Parasitic nematode transglutaminase proteins and uses thereof

The present invention relates to parasitic nematode transglutaminase proteins; to parasitic nematode transglutaminase nucleic acid molecules, including those that encode such transglutaminase proteins; to antibodies raised against such transglutaminase proteins; and to compounds that inhibit parasitic nematode transglutaminase activity. The present invention also includes methods to obtain such proteins, nucleic acid molecules, antibodies, and inhibitory compounds. Also included in the present invention are therapeutic compositions comprising such proteins, nucleic acid molecules, antibodies and/or inhibitory compounds as well as the use of such therapeutic compositions to protect animals from diseases caused by parasitic nematodes. This invention also relates to the surprising discovery that parasitic nematode transglutaminase proteins have protein disulfide isomerase activity. Accordingly, this invention relates further to inhibitors of the protein disulfide isomerase activity of said transglutaminases.Board of Regents, University of Texas Syste

A cross-sectional survey of Indian orthopaedicians to understand the place in therapy for the latest soft gel formulation of etoricoxib

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for arthritis (RA), osteoarthritis (OA), low back pain (LBP) and other musculoskeletal disorders. Novel formulations such as soft gel formulations are being introduced for NSAIDs in place of the traditional tablet formulation. The objective of this study was to quantify orthopaedicians insights for the recently available soft gel formulation of Etoricoxib.Methods: The questions for the survey instrument (Google forms) were developed by researchers upon review of scientific literature and subsequent discussions with practicing orthopaedicians. This was a cross-sectional digital survey involving 506 orthopaedicians across India via online responses collated via Google forms.Results: 81.4% doctors agreed that etoricoxib soft gel capsules are faster acting than the tablet formulation, whereas 89.6% of the doctors agree/strongly agreed that etoricoxib soft gel capsules would have better compliance because of its bitter taste masking ability. More than 96% doctors acknowledged that etoricoxib soft gel capsule’s characteristics such as higher drug dissolution and absorption would benefit their patients more than the etoricoxib tablet formulation.Conclusions: Given its advantages, the etoricoxib soft gel formulation, in the days to come, could be one of the preferred options for the management of pain and other arthritic conditions for patients in India

To study the clinicoetiological profile of children admitted with bleeding diathesis

 Background: Bleeding complications in children may be caused by disorders of secondary hemostasis or fibrinolysis. A child who presents with bleeding warrants evaluation for a significant bleeding problem. Objectives: The aim is to study the clinicoetiological profile of children admitted with bleeding diathesis. Materials and Methods: Children up to the age of 14 years presenting in the Department of Pediatrics, Pandit B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, with hemorrhagic diathesis, that is, non-traumatic spontaneous bleeding, suspected to be either due to the defective primary hemostatic mechanism (platelet– blood vessel interaction) or defective secondary hemostatic mechanism, were enrolled for this study. Frequency distribution of various bleeding disorders in various age groups was studied. Results: A total of 92 children up to the age of 14 years were taken up for study, of which, maximum cases with bleeding presented with hematemesis (23.9%) followed by melena (22.8%). A total of 73 children (79.34%) presented with skin and joint bleeds. We were able to make diagnosis in 82 children (89.1%). Among 82 patients, 31 (37.8%) had bleeding secondary to infections, 11 (13.4%) had coagulation disorder, 9 (10.97%) had Henoch–Schonlein purpura (HSP) and immune thrombocytopenic purpura (ITP) each, 6 (7.3%) had hypoplastic bone marrow, 2 (2.4%) had chronic malaria, 4 (4.9%) had leukemia, 6 (7.3%) had liver diseases, and 6 (7.3%) had hemorrhagic disease of newborn (HDN). Almost half of the children with bleeding manifestations in each age group had thrombocytopenia. The most common causes of bleeding in <1 year were septicemia with thrombocytopenia and HDN; among 1-7 years were infections, ITP, and coagulation disorders; and in more than 7 years were HSP, ITP, liver disease, and hemolytic-uremic syndrome. Conclusion: Our study foundthat the gastrointestinal tract was the most common site of bleeding in children presenting with non-traumatic spontaneous bleed, and thrombocytopenia was present in 50% of the cases in each age group. We also found that infections were the most common cause of bleeding in younger children, whereas immunological causes and coagulation disorders predominate in older children. Hence, while evaluating any child with bleeding, age at presentation is also an important parameter to find the etiological diagnosis.&nbsp

Tissue transglutaminase-induced alterations in extracellular matrix inhibit tumor invasion

BACKGROUND: Alterations in the extracellular matrix (ECM) can affect host-tumor interactions and tumor growth and metastasis. Tissue transglutaminase (TG2, EC 2.3.2.13), a calcium-dependent enzyme that catalyzes covalent cross-linking of proteins, can render the ECM highly stable and resistant to proteolytic degradation. So we determined whether TG2 expression in a tumor or nontumor (stroma) environment could affect the process of metastasis. Two hundred archived samples from patients with breast cancer were studied for the TG2 expression. Also, in an in vitro model the invasive behavior of MDA-MB-231 cells in the presence or absence of exogenous TG2 was determined. RESULTS: Tumors associated with negative nodes showed significantly higher expression of TG2 in the stroma (P < 0.001). TG2 in the stroma was catalytically active, as revealed by the presence of isopeptide cross-links. Pretreatment of Matrigel with catalytically active TG2 resulted in strong inhibition of invasion of MDA-MB-231 cells through the Matrigel Transwell filters. CONCLUSION: TG2-induced alterations in the ECM could effectively inhibit the process of metastasis. Therefore, selective induction of catalytically active TG2 at the site of tumor may offer promising approach for limiting the metastasis

To study the clinical profile of children with pleural effusion at a Tertiary Care Center in North India: A prospective study

Introduction: Pleural effusion is the most common manifestation of pleural disorders and is mostly secondary to bacterial infections&nbsp;in children. Aims and Objectives: The primary objective was to study the clinical presentation of pleural effusion in hospitalized&nbsp;children. The secondary objective was to establish the etiology. Methods: A prospective observational study conducted from&nbsp;April 2014 to September 2015. Children &gt;1 month and &lt;14 years diagnosed to have pleural effusion on clinical and radiological&nbsp;examination were included in the study. Data regarding demographic profile, presenting complaints, immunization history,&nbsp;anthropometry, biochemical and radiological investigations, and the outcome of the patients were collected. Results: Seventy-five&nbsp;patients were included in this study. The mean age of the patients was 69.97±48.23 months. Regarding etiology of pleural effusion,&nbsp;it was parapneumonic in 35 (46.6%), empyema in 18 (24%), transudative in 12 (16%), tubercular in 9 (12%), and malignant&nbsp;(non-Hodgkin’s lymphoma) in 1 (1.3%) case. The presenting complaints were fever (82.6%), cough (78.7%), respiratory distress&nbsp;(69.3%), chest pain (36%), and abdominal pain (9.3%). There was no sex predominance. About 16% patients were severely&nbsp;malnourished. Severe anemia was present in 5 (6.7%) patients. None of them required decortication surgery, and none of the patients&nbsp;expired during hospitalization. Conclusion: Pleural effusion is a major health problem with parapneumonic effusion still beingthe most common etiology. Our study also confirmed that fever, cough, and respiratory distress were the most common presenting&nbsp;complaints and most of the children were malnourished. A high index of suspicion is required to avoid delays in diagnosis that may&nbsp;influence treatment and outcome

A cross-sectional survey of orthopaedicians to understand the prescribing pattern of disease modifying osteoarthritis drugs in osteoarthritis

Background: Numerous dietary supplements with disease-modifying action are available in Indian market. However, doctor’s preferences for these disease modifying osteoarthritis drugs (DMOADs) to prevent progression of OA are not known. The objective of this study was to quantify doctor preferences for potential DMOADs.Methods: The survey instrument (online survey questionnaire at survey monkey) was developed by researchers upon review of existing literature and detailed discussion with practicing clinicians. Face and content validity and reliability (test-retest method) was assessed through a focused panel of clinicians to determine if content was adequate to obtain the necessary data. This was a cross-sectional digital survey of 207 orthopaedicians during Indian Orthopaedic Association Conference-2018 organized at Coimbatore.Results: NSAIDs + DMOAD combinations were the most preferred treatment option for newly diagnosed OA patients. 44% orthopaedicians prefer to start the treatment with combination of NSAID and DMOAD as compared to 10% with paracetamol monotherapy. Glucosamine/chondroitin combinations are the most commonly preferred DMOAD by the orthopaedicians; followed by undenatured type II collagen. 66% of the doctors surveyed opined that the efficacy of undenatured type-II collagen is better as compared to other DMOADs.Conclusions:The findings from the survey suggest that majority of orthopaedicians prefer to prescribe NSAID with DMOAD combinations for newly diagnosed osteoarthritis patients.

Role of nutritional supplements in the management of tendinopathies: focus on combination of type 1 collagen, vitamin C and mucopolysaccharides

Tendinopathy is a common disease that is difficult to manage due to its recurrent nature. It is associated with increased healthcare costs and significantly impacts quality of life of patients. Also, according to recent studies patients with high cholesterol and diabetes are at a higher risk of developing tendinopathy. There has been rise in the incidence of tendinopathies due to increase in sport activities, life expectancy and some other factors (environment, diet and some drug therapies). Approximately 30% of visits for musculoskeletal pain in general practice are related to tendon injury. Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids remain the mainstay of treatment. Despite the use of current therapies, there is need of a supportive therapy that can help in the healing process towards development of physiologically normal tendons. Nutraceuticals have been used as supportive therapy for management of tendinopathies. This review focuses on the management of tendinopathy with special attention on role of nutraceuticals such as type I collagen, mucopolysaccharides and vitamin C in the management of tendinopathy. Clinical data suggests that this combination (type I collagen, mucopolysaccharides and vitamin C) promotes the endogenous synthesis of collagen type I, avoiding the accumulation of collagen type III and aggrecan, thus interfering with the degeneration of tendon tissue. Based on the available clinical data, combination of type I collagen, mucopolysaccharides and vitamin C not only reduce the clinical symptoms but also improve structural evolution of different types of tendinopathies as well as plantar fascitis

Efficacy and safety of intravenous and/or oral levonadifloxacin in the management of secondary bacterial pulmonary infections in COVID-19 patients: findings of a retrospective, real-world, multi-center study

Background: Owing to dysregulated immune response, secondary bacterial pulmonary infections involving both gram-positive and gram-negative pathogens are common in COVID-19 patients and are often associated with higher mortality. This is a first ever report on the safety and efficacy of levonadifloxacin in the treatment of secondary bacterial pulmonary infections in patients with COVID-19 pneumonia.Methods: This multi-center, retrospective, post-marketing and real-world study assessed the safety and efficacy of IV and/or oral levonadifloxacin in the treatment of bacterial infections encountered in COVID-19 patients. Data for 154 male/female patients above 18 years of age who received levonadifloxacin (injectable and/or oral) was collected from 44 participating sites. Study outcomes were the clinical and microbial success at the end of therapy. Safety was assessed based on clinical and laboratory adverse events.Results: Among the 154 patients assessed, 121 (78.6%) were males and 142 (92.2%) were hospitalized. Majority of the patients (119) received all-IV therapy while 11 patients were prescribed with IV followed by oral regimen. All-oral therapy was received by 24 patients. The most common co-morbid conditions were diabetes (19.6%) and hypertension (19.2%). Post-treatment with levonadifloxacin, clinical and microbial success rates were 96.8% and 97.0% respectively.Conclusions: Levonadifloxacin showed promising safety and efficacy when used as IV and/or oral therapy for the treatment of secondary bacterial pulmonary infections in COVID-19 patients. Clinically relevant features of levonadifloxacin such as availability of both IV and oral options, broad spectrum coverage and reassuring safety in patients with significant co-morbidities could help simplify the management.Trial registration no. CTRI/2020/09/028152 [Registered on: 30/09/2020]

Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells

INTRODUCTION: The expression of proinflammatory protein tissue transglutaminase 2 (TG2) is frequently upregulated in multiple cancer cell types. However, the exact role of TG2 in cancer cells is not well-understood. We recently initiated studies to determine the significance of TG2 in cancer cells and observed that sustained expression of TG2 resulted in epithelial-to-mesenchymal transition (EMT) and promoted cancer stem cell (CSC) traits in mammary epithelial cells. These results suggested that TG2 could serve as a promising therapeutic target for overcoming chemoresistance and inhibiting metastatic spread of cancer cells. METHODS: Using various mutant constructs, we analyzed the activity of TG2 that is essential for promoting the EMT-CSC phenotype. RESULTS: Our results suggest that catalytically inactive TG2 (TG2-C277S) is as effective as wild-type TG2 (TG2-WT) in inducing the EMT-CSC in mammary epithelial cells. In contrast, overexpression of a GTP-binding-deficient mutant (TG2-R580A) was completely incompetent in this regard. Moreover, TG2-dependent activation of the proinflammatory transcription factor NF-κB is deemed essential for promoting the EMT-CSC phenotype in mammary epithelial cells. CONCLUSIONS: Our results suggest that the transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide a strong rationale for developing small-molecule inhibitors to block GTP-binding pockets of TG2. Such inhibitors may have great potential for inhibiting the TG2-regulated pathways, reversing drug resistance and inhibiting the metastasis of cancer cells