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Tolvaptan is the first orally active vasopressin receptor 2 antagonist approved by FDA in 2009 for the treatment of clinically significant hypervolemic and euvolemic hyponatremia associated with heart failure, syndrome of inappropriate antidiuretic hormone secretion, liver cirrhosis. Binding of vasopressin to V2 receptors which are located on renal collecting duct cells were competitively inhibited by Tolvaptan thus prevents vasopressin-mediated activation of these receptors and leads to an increase in the water permeability of the collecting duct causing an increase in the concentration of urine, results in an increase in free water clearance, a decrease in urine osmolality and a fall in serum sodium concentration. Tolvaptan is different from other conventional diuretics because it does not stimulate the sodium channel and increases free water excretion without affecting urinary sodium and potassium excretion. It is metabolized principally via the cytochrome P 450 (CYP 3A) isoenzymes and is eliminated by routes other than renal. Concurrent administration of tolvaptan with ketoconazole or other strong CYP 3A inhibitor decrease the total clearance of tolvaptan and increases tolvaptan concentrations. Urine sodium potassium ratio, weight loss, soluble CD14, urinary aquaporin 2 levels are known predictors of tolvaptan response. Tolvaptan is associated with decreased cost and high effectiveness.

BACKGROUND Studies comparing phenylephrine and norepinephrine for the treatment of postspinal hypotension in pre-eclamptic patients are limited. OBJECTIVE To compare bolus doses of phenylephrine and norepinephrine for treating hypotension in pre-eclamptic mothers undergoing caesarean section under spinal anaesthesia. It was hypothesised that norepinephrine and phenylephrine use would be associated with similar neonatal outcome. DESIGN Randomised controlled study. SETTING Single centre, tertiary care, university teaching hospital, from December 2018 to March 2020. PATIENTS A total of 86 women with pre-eclampsia and a singleton pregnancy who developed postspinal hypotension during caesarean section. INTERVENTIONS Patients received intravenous phenylephrine (50 μg) or norepinephrine (4 μg) for treatment of hypotension, defined as a fall in baseline systolic BP by ≥ 20% or an absolute value

Objectives: Breast cancer is the most frequent cancer in women worldwide and it accounts for 27% of all cancer cases among women in India. This study aims to assess the awareness of the patients regarding the breast cancer and also to check their knowledge toward the symptoms of breast cancer as well as the breast self-examination process. This study also determines the attitude of patients regarding the breast cancer and breast self-examination. Methods: A prospective educational study was done using a pre-designed questionnaire on 523 patients in a tertiary care teaching hospital for a period of 6 months. All women greater than 20 years admitted in the Department of General Medicine and General Surgery in-patient female ward of SVRRGGH were included in the study. Results: Out of 523 women, a greater proportion respondents 515 (98%) had poor knowledge of breast cancer. Two hundred and eighty-one (53%) show positive attitude while 225 (43%) show neutral attitude and 17 (4%) show negative attitude toward breast cancer. Only 18 (0.3%) know how to perform breast self-examination while the remaining patients have never performed the breast self-examination. Two hundred and one (38%) have agreed to consult a doctor if they found any lumps in the breast whereas the remaining did not respond. After the counseling session with patients, their knowledge regarding the above problems related to breast cancer has significantly increased. Conclusion: Majority of the participants had poor knowledge of breast cancer as well as low level of practice of breast cancer screening procedures. However, patients do have a positive attitude toward the breast cancer which can help to detect the cancer in early stages. Hence, a greater focus on providing breast cancer education programs can create awareness among women in respect to screening programs which, in turn, can decrease the risk of death due to its late discovery.

Otalgia or ear ache is a symptom which will hamper the daily activities of individual, and a cause of unease or discomfort. There might not be any single individual who has not affected with earache in their lifetime, atleast once in their span of life..Even today there is no specific permanent remedy to this condition in advance modern medical system despite of some Otogesics which will only mask the pain. The common Over the Counter medicines available on medical stores are having side effects on continuous usage. So there is a need for safe Ayurvedic medicine which can acts better like modern analgesics but less side effects. Methodology: In this comparative study of Lasuna putapaka swarasa (Garlic Drops) and Benzocaine Otogesic drops, 40 patients of Otalgia were randomly selected and divided to two groups of 20 patients each. Group A was treated with the ear drops of Lasunaputapaka swarasa (Garlic Drops) and Group B was treated with Benzocaine Otogesic ear drops. Observations: It was observed in the present study that Group A showed better results in reducing the symptoms of Otalgia. Re-occurrence of symptoms were merely less in Group A patients compared to Group B patients. Conclusion: There is a false assumption that Ayurvedic medicines are slow acting and desperately using for pain management and acute conditions. But this study throwing a light to substantiate that, Ayurvedic medicines are potent enough to manage acute otalgia also, just like Otogesics in Modern Medical Science. The study revealed that the re-occurrence rate of symptoms was very less in patients who used Garlic drops and was safe acting also.

Introduction: Shotha1 is the generic name told by Ayurveda Aacharyas correlating to inflammation or oe-dema affecting in any part of the body. Detailed description of anti-inflammatory measures is available in Ayurveda classics to handle such ailments. Ekanga Shopha is explained in Ayurveda Bruhathrayees, as an inflammation in any particular part of the body or organ, Papilledema is also such local inflammation which we can take into consideration as Ekanga Sopha. Papilledema is defined as passive oedema of optic disc in the eyes, secondary to raised intracranial pressure. Its incidence is getting increased day by day due to defective lifestyle and other aetiologies. Objectives: The objectives of this study are to evaluate the effi-cacy of Shodha Chikitsa in the management of papilledema. Methodology: A 64-year-old female patient having symptoms of papiledema selected for the study. By considering the papiledema as Drushti Anthara Sopha or Drishti Nadishotha and adopted the Shobha Chikitsa. The patient underwent with Nasya, Seka, and Thakradhara for 14 days. Punarnavashtaka kashaya, Navayasa choorna, Chandraprabha vati, Sapthamrutha loha given as internal medicine for 2 months. Results: The papilledema got regressed after 2 months of treatments and the patient got continuously monitored for one year and no reoccurrence found. Conclusion: Papilledema is a serious eye ailment which is not having permanent solution in other medical science but can be easily managed with Ayurvedic medicaments. It is the Yukthi of the Vaidya to adopt the treatments like Sothahara Chikitsa etc. to make the patients get recover from ailments like optic disc oede-ma or Papilledema.

Background Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. Methods A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. Results A total of 378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95–18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). Conclusions We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population., We examined acute hepatitis C virus (HCV) incidence in men who have sex with men and living with human immunodeficiency virus between 2013 and 2018 in London and Brighton, United Kingdom. Incidence rates peaked in 2015 at 14.57/1000 person-years of follow-up (95% confidence interval, 10.95 to 18.20). Following this there was a 68% reduction in HCV incidence by 2018, coinciding with wider access to direct-acting antivirals.

Background Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD. Methods and Results Twenty‐two US pediatric institutions participated in a 10‐year review (2008–2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract‐based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community deprivation were obtained. Data for 947 cases showed median age at diagnosis of 9 years; 51% and 56% identified as male and non‐White, respectively. Most (89%) had health insurance and were first diagnosed in the United States (82%). Only 13% reported travel to an endemic region before diagnosis. Although 96% of patients were prescribed secondary prophylaxis, only 58% were prescribed intramuscular benzathine penicillin G. Higher deprivation was associated with increasing disease severity (odds ratio, 1.25; 95% CI, 1.08–1.46). Conclusions The majority of recent US cases of ARF and RHD are endemic rather than the result of foreign exposure. Children who live in more deprived communities are at risk for more severe disease. This study demonstrates a need to improve guideline‐based treatment for ARF/RHD with respect to secondary prophylaxis and to increase research efforts to better understand ARF and RHD in the United States.

Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder which is categorized into congenital, idiopathic and secondary types. There is a marked paucity of literature from the Indian subcontinent that analyses the causation of PAP. Methods: We studied clinical features, histopathological findings and cytological features in 19 bronchoalveolar lavage (BAL) cytology confirmed cases of PAP diagnosed over a 28-year period. Results: One or more risk factors for PAP were noted in 11 cases (57.89%) and included exposure to silica dust, chemicals, smoke and flour, immunological diseases, tuberculosis, retroviral disease and monoclonal gammopathy. Three patients had more than one risk factor. Only one patient was tested for anti-granulocyte-monocyte colony-stimulating-factor (anti-GM-CSF) antibodies. Elevated anti-GM-CSF antibodies and absence of an identifiable risk factor was noted in this patient. Super-infection was noted in three (15.79%); with tuberculosis in two and aspergillosis in one. Six patients had a recent past history of anti-tuberculosis therapy but only one among them had documented acid fast bacilli positivity confirming tuberculosis and autopsy revealed tuberculosis in one patient. Conclusion: The present study observed that a considerable proportion of cases were associated with known risk factors for PAP. A variable relationship of PAP and tuberculosis was observed where the latter was noted as a possible risk factor, a co-existing disease at presentation, a superinfection, or even a possible cause of a misdiagnosis of PAP as tuberculosis. These findings are of great relevance in view of the endemicity of tuberculosis in India.

Total anomalous pulmonary venous return (TAPVR) is a rare congenital cardiac defect, accounting for 1.5-3% of cases of congenital heart disease. With prenatal ultrasonography, the majority of these patients are diagnosed in utero with definitive surgery performed during the neonatal period. However, as prenatal screening may not be available in developing countries, patients may present in later infancy. We present successful surgical repair of a 6-month-old infant with TAPVR who presented for medical care at 5 months of age in Lima, Peru. The late presentation of such infants and the limited resources available for the treatment of elevated pulmonary vascular resistance may impact successful surgical correction of such defects. The perioperative care of such infants in developing countries is discussed and strategies for managing postoperative pulmonary hypertension is reviewed. Cardiol Res. 2018;9(1):53-58 doi: https://doi.org/10.14740/cr651w

Background: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are hematologic malignancies characterized by clonal myeloid expansion in the peripheral blood, bone marrow, and/or other tissues. During the past several years, the number of available FDA approved therapies for AML has dramatically increased, and multiple novel therapies for AML and MDS are in the pipeline. Not all patients will respond to these therapies, and early molecular markers of sensitivity vs resistance could facilitate selection of initial therapies or enable therapeutic pivots and personalization of treatment. Therefore, a sensitive method is required that will enable rapid identification of patients who are likely to benefit (or not benefit) from a therapy. In this study, we explore the feasibility of ex vivo drug screening to predict sensitivity and resistance to chemotherapy and to identify novel synergy between drug classes. Study Rationale: This study will test ex vivo sensitivity to chemotherapies before and during treatment to test the hypotheses that 1) ex vivo sensitivity prior to standard chemotherapy correlates with subsequent clinical outcomes; 2) increased ex vivo resistance following initial exposure to chemotherapy provides greater correlation with early treatment failure and clinical outcomes; 3) whether in vivo chemotherapy exposure leads to changes in ex vivo drug sensitivity and 4) whether patterns of ex vivo drug sensitivity can identify novel drug combinations and predict clinical outcomes. Study Design and Methods: This is a prospective, multi-arm, non-randomized single institution study enrolling subjects with AML and MDS who are anticipating treatment with one of four standard of care regimens (Figure 1). Primary endpoint: Determine whether Day 0 ex vivo drug sensitivity, as measured by a normalized blast count score, correlates with clinical responses for all cohorts. Key Secondary endpoints:Determine whether the drug sensitivity score obtained for Day 0 ex vivo treatments for all cohorts correlates with molecular responses.Determine whether the drug sensitivity score obtained for Day 0 ex vivo treatments for all cohorts correlates with survival.Determine whether an increase in the drug sensitivity score for Day 3 ex vivo sensitivity correlates with reduced clinical outcomes.Determine whether in vivo chemotherapy leads to increased ex vivo sensitivity to any class of drugs in more than 20% of patients treated on any study arm.Determine whether decitabine and azacitidine are associated with overlapping or unique profiles in drug sensitivity changes on Day 5.Determine whether ex vivo drug sensitivity correlates with the presence of clinically available mutations. Key Inclusion Criteria:Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)Peripheral blood blasts > 1%Peripheral white blood cell count > 1,000/μl.Age ≥ 18 yearsAnticipated treatment with any of the regimens in Figure 1ECOG performance status ≤ 3 Key Exclusion CriteriaPrior chemotherapy with hypomethylating agentsMust not have received any chemotherapy within 7 days of enrollment, and any acute treatment-related toxicities must have returned to baseline. Patients may have received hydrea, but must discontinue at the time of enrollment. Prior TKI therapy is allowed, but must be discontinued within 3 days of baseline blood collection.Currently receiving any other investigational agents. Statistical Methods: Clinical responses for AML will be assessed according to the 2017 ELN AML Recommendations. For MDS, clinical responses will be assessed for response according to the 2006 IWG criteria. Descriptive statistics will be used to summarize baseline patient characteristics, therapies, clinical outcomes, and collection of biospecimens. Hierarchical clustering using Euclidean distance metrics and Ward minimum variance will be used to identify patient clusters with distinct ex vivo drug sensitivity patterns within a particular treatment cohort. For the primary endpoint, the correlation between clinical response and drug sensitivity will be assessed using the area under the receiver-operator curve (AUROC) and bootstrapping to test for significance. A generalized estimation equation model will be used to identify associations between mutations and ex vivo sensitivity to various drug classes within specific treatment cohorts. Figure Disclosures Welch: Agios: Membership on an entity's Board of Directors or advisory committees; Janssen research: Research Funding; ArcherDx: Membership on an entity's Board of Directors or advisory committees; Notable labs: Research Funding. Richardson:Notable Labs: Current Employment, Current equity holder in private company. Kita:Notable Labs: Current Employment, Current equity holder in private company. Wen:Notable Labs: Current Employment, Current equity holder in private company. Tada:Notable Labs: Current Employment, Current equity holder in private company.

We present a non-arteritic anterior ischemic optic neuropathy (NAION) with unknown cause, but good recovery after the management with antiplatelet therapy in a 45-year-old male patient who came to the hospital with complaints of sudden painless loss of vision.

The paper aims developing a computational framework of signaling using the principles of biochemical systems theory as a model for Parkinson’s disease. Several molecular interactions aided by TNFα, a proinflammatory cytokine play key roles in mediating glutamate excitotoxicity and neuroinflammation, resulting in neuronal cell death. In this paper, initial concentrations and rate constants were extracted from literature and simulations developed were based on systems of ordinary differential equations following first-order kinetics. In control or healthy conditions, a decrease in TNFα and neuronal cell death was predicted in simulations matching data from experiments, whereas in diseased condition, a drastic increase in levels of TNFα, glutamate, TNFR1 and ROS were observed similar to experimental data correlating diseased condition to augmented neuronal cell death. The study suggests toxic effects induced by TNFα in the substantia nigra may be attributed to Parkinson’s disease conditions.

Fatigue is common during physical activity and can have an effect on ankle biomechanics during different actions, such as a jump. Yet current research on the topic is very heterogeneous and hinders clarity on what changes are actually due to fatigue. Therefore, the aim of this review was to summarise and analyse the current literature that investigates the effects of fatigue on ankle biomechanics during a jump. Searches were conducted in five databases and studies with activities eliciting fatigue and comparing outcomes under a fatigue and non-fatigue conditions were selected. Twelve studies were included, six analysed double legged jumps and six single legged jump. When comparing ankle biomechanics between a fatigued condition and a non-fatigued condition, findings suggested that at initial contact at landing, dorsiflexion increased in single legged jump and plantarflexion increased in double legged jump; at maximum knee flexion after landing, dorsiflexion decreased in double legged jumps and plantarflexion increased at full foot contact in single legged jumps. Also, ankle power (for double legged jump) and ground reaction force (for double and single legged jump) reduced at initial contact to maximum knee flexion at landing after fatigue and ankle power also reduced at takeoff in single legged jumps. The current review shows that fatigue affect ankle biomechanics by reducing dorsiflexion, from initial contact to maximum knee flexion at landing, and power during the jump takeoff. Such information could have implications for injury prevention.

The ability to tune cellular functions in response to nutrient availability has important consequences for immune homeostasis. The activity of the receptor Notch in regulatory T (Treg) cells, which suppress the functions of effector T cells, is indispensable for Treg cell survival under conditions of diminished nutrient supply. Anti-apoptotic signaling induced by the Notch1 intracellular domain (NIC) originates from the cytoplasm and is spatially decoupled from the nuclear, largely transcriptional functions of NIC. We showed that Sirtuin 1 (Sirt1), which is an NAD+ (nicotinamide adenine dinucleotide)-dependent lysine deacetylase that inhibits NIC-dependent gene transcription, stabilized NIC proximal to the plasma membrane to promote the survival and function of activated Treg cells. Sirt1 was required for NIC-dependent protection from apoptosis in cell lines but not for the activity of the anti-apoptotic protein Bcl-xL. In addition, a variant NIC protein in which four lysines were mutated to arginines (NIC4KR) retained anti-apoptotic activity, but was not regulated by Sirt1, and reconstituted the functions of nonnuclear NIC in Notch1-deficient Treg cells. Loss of Sirt1 compromised Treg cell survival, resulting in antigen-induced T cell proliferation and inflammation in two mouse models. Thus, the Sirt1-Notch interaction may constitute an important checkpoint that tunes noncanonical Notch1 signaling.

Increasing use of the new oral anticoagulants (NOACs) – dabigatran, rivaroxaban, and apixaban – has prompted considerable discussion in the medical community even as warfarin remains the mainstay of therapy. This article raises 10 controversial issues regarding the use of NOACs for stroke prevention in patients with atrial fibrillation, and offers a review of the latest available evidence. We provide a brief overview of the mechanism and dosing of these drugs, as well as a summary of the key clinical trials that have brought them into the spotlight. Comparative considerations relative to warfarin such as NOAC safety, efficacy, bleeding risk, reversibility, drug-transitioning and use in patients well controlled on warfarin are addressed. Use in select populations such as the elderly, those with coronary disease, renal impairment, or on multiple anti-platelet drugs is also discussed. Finally, we consider such specific issues as comparative efficacy, off-label use, cost, rebound and management during events. Ultimately, the rise of the NOACs to mainstream use will depend on further data and clinical experience amongst the medical community.

Polycystic ovary syndrome (PCOS) is the most common metabolic abnormality occurring in young women of reproductive age. Low vitamin D levels were found to be associated with the development of obesity and insulin resistance in young women with PCOS. The study was conducted as a prospective observational study involving 121 women with PCOS. The diagnosis of PCOS cases were based on the revised Rotterdam consensus criteria. Vitamin D levels were compared in the obese and non obese PCOS groups and also with the controls. In the PCOS group, sixty subjects were obese with BMI of ≥25 kg/m 2 and forty seven subjects were found to be non obese. In the control group, sixteen subjects were obese and sixty five subjects were non obese. The mean vitamin D level in the PCOS group was 15.45±7.88 ng/ml and in the control group was 12.83±5.76ng/ml. The mean vitamin D levels in the obese and non obese group with PCOS were 16.11±8.9ng/ml and 14.61±6.1ng/ml respectively. Majority of the patients and controls had vitamin D deficiency and there was no difference in the vitamin D levels in PCOS group and controls as well as obese and non obese groups.

Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established.We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations.

Background: Assessing disparity in IQ is important in selecting an occupation and thus helping people lead a productive life. In Turner syndrome patients, this shall be more important as assessment of verbal IQ- and performance IQ disparity could be used in helping them select an occupation so that productivity and quality of life is not grossly compromised. Methods: Based on karyotyping, 30 patients with turner syndrome and 30 patients with primary amenorrhoea due to other aetiologies were selected for the study. Cytogenetic analysis was done for every case using G-banding technique. Assessment of intellectual functions was done using Wechsler Adult Intelligence Scale (WAIS). Results: Mean value of PIQ of X0 (turner) was 74.67 and that of XX (other amenorrhoea patients) was 90.30. Mean value of VIQ of X0 (turner) was 93.67 and that of XX (other amenorrhoea patients) was 93.60. Mean value of VIQ and PIQ disparity of X0 (turner) was 18.67 and that of XX (other amenorrhoea patients) was 3. Conclusions: Turner syndrome patients have high VIQ-PIQ disparity when compared to other primary amenorrhoea patients.

With limited regenerative capacity and most complex structural and electrophysiological properties; recapitulating the cardiac tissue is a challenging task for the researchers. The cell injection was found unreliable due to the cell loss and low retention of the transplanted cells. This could be overcome by the technique of cell sheet engineering. Scaffold free, thick, cell dense, three dimensional constructs could be generated for suture free transplantation. For the generation of the cardiac constructs the neonatal cardiomyocytes and myoblasts were mostly used. They were tedious to isolate and culture and the risk of arrhythmogenic foci prevailed. Hence the concept of differentiating a suitable allogeneic cell source to myocardial lineage seemed relevant. Human umbilical cord mesenchymal stem cells (hUCMSCs) are emerging with the assistance of differentiating agents and cell sheet engineering for addressing the cardiac regeneration. The preliminary report on this regard has been published. The cells attained cardiomyocyte-like morphology with the expression of alpha-actinin and myosin heavy chain on culturing with cardiac conditioned medium and the inducer sphingosine-1-phosphate. It presented cardiomyocyte-like action potential and voltage gated currents. Hence the cell sheet engineering approach with cells differentiated to cardiac lineage using specific agents is a recent area to be explored.

OBJECTIVE: The posterior most among the paranasal sinuses, the sphenoid sinuses exhibit high variability in their structure, pneumatisation and relation to surrounding neurovascular structures. The protrusion of optic nerve (ON) into the superolateral wall of the sinus has been reported in literature wit h varied incidence. The pneumatisation of sphenoid sinus and its extension to anterior clinoid process (ACP) is also been mentioned in few studies. The variability in the incidence and the inconsistency in the association between optic nerve protrusion and degree of pneumatisation seen in studies done in different ethnicity and with paucity of Indian studies necessitated this study on positional variation of optic nerve in relation to sphenoid sinuses and its association with pneumatisation of anterior clin oid process in South Indian ethnicity. THE METHODS: CT scan images in coronal section collected from 114 patients with sinusitis with in the age group of 16 - 64 years belonging to both sexes were studied. The CT images were evaluated for the position of ON with sphenoid sinuses, protrusion of it into the sinus walls, bony dehiscence, pneumatisation of ACP. The position of ON was classified into Delano’s four types and their incidence noted. RESULTS: Type 1 position of ON was observed predominantly in 65.8% s ides while Type 2, 3, 4 were seen in 29.8%, 1.8% and 2.6% sides respectively out of 228 sides studied. Associated bony dehiscence was noted in only 5 out of 228sides (2.1%) studied. The pneumatisation of ACP was observed in 23.6% of the CT scans studied. T he association between ON protrusion and ACP pneumatisation was found to be statistically significant with P= 0.008 . CONCLUSION: The varying position of ON, its protrusion with or without dehiscence in to the sphenoid sinus wall with statistically signific ant association with ACP pneumatisation in south Indian ethnicity warrants a systematic CT evaluation pre operatively to ensure efficient surgery with minimal complications.

To highlight an uncommon bone malignancy, which presented to our institute, as a neck swelling in the supraclavicular region. A 30 year old man presented with history of swelling on the left side of neck since 1 year and numbness of left upper limb since 6 months. Magnetic Resonance Imaging of the Cervical spine & MR Angiography showed a 7.4 × 4.6 cm expansile lesion involving transverse process of C5-C7 vertebrae. As the tumour was found to be deep to the phrenic nerve & brachial plexus, a dual approach was used, anteriorly via neck incision and posteriorly via the spine. The tumour was resected & iliac crest grafted along with stabilization of the cervical spine. Patient is disease free and the cervical spine stabilized with normal movements at two and half years follow up. We need to consider tumour arising from the vertebra as a differential diagnosis for any deep seated hard neck swelling in the supraclavicular region. Even low grade malignancy of this region when resected en-bloc will have a good prognosis.

Tissue homeostasis is a dynamic process involving proliferation and the removal of redundant or damaged cells. This is exemplified in the coordinated deletion - triggered by limiting trophic factors/cytokines in the extracellular milieu - of differentiated T cells overproduced during the mammalian immune response. However, mechanisms by which extracellular cues are perceived and transduced as apoptotic triggers remain incompletely understood. T-effectors are dependent on cytokines for survival and undergo apoptosis following cytokine withdrawal. Here we report that leptomycin B (LMB), an inhibitor of nuclear export machinery, protected T-effectors from apoptosis implicating a nuclear intermediate in the apoptotic pathway. Evidence is presented that the linker histone H1.2 localizes to the cytoplasm, by a mechanism sensitive to regulation by LMB, to activate apoptotic signaling culminating in nuclear and mitochondrial damage in T-effectors in response to cytokine deprivation. H1.2 is detected in a complex with the proapoptotic mitochondrial resident Bak and its subcellular localization regulated by Jun-N-terminal kinase (JNK), an intermediate in the apoptotic cascade in T-effectors. These data suggest that metabolic stressors may impinge on H1.2 dynamics favoring its activity at the mitochondrion, thereby functioning as a molecular switch for T-effector apoptosis. � 2014 Megha Garg et al.

Epigenetic modifications represent a promising new approach to modulate cell functions as observed in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that has been observed with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is α-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM respectively. Additionally, Tubastatin inhibited nitric oxide (NO) secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 μM and induced α-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw volume at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clinical scores (~70%) by Tubastatin was confirmed histopathologically and was found comparable to dexamethasone (~90% inhibition of clinical scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin.

In this work, Hemigraphis alternata extract incorporated chitosan scaffold was synthesized and characterized for wound healing. The antibacterial activity of Hemigraphis incorporated chitosan scaffold (HIC) against Escherichia coli and Staphylococcus aureus was evaluated which showed a reduction in total colony forming units by 45-folds toward E. coli and 25-fold against S. aureus respectively. Cell viability studies using Human Dermal Fibroblast cells (HDF) showed 90% viability even at 48 h when compared to the chitosan control. The herbal scaffold made from chitosan was highly haemostatic and antibacterial. The obtained results were in support that the herbal scaffold can be effectively applied for infectious wounds.

Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor-dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (T(regs)) in vitro and in vivo and was compromised by T cell-specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1(-/-) T(regs) from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin complex 2 (mTORC2) for this cell survival function. Biochemical and imaging approaches revealed a membrane-proximal complex containing NICD and the mTORC2 component Rictor, and this complex was stabilized by specific interactions with the Notch ligand Delta-like-1 and mediated the survival of T(regs). Together, our evidence for the spatial control of Notch and the crosstalk of Notch signaling with other pathways reveals coupling between the localization of Notch and diverse intracellular signaling pathways.

Cellular differentiation programs are accompanied by large-scale changes in nuclear organization and gene expression. In this context, accompanying transitions in chromatin assembly that facilitates changes in gene expression and cell behavior in a developmental system are poorly understood. Here, we address this gap and map structural changes in chromatin organization during murine T-cell development, to describe an unusual heterogeneity in chromatin organization and associated functional correlates in T-cell lineage. Confocal imaging of DNA assembly in cells isolated from bone marrow, thymus and spleen reveal the emergence of heterogeneous patterns in DNA organization in mature T-cells following their exit from the thymus. The central DNA pattern dominated in immature precursor cells in the thymus whereas both central and peripheral DNA patterns were observed in naïve and memory cells in circulation. Naïve T-cells with central DNA patterns exhibited higher mechanical pliability in response to compressive loads in vitro and transmigration assays in vivo, and demonstrated accelerated expression of activation-induced marker CD69. T-cell activation was characterized by marked redistribution of DNA assembly to a central DNA pattern and increased nuclear size. Notably, heterogeneity in DNA patterns recovered in cells induced into quiescence in culture, suggesting an internal regulatory mechanism for chromatin reorganization. Taken together, our results uncover an important component of plasticity in nuclear organization, reflected in chromatin assembly, during T-cell development, differentiation and transmigration.

BACKGROUND: Both type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes. METHODS: We studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations. RESULTS: Significant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups. CONCLUSIONS: Our data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease.

Effects of methanolic extract of root bark of Beli (Aegle marmelos Corr.), an Ayurvedic crude drug used for heart diseases, and constituents isolated from the extract on spontaneous beating of cultured mouse myocardial cells were examined. The extract at a concentration of 100 micrograms/ml inhibited the beating rate by approximately 50%. Among the isolated constituents, aurapten was the most potent inhibitor; the IC50 of aurapten is 0.6 microgram/ml, which is comparable with that of verapamil, a calcium antagonist. Addition of aurapten at concentrations higher than 1 microgram/ml significantly reduced the ratio of morphologically changed myocardial cells which originated from calcium overload caused by successive treatment with calcium-free and calcium-containing solutions.

Voriconazole is the second oral drug licensed for the treatment of aspergillosis. A retrospective non-comparative study was conducted in 16 patients with chronic cavitary pulmonary aspergillosis (CCPA) treated with voriconazole. All patients had failed or were intolerant of itraconazole. The duration of therapy varied from 3 days to 16.5 months. Eleven patients received at least 3 months of therapy with no significant adverse events. Overall seven (64%) patients had a response at 3 months as assessed by at least some fall in inflammatory markers, weight gain and reduction in pulmonary symptoms and two (18%) remained stable. Inflammatory markers improved in 5/11 (46%) with a mean fall in CRP of 0.08 mg/l and ESR of 12.8 mm/h. Aspergillus precipitins were quantitated by numbers of arcs and serum dilution and 11 (100%) showed improvement of at least one band or fall of titre. Total serum IgE was elevated (>200 IU/mL) in 5/11, and fell by a median of 118 kIU/l. Two patients failed therapy. Of the 17 patients, five (27%) had to discontinue therapy as a result of adverse events (three in under 1 week). Adverse events included erythematous rash (5), headaches (4), hepatotoxicity (3), photosensitive rash (3), retinal flashes (3) and neurological symptoms (3). Voriconazole is a useful alternative therapy for CCPA, with a response rate of 64%, over 3 months, and continuing partial remission of disease for much longer periods. © 2005 The British Infection Society.

Background & objectives: Plasma amino acid levels are known to be altered in conditions like sepsis and burns which are situations of metabolic stress. Polycystic ovary syndrome (PCOS), a condition which affects a woman throughout her life, is said to be associated with metabolic stress. This study was undertaken to assess if there were significant alterations in the levels of plasma amino acids in women with PCOS. Methods: Sixty five women with PCOS along with the similar number of age matched normal controls were included in this study. Levels of 14 amino acids were determined using reverse phase high performance liquid chromatography. Results: The levels of methionine, cystine, isoleucine, phenylalanine, valine, tyrosine, proline, glycine, lysine and histidine were found to be significantly (P