Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world’s human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis.
Fasciotomy incisions lead to large, unsightly, chronic wounds after surgical intervention. Classic management was to use split-thickness skin grafts, but this leads to insensate skin with reports that as many as 23% of patients are dissatisfied by the appearance of the wound. Since no skin loss has occurred with the fasciotomy incision, utilizing the dermal properties of creep, stress relaxation and load cycling, closure can be achieved in a better way. We describe using dermotaxis for skin edge approximation that is done using inexpensive equipment available readily in any standard operating room. Twenty-five patients had fasciotomy wounds closed either by dermotaxis or a loop suture technique with the inclusion criteria being closed fractures, no concomitant skin loss, fracture-related compartment syndrome and fasciotomy performed within 36 h. The fasciotomy incision was closed in a single stage by loop suture technique or gradually by dermotaxis once the oedema had settled between 3 and 5 days. Results were graded as excellent if approximation could be achieved, good if sutures had to be applied for protective care and poor if wounds needed to be skin-grafted. In the dermotaxis group, results were excellent in 15, good in 8 and poor in 2 cases. In the loop suture technique group, results were excellent in 20, good in 4 and poor in 1 case. Dermal apposition using inexpensive, readily available equipment is an alternative method for closure of fasciotomy wounds. If limb oedema has settled sufficiently, closure using a loop suture can be done in a single stage. If the limb remains oedematous, gradual closure can be done using dermotaxis.
Plasmodium vivax ( Pv ) malaria continues to be geographically widespread with approximately 15 million worldwide cases annually. Along with other proteins, Duffy-binding proteins (DBPs) are used by plasmodium for RBC invasion and the parasite-encoded receptor binding regions lie in their Duffy-binding-like (DBL) domains—thus making it a prime vaccine candidate. This study explores the sequence diversity in Pv DBL globally, with an emphasis on India as it remains a major contributor to the global Pv malaria burden. Based on 1358 Pv DBL protein sequences available in NCBI, we identified 140 polymorphic sites within 315 residues of Pv DBL. Alarmingly, country-wise mapping of SAAPs from field isolates revealed varied and distinct polymorphic profiles for different nations. We report here 31 polymorphic residue positions in the global SAAP profile, most of which map to the Pv DBL subdomain 2 ( α 1– α 6). A distinct clustering of SAAPs distal to the DARC-binding sites is indicative of immune evasive strategies by the parasite. Analyses of Pv DBL-neutralizing antibody complexes revealed that between 24% and 54% of interface residues are polymorphic. This work provides a framework to recce and expand the polymorphic space coverage in Pv DBLs as this has direct implications for vaccine development studies. It also emphasizes the significance of surveying global SAAP distributions before or alongside the identification of vaccine candidates.
BackgroundIn bacteria polyphosphates (poly-P) are involved in cellular metabolism and development especially during stress. The enzyme, principally involved in polyphosphate biosynthesis and its mobilization leading to generation of NTPs, is known as polyphosphate kinase (PPK).Principal FindingsAmong two genes of polyphosphate kinases present in Mycobacterium tuberculosis, we cloned and expressed PPK1 in Escherichia coli as histidine-tagged protein. This ∼86 kDa protein is capable of autophosphorylation and synthesis of poly-P as well as NTP. Among 22 conserved histidine residues, we found only His-491 is autophosphorylated and crucial for any enzymatic activity. Substitution of His-510 caused mPPK1 protein deficient but not defective in autophosphorylation, thereby contrary to earlier reports negating any role of this residue in the process. However, mutation of His-510 with either Ala or Gln affected ATP or poly-P synthesis depending on the substitution; while such effects were severe with H510A but mild with H510Q. Furthermore, mPPK1 also renders auxiliary nucleotide diphosphate kinase function by synthesizing virtually all NTPs/dNTPs from their cognate NDPs/dNDPs by utilizing poly-P as the phosphate donor albeit with varied efficiency. To assess the influence of other catalytic domain residues of mPPK1 towards its functionality, we designed mutations based on E. coli PPK1 crystal structure since it owes 68% amino acid sequence similarity with mPPK1. Interestingly, our results revealed that mutations in mPPK1 affecting poly-P synthesis always affected its ATP synthesizing ability; however, the reverse may not be true.Conclusions/SignificanceWe conclude that amino acid residues involved in poly-P and ATP synthesizing activities of mPPK1 are distinct. Considering conserved nature of PPK1, it seems our observations have broader implications and not solely restricted to M. tuberculosis only.
310 cases of chronic middle ear disease were managed by Intact canal wall tympanomastoid surgery. Intact canal wall tympanomastoid surgery technique used in this study has been compared with the Jansen's classic ICW technique. A retrospective analysis of 310 cases of chronic middle ear pathology managed by Intact canal wall technique over a period of 10 years (January 1996 to December 2005) was conducted. Patients information was collected from the patients record. 310 patients, aged 5-60 years, were managed by Intact canal wall technique and followed for a minimum period of 5 years. The male:female ratio in our study was 1.25:1 (172 males:138 females). The ratio of adult to pediatric patients was 2.7:1 (226 adults:84 children). Out of 274 (88.4%) cases having a regular follow up, 196 (71.6%) were found to be stable. Postoperative retraction of the tympanic membrane was observed in 24 (8.8%) cases and was managed by the placement of ventilation tube. Secretory otitis media was seen in 14 (5%) cases and was managed by myringotomy and placement of ventilation tube. 17(12.4%) cases were revised including recurrent disease (10 cases), residual disease (6 cases), graft failure (12 cases), stenosis of the ear canal (4 cases), meatomastoid fistula (2 case). Our technique of Intact canal wall tympanomastoid surgery takes less time than the classic Jansen's technique, is easily reproducible and taught, is a single stage procedure and can be universally applied to various chronic middle ear pathologies as the primary treatment with low recidivism rate.
Even with symptoms of spinal cord compression, some patients with TB infection of the posterior elements of vertebrae can be managed medically without surgery.
Transnasal endoscopic repair of cerebrospinal fluid fistula is recommended for patients with post-traumatic cerebrospinal fluid leaks who do not respond to conservative treatment. It is a safer and more successful alternative to transcranial surgery. We present our experience of using septal cartilage and temporalis fascia in this transnasal endoscopic approach for the repair of the large defect of anterior skull base cerebrospinal fistula and meningoencephalocele. Use of microdebrider is highlighted in the technique for the debridement of the encephalocele and complete exposure of the defect.
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