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Shah P.,Central Drug Research Institute | Kumar S.,National Institute of Pharmaceutical Education and Research | Tiwari S.,C.S.M.M.U. | Siddiqi M.I.,Central Drug Research Institute
Journal of Chemical Biology | Year: 2012

A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking and 3D quantitative structure-activity relationship studies. Genetic algorithm-based criteria was adopted for selection of training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model development and validation. Both the comparative molecular field analyses (q 2 LOO = 0:841, r 2 ncv = 0:99) and comparative molecular similarity indices analyses (q 2 LOO = 0:757, r 2 ncv = 0:943) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules and will assist in the design of more potent inhibitors of PfDHODH. © Springer-Verlag 2012.

Sharma K.L.,Sanjay Gandhi Post Graduate Institute of Medical Sciences | Misra S.,CSMMU | Kumar A.,Sanjay Gandhi Post Graduate Institute of Medical Sciences | Mittal B.,Sanjay Gandhi Post Graduate Institute of Medical Sciences
Liver International | Year: 2012

Background: Matrix metalloproteinase belong to family of pericellular collagenases which degrade extracellular matrix (ECM), and is involved in the modulation and susceptibility of various cancers. Methodology: The present study included 410 gallbladder (GBC) cases and 230 healthy controls from North India. Study examined the associations of polymorphisms of MMP-2c.735C>T (rs2285053), MMP-2c.1306 C>T (rs243865), MMP7c.181A>G (rs11568818), MMP-9p.R279Q (rs17556) MMP-9p.P574R (rs2250889), MMP-9 p.R668Q (rs17577) and TIMP2c.418 G>C (rs8179090) to GBC susceptibility. Genotyping was carried out by PCR-RFLP. Statistical analysis was performed by using SPSS ver16. Results: The MMP-2 c.735 [CT+TT], MMP-2c.1306 [CT+TT], MMP7 c.181 [AG+GG] and MMP-9 p.668 [RQ+QQ],TIMP2c.418 [GG+GC] genotypes were significantly associated with increased risk of GBC (P = 0.01; [OR]1.87, P = 0.02; [OR] 1.68, P = 0.02; [OR]=1.61, P = 0.002; [OR]=1.91,P = 0.01; [OR]=1.78 and (P = 0.03; [OR]=1.68; P = 0.01; [OR]=1.78 respectively). Haplotypes [C-735-T-1306] and [T-1306-C-735] of MMP-2 (P = <0.005; [OR] =1.78 P = <0.0001; [OR] =2.09) and haplotype [Q279-P574-Q668]of the MMP-9 (P = 0.04; [OR] =2.75) were significantly associated with GBC risk. On stratification of GBC patients with/without gallstones, MMP-2 haplotypes were associated with higher GBC risk in patients accompanying gallstones whereas MMP-9 haplotypes showed risk in patients without stones. Combined effect of > 3 MMP/TIMP variant containing genotypes imparted increased risk of GBC (P < 0.0001; [OR] =3.36). Multivariate logistic regression results also supported association of MMP-2 (c.735C>T, c.1306 C>T), MMP-9 p.R668Q and TIMP2c.418G>C variants with GBC susceptibility. Conclusion: This study suggests that genetic variants in MMP-2,7,9 and TIMP-2genes are associated with higher susceptibility of gallbladder cancer. © 2012 John Wiley & Sons A/S.

Husain N.,Dr. Ram Manohar Lohia Avadh University | Verma N.,CSMMU
Indian Journal of Surgical Oncology | Year: 2011

Soft tissue sarcomas (STS) constitute a heterogeneous category of soft tissue neoplasia composed mostly of uncommon tumors of diverse histology, different biology and varied outcomes. Substantial developments in immunohistochemistry (IHC), cytogenetics and molecular genetics of STS have caused a significant change in the classification and diagnosis of these tumors with a direct implication for clinical management and prognosis. In this review we discuss newer developments impacting diagnosis and prediction. © 2012 Indian Association of Surgical Oncology.

Long-term phenytoin therapy is known to cause disturbance in calcium and bone homeostasis. Dental tissues being calcified tissues can also be affected by this derangement of mineral metabolism, especially during developmental phases. This report describes a case of an epileptic child who presented with short roots, enlarged pulp chambers, blunt apices and delayed eruption of permanent dentition, which might be attributed to long-term phenytoin therapy. The purpose of this case report is to increase awareness among the clinicians about its possible dental implications and emphasise upon the need of regular dental check-ups in epileptic children.

Rai R.,Sanjay Gandhi Post Graduate Institute of Medical Sciences | Sharma K.L.,Sanjay Gandhi Post Graduate Institute of Medical Sciences | Tiwari S.,Sanjay Gandhi Post Graduate Institute of Medical Sciences | Misra S.,CSMMU | And 2 more authors.
Gene | Year: 2013

Background and aim: GBC is a lethal and multifaceted disease. Deleted in colorectal carcinoma (DCC) is a well known tumor suppressor gene. Recently a small genome-wide association study (GWAS) identified DCC to be significantly associated with gallbladder cancer (GBC) susceptibility in a Japanese population sample. However, the study sample size was small and lacked independent replication. Therefore, the present study was carried out to replicate the association of two GWAS identified DCC SNPs (A>Grs4078288, C>Trs7504990) and two other SNPs (C>Grs2229080 and A>Grs714) previously associated with various cancers. Methodology: The study was accomplished in 406 GBC cases and 260 healthy control samples from North India. Genotyping was carried out by PCR-RFLP and Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16 and functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). Result: We did not observe association with GWAS-identified SNPs of DCC but other SNPs showed significant association. In addition, a DCC haplotype Grs2229080-Ars4078288-Crs7504990-Ars714 conferred high risk of GBC in India. The haplotype associated risk was independent of gallstone, sex or tobacco usages which are well-known modifiers of GBC risk. Further analysis suggested DCC A>Grs714 as a major risk conferring SNP in the Indian population. Conclusion: This study re-affirms the role of plausible tumor suppressor DCC variants, in gallbladder carcinogenesis and the risk haplotype may be explored as a useful marker for GBC susceptibility. © 2013 Elsevier B.V.

Gutch M.,CSMMU | Agarwal A.,CSMMU | Amar A.,CSMMU
Journal of Natural Science, Biology and Medicine | Year: 2012

Dengue is the most important mosquito-borne, arboviral infection found in tropical and sub-tropical climates. Clinical presentation varies from a severe flu-like illness to a potentially lethal dengue hemorrhagic fever. Dengue has been regarded as a nonneurotropic virus. However, there are reports describing neurological involvements in dengue virus infection. The neurological involvement in dengue virus infection includes encephalitis, acute disseminated encephalomyelitis, transverse myelitis, and Guillain-Barre syndrome. The neurological spectrum of dengue patients has been limited because of small number of case reports, paucity of imaging, and neurophysiologic studies. There are only a few isolated case reports and case series documenting acute pure motor quadriparesis in dengue fever. We report acute pure motor reversible quadriparesis due to hypokalemia. Clinicians in the endemic area should be aware of such association of acute pure motor reversible quadriparesis with dengue fever.

Gupta S.,C.S.M.M.U. | Awasthi S.,C.S.M.M.U.
Indian Journal of Human Genetics | Year: 2010

Context: Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below. Evidence Acquisition: A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words "pharmacogenomics of asthma", "pharmacogenomics of-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma". Results: Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants. Conclusion: It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.

A 28-year-old woman without any history of prior antituberculosis treatment presented with cervical lymphadenopathy and a cold abscess near medial end of clavicle of 5 months duration. Pus culture and sensitivity revealed Mycobacterium tuberculosis resistant to rifampicin and isoniazid. Thus she was diagnosed as a case of primary multidrug-resistant tuberculosis and treated with second line drugs according to culture susceptibility pattern. On completion of therapy, patent showed good clinical response. This case highlights the observation that even extra-pulmonary primary multidrug-resistant tuberculosis can be successfully treated with currently available second line drugs.

Mishra A.,CSMMU
Journal of Laryngology and Otology | Year: 2011

Objective: To present a conservative surgical approach, via the transorbital route, for selected cases of infratemporal fossa involvement or inferolateral orbital tumours extending to the infratemporal fossa. Design: Case series report. Setting: Department of ENT, CSM Medical University (King George Medical College), Lucknow, India. Participants: One patient.Main outcome measures: Operative feasibility, intra-operative access, post-operative morbidity and cosmesis. Results: This novel and relatively conservative technique provides excellent exposure in selected cases of infratemporal fossa involvement and has minimal post-operative morbidity. Cosmesis is excellent, as osteotomy is not required and scarring is minimal. There is no risk of trismus, Vth or VIIth cranial nerve injury, or cerebrospinal fluid leakage, and haemostasis is easily achieved. Conclusion: Classical, open approaches to the infratemporal fossa involve considerable morbidity, while conservative approaches have their limitations. Diagnostic uncertainty over a small infratemporal fossa mass (perhaps an extension from an inferolateral orbital tumour) is an uncommon clinical challenge. The transorbital approach described is suited to benign and early malignant tumours, and has excellent results when combined with orbital exenteration (if needed). This paper discusses this approach's technical details and feasibility in different clinical situations, and compares it with other infratemporal fossa approaches. © JLO (1984) Limited, 2011.

Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling connective tissue disorder of unknown aetiology. Its occurrence is usually sporadic but may be an inherited autosomal-dominant condition with wide range of expression. FOP is characterised by congenital malformations of the great toes and abnormal progressive heterotopic ossification of striated muscles, tendons, ligaments, fascia and aponeuroses of the trunk and extremities leading to painful swellings. The ossifications typically appear within the first decade of life, resulting in progressive morbidity and severe disability. So far, there has been no effective treatment or prevention. In the early localised phase of disease it may be misdiagnosed, hence the role of correct diagnosis through imaging is essential. Herein, we report a case of a 10-year-old female who was evaluated radiologically and diagnosed as a case of FOP. The findings of plain radiography are described and the role of CT is highlighted.

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