Regulation of NOXO1 Activity through Reversible Interactions with p22phox and NOXA1

Reactive oxygen species (ROS) have been known for a long time to play important roles in host defense against microbial infections. In addition, it has become apparent that they also perform regulatory roles in signal transduction and cell proliferation. The source of these chemicals are members of the NOX family of NADPH oxidases that are found in a variety of tissues. NOX1, an NADPH oxidase homologue that is most abundantly expressed in colon epithelial cells, requires the regulatory subunits NOXO1 (NOX organizing protein 1) and NOXA1 (NOX activating protein 1), as well as the flavocytochrome component p22phox for maximal activity. Unlike NOX2, the phagocytic NADPH oxidase whose activity is tightly repressed in the resting state, NOX1 produces superoxide constitutively at low levels. These levels can be further increased in a stimulus-dependent manner, yet the molecular details regulating this activity are not fully understood. Here we present the first quantitative characterization of the interactions made between the cytosolic regulators NOXO1 and NOXA1 and membrane-bound p22phox. Using isothermal titration calorimetry we show that the isolated tandem SH3 domains of NOXO1 bind to p22phox with high affinity, most likely adopting a superSH3 domain conformation. In contrast, complex formation is severely inhibited in the presence of the C-terminal tail of NOXO1, suggesting that this region competes for binding to p22phox and thereby contributes to the regulation of superoxide production. Furthermore, we provide data indicating that the molecular details of the interaction between NOXO1 and NOXA1 is significantly different from that between the homologous proteins of the phagocytic oxidase, suggesting that there are important functional differences between the two systems. Taken together, this study provides clear evidence that the assembly of the NOX1 oxidase complex can be regulated through reversible protein-protein interactions

Outcomes of early active mobilization after surgical repair of injured extensor tendon of hand and forearm

Background: Extensor tendon injuries in the hand and forearm, if left untreated, can significantly impair backhand function. Timely and effective treatment is crucial. Recent evidence suggests that early active mobilization post-surgery yields better short-term outcomes, with less disparity in long-term results. Methods: This prospective observational study was conducted at the department of orthopedic surgery, BSMMU, Dhaka, Bangladesh, from March 2014 to August 2016, with a total of 40 patients. Results: The study evaluated the efficacy of early active mobilization following surgical repair of extensor tendon injuries in zones V-VIII of the hand and forearm. At 12 weeks post-surgery, 75% of patients reported no pain, increasing to 90% at 6 months and stabilizing at 85% by 12 months. Furthermore, 75% of patients regained a range of motion greater than 120 degrees at 6 months, with 60% maintaining this at 12 months. Notably, 90% of the patients maintained normal grip strength at both 6 and 12 months. Final assessments using the Mayo wrist score showed satisfactory outcomes for 70% of patients at 12 weeks, 90% at 6 months, and 95% at 12 months. The Dargan criteria echoed these positive results, with satisfaction rates of 80% at 12 weeks, 90% at 6 months, and 95% at 12 months. Complications were minimal, including superficial skin infections (5%), hypertrophic scars (10%), and tendon rupture (5%). Conclusions: The study concludes that early active mobilization, complemented by a simple static splint, facilitates faster recovery, full range of motion, improved grip strength, and earlier return to work in the early postoperative period

Shigella dysenteriae Serotype 1, Kolkata, India

Since July 2002, bacteriologically confirmed shigellosis cases have increased, and multidrug-resistant Shigella dysenteriae serotype 1 strains have reemerged in patients hospitalized with diarrhea in Kolkata, India. The isolated strains of S. dysenteriae 1 showed resistance to chloramphenicol (80%), ampicillin (100%), tetracycline (100%), co-trimoxazole (100%), nalidixic acid (100%), norfloxacin (100%), and ciprofloxacin (100%). Emergence of fluoroquinolone resistance in S. dysenteriae 1 strains complicated treatment of shigellosis patients. Six strains belonging to provisional serovars of S. dysenteriae were also identified for the first time in patients hospitalized with diarrhea in Kolkata, India

Visceral Leishmaniasis

Clinically, leishmaniasis is of three types—visceral leishmaniasis (VL) or kala-azar, cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Post-kala-azar dermal leishmaniasis (PKDL) is considered as a complication of VL. VL is characterized by fever, anemia and splenomegaly in a VL-endemic area (malaria excluded). A subject with such symptoms should be subjected to an rK39 strip test. Confirmation of diagnosis is made by demonstration of the parasite (Leishmania donovani) from samples obtained by aspiration of bone marrow or iliac crest puncture. Miltefosine, stibogluconate, amphotericin B, liposomal amphotericin B and paromomycin are effective available anti-leishmaniasis drugs. Vector (Phleblotomus argentipes) control for reduction of transmission and early diagnosis and complete treatment are essential elements of case management. There is no effective vaccine against VL. This review on VL aims at providing state-art knowledge on epidemiology, diagnosis and case-management and vaccine development

IN-VIVO CHARACTERIZATION OF TOTAL PROTEIN, ALBUMIN CONTENT, LIPID PROFILE AND ENZYMATIC PROPERTY OF BALAJIRAKADI KVATHA CURNA (BLJ) IN ALBINO RAT PLASMA

The study was devised to evaluate the effect of total protein, albumin content, enzymatic property and lipid profile in rats plasma after chronic administration of Balajirakadi Kvatha Curna (BLJ), a classical Ayurvedic preparation that is widely used in cough. The drug was administered per oral route at a dose of 40 ml/kg of the body weight for 45 consecutive days. Eight-week old albino rats (Rattus novergicus : Sprague - Dawley strain,) of both sexes, bred and maintained at the Animal House of the Department of Pharmacy, Jahangirnagar University were used for the experiment. All experiments on rats were carried out in absolute compliance with the ethical guide for care and use of laboratory animals. After the administration of BLJ preparation for a period of 45 days, the following biochemical parameters (protein, albumin, triglyceride, cholesterol, LDL, VLDL, HDL, sGPT sGOT and ALP) in the plasma of both the male and female rats were determined. An increased level of Total protein, the Albumin content and triglyceride in the plasma found in the both male and female rats, none of these changes were significantly different from their corresponding control values but noticeable. On the contrary in both female and male rats the decreased level in the total Cholesterol, VLDL, LDL and HDL was noticed and among which Total Cholesterol and VLDL are significant. Surprisingly the LDL content was almost similar to the corresponding control value and decrease in HDL was not significant. A statistically very highly significant increase in the sGPT sGOT and ALP activities in the plasma of male rats was found while in the female rats it has been showed a statistically very highly significant decrease in sGPT and sGOT but ALP activities in the plasma was statistically insignificant

Use of oral cholera vaccine as a vaccine probe to define the geographical dimensions of person-to-person transmission of cholera.

BACKGROUND: Cholera is known to be transmitted from person to person, and inactivated oral cholera vaccines (OCVs) have been shown to confer herd protection via interruption of this transmission. However, the geographic dimensions of chains of person-to-person transmission of cholera are uncertain. The ability of OCVs to confer herd protection was used to define these dimensions in two cholera-endemic settings, one in rural Bangladesh and the other in urban India. METHODS: Two large randomized, placebo-controlled trials of inactivated OCVs, one in rural Matlab, Bangladesh and the other in urban Kolkata, India, were reanalyzed. Vaccine herd protection was evaluated by relating the risk of cholera in placebo recipients to vaccine coverage of surrounding residents residing within concentric rings. In Matlab, concentric rings in 100-m increments up to 700m were evaluated; in Kolkata, 50-m increments up to 350m were evaluated. RESULTS: One hundred and eight cholera cases among 24667 placebo recipients were detected during 1year of post-vaccination follow-up at Matlab; 128 cholera cases among 34968 placebo recipients were detected during 3 years of follow-up in Kolkata. Consistent inverse relationships were observed between vaccine coverage of the ring and the risk of cholera in the central placebo recipient for rings with radii up to 500m in Matlab and up to 150m in Kolkata. CONCLUSIONS: These results suggest that the dimensions of chains of person-to-person transmission in endemic settings can be quite large and may differ substantially from setting to setting. Using OCVs as 'probes' to define these dimensions can inform geographical targeting strategies for the deployment of these vaccines in endemic settings

Immune responses to Vi capsular polysaccharide typhoid vaccine in children 2 to 16 years old in Karachi, Pakistan, and Kolkata, India

The geometric mean concentration (GMC) and the proportion maintaining a protective level (150 enzyme-linked immunosorbent assay (ELISA) units [ELU]/ml) 2 years following a single dose of 25 μg of injectable Vi capsular polysaccharide typhoid vaccine was measured against that of the control hepatitis A vaccine in children 2 to 16 years old in cluster randomized trials in Karachi and Kolkata. The GMC for the Vi group (1,428 ELU/ml) was statistically significantly different from the GMC of the control hepatitis A vaccine group (86 ELU/ml) after 6 weeks. A total of 117 children (95.1%) in the Vi group and 9 (7.5%) in the hepatitis A group showed a 4-fold rise in Vi IgG antibody concentrations at 6 weeks (P \u3c 0.01). Protective antibody levels remained significantly different between the two groups at 2 years (38% in the Vi vaccine groups and 6% in the hepatitis A group [P \u3c 0.01]). A very small proportion of younger children (2 to 5 years old) maintained protective Vi IgG antibody levels at 2 years, a result that was not statistically significantly different compared to that for the hepatitis A group (38.1% versus 10.5%). The GMCs of the Vi IgG antibody after 2 years were 133 ELU/ml for children 2 t