An Exploratory, Randomized, Crossover MRI Study of Microbicide Delivery with the SILCS Diaphragm Compared to a Vaginal Applicator

Background—Microbicide gels studied for HIV prevention often are delivered via a single-use vaginal applicator. Using a contraceptive diaphragm such as the SILCS diaphragm for gel delivery could have advantages, including lower cost and additional pregnancy prevention. Study Design—We performed an exploratory, nonblinded, randomized, crossover study among healthy, sexually active, nonpregnant women. Using BufferGel®, we evaluated three microbicide delivery methods for gel distribution and retention: SILCS single-sided gel delivery, SILCS double-sided gel delivery and a vaginal applicator (without SILCS). Magnetic resonance images were taken at baseline, after gel insertion, and immediately and 6 h after simulated intercourse. Three women completed all gel delivery methods described in this article. Results—Magnetic resonance imaging analysis indicated similar gel spread in the vagina among all three methods. SILCS single-sided gel application resulted in the most consistent longitudinal coverage; SILCS double-sided gel application was the most consistent in the transverse dimension. Conclusions—Gel coverage was similar with all three methods. These results suggest that the SILCS microbicide delivery system is comparable to vaginal applicators for delivery of gel products intravaginally

Mucosal Integrity and Inflammatory Markers in the Female Lower Genital Tract as Potential Screening Tools for Vaginal Microbicides

Background—In the female genital tract, vaginal colposcopy, endometrial mucosal integrity and inflammatory mediators are potential in vivo biomarkers of microbicide and contraceptive safety. Study Design—A randomized, blinded crossover trial of 18 subjects comparing effects of Gynol II (putative inflammatory gel), HEC (putative inert gel) and no gel exposure on endometrial and vaginal epithelial integrity and endometrial and vaginal inflammatory markers (IL-1β, IL-6, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α, IL-1RA, IL-10, SLPI). Results—Gynol II was associated with more vaginal lesions. No endometrial disruptions were observed across conditions. In the vagina, RANTES (p=0.055) and IL-6 (p=0.04) were higher after HEC exposure than at baseline. In the endometrium, IL-1β (p=0.003) and IL-8 (p=0.025) were lower after Gynol II cycles than after no gel. Conclusions—Gynol II and HEC may modulate inflammatory markers in the vagina and endometrium. How these changes relate to infection susceptibility warrants further study

Theoretical Engineering of the Gut Micro biome for the Purpose of Creating Superior Soldiers

The purpose of this review is to highlight research raising the possibility of exploiting the host-microbiome gut axis for military purposes. Through optimizing the gut-microbiome environment it is possible to enhance nutritional access to indigestible material, provide local and systemic analgesia, enhance psychological robustness to battlefield stress, produce endogenous steroids, reduce muscle fatigue, and promote peripheral wound healing. However, this approach is still in its early stages and thus has not been explored to its full potential. The challenges that are currently preventing the practical use of gut bacteria include the following: inconsistency of clinical outcomes, transient effects requiring continuous supplementation, the type of regimen selected, the initiation and cessation of regimen, and the broader clinical studies needed to validate this research. This review is intended to shed light on the numerous and varied positive impacts such an approach could have for the military if further developed

Investigating the neuroprotective and anti-epileptogenic mechanisms of inducible nitric oxide synthase and Src family kinase/Fyn inhibitors in experimental models of temporal lobe epilepsy

Epilepsy is a neurological disorder characterized by spontaneous recurrent seizures (SRS) that affects over 65 million people worldwide, making it one of the most common neurological disorder globally. Etiology for epilepsy is unknown, however, gene mutation and exposure to neurotoxins or head trauma can cause seizures predisposing brain to epilepsy. In an acquired experimental models of temporal lobe epilepsy (TLE), epileptogenesis occurs soon after the induction of status epilepticus. We show herein, through the characterization of a mouse kainate model, the classical features of epileptogenesis such as development of SRS and epileptiform spiking patterns to understand neuronal hyper-excitability, and immunohistochemistry (IHC) on brain sections to investigate the mechanisms of neuroinflammation caused by reactive gliosis, synaptic reorganization, and neurodegeneration. These parameters served as a readout for interventional studies in the rat KA model of TLE. An inducible nitric oxide synthase (iNOS) and Src family kinase (SFK) mutually regulate each other’s expression and promote neuroinflammation and neurodegeneration. Therefore, we tested the disease modifying properties of 1400W, an iNOS inhibitor, and Saracatinib (SAR), SFK inhibitor, in our rat model. The results conclusively demonstrated that both 1400W and SAR significantly reduced spike frequency and SRS in 4-6 month of continuous EEG studies when compared to the vehicle-treated group. IHC on brain sections and Western blot results revealed reduced gliosis, serum albumin and neurodegeneration and enhanced Kir4.1 channel levels after 1400W treatment. In addition, SAR decreased translocation of Fyn and PKCδ into the nucleus with diminished expression of TNFα, IL-1β and iNOS mRNA; serum IL-6, IL-12, TNFα, IL-1β levels; and nitro-oxidative stress markers 4-HNE, gp91phox, 3-NT and iNOS in the hippocampus suggesting the role of Fyn as an upstream mediator of neuroinflammation in epileptogenesis. IHC results further revealed a significant reduction in Fyn and PKCδ immunopositive reactive glia and neurons and neurodegeneration in the brain after SAR treatment. In the vehicle treated group, Fyn and PKCδ levels were persistently upregulated during post-SE suggesting that Fyn-PKCδ drives neuroinflammation during epileptogenesis. Collectively, these findings reveal that iNOS and SFK/Fyn are principal mediators of neuroinflammation during epileptogenesis, and are potential therapeutic targets to prevent/treat epilepsy

Investigating the neuroprotective and anti-epileptogenic mechanisms of inducible nitric oxide synthase and Src family kinase/Fyn inhibitors in experimental models of temporal lobe epilepsy

Epilepsy is a neurological disorder characterized by spontaneous recurrent seizures (SRS) that affects over 65 million people worldwide, making it one of the most common neurological disorder globally. Etiology for epilepsy is unknown, however, gene mutation and exposure to neurotoxins or head trauma can cause seizures predisposing brain to epilepsy. In an acquired experimental models of temporal lobe epilepsy (TLE), epileptogenesis occurs soon after the induction of status epilepticus. We show herein, through the characterization of a mouse kainate model, the classical features of epileptogenesis such as development of SRS and epileptiform spiking patterns to understand neuronal hyper-excitability, and immunohistochemistry (IHC) on brain sections to investigate the mechanisms of neuroinflammation caused by reactive gliosis, synaptic reorganization, and neurodegeneration. These parameters served as a readout for interventional studies in the rat KA model of TLE. An inducible nitric oxide synthase (iNOS) and Src family kinase (SFK) mutually regulate each other’s expression and promote neuroinflammation and neurodegeneration. Therefore, we tested the disease modifying properties of 1400W, an iNOS inhibitor, and Saracatinib (SAR), SFK inhibitor, in our rat model. The results conclusively demonstrated that both 1400W and SAR significantly reduced spike frequency and SRS in 4-6 month of continuous EEG studies when compared to the vehicle-treated group. IHC on brain sections and Western blot results revealed reduced gliosis, serum albumin and neurodegeneration and enhanced Kir4.1 channel levels after 1400W treatment. In addition, SAR decreased translocation of Fyn and PKCδ into the nucleus with diminished expression of TNFα, IL-1β and iNOS mRNA; serum IL-6, IL-12, TNFα, IL-1β levels; and nitro-oxidative stress markers 4-HNE, gp91phox, 3-NT and iNOS in the hippocampus suggesting the role of Fyn as an upstream mediator of neuroinflammation in epileptogenesis. IHC results further revealed a significant reduction in Fyn and PKCδ immunopositive reactive glia and neurons and neurodegeneration in the brain after SAR treatment. In the vehicle treated group, Fyn and PKCδ levels were persistently upregulated during post-SE suggesting that Fyn-PKCδ drives neuroinflammation during epileptogenesis. Collectively, these findings reveal that iNOS and SFK/Fyn are principal mediators of neuroinflammation during epileptogenesis, and are potential therapeutic targets to prevent/treat epilepsy.</p

The Ricochet of a Subaltern

<p>This is the story of a young subaltern who saw his battalion divided in half due to partition of the erstwhile British Indian Army, 1947.</p

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan-L trial

Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin. Data from LixiLan-L were used to estimate changes in fasting lipid levels from baseline to week 30, overall and in patients stratified by achievement of glycaemic targets 2-hour postprandial glucose [≤10, &gt;10 mmoL/L], fasting plasma glucose [≤6.1, &gt;6.1 mmoL/L], HbA1c [≤7, &gt;7% (≤53, &gt;53 mmol/mol)]. At week 30, median percentage change in triglycerides remained nearly unchanged (0.3% increase) with iGlarLixi versus a 6.5% increase with iGlar (P = 0.035; overall); similarly, trends towards better total and LDL cholesterol levels were observed with iGlarLixi versus iGlar. In patient subgroups achieving glycaemic targets, all lipid variables except for HDL cholesterol improved with iGlarLixi but not with iGlar. In summary, patients with type 2 diabetes uncontrolled on basal insulin showed improved fasting lipid profiles with iGlarLixi compared with iGlar, particularly when achieving glycaemic targets

COVID-19 Vaccination in Paediatric Population of India: Current Status, Trends, Challenges and Recommendations

Paediatric population is the high-risk segment for the infection of COVID-19 due to weak immune status and low compliance to COVID-19 prevention protocols. The first dose of vaccination for the paediatric population is started in the fifth phase of vaccination, after the vaccination was administered to health workers, elderly individuals, and young adults. Present article aims to analyse the status, trends, and challenges in the implementation of the paediatric vaccination for COVID-19 and provide recommendations that could be taken under consideration by healthcare authorities while designing the second and third vaccination protocols for the paediatric population. Relevant articles published by various journals related to paediatric COVID-19 vaccination were searched from the different databases and analysed for the current status of vaccination, trends, challenges, compliance level, implementation hurdles, and other relevant information. Limited research is available in the paediatric domain for the COVID-19 vaccination. Few vaccines are approved for the paediatric population in India, including the Covaxin, ZyCoV-D, Corbevax and Covovax. It is recommended that the vaccination trials should be accelerated by the government agencies to make COVID vaccines available from other indigenous manufacturers. It is also recommended that the COVID-19 prevention protocol should be made in such a manner that children find that interesting and like to follow them