Structure-Based Drug Design of Novel,Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors

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Knowledge,Attitude and Awareness of Speciality of Oral and Maxillofacial Surgery Amongst Medical Consultants of Vadodara District in Gujarat State

Background and Aim

Aim of this study was to survey the knowledge, attitude and awareness of the subject of oral and maxillofacial surgery speciality amongst the consultants and practitioners of medicine in district of Vadodara.

Materials and Methods

List of members of various specialities in medical faculty were obtained from Indian Medical Association, Baroda branch and staff members of medical colleges of Vadodara district. A questionnaire survey was made which was distributed and their options were noted.

Results

Surgical removal of third molar, oral submucous fibrosis and implants were the problems where oral surgeons were preferred. For maxillofacial trauma plastic surgeons and orthopaedic surgeons were preferred than oral surgeons. For maxillofacial pathology E.N.T surgeons were mostly preferred. There is low awareness regarding oral and maxillofacial surgery amongst the general practitioners and medical consultants in Vadodara district.

Conclusion

Survey shows that our training needs to be upgraded and revamped so that our trainees (post graduates in oral surgery) and have a greater “hands-on” exposure during their postgraduate training. They will then be able to handle increasingly complex cases in a multispecialty setup when they graduate and earn the mutual respect of the medical and dental fraternity and also the general public. MBBS students during their dental postings should be made aware of the depth and scope of oral surgery branch.     

Homology Modeling of NAD+-Dependent DNA Ligase of the Wolbachia Endosymbiont of Brugia malayi and Its Drug Target Potential Using Dispiro-Cycloalkanones

Lymphatic filarial nematodes maintain a mutualistic relationship with the endosymbiont Wolbachia. Depletion of Wolbachia produces profound defects in nematode development, fertility, and viability and thus has great promise as a novel approach for treating filarial diseases. NAD⁺-dependent DNA ligase is an essential enzyme of DNA replication, repair, and recombination. Therefore, in the present study, the antifilarial drug target potential of the NAD⁺-dependent DNA ligase of the Wolbachia symbiont of Brugia malayi (wBm-LigA) was investigated using dispiro-cycloalkanone compounds. Dispiro-cycloalkanone specifically inhibited the nick-closing and cohesive-end ligation activities of the enzyme without inhibiting human or T4 DNA ligase. The mode of inhibition was competitive with the NAD⁺ cofactor. Docking studies also revealed the interaction of these compounds with the active site of the target enzyme. The adverse effects of these inhibitors were observed on adult and microfilarial stages of B. malayi in vitro, and the most active compounds were further monitored in vivo in jirds and mastomys rodent models. Compounds 1, 2, and 5 had severe adverse effects in vitro on the motility of both adult worms and microfilariae at low concentrations. Compound 2 was the best inhibitor, with the lowest 50% inhibitory concentration (IC₅₀) (1.02 μM), followed by compound 5 (IC₅₀, 2.3 μM) and compound 1 (IC₅₀, 2.9 μM). These compounds also exhibited the same adverse effect on adult worms and microfilariae in vivo (P < 0.05). These compounds also tremendously reduced the wolbachial load, as evident by quantitative real-time PCR (P < 0.05). wBm-LigA thus shows great promise as an antifilarial drug target, and dispiro-cycloalkanone compounds show great promise as antifilarial lead candidates.     

Inhibition of Sphingosine Kinase Prevents Lipopolysaccharide-Induced Preterm Birth and Suppresses Proinflammatory Responses in a Murine Model

Premature delivery occurs in 12% of all births, and accounts for nearly half of long-term neurological morbidity, and 60% to 80% of perinatal mortality. Despite advances in obstetrics and neonatology, the rate of premature delivery has increased approximately 12% since 1990. The single most common cause of spontaneous preterm birth is infection. Several lines of evidence have demonstrated the role of endothelin-1 as both a constrictor of uterine myometrial smooth muscle and a proinflammatory mediator. Endothelin-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. Rescue of pups from premature abortion with an SphK inhibitor occurs by suppression of the proinflammatory cytokines tumor necrosis factor α, Il-1β, and Il-6 and attenuation of polymorphonuclear inflammatory cells into the placental labyrinth. Moreover, we postulate that inhibition of SphK leads to suppression of endothelin-converting enzyme-1 expression, indicating the presence of an endothelin-converting enzyme 1/endothelin 1–SphK positive feedback loop. This work introduces a novel approach for the control of infection-triggered preterm labor, a condition for which there is no effective treatment.Preterm birth (PTB), defined as any birth before 37 complete weeks of gestation, accounts for 11.1% of all deliveries worldwide, but next to congenital anomalies, accounts for most perinatal morbidity and mortality. The United States, with a rate of PTB of 11.7%, ranks among the 10 countries that have the highest rates of PTB.¹ The single most common cause of spontaneous PTB is infection.² Intrauterine bacteria interact with cell surface recognition molecules, such as Toll-like receptor-2 (Tlr2) and Tlr4,^3,4 leading to release of T helper cell 1 cytokines, such as Il-1β and tumor necrosis factor α (TNFα).^5–7 This inflammatory response culminates in the final steps of the parturition cascade, consisting of decreased prostaglandin metabolism, functional progesterone withdrawal, increased expression of proteases and contraction-associated proteins, and increased uterine contractile activity.^8–10We have previously shown that endothelin 1 (Edn1) is a key player in lipopolysaccharide (LPS)–induced PTB in a murine model.^11–14 Specifically, we have previously reported that endothelin-converting enzyme 1 (Ece1), the enzyme that synthesizes Edn1, colocalizes with its substrate in the placenta¹⁵ and that the Ece1 inhibitor, phosphoramidon, decreases rates of PTB in a murine model of infection-associated preterm labor.¹¹ Subsequently, we have also shown that Ece1 levels are increased in a mouse model of PTB and that rates of preterm delivery are decreased with endothelin-A receptor antagonists.^12–14 Finally, we have shown that virtually complete control of PTB is achieved in this model by silencing Ece1 mRNA.¹³ LPS, a Gram-negative bacterial wall component that activates Tlr4, stimulates the synthesis of Edn1 by monocytes and endothelial cells in vitro and in vivo.^16–18The activation of the phospholipase C pathway by Edn1 leads to activation of protein kinase C (PKC), which acts upstream of sphingosine kinase (SphK).^19,20 SphK, in turn, can activate Rho kinase, ultimately leading to contraction of myometrial tissue. SphK is the only enzyme that catalyzes the conversion of SphK to sphingosine-1-phosphate, which behaves in an autocrine manner in myometrial tissues and, in orchestration with SphK, PKC, and extracellular signal–regulated kinase, leads to the induction of cyclooxygenase-2 and to labor.²¹Two human SphK isozymes, SphK1 and SphK2, have been identified,²² both of which are inhibited by sphingosine kinase inhibitor II (SKI II), the compound used in the work reported herein. We show herein, for the first time, that inhibition of SphK and consequent suppression of the SphK1-dependent inflammatory pathway prevents infection-triggered PTB.     

Mycobacterium abscessus: Causing fatal endocarditis after cardiac catheterization

Mycobacterium abscessus is an unusual cause of infection in immunocompetent patients. The intrinsic and acquired resistance of this organism to multiple antibiotics is a major issue in planning treatment regimens. We report a case of M. abscessus endocarditis of the native aortic valve in an immunocompetent patient following coronary angiography with a fatal outcome. The case highlights an unfortunate intervention – related nosocomial infection and the difficulties in chemotherapeutic options for this organism, particularly in the presence of renal failure.KEY WORDS: Endocarditis, Mycobacterium abscessus, nosocomial     

Immunohistochemical and Molecular Approaches for the Diagnosis of Campylobacter fetus subsp. venerealis in Natural Cases of Bovine Abortion

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Rapid and precise diagnosis in natural field cases of bovine abortion caused by Campylobacter fetus subsp....     

Efficacy of Therapies for Postural Tachycardia Syndrome: A Systematic Review and Meta-analysis

Objective

To identify the evidence base and evaluate the efficacy of each treatment for postural tachycardia syndrome (POTS) in light of a recent consensus statement highlighting the lack of treatment options with clear benefit to risk ratios for this debilitating condition.

Normothermic CPB in congenital heart disease—an experience of 653 cases

Background  

Lichenstein first established normothormic cardio pulmonary bypass as safe and effective method. We have been using normothromic CPB in all case including infants and neonates. The safety and efficacy in 653 congenital heart disease cases were retrospectively analyzed.