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Allosteric peptide inhibitors of thymidylate synthase (hTS) bind to the dimer interface and stabilize the inactive form of the protein. Four interface residues were mutated to alanine, and interaction studies were employed to decode the key role of these residues in the peptide molecular recognition. This led to the identification of three crucial interface residues F59, L198, and Y202 that impart activity to the peptide inhibitors and suggest the binding area for further inhibitor design.

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 mu M, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC(50)s and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.

A 45 -ear-old man presented with complaints of cough with minimal expectoration for 3 months. He was a known case of type 2 diabetes mellitus for the past 2 years. His complete blood count, renal function and liver function tests were within normal limits. His haemoglobn A1C was 8.2%. There were

Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate analog inhibitor. Given the active site similarities between Mycobacterium tuberculosis ThyX (Mtb-ThyX) and Tm-ThyX, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as scaffold for the development of Mtb-ThyX inhibitors.

The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thoracic aortic aneurysms (TAA) are rarely symptomatic. A 55 year old male presents with longstanding chronic backache. CXR showed left hilar shadow with collapse of left lung. Considering the CXR findings and with the patient being chronic smoker a strong possibility of carcinoma lung with bony metastasis was kept and further CECT chest was done. The CECT chest was suggestive of a thoracic aorta aneurysm with thrombosis compressing left principal bronchus and its lower lobar branch resulting in distal area of collapse and consolidation of left lower lobe. These findings were further confirmed on CT angiography. The patient was thus diagnosed as a case of descending thoracic aorta aneurysm probably of atherosclerotic etiology with thrombosis. Patient was started on beta blockers and ACE inhibitors along with supportive and symptomatic treatment and was further transferred to the department of CTVS for surgical intervention. Thus, this case report here signifies that possibility of thoracic aorta aneurysm should always be considered in a patient with chronic backache specially in presence of mediastinal shadow on CXR.

Background: Diabetes mellitus is one of the most frequently encountered diseases in clinical practice and since the diabetic patients are at an increased risk of infections specially those of the urinary tract it is imperative for a physician to be aware of the prevalence and antibiotic susceptibility patterns of urinary pathogens. Thus, in this study we assess the recent trends in antimicrobial susceptibility patterns of urinary pathogens in type II diabetes mellitus.Methods: Ninety-three eligible type II diabetes mellitus cases without genitourinary symptoms or abnormalities along with 93 non-diabetic healthy controls were recruited. Mid-stream urine was collected after taking informed consent and each sample tested using the dipstick, microscopy and culture techniques. Isolates were identified using standard biochemical tests.Results: Prevalence of asymptomatic bacteriuria (ASB) in our study was found to be 34.4% among cases of type II diabetes mellitus while it was 6.45% among non-diabetic healthy controls. E. coli was the most common urinary pathogen isolated. E. coli susceptibility towards amikacin was 85.71%, towards ceftriaxone and nitrofurantoin was 71.73% and for meropenem and doxycycline 66.67% susceptibility was observed. In the one case where pseudomonas was cultured, it was susceptible to meropenem, gentamycin, cefoperazone-sulbactum and cefuroxime. In an isolated case where Proteus species was grown, it showed susceptibility to meropenem, norfloxacin, levofloxacin and co-trimoxazole. Enterobacter species which was grown, showed susceptibility to meropenem, vancomycin, amikacin, nitrofurantoin, norfloxacin, levofloxacin and co-trimoxazole. Gram positive bacteria mainly showed susceptibility to ceftriaxone, teicoplanin, vancomycin and doxycycline.Conclusions: The prevalence of bacteriuria is significantly higher in diabetics as compared to non-diabetics and with the recent trends suggestive of emerging resistance among urinary pathogens to some of the commonly used anti-microbials it is of utmost importance to carry out regular surveillance of bacterial profile and their anti-microbial susceptibilities to formulate updated guidelines for effectively treating urinary infections in diabetic patients.

We report a 42 year old non-smoker male who presented with progressive exertional dyspnoea, productive cough with streaky hemoptysis and progressive pedal edema. His physical examination, ECG, chest X-ray and 2D-ECHO revealed features suggestive of right heart failure and pulmonary hypertension. On further evaluation for the cause of pulmonary hypertension, his CT pulmonary angiography revealed features of chronic pulmonary thromboembolism with calcified thrombus in the main pulmonary artery along with pulmonary hypertension. Incidentally the CT also revealed a cavity in the right lung with soft tissue within it. A, trans-thoracic needle aspiration of this tissue was suggestive of an aspergilloma. This is a rare case report of co-existence of two uncommon complications of pulmonary embolism-chronic thrombo-embolic pulmonary hypertension and pulmonary Aspergilloma in the same patient.

Background: With the dawn of modern era the diabetes epidemic has spread over continents affecting the developed and the developing nations alike. Asymptomatic bacteriuria which is quite prevalent in the diabetic population is associated with increased diabetic complications and thereby increased morbidity. Thus, the aim of this study was to assess the proportion of cases with asymptomatic bacteriuria (ASB) among type II diabetes mellitus patients as compared to non-diabetic healthy controls and studying the factors associated with ASB.Methods: 93 eligible type II diabetes mellitus cases without genitourinary symptoms or abnormalities along with 93 non-diabetic healthy controls were recruited. Mid-stream urine was collected after taking informed consent and each sample tested using the dipstick, microscopy and culture techniques. Isolates were identified using standard biochemical tests.Results: Prevalence of ASB in our study was found to be 34.4% among cases of type II diabetes mellitus while it was 6.45% among non-diabetic healthy controls. Amongst the diabetics with ASB 71.9 % were females and 28.13 % were males. E. Coli was isolated in 21 subjects among diabetic cases (22.58%) and in 5 subjects among non-diabetic healthy controls (5.38%). Fasting blood sugar (FBS) in diabetic cases group was 151.08 ± 48.16 and in control group was found to be 98.57 ± 25.95 (p

Shrinking lung syndrome (SLS) is a infrequently reported manifestation of systemic lupus erythematosus (SLE). Reported prevalence of SLS is about 0.5% in SLE patients. Pathogenesis is not fully understood and different therapeutic modalities have been employed with variable results, as only 77 cases of SLS have been documented in literature. SLS in SLE-Scleroderma overlap has not been reported yet. We report a patient of SLE - scleroderma overlap presenting with dyspnea, intermittent orthopnea and pleuritic chest pain. Evaluation revealed elevated hemidiaphragms and severe restrictive defect. She was eventually diagnosed as a case of SLS. This case report is a reminder to the medical fraternity that SLS although a rare complication must be thought of in the special subset of patients of SLE having respiratory symptoms.

In this issue of the PCRJ, Bishara et al.1 present a case report about the treatment of a pregnant woman with tuberculosis (TB). She had emigrated from a country with a high prevalence of TB to one with a lower prevalence. This presented a challenge to her physicians who were faced with identifying and treating close contacts who were also infected. This Perspective article explores in more depth some of the questions raised by this case report. It discusses the role of primary care physicians in low prevalence countries who can implement evidence-based screening programmes, it discusses effective strategies for the diagnosis and treatment of TB in countries with high TB prevalence, and it presents insights from medical anthropology that can help practitioners overcome the barriers to TB diagnosis, treatment and screening described in the case report.

Thymidylate synthase (TS) is a target for pemetrexed and the prodrug 5-fluorouracil (5-FU) that inhibit the protein by binding at its active site. Prolonged administration of these drugs causes TS overexpression, leading to drug resistance. The peptide lead, LR (LSCQLYQR), allosterically stabilizes the inactive form of the protein and inhibits ovarian cancer (OC) cell growth with stable TS and decreased dihydrofolate reductase (DHFR) expression. To improve TS inhibition and the anticancer effect, we have developed 35 peptides by modifying the lead. The d-glutamine-modified peptide displayed the best inhibition of cisplatin-sensitive and -resistant OC cell growth, was more active than LR and 5-FU, and showed a TS/DHFR expression pattern similar to LR. Circular dichroism spectroscopy and molecular dynamics studies provided a molecular-level rationale for the differences in structural preferences and the enzyme inhibitory activities. By combining target inhibition studies and the modulation pattern of associated proteins, this work avenues a concept to develop more specific inhibitors of OC cell growth and drug leads.

Ecthyma gangrenosum (EG) is a relatively rare skin manifestation that is most commonly described in Pseudomonas aeruginosa bacteremia. It is more frequently seen in immunocompromised individuals. We report a case of 60-year-old renal transplant recipient on triple immunosuppressants and diabetes mellitus type 2 on insulin therapy who developed EG-like lesions due to disseminated mycobacterial tuberculosis (MTB) infection. To the best of our knowledge, this is the first case report of EG-like lesions associated with disseminated kochs.

The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.

Central venous catheterization is one of the most prevalent procedures in the Intensive Care Unit. Complications are reported in about 15% of the patients and usually comprise of infection, arterial puncture, malpositioning, pneumothorax, local hematoma, hemothorax, and so on. Chylothorax is a rare complication of this procedure. We present a 42-year-old lady, who developed bilateral massive chylothorax after cannulation of her left internal jugular vein (IJV), due to direct injury to the thoracic duct during the procedure. The patient was successfully managed with bilateral chest tube drainage and omission of oral feeds for four days. Development of bilateral chylothorax as a complication of IJV cannulation is rare, but merits reporting, in view of a large number of central venous cannulations being undertaken. Critical care professionals should be aware of this rare complication of a common procedure to facilitate early identification and institute appropriate therapy.

Endobronchial hamartoma is a rare benign tumor of lung that may present with symptoms of airway obstruction with wheezing, stridor, recurrent pneumonia or atelectasis. We report a case of a patient with endobronchial hamartoma, recurrent pneumonia, who presented to us with sputum smear and culture positive pulmonary tuberculosis. He was treated with antitubercular treatment and endobronchial hamartoma was resected completely by diode laser through fiberoptic bronchoscope.

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.

This study reports source apportionment of polycyclic aromatic hydrocarbons (PAHs) in particulate depositions on vegetation foliages near highway in the urban environment of Lucknow city (India) using the principal components analysis/absolute principal components scores (PCA/APCS) receptor modeling approach. The multivariate method enables identification of major PAHs sources along with their quantitative contributions with respect to individual PAH. The PCA identified three major sources of PAHs viz. combustion, vehicular emissions, and diesel based activities. The PCA/APCS receptor modeling approach revealed that the combustion sources (natural gas, wood, coal/coke, biomass) contributed 19-97% of various PAHs, vehicular emissions 0-70%, diesel based sources 0-81% and other miscellaneous sources 0-20% of different PAHs. The contributions of major pyrolytic and petrogenic sources to the total PAHs were 56 and 42%, respectively. Further, the combustion related sources contribute major fraction of the carcinogenic PAHs in the study area. High correlation coefficient (R2 > 0.75 for most PAHs) between the measured and predicted concentrations of PAHs suggests for the applicability of the PCA/APCS receptor modeling approach for estimation of source contribution to the PAHs in particulates.

A 10 years surface water quality data set pertaining to a polluted river was analyzed using partial least squares (PLS) regression models. Both the unfold-PLS and N-PLS (tri-PLS and quadri-PLS) models were calibrated through leave-one out cross-validation method. These were applied to the multivariate, multi-way data array with a view to assess and compare their predictive capabilities for biochemical oxygen demand (BOD) of river water in terms of their relative mean squares error of cross-validation, prediction and variance captured. The sum of squares of residuals and leverages were computed and analyzed to identify the sites, variables, years and months which may have influence on the constructed model. Both the tri- and quadri-PLS models yielded relatively low validation error as compared to unfold-PLS and captured high variance in model. Moreover, both of these methods produced acceptable model precision and accuracy. In case of tri-PLS the root mean squares errors were 1.65 and 2.17 for calibration and prediction, respectively; whereas these were 2.58 and 1.09 for quadri-PLS. At a preliminary level it seems that BOD can be predicted but a different data arrangement is needed. Moreover, analysis of the scores and loadings plots of the N-PLS models could provide information on time evolution of the river water quality.

Growing skull fractures or craniocerebral erosions are rare sequel to cranial fractures where progressively growing cranial defects follow lacerations involving the duramater. Their usual site is the parietal region. They present as a cystic, non-tender swelling with an underlying palpable bony defect. One such case is reported.

Stroke in young poses a major health problem. Thrombophilic factors have been implicated in 4-8% of the young strokes worldwide. Protein S deficiency is a rare cause of recurrent ischemic stroke in young population. Only a few sporadic cases have been described in the literature. We are reporting a case of protein S deficiency-related recurrent ischemic stroke in a 16-year-old girl. Early diagnosis and targeted approach can help such patients to prevent recurrent thrombotic episodes.

The procurement function refers to the purchase of items (e.g. raw materials, standard production items, capital goods, and services) to support business operations. Increasingly, companies are recognising that procurement is a profit-contributing activity, instead of a routine-order placing function. However, the absence of an adequate software support system to assist the purchasing manager results in inefficient and ineffective procurement, and thus may affect the profitability of the entire organisation. A prototype decision support system for procurement was developed during this research. It focuses primarily on procurement operations within a manufacturing environment. The system assists the purchasing manager in his decision-making process, including vendor selection and the development of an optimal procurement strategy. Integer programming and analytical hierarchy process models are incorporated to support these objectives. 'What-if' analysis features are also included to help determine favourable alternatives in a changing market environment.