Osteomyelitis and Pathologic Fracture of Mandible in Undiagnosed Osteopetrosis.

Osteopetrosis (OP) is a heterogeneous group of rare, heredity bone disorders with variable clinical features involving the bones of the body. OP is characterized by increased bone density, which is caused by aberrant osteoclast-mediated bone resorption. This syndromic disorder comes with a series of problems and, unless recognized and treated early, can lead to a multitude of further grave complications. We report a rare case of a female patient who reported chronic unhealed extraoral draining sinus present over the left submandibular region with pathologic fracture of the left mandibular angle, which, if, was diagnosed early with the identification of the osteopetrosis syndrome, could have been managed more conservatively.

6-Aminocoumarin oxime-ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies.

Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6-aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with Ki ranging from 0.51 to 1.18 µM and 0.89-4.43 µM. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with Ki 0.89 and 0.51 µM, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a Ki of 1.055 and 0.70 µM, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.

Oxiconazole Potentiates Gentamicin against Gentamicin-Resistant Staphylococcus aureus In Vitro and In Vivo.

Amid the mounting burden of multidrug-resistant (MDR) bacterial infections on health care worldwide, drug repurposing, a time and cost-effective strategy to identify new applications for drugs approved for other indications, can effectively fill the void in the current antibiotic pipeline. In this study, we have repurposed a topical antifungal agent, oxiconazole, in combination with gentamicin against skin infections caused by multidrug-resistant Staphylococcus aureus. Oxiconazole was identified as having antibacterial activity against S. aureus via whole-cell screening assays against clinically relevant bacterial pathogens. It exhibited a potent in vitro profile, including equipotent activity against clinical drug-susceptible and -resistant S. aureus and Enterococcus spp. Checkerboard assays and time-kill kinetics studies demonstrated its concentration-dependent killing and ability to synergize with the approved antibiotics daptomycin and gentamicin against susceptible and MDR S. aureus strains. Oxiconazole also significantly eradicated preformed S. aureus biofilms in vitro. Eventually, in an assessment of its ability to generate resistant S. aureus mutants via serial passaging, oxiconazole displayed an extremely low propensity for developing stable resistance in S. aureus. Its in vivo efficacy alone and in combination with synergistic antibiotics was assessed in a murine superficial skin infection model of S. aureus, where it strongly synergized with gentamicin, exhibiting superior activity to the untreated control and drug-alone treatment groups. Thus, oxiconazole can be repurposed as an antibacterial alone and in combination with gentamicin against susceptible and gentamicin-resistant S. aureus infections. IMPORTANCE Staphylococcus aureus, which causes the majority of nosocomial and community-acquired infections globally, is a WHO high-priority pathogen for antibiotic research and development. In addition to invasive infections, it is the causative agent of moderate to severe skin infections, with an increasing prevalence of infections caused by MDR strains such as methicillin-resistant S. aureus (MRSA). Our study highlights the repurposing of oxiconazole, a topical antifungal agent, as an ideal candidate for combination therapy with gentamicin against susceptible and drug-resistant S. aureus skin infections due to its extremely low propensity for resistance generation in S. aureus, activity against MDR strains, bactericidal killing kinetics alone and in combination, broad antifungal efficacy, and excellent safety and tolerability profile.

Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII.

The Carbonic anhydrase isoforms IX and XII play a significant role in regulating the intracellular and extracellular pH in hypoxic tumours abetting the metastasis of solid tumours. Selective and potent inhibitors targeting carbonic anhydrase IX and XII reduce the activity of these isoforms in hypoxic tumours, representing an antitumor and antimetastatic mechanism. Coumarin-based derivatives are selective inhibitors of CA isoforms IX and XII. In this study, we report the design and synthesis of new 3-substituted coumarin derivatives with different functional moieties and their inhibitory activity against various carbonic anhydrase isoforms. We found that the tertiary sulphonamide derivative 6c showed selective inhibition against CA IX with IC50 of 4.1 µM. Similarly, the carbothioamides 7c, 7b and oxime ether derivative 20a exhibited good inhibition against CA IX and CA XII. Additionally, the binding mode was predicted and validated using molecular docking and dynamic simulations.

A comprehensive review on potential therapeutic inhibitors of nosocomial Acinetobacter baumannii superbugs.

Acinetobacter baumannii, a Gram-negative, glucose non-fermentative coccobacilli are responsible for causing a wide range of opportunistic nosocomial infections, thus listed as a WHO "critical priority pathogen", for which identification and development of new antibacterial agents are an urgent unmet medical need. The current review attempts to present an overview of various mechanisms (enzymatic and non-enzymatic), virulence factors responsible for A. baumannii resistance. Furthermore, inhibitors of A. baumannii are categorized into different classes highlighting their MDR inhibition properties. In addition, novel adjuvants that potentiate existing antibiotics, as well as natural and synthetic compounds that limit biofilm formation in A. baumannii infections are discussed.

SmI2 -mediated C-alkylation of Ketones with Alcohols under Microwave Conditions: A Novel Route to Alkylated Ketones.

A novel protocol is developed towards the preparation of alkylated ketones from alcohols in presence of catalytic amount of SmI2 and base with the elimination of water as a single by-product under microwave irradiation conditions. Furthermore, applicability of this methodology to the synthesis of Donepezil and late-stage functionalization in Pregnenolone is also reported. Successful application of this methodology in Friedländer quinolone synthesis using 2-aminobenzyl alcohol and various acetophenones expand the synthetic utility of this protocol.

Solvent-Controlled, Tunable Domino Reaction of 3-Ylideneoxindoles with in Situ-Generated α-Aryldiazomethanes: A Facile Access to 3-Spirocyclopropyl-2-oxindole and Pyrazoloquinazolinone Scaffolds.

A mild and efficient solvent-controlled, metal-free switchable 1,3-dipolar cycloaddition/ring contraction or ring expansion domino reaction of 3-ylideneoxindoles with in situ-generated α-aryldiazomethanes has been developed. This domino reaction provided a series of aryl-substituted 3-spirocyclopropyl-2-oxindoles and pyrazoloquinazolinones with excellent regio- and diastereoselectivity from common substrates under varying solvent conditions.

Epilepsy in Punjab (India): A Population-Based Epidemiologic Study.

AIMS: To assess the prevalence of epilepsy in a rural area adjoining a city. METHODS: A door-to-door, cross-sectional epidemiological survey was carried out covering an entire rural population of 103,693 people. RESULTS: Crude period and point prevalence rates for active epilepsy were 7.67 and 7.44 per 1,000 respectively. Crude incidence rate was 60.76 per 100,000 during the year 2007. Mean, SD, median and variance were 17.2, 16, 13 and 257.6 years respectively for age at onset of active epilepsy patients. The overall prevalence patterns among males and females were not significantly different. Active epilepsy cases (n = 795) included electro-clinical syndromes and constellations (n = 117, 14.7%), symptomatic epilepsy (n = 153, 19.2%), epilepsy due to unknown cause (n = 513, 64.5%) and dual diagnosis (n = 12, 1.5%). CONCLUSIONS: The present study showed that the prevalence rate, in the rural area adjoining a city, was comparable to that of the urban area and significantly less than that of the remote rural area as described by another study. Age- and sex-specific prevalence and incidence rates were similar to the rates reported by other studies. The reason for a lower number of symptomatic cases to be reported, per this study, may be due to lack of neuroimaging.