Reducing the Gap in Knowledge and Expectations between Clinicians and People with Polycystic Ovary Syndrome or Adrenal Conditions: Simulation via Instant Messaging-Birmingham Advance: Patient and Public Involvement (SIMBA-PPI) Study.

BACKGROUND: To evaluate the efficacy of SIMBA as an educational intervention for both HCPs and people with either PCOS or adrenal conditions and to study the change in knowledge of people with PCOS or adrenal conditions about the conditions and expectations from the HCPs involved in their care following SIMBA-PPI sessions. METHODS: Two SIMBA-PPI sessions (SIMBA-PPI Polycystic ovary syndrome (SIMBA-PCOS) and SIMBA-PPI Adrenal conditions (SIMBA-Adrenal conditions)) were conducted in September 2021 and March 2022. In both sessions, HCPs interacted with moderators on patient management through WhatsApp. Patients with respective conditions underwent workshop-style learning in the same cases. SIMBA-PCOS transcripts were also translated into Brazilian Portuguese and workshops were held in both Brazilian Portuguese and English. The two groups (HCPs and patients) were then brought together to discuss exploring gaps in knowledge and expectations. The Wilcoxon Signed-Rank test compared differences in pre- and post-SIMBA self-reported confidence levels in HCPs and patients. Qualitative data from the online recordings were transcribed and analysed with inductive thematic analysis to identify gaps in knowledge and expectations from managing the cases. RESULTS: 48 HCPs and 25 patients participated in our study. When compared to pre-SIMBA confidence levels, SIMBA-PPI sessions effectively improved clinicians' confidence in managing PCOS (40.5%, p < .001) and adrenal conditions (23.0%, p < .001) post-SIMBA. Patient participants' confidence in HCPs significantly increased in the PCOS session (SIMBA-PCOS: 6.25%, p = 0.01). CONCLUSIONS: Integration of PPI into SIMBA improved HCPs' confidence in managing PCOS and adrenal conditions. SIMBA-PPI also improved patients' confidence in HCPs. Our findings suggest that participating in SIMBA-PPI sessions can reduce the gap in knowledge and expectations between patients and HCPs involved in their care.

Cytokeratin (CK5, CK8, CK14) expression and presence of progenitor stem cells in human fetal thymuses.

The aim of the current study was to observe the expression of cytokeratins in human fetal thymuses. Specific cytokeratin markers in adult humans and mice have been well described but there has been little similar work on human fetuses. We also aimed to see whether progenitor stem cells that could be harvested to treat various immunodeficiency disorders are present in fetal thymic tissue. Thymuses obtained from 30 aborted human fetuses (12 to 31 weeks) were examined immunohistochemically to investigate changes in cytokeratin expression in the epithelial cells (TEC) at various gestational ages. Before 16 weeks of gestation, cortical (cTEC) and medullary (mTEC) TEC exhibited homogenous staining for cytokeratins CK8 and CK5. After 16 weeks there was differential staining, with cTEC positive for CK8 and mTEC for CK5 and CK14. Interestingly, both CK5 + CK8+ progenitor stem cells were present in the fetal thymic cortex at all gestational ages, with a relatively high number from 12 to 16 weeks. Cytokeratin expression in fetal thymuses was quite different from that in the adult thymus owing to the presence of undifferentiated progenitor stem cells in fetal thymic stroma along with differentiated TEC. The best time to harvest these progenitor stem cells from fetal thymic stroma in order to treat various immune deficiency disorders appears to be 12-16 weeks. Clin. Anat. 29:711-717, 2016. © 2016 Wiley Periodicals, Inc.

Superficial upper limb vasculature and its surgical implications.

Any kind of anatomical variation whether encountered during cadaveric dissections or routine clinical or surgical procedures needs to be reported and taken into account. This can be quite helpful in planning surgeries accordingly and avoid disastrous complications. During routine cadaveric dissection, authors found a superficial course of arteries of the arm as well as the forearm, unilaterally in one cadaver. In this case, there were two brachial arteries - superficial and deep. Superficial brachial artery terminated into superficial radial and superficial ulnar artery. Deep brachial artery was trifurcated into common interosseous, medial and lateral artery branches. Authors have also discussed the developmental anomaly, which could have led to the observed morphological variation. Superficial vessels can provide large size pedicles for raising flaps for local reconstructive surgeries in the region of axilla, elbow, wrist or hand, or other regions.

Anatomical study of the infraorbital foramen: A basis for successful infraorbital nerve block.

Detailed knowledge of variations of the infraorbital foramen (IOF) and the establishment of a constant reference point for needle insertion are important for safe and successful regional block and for avoiding iatrogenic injury to the nerve during surgery in the midfacial region. Infraorbital foramina from 133 sides of 67 dry intact adult skulls of undetermined gender were examined for variations in shape, number, location in relation to bony landmarks, and relationship to the maxillary teeth. The angles of needle insertion in the sagittal and Frankfurt planes were determined. The infraorbital foramina were located at an average distance of 6.33 ± 1.39 mm below the infraorbital margin, 25.69 ± 2.37 mm from the median plane, 15.19 ± 1.70 mm from the lateral margin of the piriform aperture, and 28.41 ± 2.82 mm above the maxillary alveolar border. The average angles of needle insertion through the IOF with the sagittal and Frankfurt planes were 21.14° ± 10.10° and 31.79° ± 7.68°, respectively. Multiple foramina were found in 21% of the hemi-skulls. The foramen was less than 2 mm in size in 23.31% of the hemi-skulls. The position of the IOF with respect to the maxillary teeth varied from the interval between the canine and first premolar to the first molar, but in half of the specimens it lay in line with the second maxillary premolar tooth. The observations made in this study should be useful for planning infraorbital nerve block or surgery around the IOF.

Drug therapy in stroke: from preclinical to clinical studies.

BACKGROUND: Stroke is one of the major challenges to health and the reason for increasing disability-adjusted life years. Despite tremendous progress in preclinical studies, none of the treatment options has proven efficacious in clinical studies. The basic aim of neuroprotection is to interfere with the events of the ischemic cascade, halt the pathological processes and prevent the death of vulnerable nerve cells in the ischemic penumbra. SUMMARY: This review will provide a brief overview of the current understanding of stroke, including the global epidemiology of stroke, its pathophysiology, the targeting of specific pathways and the success and failure of preclinical as well as clinical studies, and it will discuss the emerging targets for novel therapeutic strategies under investigation. KEY MESSAGES: New advancing investigational drugs for the prevention and treatment of stroke are on the way and may someday give hope to neuroscientists and clinicians. A novel approach should adopt preclinical testing, advance the understanding of the pathophysiology of stroke and make it possible to translate it from bench to bedside. We should learn from the past failures and move on with more enthusiasm.

Neurological manifestations of SARS-CoV-2: complexity, mechanism and associated disorders.

BACKGROUND: Coronaviruses such as Severe Acute Respiratory Syndrome coronavirus (SARS), Middle Eastern Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are associated with critical illnesses, including severe respiratory disorders. SARS-CoV-2 is the causative agent of the deadly COVID-19 illness, which has spread globally as a pandemic. SARS-CoV-2 may enter the human body through olfactory lobes and interact with the angiotensin-converting enzyme2 (ACE2) receptor, further facilitating cell binding and entry into the cells. Reports have shown that the virus can pass through the blood-brain barrier (BBB) and enter the central nervous system (CNS), resulting in various disorders. Cell entry by SARS-CoV-2 largely relies on TMPRSS2 and cathepsin L, which activate S protein. TMPRSS2 is found on the cell surface of respiratory, gastrointestinal and urogenital epithelium, while cathepsin-L is a part of endosomes. AIM: The current review aims to provide information on how SARS-CoV-2 infection affects brain function.. Furthermore, CNS disorders associated with SARS-CoV-2 infection, including ischemic stroke, cerebral venous thrombosis, Guillain-Barré syndrome, multiple sclerosis, meningitis, and encephalitis, are discussed. The many probable mechanisms and paths involved in developing cerebrovascular problems in COVID patients are thoroughly detailed. MAIN BODY: There have been reports that the SARS-CoV-2 virus can cross the blood-brain barrier (BBB) and enter the central nervous system (CNS), where it could cause a various illnesses. Patients suffering from COVID-19 experience a range of neurological complications, including sleep disorders, viral encephalitis, headaches, dysgeusia, and cognitive impairment. The presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of COVID-19 patients has been reported. Health experts also reported its presence in cortical neurons and human brain organoids. The possible mechanism of virus infiltration into the brain can be neurotropic, direct infiltration and cytokine storm-based pathways. The olfactory lobes could also be the primary pathway for the entrance of SARS-CoV-2 into the brain. CONCLUSIONS: SARS-CoV-2 can lead to neurological complications, such as cerebrovascular manifestations, motor movement complications, and cognitive decline. COVID-19 infection can result in cerebrovascular symptoms and diseases, such as strokes and thrombosis. The virus can affect the neural system, disrupt cognitive function and cause neurological disorders. To combat the epidemic, it is crucial to repurpose drugs currently in use quickly and develop novel therapeutics.

Screening of potential inhibitors against structural proteins from Monkeypox and related viruses of Poxviridae family via docking and molecular dynamics simulation.

Monkeypox virus (MPXV) is an orthopoxvirus which causes zoonotic infection in humans. Even though sporadic cases of this infection are limited to the African continent, but if the infection continues to increase unabated, it can be a cause of serious concern for the human populace. Smallpox vaccination has been in use against monkeypox infection but it only provides mild protection. In the current study, we have screened novel small molecules (estrone fused heterocycles (EH1-EH7)) exhibiting good binding with monkeypox virus protein and related proteins from Poxviridae family of viruses via computational approaches. EH1-7 series of small molecules selected for the work have been synthesized via cycloaddition methodology. Docking and Molecular Dynamics (MD) results highlight EH4 compound to have strong binding affinity towards monkeypox and other related viral proteins selected for the study. Thus, computational outcomes suggest EH4 as a good candidate against monkeypox. Currently, no antiviral medication has been approved against monkeypox and the treatment is only via therapeutics available for smallpox and related conditions that may be helpful against monkeypox. Our study is thus an attempt to screen novel compounds against monkeypox infection, which would, in turn, facilitate development of novel therapeutics against Poxviridae family. HIGHLIGHTSMonkeypox infection is a public health emergency and necessitates immediate drug discovery.Molecular docking study to screen estrone-fused heterocycles compounds against Monkeypox and other orthopoxviruses.Molecular dynamics simulations revealed interaction/high binding affinities among EH4 heterocyclic compound and profilin-like protein from the monkeypox virus.Estrone-fused heterocycles compounds are promising anti-viral agents as per our in silico analysis.Our study provides evidence for investigating estrone-fused heterocycles compounds for further pharmacological interventions.Communicated by Ramaswamy H. Sarma.

Monkeypox: This orthopoxvirus leads to mpox (monkeypox) disease which shows symptoms similar to that smallpox, however to less severe extent.Poxviridae family: This is commonly a family of double-stranded DNA viruses. The natural hosts for these viruses are arthropods and Vertebrates.Molecular Dynamic simulation: MD simulation is crucial for determining the ligand's stability and revealing the duration of its interaction with the respective macromolecular structure.Molecular Docking: Molecular docking aids in determining specific sites where the ligand binds with the macromolecule as well as its binding affinity. Bioinformatics tools such as docking have been widely employed for aiding drug discovery efforts.Protein binding energy: On docking protein with the ligand, the binding energy shows the free energy change during binding process between protein-ligand.

A rare anatomical variation of the brachial plexus: single cord anomaly.

Anatomical variations of the brachial plexus may be important in regional anesthesia and upper limb procedures. A fused single cord of the brachial plexus, although considered rare, was discovered in 4 Indian male cadavers during the dissection of 90 brachial plexuses. All 4 cases demonstrated deviation from the usual pattern starting at the division of trunks continuing to the formation of cords. The location of these single cords was lateral to the axillary artery instead of the typical perivascular relationship. A fused single cord of brachial plexus might be more common than previously thought. The impact on the performance or success of blockade remains unknown.

The caudal space in fetuses: an anatomical study.

PURPOSE: The caudal epidural space is a popular site for analgesia in pediatrics. High variation in blind needle placement is common during caudal epidurals, increasing the risk of intravascular and intrathecal spread. Knowledge of safe distances and angles for accessing the caudal epidural space in premature infants can improve the safety of caudal epidural blocks. METHODS: Thirty-nine fetuses with crown-heel length between 33 and 50 cm, corresponding to gestational age of 7-9 months, were included. The dorsal surface of the sacrum from the fourth lumbar vertebra to the tip of the coccyx was dissected, following which measurements were taken on dorsal surface and midsagittal sections. The angle of depression of the needle was measured using a goniometer following the two-step method of needle insertion. RESULTS: Right and left sacral cornua were palpable in 23 of 39 fetuses (58.97%). Termination of dural sac was at S2 in most of the fetuses (53.84%), whereas the apex of the sacral hiatus was at S3 in most (58.97%). The distance from the apex of the hiatus to the termination of dura ranged from 3 to 13 mm; the anteroposterior distance of the canal at the apex of the hiatus ranged from 1.72 to 4.38 mm. All sacral parameters correlated with crown-heel length except inter-cornual distance, depth of canal at hiatus, and height of sacral hiatus. CONCLUSION: Distances and angles for accessing the caudal epidural space in fetuses do not provide all parameters for safe performance of caudal epidural blocks in premature and low birth weight infants because the apex of the sacral hiatus and the termination of the dura show wide variation in location.

Anatomical considerations for safe scapular resection in snapping scapula syndrome.

BACKGROUND: The resection of the superomedial angle of the scapula in snapping scapula syndrome is associated with potential risk of injury to the suprascapular nerve. The aim of the present study was to determine the distance of site of resection on the upper border of the scapula from the suprascapular notch during arthroscopic resection of the superomedial angle using standard superior Bell's and medial portals at the middle of medial border. MATERIALS AND METHODS: The study was conducted on 92 intact dry adult scapulae of unknown sex. The junction of the medial two-thirds and the lateral one-third of an imaginary line joining the superomedial angle and the lateral margin of the acromion was marked as superior Bell's portal. The middle of the medial border was considered as the arthroscopic resection target. The site of resection on the upper border was found out with the help of these two points and other relevant measurements were also taken. RESULTS: The distance between the suprascapular notch and the lateral edge of resection on the upper border of the scapula was more than 10 mm in 85.9% cases and less than 10 mm in 14.1%. A statistically significant positive correlation was found between this distance and the distance between the superior angle and acromion angle of the scapula. CONCLUSION: Our study suggests that during arthroscopic resection using superior Bell's portal and medial portal, suprascapular notch hence the suprascapular nerve would have safe margin of more than 10 mm from the resection site on upper border in 85.9% cases and would be vulnerable to injury in 14% cases. The procedure would be safer in patients with a wider scapula.

Repurposing chia seed oil: A versatile novel functional food.

Chia seed oil (CSO) has been recently gaining tremendous interest as a functional food. The oil is rich in with polyunsaturated fatty acids (PUFAs), especially, alpha linolenic acid (ALA), linoleic acid (LA), tocopherols, phenolic acids, vitamins, and antioxidants. Extracting CSO through green technologies has been highly efficient, cost-effective, and sustainable, which has also shown to improve its nutritional potential and proved to be eco-friendly than any other traditional or conventional processes. Due to the presence of valuable bioactive metabolites, CSO is proving to be a revolutionary source for food, baking, dairy, pharmaceutical, livestock feed, and cosmetic industries. CSO has been reported to possess antidiabetic, anticancer, anti-inflammatory, antiobesity, antioxidant, antihyperlipidemic, insect-repellent, and skin-healing properties. However, studies on toxicological safety and commercial potency of CSO are limited and therefore the need of the hour is to focus on large-scale molecular mechanistic and clinical studies, which may throw light on the possible translational opportunities of CSO to be utilized to its complete potential. In this review, we have deliberated on the untapped therapeutical possibilities and novel findings about this functional food, its biochemical composition, extraction methods, nutritional profiling, oil stability, and nutraceutical and pharmaceutical applications for its health benefits and ability to counter various diseases.

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia.

CONTEXT: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged. OBJECTIVE: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice. MATERIALS AND METHODS: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT(1/2) blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE. RESULTS AND DISCUSSION: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE. CONCLUSION: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.

Anatomic consideration of caudal epidural space: a cadaver study.

The knowledge of sacral hiatus anatomy is imperative in clinical situations requiring caudal epidural block for various diagnostic and therapeutic procedures of the lumbosacral spine to avoid failure and dural injury. In this study, a detailed anatomic study of the sacral region was carried out on 49 male adult Indian cadavers. Dorsal surface of sacral region was dissected to study sacral cornua, sacral hiatus, and the dimensions of triangle formed by the right and left posterosuperior iliac spines with apex of the hiatus. Midsagittal sections were subjected for various anatomical measurements. The angle of needle insertion and the depth of caudal space were noted. Cornu was not palpable bilaterally in 7 (14.3%) and palpable unilaterally in 12 (24.5%) specimens. Mean (standard deviation) distance between apex of hiatus and coccyx tip was 57.5 (8.7) mm and length of sacrococcygeal ligament was 34.2 (7.4) mm. The dimensions of the triangle were found to be interchangeable in 25 cadavers. Once the needle is introduced into the canal after penetrating the sacrococcygeal ligament, it should not be advanced >5 mm to prevent dural puncture. The level of maximum curvature of sacrum was S3 in 34 (69.4%) of cases. The dural sac was found to terminate at S2 in 41 (83.6%). The mean (SD) angle of depression of the needle was 65.7 (5.5) (range 58-78). The measurements described for the identification of the sacral hiatus, optimal angle of depression, and depth of the needle may improve the safety and reliability of a caudal epidural block.

A New Therapeutic Approach for Brain Delivery of Epigallocatechin Gallate: Development and Characterization Studies.

BACKGROUND: Blood-brain permeability is the primary concern when dealing with the biodistribution of drugs to the brain in neurological diseases. OBJECTIVE: The purpose of the study is to develop the nanoformulation of Epigallocatechin gallate (EGCG) in order to improve its bioavailability and penetration into the brain. METHODS: EGCG loaded Solid Lipid Nanoparticles (SLNs) have been developed using microemulsification method and pharmacological assessments were performed. RESULTS: Surface morphology and micromeritics analysis showed the successful development of EGCG loaded solid lipid nanoparticles with an average size of 162.4 nm and spherical in shape. In vitro release studies indicated a consistent and slow drug release. Pharmacological evaluation of SLN-EGCG demonstrated a significant improvement in cerebral ischemia-induced memory impairment. CONCLUSION: The results indicate that the EGCG loaded SLNs provide a potential drug delivery system for improved delivery of EGCG to the brain, hence, enhancing its brain bioavailability.

Association of Adiponectin with Lung Function Impairment and Disease Severity in Chronic Obstructive Pulmonary Disease.

CONTEXT: Chronic obstructive pulmonary disease (COPD) is not only restricted to the pulmonary inflammation and airway obstruction but is also associated with comorbidities, which affect the therapeutic intervention and the quality of life and survival. Markers that can predict the systemic inflammation and a decline in the pulmonary function are of scientific interest. Adiponectin (APN) appears to be one such biomarker and can be used as a potential indicator of severity and response to treatment in patients of COPD. AIMS: The study aims to find out the role of APN as a marker of inflammation in the pathogenesis of COPD and explore its relationship with the severity of the disease. SETTINGS AND DESIGN: This was a cross-sectional study. SUBJECTS AND METHODS: The study group consisted of 60 patients of COPD, which included 30 males admitted with acute exacerbation of COPD (AECOPD) and 30 males with stable COPD. The study group was compared with 30 healthy, age-matched males. APN was estimated by commercially available ELISA kits. Pulmonary function tests were performed on all cases and controls using standardized protocols on SPIROLAB III. STATISTICAL ANALYSIS USED: Statistical analysis was performed using Student's t-test and Pearson's correlation coefficient. RESULTS: The levels of APN were found to be significantly higher in patients with COPD as compared to the controls and the levels increased with the severity of the disease were 16.10 ± 4.97 ng/ml and 11.43 ± 4.22 ng/ml, respectively, in AECOPD and COPD. A significant positive correlation was found between the levels of APN and interleukin (IL)-8 in patients of COPD, while the levels correlated negatively with percentage of forced expiratory volume in 1 s (FEV1%). CONCLUSIONS: The results reveal that APN is associated with the inflammatory process of COPD as suggested by its significant inverse relationship with FEV1% and positive correlation with a marker of inflammation such as IL-8. It can thus be used as a biomarker for disease severity and progression in patients of COPD, therefore aiding in risk stratification and therapeutic intervention.

Geochemical and geostatistical appraisal of fluoride contamination: An insight into the Quaternary aquifer.

Fluoride (F-) in groundwater poses a severe public health threat in the Dwarka River Basin (DRB) of West Bengal, India, where many cases of fluorosis have been reported. This research evaluates the spatial distribution patterns of major cations and anions, delineates zones of high F- concentrations within alluvial sediments of the DRB, and identifies both the sources and the geochemical processes responsible for the release of F- to groundwater. A total of 607 groundwater samples were collected from shallow and deep tube wells located within the DRB, encompassing an area of 435 km2 and including 211 villages. Fluoride levels range from 0.01 to 10.6 mg/L, and high concentrations (>1.5 mg/L) are restricted to isolated areas within the basin (occurring within nine of the villages and comprising 4.3% of the samples collected). The high-fluoride areas are characterized by mostly Na-HCO3 type groundwater, where the abundance of cations and anions are Na+ > Ca2+ > Mg2+ > K+ and HCO3- > Cl- > SO42- > F- > NO3- > Br-, respectively. Analyses of the groundwater geochemistry and sediment mineralogy suggest that fluoride is released to groundwater primarily through the hydrolysis of albite and biotite; however, the resulting alkaline conditions are also favorable for release of fluoride from weathered biotite and clay minerals through anion exchange (OH- in groundwater replacing F- within the mineral structure). Multiple linear regression models show that fluoride concentrations can be predicted from the measures of other dissolved constituents with a high degree of accuracy (R2 = 0.96 for high fluoride samples and R2 = 0.8 for low fluoride samples).

Quantitative model of Ras-phosphoinositide 3-kinase signalling cross-talk based on co-operative molecular assembly.

In growth-factor-stimulated signal transduction, cell-surface receptors recruit PI3Ks (phosphoinositide 3-kinases) and Ras-specific GEFs (guanine nucleotide-exchange factors) to the plasma membrane, where they produce 3'-phosphorylated phosphoinositide lipids and Ras-GTP respectively. As a direct example of pathway networking, Ras-GTP also recruits and activates PI3Ks. To refine the mechanism of Ras-PI3K cross-talk and analyse its quantitative implications, we offer a theoretical model describing the assembly of complexes involving receptors, PI3K and Ras-GTP. While the model poses the possibility that a ternary receptor-PI3K-Ras complex forms in two steps, it also encompasses the possibility that receptor-PI3K and Ras-PI3K interactions are competitive. In support of this analysis, experiments with platelet-derived growth factor-stimulated fibroblasts revealed that Ras apparently enhances the affinity of PI3K for receptors; in the context of the model, this suggests that a ternary complex does indeed form, with the second step greatly enhanced through membrane localization and possibly allosteric effects. The apparent contribution of Ras to PI3K activation depends strongly on the quantities and binding affinities of the interacting molecules, which vary across different cell types and stimuli, and thus the model could be used to predict conditions under which PI3K signalling is sensitive to interventions targeting Ras.

Antiepileptic drugs in development pipeline: A recent update.

Epilepsy is the most common neurological disorder which significantly affects the quality of life and poses a health as well as economic burden on society. Epilepsy affects approximately 70 million people in the world. The present article reviews the scientific rationale, brief pathophysiology of epilepsy and newer antiepileptic drugs which are presently under clinical development. We have searched the investigational drugs using the key words 'antiepileptic drugs,' 'epilepsy,' 'Phase I,' 'Phase II' and 'Phase III' in American clinical trial registers (clinicaltrials.gov), the relevant published articles using National Library of Medicine's PubMed database, company websites and supplemented results with a manual search of cross-references and conference abstracts. This review provides a brief description about the antiepileptic drugs which are targeting different mechanisms and the clinical development status of these drugs. Besides the presence of old as well as new AEDs, still there is a need of new drugs or the modified version of old drugs in order to make affected people free of seizures. An optimistic approach should be used to translate the success of preclinical testing to clinical practice. There is an urgent need to improve animal models and to explore new targets with better understanding in order to develop the novel drugs with more efficacy and safety.

Long-term effect of tobacco on unstimulated salivary pH.

AIMS AND OBJECTIVES: The aim of this study was to analyze and compare the effects of tobacco on salivary pH between tobacco chewers, smokers and controls. MATERIALS AND METHODS: A total of 60 subjects (males and females) aged 25-40 years, were divided equally into three groups: Tobacco smokers (Group A), chewers (Group B) and controls (Group C). Saliva of each subject was collected under resting condition. Salivary pH was determined using the specific salivary pH meter. RESULTS: The mean (±standard deviation) pH for Group A was 6.75 (±0.11), Group B was 6.5 (±0.29) and Group C was 7.00 (±0.28) after comparison. The significant results showed lower salivary pH in Groups A and B as compared to controls. Salivary pH was lowest in Group B compared to Group A and Group C. CONCLUSION: This study indicates that a lower (acidic) salivary pH was observed in tobacco users as compared with control. These alterations in pH due to the long-term effect of tobacco use can render oral mucosa vulnerable to various oral and dental diseases.

Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates.

BACKGROUND: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD). OBJECTIVE: Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here. METHODS: PMOs were administered once-weekly by bolus intravenous (IV) injections to male NHPs. Endpoints evaluated included plasma exposures, clinical observations, body weight/food consumption, eye exams, electrocardiograms, male reproductive hormones/endpoints, complement alternative pathway, clinical pathology, urinalysis, and macroscopic/light microscopic pathology. RESULTS: Findings in these studies were limited to the kidneys, with a common presentation of tubular basophilia, vacuolation, and/or minimal degeneration that was considered non-adverse. No necrosis, glomerular lesions, or effects on renal function tests such as serum creatinine or urea nitrogen were observed, suggesting that PMO-related kidney findings are not likely to develop into frank nephrotoxicity. There were no adverse effects on other potential target organs after repeated IV injections at the highest dose levels tested, 320 mg/kg. CONCLUSIONS: Nonclinical results in NHPs for these three PMOs, together with the excellent clinical safety established for eteplirsen to date, suggest that once-weekly IV administration of PMOs for lifetime durations at therapeutic doses will be well tolerated by patients with DMD.