NHR-49/PAARα and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase

During bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple signals are sensed by the host and how they elicit the transcription of specific host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the specific regulation of such responses is not well understood. By directly comparing C. elegans that were either starved or infected with Gram-positive bacterium Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. We found that the mechanism of fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPARa, which induced fmo-2/FMO5 and host defense cell non-autonomously. Moreover, deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO important for innate immunity in animals. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that NHR-49/PPARa contributes to host defense, and demonstrate that FMOs are important innate immunity effectors in animals

Secondary Tuberculosis of Breast: Case Report

Tuberculosis of breast is a rare disease which is difficult to differentiate from carcinoma of breast. The involvement of breast can be primary or secondary to some focus in body. A case of secondary tuberculosis of right breast in a 21-year-old female from Kashmir, India, is being reported. Presentation was as a painless discharging sinus of right breast. A tubercular foci of rib was the affecting source of disease. No other evidence of tuberculosis was present in the body. Resection of involved rib segment, along with the discharging sinus, was performed. The patient had antitubercular therapy for 9 months, with no recurrence seen in followup

Molecular Alterations and Expression Dynamics in the Etiopathogenesis of Thyroid Cancer

Thyroid carcinoma is the most prevalent endocrine malignancy and accounts for 2% of all human cancers. In the past decade, knowledge of genetic alterations of thyroid cancer (TC) has rapidly expanded, which has provided new insights into thyroid cancer etiology and has offered novel diagnostic tools and prognostic markers that enable improved and personalized management of thyroid cancer patients. Alterations in key signaling effectors seem to be the hallmark of distinct forms of thyroid neoplasia. Mutations or rearrangements in genes that encode Mitogen activated protein kinase (MAPK) pathway effectors seem to be required for transformation. Mutations in BRAF were the most recently identified MAPK effector in thyroid cancer. BRAF V600E is the most common alteration in sporadic papillary carcinoma. Three RAS proto-oncogenes (NRAS, HRAS & KRAS) are implicated in human thyroid tumorigenesis. High incidence of thyroid cancer worldwide indicates the importance of studying genetic alterations that lead to its carcinogenesis. BRAF and RAS alterations represent a novel indicator of the progression and aggressiveness of thyroid carcinogenesis. The GSα-adenylyl cyclase-cyclic AMP (cAMP) cascade is effected in thyroid cancer. Promoter hypermethylation of multiple genes especially TSHR has been identified to play a role in thyroid cancers, in particular showing a close association with BRAF mutational status. So, the main aim of the study was to elucidate the involvement of BRAF and RAS gene mutations along with BRAF expression and thyroid-stimulating hormone receptor (TSHR) hypermethylation in North Indian patients and investigate their association with clinicopathological characteristics

Role of fibreoptic bronchoscopy in haemoptysis: an analysis of 157 patients

Background: Objectives of this study were to define the role of fibreoptic bronchoscopy (FOB) in determining the etiology of haemoptysis, to determine whether bronchoscopy is useful in haemoptysis with normal chest x-ray, to determine whether early bronchoscopy is better than delayed bronchoscopy.Methods: This prospective study was conducted on 157 patients who presented with hemoptysis to the Department of Tuberculosis and Chest diseases. All these patients underwent FOB after taking proper history and examination and ruling out any contraindication to the procedure.Results: In patients with haemoptysis with normal CXR, a diagnosis was established in 54.5% by FOB while 38.6% had a normal bronchoscopy. An endoscopic diagnosis of bronchitis was made in 22.7% patients. In only 9.1% patients an endobronchial mass was seen on bronchoscopy, and all of them were more than 40 years of age. Active bleeding/bleeding site was localized in 18.1% patients. In patients with abnormal chest roentgenogram who underwent FOB, a definitive diagnosis was established in 75.4% cases with active bleeding/ bleeding site localized in 59.6%. Thirty five percent were having an endobronchial mass. Of all the patients who underwent FOB for recurrent haemoptysis, active bleeding/bleeding site was localized in 48.4% patients. Bleeding site was localized in 62.9% patients who underwent early FOB, while the yield was lower (29.4%) in patients who underwent delayed FOB.Conclusions: Fibreoptic bronchoscopy (FOB) is an important and useful investigation in patients of haemoptysis in determining the bleeding site and etiology of haemoptysis. Early FOB has higher yield in localizing the bleeding site than delayed FOB.

Relative Incidence and Molecular Analysis of Breast Cancer in Kashmiri population

Breast cancer is the third most common tumor in the world and represents 9% of global cancer burden. In India, breast cancer is the second common cancer in women after cervical cancer and has of late replaced cervical cancer as the leading site of cancer among women in Indian cities. Preliminary indications point towards an increasing trend in the occurrence of breast cancer amongst Kashmiri population. However, authentic data with regard to prevalence is almost non-existent in the state of Jammu and Kashmir. To our knowledge, this is the first attempt to examine the epidemiological distribution of different cancer typ es with particular emphasis on breast cancer in the wh ole valley. The source of our data include cancer registry in the Department of Radiation Oncology, Sheri -Kashmir Institute of Medical Sciences, Srinagar, and Department of Radiation Oncology, SMHS, Srina gar during Jan 2002 to Dec 2006 . A total of 6943 cas es registered between 1st January 2002 to 31st December 2006 comprised of 4345 males and 2598 females. The age standardized incidence rates were 34.9 per 100,000 for males an d 24.8 per 100,000 for females. Oesophagus was the leading site of cancer in both the sexes (male ASR 11.2; female ASR 8.3) followed by lung (ASR 6.5), brain (ASR 2.2), head and neck (ASR 2.2) in males and breast (ASR 5.2), skin (ASR 1.6) and rectum (ASR 0.95) in females. The incidence of cervical cancer turned out to be surprisingly lo w in Kashmir i women as compared to other Indian Registries quite contrary to the pattern in rest of the country. Our studies imply that cancer incidence was significantly lower and cancer patterns were markedly different in Kashmir. The observed cancer pattern indicates that awareness campaigns, life style and dietary habit changes, tobacco -control measures and early detection of breast cancer are very important for cancer control in this cohort of population. Abstract 2 Section II Abstract Environmental and genetic factors are attributed to explain the spectrum of geographical and ethnic variations in the development and pathogenesis of disease. The genesis of disease has been further complexed by involvement of number of genes with small effe cts and above all by population heterogeneity. Accordingly variations in genes like Brca1/Brca2 that have been strongly associated with breast cancer phenotype present a scattered mutational pattern in different populations. This study attempts to analyze the frequently mutated exons of BRCA2 for sequence variations in surgically resected breast cancer tissue samples, from a high risk ethnic Kashmiri population. PCR followed b y direct sequencing revealed presence of five variations, with four somatic mutat ions located on exon 11 and one germline variation located in UTR region of exon 2 at contig position 13870572 (rs1799943). All the four somatic mutations comprised of substitutions; two representing missense mutations leading to amino -acid substitution at codon positions 868 (novel) and 991 whereas other two were silent mutations at codon positions 846 and 1131. Codons for amino-acid positions 846 (TCC/TCA) and 868 (CCT/ACT) were seen to be present in heterozygous state in normal breast tissue samples and the heterozygous nature of both the codons was seen to be lost i n associated tumor samples in 44 out of 50 patients. Incidentally these two mutations were always found to be linked.No sequence variations were observed in exons 9, 18, 20 and 25. Gap -junction gene C onnexin 43, which codes fo r a 43 -kd gap -junction protein is a predominantly expressed gap junction protein in normal breast tissue and plays an important role in normal mammogenesis, lactogenesis and involution. Studies have shown down- re gulation of connexin 43 gap -junction protein is involved in primary tumor formation as well as metastasis in breast cancer patients and restoration of gap-junction intercellular communication by up-regulation of Abstract 3 connexins has been shown to restore normal phenotypes in vitro and reduce tumor growth in vivo . However the molecular mechanisms behind these processes remain elusive and a better understanding of the key events is necessary to gain information relevant to the designing of anti -cancer treatment models against breast cancer. In this study, coding sequence of C onnexin 43 was analyzed for polymorphic changes to establish its role (if any) in breast cancer in this cohort of population. After sequence analysis, none of the screened samples reveal ed any kind of variations in early or advanced stage of the disease. The findings from this study add to the body of knowledge about mutation prevalence and nature of different breast cancer pre -disposing genes in ethnic Kashmiri population, and may inform strategies for genetic cancer risk assessment. Our studies also imply that mutational deactivation does not play any role in the down regulation of Connexin 43 expression in Kashmiri breast cancer patients. Instead, some other regulatory mechanism like hypermethylation or mutati on of the promoter region of thegene may be involved. Additionally increased understanding of breast carcinoma pathways may enhance our ability to device targeted approaches to the preve ntion of diseas

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output [preprint]

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires the precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output

External fixation of “intertrochanteric” fractures

In developing countries, due to limited availability of modern anesthesia and overcrowding of the hospitals with patients who need surgery, high-risk patients with “intertrochanteric” fractures remain unsuita ble for open reduction and internal fixation

OSM-11 Facilitates LIN-12 Notch Signaling during Caenorhabditis elegans Vulval Development

Notch signaling is critical for cell fate decisions during development. Caenorhabditis elegans and vertebrate Notch ligands are more diverse than classical Drosophila Notch ligands, suggesting possible functional complexities. Here, we describe a developmental role in Notch signaling for OSM-11, which has been previously implicated in defecation and osmotic resistance in C. elegans. We find that complete loss of OSM-11 causes defects in vulval precursor cell (VPC) fate specification during vulval development consistent with decreased Notch signaling. OSM-11 is a secreted, diffusible protein that, like previously described C. elegans Delta, Serrate, and LAG-2 (DSL) ligands, can interact with the lineage defective-12 (LIN-12) Notch receptor extracellular domain. Additionally, OSM-11 and similar C. elegans proteins share a common motif with Notch ligands from other species in a sequence defined here as the Delta and OSM-11 (DOS) motif. osm-11 loss-of-function defects in vulval development are exacerbated by loss of other DOS-motif genes or by loss of the Notch ligand DSL-1, suggesting that DOS-motif and DSL proteins act together to activate Notch signaling in vivo. The mammalian DOS-motif protein Deltalike1 (DLK1) can substitute for OSM-11 in C. elegans development, suggesting that DOS-motif function is conserved across species. We hypothesize that C. elegans OSM-11 and homologous proteins act as coactivators for Notch receptors, allowing precise regulation of Notch receptor signaling in developmental programs in both vertebrates and invertebrates