Decreased protein C function predicts mortality in patients with cirrhosis.

INTRODUCTION: Protein C (PrC), a physiological anticoagulant, regulates inflammation and cell death and has known predictive/therapeutic roles in sepsis. Accumulating evidences suggest plasma hypercoagulability results in progression of fibrosis and formation of microclots causing end-organ dysfunction. We investigated a possible association between natural anticoagulants-PrC, protein S (PrS) and antithrombin III (AT)-and clinical outcomes in cirrhotics. METHODS: Functional PrC, PrS and AT were analysed in 515 cirrhotic patients and compared with 229 noncirrhotics. Among those with cirrhosis, we conducted multivariable predictive model on 3-month survival to assess the prognostic ability of anticoagulants. RESULTS: Protein C (P < .001), PrS (P < .001) and AT (P < .001) levels were lower in cirrhotics compared with noncirrhotics. In addition, patients with Child-Pugh (CP)-C had significantly lower (P < .05) functional PrC, PrS and AT levels than CP-B, CP-A and noncirrhotic patients. Low PrC function correlated with markers of liver dysfunction and inflammation: INR(r = -.72, P < .001), bilirubin (r = -.620, P < .001), albumin (r = .539, P < .001), creatinine (r = -.417, P < .001), ferritin (r = -.68, P = .035), procalcitonin (r = -.79, P = .01), raised ESR (r = .56, P < .001) and liver fibrosis (r = -.840, P < .001). Patients who died (n = 160) had significantly lower median PrC function (23.8%, 16.3-33.0]) compared with those who remained alive (74.9%, [59.7-92.5]); P < .001. In a multivariable predictive model using PrC, and MELD score, we found a significant impact of low PrC levels on survival (P < .001, IRR = 0.97, 95% CI = 0.96-0.98). Receiver operating characteristic (ROC) curve analysis revealed that functional PrC levels <52% were associated with increased mortality (P < .001). CONCLUSION: Low functional protein C level correlated with markers of liver dysfunction, inflammation and sepsis and independently predicted mortality at 3 months in cirrhotics, especially if functional levels were <52%.

Biochemical and structural studies of Mycobacterium smegmatis MutT1, a sanitization enzyme with unusual modes of association.

Mycobacterium smegmatis MutT1, which is made up of a Nudix domain (domain 1) and a histidine phosphatase domain (domain 2), efficiently hydrolyses 8-oxo-GTP and 8-oxo-dGTP to the corresponding nucleoside diphosphates and phosphate in the presence of magnesium ions. Domain 1 alone hydrolyses nucleoside triphosphates less efficiently. Under high concentrations and over long periods, the full-length enzyme as well as domain 1 catalyses the hydrolysis of the nucleoside triphosphates to the respective nucleoside monophosphates and pyrophosphate. The role of domain 2 appears to be limited to speeding up the reaction. Crystal structures of the apoenzyme and those of ligand-bound enzyme prepared in the presence of 8-oxo-GTP or 8-oxo-dGTP and different concentrations of magnesium were determined. In all of the structures except one, the molecules arrange themselves in a head-to-tail fashion in which domain 1 is brought into contact with domain 2 (trans domain 2) of a neighbouring molecule. The binding site for NTP (site A) is almost exclusively made up of residues from domain 1, while those for NDP (site B) and NMP (site C) are at the interface between domain 1 and trans domain 2 in an unusual instance of intermolecular interactions leading to binding sites. Protein-ligand interactions at site A lead to a proposal for the mechanism of hydrolysis of NTP to NDP and phosphate. A small modification in site A in the crystal which does not exhibit the head-to-tail arrangement appears to facilitate the production of NMP and pyrophosphate from NTP. The two arrangements could be in dynamic equilibrium in the cellular milieu.

A study of the outbreak of Chikungunya fever.

BACKGROUND AND OBJECTIVES: Chikungunya fever occurred in an epidemic form in the state of Maharashtra after a gap of about 32 years. Many cases with symptoms which were suggestive of Chikungunya fever were reported from the village Kasegaon, Dist Sangli, Maharashtra, India. Hence, this study was done to assess the magnitude of the outbreak and to identify the possible socio-environmental factors which are responsible for Chikungunya fever. MATERIAL AND METHODS: This cross sectional study was carried out at Kasegaon by a team from the Krishna Institute of Medical Sciences, Karad, Maharashtra, in collaboration with the Primary Health Centre, Kasegaon, Distt. Sangli. RESULTS AND CONCLUSION: The Chikungunya prevalence was 9.6%. There were 154 clinically suspected Chikungunya fever cases. Of these, 54.5% were males and 45.5% were females. About 72.7% of the cases were in the age range of 11-50 years, which is the active age group. The main symptoms were an acute onset of fever with joint pain (100%). Multiple joints were involved in (89.6%) cases. The mean duration of the fever was 3 days (range 1-10 days). About 40.3% people preferred to consult a government health facility. In the affected area, 83.1% people were aware of Chikungunya fever. Only few (1.1%) knew the vectors which were responsible for the Chikungunya transmission. Among the people in the affected area, 33.1% had knowledge on insecticide spraying, 23.2% had knowledge on the use of mosquito nets and repellents, 12.5% had knowledge on source reduction and 0.8% had knowledge on larvicides.

Surgical management of Stenson's duct injury using epidural catheter: a novel technique.

Stenson's duct of parotid gland is a major duct which drains saliva into the oral cavity. Deep penetrating wound in the form of cut or crush injury to the buccal area carries the risk of parotid duct injury. It is in the form of ductal exposure, laceration, total severing, or crushing of the duct. These conditions are difficult to diagnose because of complex anatomy and variable nature of injury. Successful management of parotid duct injury depends on early diagnosis and appropriate intervention, failing of which may lead to complications like sialocele or salivary fistula. Many techniques have been proposed for diagnosis and management of parotid duct injuries. This article presents an easy and novel technique to diagnose and manage the parotid duct injuries using an "epidural catheter" which is often used for inducing spinal anesthesia. The technique of epidural catheter usage, its advantages, and limitation over other techniques proposed for the management of parotid duct injury are discussed.

Crystallization and preliminary X-ray studies of MutT1 (MSMEG_2390) from Mycobacterium smegmatis.

MutT1 (MSMEG_2390) from Mycobacterium smegmatis has been crystallized and the crystals have been characterized using X-ray diffraction. The crystals belonged to space group P2(1)2(1)2(1). The Matthews coefficient suggested the possibility of one protein molecule in the asymmetric unit of the orthorhombic unit cell. Solution of the structure using the known three-dimensional structure of a bacterial MutT1 is anticipated.

Development of botanical principles for clinical use in cancer: where are we lacking?

Development of drugs from plant sources (botanicals) for the treatment of cancer has not been successful in India, despite a plethora of medicinal plants and an equal number of experiments demonstrating anti-cancer activity of plant principles in vitro. There are several pitfalls in our approach to botanical drug development. Foremost is the lack of industry-academia collaborations in this field. Research goals in Indian academic institutions are generally short-term and mostly aimed at fulfilling the minimum requirements of a doctoral/MD or MPharm thesis. Secondly, quality assurance of herbal formulations is difficult to achieve and good manufacturing practices are expensive to implement. This could introduce bias during the biological evaluation of botanicals. A systematic approach covering a wide range of investigations including but not limited to mechanistic studies, potential herb-drug interactions, pharmacokinetics and bioavailability could help in the optimization of herbal formulations in the preclinical stage of development before they can be considered for clinical trials. Government initiatives such as Ayurveda, Unani, Siddha and Homeopathic have encouraged research in these areas, but are insufficient to promote focused and aggressive evaluation of potential herbs. Particular emphasis should be given to clinical pharmacokinetics, drug interactions and clinical trials in specific cancers for the evaluation of dosage, safety, efficacy and concomitant use with chemotherapy. Only such policies can result in meaningful evaluation of botanicals for cancer therapy.

Statistical analysis of RR series variability in spinal cord injured persons.

Disabled persons with spinal cord injury are prone to cardiovascular dysfunction and an increased risk of cardiovascular disease. Rehabilitation of the disabled person is a critical task as it involves multiple therapies. Physical exercise is an important component of rehabilitation, and depends on cardiovascular health. Reduced RR variability is a marker of poor cardiac health. Time domain RR variability analysis of 38 normal healthy subjects and 20 spinal cord injured subjects has been carried out and compared. In this study, RR intervals were recorded in three different modes or positions: supine, sitting and five-second rhythm respiration. At a time of 150 s RR interval data were acquired in each mode and analysed. Statistical parameters (mean, HR, STD, NN50 and pNN50) were calculated. It was observed that most of the indices were significantly and substantially altered in spinal cord injured persons.