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As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach.A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members.Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition.

Background: In India, asthma imposes a substantial burden; though the disease still remains under-recognized, underestimated and under-treated in masses.With a global need of promoting rational drug use in healthcare, drug utilization pattern studies could provide feedback to prescribers and help in fostering rational drug usage. The present study was planned to study the drug utilization pattern in patients of asthma in a tertiary care set-up in eastern India and to evaluate it with respect to GINA guidelines. Materials and Methods: The study was carried out over a period of one year where cases with confirmed diagnosis of asthma, who gave informed consent to participate were included.Drug usage pattern was determined in the light of drugs prescribed, mean drugs per prescription, percentage of drugs prescribed in generic name and having conformation to national essential drug list. Percentage of inhalational, injectable, fixed dose combination and antibiotics per prescription were noted. Data were checked for completeness and statistically analysed. Results: The present study included 370 participants. A total of 1514 drugs were prescribed, with 4.09 drugs per prescription. 12.55% of drugs prescribed were from national essential drug list. A total of 1031 anti-asthma drugs were prescribed with 2.8 anti-asthma drugs per prescription. Among the various classes of anti-asthma drugs, maximum prescribed were inhalational corticosteroids, followed by long acting inhalational beta 2 agonist and anti-leukotriene drugs. 96.5% of total patients were on inhalational drugs, with budesonide and formeterol being majorly prescribed. Conclusion: The usage pattern as assessed in our study was in conformation to GINA guidelines. Guidelines like GINA have enlightened physicians about the rational prescribing in asthmatic patients.

Aim:To study the difference in clinical presentation, baseline laboratory parameters, radiological parameters, CSF picture, response to treatment, in-hospital outcome, nal outcome in follow up & any parameters signifying poor outcome in advance in patients of TBM both in HIV+ve& HIVve group. Material and methods:This comparative non-randomised prospective study was conducted from 16th June,2012 to 15th June,2013 in Medical College Hospital. Total 53 patients were referred where 23 patients had TB Meningitis with HIVand 30 patients had TB Meningitis without HIV. Result: In our study we have found no statistically signicant differences in age distribution, and distribution of symptoms at presentation. The classical symptoms like fever, headache, and vomiting, altered sensorium all are present in both groups and the differences are not statistically signicant. Conclusion:HIV+ve patients show relatively less intense reduction of CSF sugar level in relation to blood sugar level estimated simultaneously.Two factors with high mortality are advanced stage of TB meningitis at presentation, low CD4 count.

The molecular regulation of Sertoli cells and their crosstalk with germ cells has not been fully characterized. SUMO proteins are essential for normal development and are expressed in mouse and human Sertoli cells; However, the cell-specific role of sumoylation in those cells has only started to be elucidated. In other cell types, including granulosa cells, sumoylation is regulated by a SUMO ligase KAP1/Trim28. Deletion of KAP1 in Sertoli cells causes testicular degeneration; However, the role of KAP1 in those cells has not been identified. Here we show that both mouse and human Sertoli undergo apoptosis upon inhibition of sumoylation with a chemical inhibitor or via a siRNA technology. We have additionally detected changes in the Sertoli cell proteome upon the inhibition of sumoylation, and our data suggest that among others, the expression of ER/stress-related proteins is highly affected by this inhibition. Sumoylation may also regulate the NOTCH signaling which is important for the maintenance of the developing germ cells. Furthermore, we show that a siRNA-down-regulation of KAP1 in a Sertoli-derived cell line causes an almost complete inactivation of sumoylation. In conclusion, sumoylation regulates important survival and signaling pathways in Sertoli cells, and KAP1 can be a major regulator of sumoylation in these cells.

Aims: 1 Describe the epidemiology and determine risk factors for COVID-19 associated mucormycosis. 2 Elaborate the clinical spectrum of Rhino-Orbital-Cerebral Mucormycosis (ROCM), pattern of neuroaxis involvement and it's radiological correlates. Methods Observational study. Consecutive, confirmed cases of mucormycosis (N = 55) were included. A case of mucormycosis was defined as one who had clinical and radiological features consistent with mucormycosis along with demonstration of the fungus in tissue via KOH mount/culture/histopathological examination (HPE). Data pertaining to epidemiology, risk factors, clinico-radiological features were analysed using percentage of total cases. Results Middle aged, diabetic males with recent COVID-19 infection were most affected. New onset upper jaw toothache was a striking observation in several cases. Among neurological manifestations headache, proptosis, vision loss, extraocular movement restriction; cavernous sinus, meningeal and parenchymal involvement were common. Stroke in ROCM followed a definitive pattern with watershed infarction. Conclusions New onset upper jaw toothache and loosening of teeth should prompt an immediate search for mucormycosis in backdrop of diabetic patients with recent COVID-19 disease, aiding earlier diagnosis and treatment initiation. Neuroaxis involvement was characterized by a multitude of features pertaining to involvement of optic nerve, extraocular muscles, meninges, brain parenchyma and internal carotid artery.

Persistent hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms that establish CHC and cause its subsequent development into LC and HCC are poorly understood. We have identified a cytoplasmic double-stranded RNA binding protein, Stau1, which is crucial for HCV replication. In this study, Stau1 specifically interacted with the variable-stem-loop region in the 3′ NTR and domain IIId of the HCV-IRES in the 5′ NTR, and promoted HCV replication and translation. Stau1 coimmunoprecipitates HCV NS5B and a cell factor, protein kinase R (PKR), which is critical for interferon-induced cellular antiviral and antiproliferative responses. Like Stau1, PKR displayed binding specificity to domain IIId of HCV-IRES. Stau1 binds to PKR and strongly inhibits PKR-autophosphorylation. We demonstrated that the transport of HCV RNA on the polysomes is Stau1-dependent, being mainly localized in the monosome fractions when Stau1 is downregulated and exclusively localized in the polysomes when Stau1 is overexpressed. Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR-mediated inhibition of eIF2α, which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication.

Introduction: Contrast enhanced computed tomography (CECT) thorax & Fibre Optic Bronchoscopy (FOB) are main investigations in patients of hemoptysis with normal chest X-ray. But there are limited data on their diagnostic yield especially from South East Asia. Methods : An observational study on 60 patients with hemoptysis with normal chest X -ray was conducted from April 2012 to April 2014. CECT thorax and FOB were done in all of them. Results : Out of 60 patients 38 (63.3%) were male with even age distribution. Yield of CECT was 40% (24 patients) and main diagnosis were bronchiectesis (25%) and tuberculosis (11.6%). Diagnostic yield of FOB was 47% (28 patients) with predominant diagnosis of tuberculosis (18.33%), bronchitis (18.33%) and bronchogenic carcinoma (6.66%). Overall diagnostic yield was 76.6% (46 cases). Bronchogenic carcinoma cases were all male smokers and 3 of them were more than 40 years old. Conclusion : CECT thorax and FOB are complimentary to each other in evaluation of hemoptysis with normal chest x-ray. Bronchogenic carcinoma and tuberculosis cases require specific treatment and they were diagnosed in confirm way only by FOB. So, FOB have advantage over CT scan, especially among patients with increased risk of bronchogenic carcinoma (male-smokers with age > 40 years).

Context: Hyponatraemia is one of the common electrolytic disorders which are associated with lung cancer. Hyponatraemia may influence the ECOG performance status at presentation. Also, to the best of our knowledge, we found only limited Indian studies where the ECOG score was correlated with the serum sodium status in lung cancer patients on presentation. Aim: To assess the incidence of hyponatraemia among the patients of carcinoma of the lung before putting them into the specific treatment category for cancer and to check the effects on their ECOG performance status. Settings and Design: A cross–sectional, observational study was conducted on 116 consecutive patients of lung cancer during the period from November 2011 to October 2012. Material and Methods: The patients with a histologically proven diagnosis of lung cancer were grouped initially according to their ECOG performance statuses. The serum sodium value of each patient was measured and the hyponatraemic patients were given treatment according to the protocol. The correlation of the ECOG performance status with the serum sodium of the lung cancer patients was measured. To check for any laboratory error in serum sodium, we selected (n = 58) age, sex and socioeconomic matched control patients. Results: At presentation 44.8% of the lung cancer patients showed hyponatraemia [52/116]. The ECOG score was significantly poor in the advanced clinical stages (ECOG ≤2 Vs ECOG ≥ 3 in NSCLC cases, χ2 =11.25, P=.0008). The ECOG performance status score at admission showed a negative correlation with the serum sodium status which was measured on admission among all the patients (Pearson correlation coefficient = – 0.186). The clinical stage of the lung cancer also showed a positive correlation with the ECOG score at admission in our study (Pearson correlation coefficient = 0.295). Conclusion: Hyponatraemia is not an uncommon condition and it should be suspected and screened in each patient, as it may influence the ECOG performance status score, which serves as an important factor in the prognosis of lung cancer.

Background: Stroke accounts as one of the leading cause of morbidity and mortality and third most common cause of death worldwide. In a significant percentage of stroke patients no definite cause can be identified. These group of unknown cause, the so-called ‘cryptogenic strokes’ are associated with some novel risk factors and now a major focus for clinical discussion. Objectives: To find out conventional risk factors behind ischemic stroke and to establish correlation between ischemic stroke with elevated lipoprotein(a), Homocysteinemia, elevated High-sensitivity C-reactive protein (hs CRP),Systemic Lupus Erythematous (SLE) and chronic H.pylori infection and carotid intimo-medial thickness(CIMT). Materials and methods: Thirty (30) admitted ischemic stroke patients based on WHO definition and confirmed by axial CT and or MRI Scan. were included. Thirty (30) controls were recruited from close relatives of the patients attending the Medicine OPD without any prior history of stroke or coronary heart diseases. Risk factors were documented on the basis of biochemical tests performed. Results : Statistically significant association of ischaemic stroke with diabetes,hypertension, smoking, homocysteine, Lp(a), hsCRP, LVH, CIMT,H.pylori infection. No association of valvular heart disease, atrial fibrillation, A.N.A was found with ischaemic stroke. Conclusion: In addition to measures that include blood sugar, blood pressure and lipid control routine estimation of Lp(a), homocysteine level, monitoring of atherosclerotic changes in carotid artery by Doppler study, echocardiographic monitoring of LVH should be done so that appropriate steps can be taken to avert an attack of stroke. Lastly early detection and eradication of H.pylori is always advisable to reduce the incidence of ischemic stroke. DOI: http://dx.doi.org/10.3329/jom.v14i1.13165 J MEDICINE 2013; 14 : 11-17

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant inherited disorder of the vascular system. It can be asymptomatic but when symptomatic most common presentation being epistaxis. It can involve any organs of the body like lungs, skin, liver brain, GI mucosa etc. We are reporting a case of HHT presented to us with dyspnea and severe anemia. He had arteriovenous malformations of different visceral organs and telangiectasia of skin along with presence of similar history in first-degree relatives.

Chronic arsenic exposure causes cutaneous effects like hyperkeratosis, peripheral vascular disease, hypertension, ischemic heart disease, non-cirrhotic portal hypertension, hepatomegaly, peripheral neuropathy, respiratory involvement, bad obstetrical outcome, hematological disturbances, and diabetes mellitus. Here we present a case of a 24-year-old lady, with chronic exposure to arsenic, presenting to us with progressive dyspnea. We found pulmonary arterial hypertension (PAH) as a cause of her dyspnea. PAH can occur in arsenicosis, secondary to arsenic-induced chronic obstructive pulmonary disease (COPD), lung fibrosis, and portal hypertension, which we excluded by appropriate investigations in our case. We also excluded a familial or heritable form of PAH. Thus, with the exclusion of all these secondary causes of PAH, as well as a hereditary cause, we came to a conclusion that this PAH might be due to chronic arsenic exposure. To the best of our knowledge, no case of PAH in chronic arsenicosis has been reported to date.

Introduction: Cytokine profiles of peripheral blood and cerebrospinal fluid (CSF) are used to predict stroke outcomes. Yet, the cytokine profiles of some patients do not match the predicted outcomes. Hypothesis: We hypothesize that peripheral blood is not an accurate resource for cytokine profiling because the supply of cytokines in the blood and CSF is unknown. Specifically, we postulate that cytokine profiling from a resource that is local to the stroke site is a more accurate method for predicting stroke outcomes. In this study, we collected thrombi from thrombectomy procedures performed on stroke patients who presented to our university affiliated comprehensive stroke center and examined the presence of TNF-alpha. Methods: This study was approved by the IRB at our university affiliated comprehensive stroke center. All samples were collected with the consent of the donor. Thrombi were collected from stroke patients that underwent thrombectomies at our university affiliated comprehensive stroke center. Thrombi were placed in a lysis buffer containing protease inhibitors. Thrombi were stored at 4C in the neurointerventional lab for a maximum of 12 hrs. Thrombi were then frozen at -80C for long-term preservation. For controls, blood was collected from healthy volunteers. Blood was allowed to coagulate for 30 mins at room temperature to form a clot. The formed clot was then put in lysis buffer for 1 hr. Thrombi lysis from patients and healthy volunteers were subjected to Western bloting. Results: A total of 10 patients participated, clots were extracted within 8 hours of stroke onset in all. Ten healthy volunteers served as controls. Western Blot showed that TNF-alpha is detected in clots extracted from stroke patients that underwent thrombectomies, but not in clots formulated from healthy volunteers. Conclusion: Our results show that it is feasible to extract thrombi for cytokine profiling. TNF-alpha was elevated in thrombectomy-extracted clots and TNF-alpha was not detected in healthy volunteers. Our results suggest that proinflammatory cytokines are within the stroke area and our method is a feasible method for cytokine detection. In future studies, we will correlate cytokine quantity with NIHSS.

Given the widespread use of insecticides in the environment, it is important to perform studies evaluating their potential effects on humans. Organophosphate insecticides, such as chlorpyrifos, are being phased out; however, the use of pyrethroids in household pest control is increasing. While chlorpyrifos is relatively well studied, much less is known about the potential neurotoxicity of cyfluthrin and other pyrethroids. To gain insights into the neurotoxicity of cyfluthrin, we compared and evaluated the toxicity profiles of chlorpyrifos and cyfluthrin in primary human fetal astrocytes. We found that at the same concentrations, cyfluthrin exerts as great as, or greater toxic effects on the growth, survival, and proper functioning of human astrocytes. By using microarray gene expression profiling, we systematically identified and compared the potential molecular targets of chlorpyrifos and cyfluthrin, at a genome-wide scale. We found that chlorpyrifos and cyfluthrin affect a similar number of transcripts. These targets include molecular chaperones, signal transducers, transcriptional regulators, transporters, and those involved in behavior and development. Further computational and biochemical analyses show that cyfluthrin and chlorpyrifos upregulate certain targets of the interferon-gamma and insulin-signaling pathways and that they increase the protein levels of activated extracellular signal-regulated kinase 1/2, a key component of insulin signaling; interleukin 6, a key inflammatory mediator; and glial fibrillary acidic protein, a marker of inflammatory astrocyte activation. These results suggest that inflammatory activation of astrocytes might be an important mechanism underlying neurotoxicity of both chlorpyrifos and cyfluthrin.

Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes.

Hamartoma is one of the common benign tumor of lung. These lesions represent an abnormal proliferation and mixing of the normal components of the lung tissue. Most hamartomas are asymptomatic. We report a rare case of giant pulmonary hamartoma (12 cm in diameter) occupied almost whole of left hemithorax. Computed tomography guided fine-needle aspiration cytology revealed a benign cartilaginous neoplasm, suggestive of chondroid hamartoma. Tru-cut biopsy of the tumor confirmed the diagnosis. Complete resection of the tumor was performed. Patient was on a regular follow-up postoperatively for 6 months without any clinical and radiological relapse.

Antitubercular drug (ATD) induced eosinophilic lung disease is a rare phenomenon. It usually occurs due to isoniazid and para amino salicylic acid. A 34-year-male of sputum positive pulmonary tuberculosis, on antitubercular drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide) for last 3 weeks, presented with generalized arthralgia and maculopapular rash for last 2 weeks and shortness of breath for last 1 week. Chest X-ray and High resolution computerized tomographic scan thorax showed bilateral peripheral airspace opacification. Bronchoalveolar lavage revealed 51% eosinophils of total cellularity (1200/cmm) confirming the diagnosis of pulmonary eosinophilia. ATD was stopped for 2 weeks and then reintroduced one by one. Patient again developed similar kind of symptoms with reintroduction of ethambutol. According to criteria for drug induced pulmonary eosinophilia, he was diagnosed as a case of ethambutol induced pulmonary eosinophilia.

The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment.

Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, reduces the clinical deterioration in moderate-to-severe Alzheimer disease (AD) for which other treatments are not available. The activity of protein phosphatase (PP)-2A is compromised in AD brain and is believed to be a cause of the abnormal hyperphosphorylation of tau and the consequent neurofibrillary degeneration. Here we show that memantine inhibits and reverses the PP-2A inhibition-induced abnormal hyperphosphorylation and accumulation of tau in organotypic culture of rat hippocampal slices. Such restorative effects of memantine were not detected either with 5,7-dichlorokynurenic acid or with d(−)-2-amino-5-phosphopentanoic acid, NMDA receptor antagonists active at the glycine binding site and at the glutamate binding site, respectively. These findings show (1) that memantine inhibits and reverses the PP-2A inhibition-induced abnormal hyperphosphorylation of tau/neurofibrillary degeneration and (2) that this drug might be useful for the treatment of AD and related tauopathies.

Clinical data show that disease adversely affects tissue elasticity or stiffness. While macrophage activity plays a critical role in driving disease pathology, there are limited data available on the effects of tissue stiffness on macrophage activity. In this study, the effects of substrate stiffness on inflammatory mediator production by macrophages were investigated. Bone marrow-derived macrophages were grown on polyacrylamide gels that mimicked the stiffness of a variety of soft biological tissues. Overall, macrophages grown on soft substrates produced less proinflammatory mediators than macrophages grown on stiff substrates when the endotoxin LPS was added to media. In addition, the pathways involved in stiffness-regulated proinflammation were investigated. The TLR4 signaling pathway was examined by evaluating TLR4, p-NF-κB p65, MyD88, and p-IκBα expression as well as p-NF-κB p65 translocation. Expression and translocation of the various signaling molecules were higher in macrophages grown on stiff substrates than on soft substrates. Furthermore, TLR4 knockout experiments showed that TLR4 activity enhanced proinflammation on stiff substrates. In conclusion, these results suggest that proinflammatory mediator production initiated by TLR4 is mechanically regulated in macrophages.

A young lady presented with cough for three months and dyspnoea for one month along with clinical signs of bilateral consolidation of lung. On CT scan thorax there were bilateral air bronchograms with alveolar filling opacities predominantly in lower lobes. After bronchoscopy when there was presence of suspicious malignant cells on bronchoalveolar lavage fluid, transbronchial lung biopsy diagnosed the case as squamous cell lung cancer. Radiological presentation of squamous cell lung cancer as air bronchogram is not a very common phenomenon and can present a diagnostic challenge to the clinician.

Tau protein from Alzheimer disease (AD) brain is hyperphosphorylated by both proline-dependent protein kinases (PDPKs) and non-PDPKs. It is presently unclear how PDPKs and non-PDPKs interact in tau hyperphosphorylation. Previously we have shown that non-PDPKs can positively modulate the activity of a PDPK (GSK-3) in tau phosphorylation (Singh et al. (1995) FEBS Lett. 358, 267-272). In this study we have investigated whether (A) non-PDPKs can also modulate the activity of the PDPK, cdk5, (B) a PDPK can modulate the activities of another PDPK, as well as non-PDPKs. We found that, like GSK-3, the activity of cdk5 is stimulated if tau were first prephosphorylated by any of several non-PDPKs (A-kinase, C-kinase, CK-1, CaM-kinase II). Prephosphorylation of tau by cdk5 stimulated both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3. Under these conditions thr 231 phosphorylation was especially enhanced (9-fold). No significant stimulation of phosphorylation was obser ved when the order of these kinases was reversed (i.e. GSK-3 followed by cdk5). By contrast, prephosphorylation of tau by cdk5 served to inhibit subsequent phosphorylation catalyzed by C-kinase and CK-1, but not by A-kinase or CaM-kinase II. Our results suggest that in tau hyperphosphorylation in AD brain, cdk5-catalyzed phosphorylation may serve to up-regulate the activity of GSK-3 and down-regulate the activities of C-kinase and CK-1. (Mol Cell Biochem 167: 99-105, 1997)

The 6-min walk test (6MWT) is a simple, inexpensive test of functional exercise capacity. The 6MWT distance (6MWD) in healthy adults varies geographically, emphasizing the need for population-specific reference equations. The purpose of the present study was to investigate the influences of the habitual physical activity (HPA) score and other anthropometric and demographic parameters on the variability of the 6MWD among healthy adults and to propose a reference equation.This was a prospective, cross-sectional, observational study. The 6MWT was conducted in a 30-m hospital corridor on 201 healthy volunteers, 125 men and 76 women, aged 20-60 years. The HPA in the previous 6 months was assessed using Baecke's questionnaire. Univariate analysis followed by multiple regression analysis was performed to analyze the significance levels of different probable predictors.The 6MWD was significantly greater in more active than in less active subjects (663.8±55.4m vs. 599.9±67.8m, p0.001). The regression analysis showed that the subject's age in years (p=0.017), gender (p=0.006), height in cm (p=0.004), weight in kg (p0.001), total activity score (TS) (p0.001), and absolute difference in heart rate before and after exercise (p0.001) could explain 48.9% of the variability in the 6MWD in healthy adults.The HPA score is probably the most appropriate variable to include in the reference equation predicting the 6MWD in healthy adults from the Indian subcontinent.

The neurotransmitter dopamine (DA) is known to inhibit prolactin (PRL) secretion and the proliferation of lactotropes in the pituitary gland. Dopamine-2 (D2) receptor short (D2S) isoform is expressed in a reduced level while the D2 receptor long (D2L) isoform is expressed in an elevated level during estradiol (E2)-induced PRL production and cell proliferation in lactotropes. To evaluate the role of these D2 receptor isoforms in E2-regulated lactotropic cell function, we compared E2effects on the level of PRL, cell proliferation, and G proteins in enriched lactotropes and lactotrope-derived PR1 cells containing only D2S isoform (D2S cells), D2L isoform (D2L cells), or no D2 receptor (V cells). Additionally, we determined the effects of G protein blockade on the E2-induced PRL production and cell proliferation in these cells. We here show that E2actions on G proteins, PRL production, and cell proliferation were maximally achieved in D2S cells, oppositely or marginally achieved in D2L cells, and absent in V cells. We also show that the DA and pertussis toxin modulations of E2actions on PRL, G proteins, and cell proliferation were maximally achieved in D2S cells compared with in D2L or V cells. Furthermore, we provide evidence for the existence of an inhibitory action of Gi3 on Gs that is under the control of the D2S receptor and is inhibited by E2. These results suggest that the suppression of D2S-regulated Gi3 inhibition of Gs protein may be one of the mechanisms controlling E2-activated PRL synthesis and cell proliferation in lactotropes.

In developing country like India arsenic poisoning is a major public health problem. Association of chronic eosinophilic pneumonia and chronic diarrhea with arsenicosis is rare. Also pulmonary cavity formation in chronic eosinophilic pneumonia is very uncommon. A 44-year-old male patient, resident of an arsenic affected area was admitted for evaluation of chronic diarrhoea, persistent peripheral eosinophilia along with radiologically visible cavity in right upper zone. There were dermatological manifestations of arsenicosis along with presence of noncirrhotic portal fibrosis and peripheral eosinophilia. On bronchoalveolar lavage study, eosinophil comprised 40% of total cellularity making the diagnosis of chronic eosinophilic pneumonia. After ruling out all possible causes of diarrhoea and chronic eosinophilic pneumonia, we came to conclusion that arsenic could be implicated as causative agent. Keywords: Arsenicosis, chronic diarrhoea, chronic eosinophilic pneumonia, noncirrhotic portal fibrosis.

In the natural killer (NK) cells, δ-opiate receptor (DOR) and μ-opioid receptor (MOR) interact in a feedback manner to regulate cytolytic function with an unknown mechanism. Using RNK16 cells, a rat NK cell line, we show that MOR and DOR monomer and dimer proteins existed in these cells and that chronic treatment with a receptor antagonist reduced protein levels of the targeted receptor but increased levels of opposing receptor monomer and homodimer. The opposing receptor-enhancing effects of MOR and DOR antagonists were abolished following receptor gene knockdown by siRNA. Ethanol treatment increased MOR and DOR heterodimers while it decreased the cellular levels of MOR and DOR monomers and homodimers. The opioid receptor homodimerization was associated with an increased receptor binding, and heterodimerization was associated with a decreased receptor binding and the production of cytotoxic factors. Similarly, in vivo, opioid receptor dimerization, ligand binding of receptors, and cell function in immune cells were promoted by chronic treatment with an opiate antagonist but suppressed by chronic ethanol feeding. Additionally, a combined treatment of an MOR antagonist and a DOR agonist was able to reverse the immune suppressive effect of ethanol and reduce the growth and progression of mammary tumors in rats. These data identify a role of receptor dimerization in the mechanism of DOR and MOR feedback interaction in NK cells, and they further elucidate the potential for the use of a combined opioid antagonist and agonist therapy for the treatment of immune incompetence and cancer and alcohol-related diseases.

Microtubule associated protein tau is abnormally hyperphosphorylated in Alzheimer disease (AD) brain. To investigate the role of protein kinases involved in this lesion, metabolically active slices made from brains of adult rats were treated with or without various specific kinase activators in oxygenated artificial cerebrospinal fluid. The basal kinase activities of protein kinase-A (PKA), CaM Kinase II and GSK-3 were stimulated more than two-fold by isoproterenol, bradykinin and wortmannin, respectively. We found that cdk5 activity was co-stimulated with PKA by isoproterenol. Sequential activation of PKA (+cdk5), CaM Kinase II and GSK-3 produced hyperphosphorylation of tau at Ser-198/Ser-199/Ser-202, Ser-214, Thr-231/Ser-235, Ser-262, Ser-396/Ser-404 and Ser-422 sites. Like AD P-tau, the P-tau from brain slices bound to normal tau and its binding to tubulin was inhibited. These studies suggest that PKA, cdk5, CaM Kinase II and GSK-3 are involved in the regulation of phosphorylation of tau and that AD-type phosphorylation of tau is probably a product of the synergistic action of two or more of these kinases.

Microtubule associated protein tau, which is expressed in six alternatively spliced molecular isoforms in human brain, is abnormally hyperphosphorylated in Alzheimer disease and related tauopathies. Here we show (i) that GSK-3α and neither GSK-3β nor cdk5 can phosphorylate tau at Ser262 and phosphorylation at Ser235 by cdk5 primes phosphorylation at Thr231 by GSK-3α/β; (ii) that tau isoforms with two N-terminal inserts (τ4L, τ3L) are phosphorylated by cdk5 plus GSK-3 at Thr231 markedly more than isoforms lacking these inserts (τ4, τ3); and (iii) that Thr231 is phosphorylated ~50% more in free tau than in microtubule-bound tau, and the phosphorylation at this site results in the dissociation of tau from microtubules. These findings suggest that the phosphorylation of tau at Thr231 and Ser262 by cdk5 plus GSK-3, which inhibits its normal biological activity, is regulated both by its amino terminal inserts and its physical state.

Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated, whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-γ signaling pathway were up-regulated by Mn 2+ . In addition, 68 genes were found to be similarly up- or down-regulated by both Mn 2+ and hypoxia. These results from genomic analysis are further supported by data from real-time RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn 2+ selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity.

A 44-year-old male presented with dizziness, blurring of vision, unproductive cough, dyspnoea, heaviness of head, fever and hepatosplenomegaly along with reticulonodular infiltration in chest x-ray. His serum showed monoclonal IgM gammopathy. Peripheral blood smear, bone marrow examination and serum protein electrophoresis suggested it was a case of Waldenstrom's macroglobulinaemia. Chest x-ray and CT scan of thorax were suggestive of pulmonary involvement in the form of interstitial lung disease.

Defective heme synthesis may cause acute porphyrias, which are associated with a wide array of neurological disturbances involving both the central and peripheral nervous systems. Thus, the understanding of the roles of heme in neuronal cell function may provide insights into the molecular events underlying the pathogenesis of neuropathies associated with defective heme synthesis. In this report, we use rat pheochromocytoma (PC12) clonal cells as a model system for studying the role of heme in neuronal cell survival. We examined the effects of inhibition of heme synthesis on signaling pathways and gene expression in nerve growth factor (NGF)-induced PC12 cells. We found that succinyl acetone-induced heme deficiency selectively caused apoptosis in NGF-induced PC12 cells. Further, we found that in succinyl acetone-treated, NGF-induced cells, the pro-survival Ras-ERK1/2 signaling pathway was inactivated and the pro-apoptotic JNK signaling pathway was activated. In these cells, the activation of caspase and the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) were also evident. Importantly, microarray gene expression analysis showed that more than 20 key neuronal genes that were induced by NGF were suppressed by succinyl acetone. These genes include those encoding survival motor neuron protein, synaptic vesicle protein SVOP, and neural cell adhesion molecule NCAM. These results indicate that heme is important for neuronal cell signaling and the proper functioning of neuronal cells.

A 22 years old male presented with right sided scrotal swelling of 5 months duration. On examination it was found to be of orange-sized, firm to hard in consistency with mild tenderness. Ultrasonography of testes failed to arrive at a diagnosis. However, fine needle aspiration cytology of the testicular swelling confirmed the diagnosis of testicular tuberculosis. Even conservative approach in the management gave satisfactory result.

Neurofibrillary degeneration is a key histopathological brain lesion of Alzheimer disease (AD) and related neurodegenerative disorders such as frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), commonly referred to as tauopathies. Microtubule associated protein (MAP) tau, which is a major MAP of a normal mature neuron is abnormally hyperphosphorylated in tauopathies and is the major protein subunit of paired helical filaments (PHF)/straight filaments (SF) which accumulate in the soma (as neurofibrillary tangles) and dystrophic neurites (as neuropil threads and as dystrophic neurites surrounding the beta-amyloid core in neuritic plaques in AD) of the affected neurons. Unlike normal tau which stimulates assembly and stabilizes microtubules, the abnormally hyperphosphorylated tau inhibits assembly and disrupts microtubules. The abnormally hyperphosphorylated tau competes with tubulin/microtubules in associating with normal tau, MAP1 and MAP2. This sequestration of normal MAPs by the abnormal tau results in the breakdown of the microtubules. The association of the abnormal tau with normal tau and not with MAP1 or MAP2 results in the formation of tangles of tau filaments. All these toxic properties of the abnormally hyperphosphorylated tau are eliminated by its enzymatic dephosphorylation. Activities of phosphoseryl/phosphothreonyl protein phosphatases (PP)-2A and PP-1 which can dephosphorylate the abnormal tau to a normal-like state are compromised in AD brain. Dephosphorylation by PP-2A and PP-2B and to a lesser extent by PP-1 restores the normal microtubule assembly promoting activity in AD P-tau in vitro. Neurofibrillary tangles of PHF isolated from AD brain are also dissociated on in vitro dephosphorylation with PP-2A, and the tau released by this treatment can stimulate microtubule assembly. Thus, it appears that the abnormal hyperphosphorylation of tau leads to neurodegeneration through breakdown of the microtubule network and that the abnormal tau on association with normal tau forms neurofibrillary tangles of tau filaments i.e. PHF/SF. Increase in tau phosphatase activity is a promising approach to inhibit neurofibrillary degeneration and thereby the diseases characterized by this lesion.

The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.

Breast metastases from extramammary neoplasm are uncommon with an incidence of 0.5% to 3% of patients with extramammary malignancy. We reported an extremely rare case of breast metastasis from squamous cell lung carcinoma. A 60-year-old woman suffered from dry cough with shortness breath for one month with simultaneous development of breast lump. The histological diagnosis, achieved by bronchoscopic lung biopsy with the aid of immunohistochemistry was squamous cell lung carcinoma. Breast lump was a metastasis from lung, confirmed by histopathology and immunohistochemistry after core needle biopsy. Secondary malignancy metastatic to the breast is uncommon, yet this entity does exist. In view of the therapeutic implication, a metastatic breast lesion should not be mistaken for a primary breast carcinoma. Only with the awareness of such a possibility can prompt diagnosis and optimal treatment be achieved.