AODV (Ad hoc on demand distance vector protocol) for routing, Principle of RBS for threshold setting and ACK, for reliability of communication, are combined to detect and isolate wormhole attacks in ad hoc networks. That manages how the nodes are going to behave and which to route the packets insecured way