Optimization of warfarin dose by population-specific pharmacogenomic algorithm.

To optimize the warfarin dose, a population-specific pharmacogenomic algorithm was developed using multiple linear regression model with vitamin K intake and cytochrome P450 IIC polypeptide9 (CYP2C9(*)2 and (*)3), vitamin K epoxide reductase complex 1 (VKORC1(*)3, (*)4, D36Y and -1639 G>A) polymorphism profile of subjects who attained therapeutic international normalized ratio as predictors. New algorithm was validated by correlating with Wadelius, International Warfarin Pharmacogenetics Consortium and Gage algorithms; and with the therapeutic dose (r=0.64, P<0.0001). New algorithm was more accurate (Overall: 0.89 vs 0.51, warfarin resistant: 0.96 vs 0.77 and warfarin sensitive: 0.80 vs 0.24), more sensitive (0.87 vs 0.52) and specific (0.93 vs 0.50) compared with clinical data. It has significantly reduced the rate of overestimation (0.06 vs 0.50) and underestimation (0.13 vs 0.48). To conclude, this population-specific algorithm has greater clinical utility in optimizing the warfarin dose, thereby decreasing the adverse effects of suboptimal dose.

Current status of malaria control.

Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.

DBU-assisted cyclorelease elimination: combinatorial synthesis and gamma-glutamyl cysteine synthetase and glutathione-S-transeferase modulatory effect of C-nucleoside analogs.

A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial gamma-GCase, whereas, most of them stimulated filarial GSTs.

Study of tumour ploidy in early stages of buccal mucosa cancer.

The purpose of this study was to determine whether a tumour's DNA content is a prognostic factor in screening out the biologically aggressive varieties of early buccal mucosa cancer. Seventy-eight cases of early squamous cell carcinoma of the buccal mucosa were studied, including 73 with aneuploid and diploid tumours. T1 and T2 tumours, pathological differentiation, vascular and perineural invasion, and the recurrence and disease-free survival rate in relation to aneuploid and diploid content were ascertained. The recurrence rate in aneuploid tumours is 72%, whereas in diploid tumours it is 6% (P<0.001). A Cox regression analysis demonstrated that tumour ploidy was a prognostic factor in disease-free survival, independent of other clinico-pathological characteristics examined. Aneuploidy is the most accurate predictor of biological aggressiveness of cancer of the buccal mucose. Aneuploid early buccal mucosa cancers should be treated by multimodal therapy to achieve a cure.

Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective randomized trial.

Squamous cell carcinoma of the buccal mucosa is a common cancer in India. We are referred a large number of locally advanced lesions where curative surgery is still possible. The objective of this study is to determine the role of post-operative radiotherapy in enhancing disease-free survival. Patients with stages III and IV cancer of the buccal mucosa potentially curable by surgery were randomized to surgery only or post-operative radiotherapy. Patients were followed up for 3 years. The clinico-pathological features in both arms were comparable. Disease-free survival at the end of the study was found to be 38% and 68% (P<0.005) respectively. Post-operative radiotherapy was thus seen to improve disease-free survival in squamous cell carcinoma of the buccal mucosa.

Tumour thickness and relationship to locoregional failure in cancer of the buccal mucosa.

AIMS: The TNM system is the main parameter in treatment planning and the prediction of survival in oral cancer. Here, we investigate the role of tumour thickness as a predictor of locoregional failure and survival in node-negative patients. METHODS: We studied 176 node-negative and early stage gingivo-buccal squamous cell carcinoma patients retrospectively. Clinico-pathological factors investigated for tumour failure prediction were: T stage; tumour differentiation; tumour thickness; and treatment. Tumour thickness was measured using an ocular micrometer. RESULTS: Locoregional tumour failure was found in 34% of cases (60 of 176). Tumour differentiation was found not to be statistically significant in predicting tumour failure. The covariates predicting tumour failure were T stage (P<0.05); type of surgical treatment (P<0.05); and tumour thickness (P<0.001). The mean tumour thickness found was 4 mm. Tumours 4 mm in thickness behaved similarly in all three stages and those >4 mm had a higher rate of lymph-node metastasis. No distant metastasis was found in this series. CONCLUSION: Tumour thickness was found to be an accurate predictor of locoregional failure in early stage cancer of the buccal mucosa.

Balloon mitral commissurotomy: an intraoperative assessment.

OBJECTIVE: Advances in balloon catheter technology have revolutionized the management of obstructive cardiovascular diseases. For lesions like mitral stenosis, balloon commissurotomy has emerged as an alternative to surgical relief showing definite functional benefits in a few clinical trials, albeit with variable results. Such variability necessitated objective evaluation of the efficacy of balloon mitral commissurotomy. METHODS: The balloon mitral commissurotomy was carried out in 11 patients suffering from isolated mitral stenosis, under vision in a surgical setting. All patients were in NYHA class III/IV. Initially single balloon was used for mitral commissurotomy followed by double balloon, before completing the mitral valvotomy with surgical instruments whenever required. The commissural split was measured by firmly stretching the two commissures using nerve hooks and measuring the distance between the two hooks with the help of a caliper. Assessment of balloon dilation was made by calculating exact percentage of residual commissural split following balloon dilation as compared with completed mitral valvotomy. The exact percentage of commissural split was thus obtained by subtracting residual commissural split following balloon dilation from commissural split obtained after surgical open mitral valvotomy. RESULTS: Complete commissurotomy using the balloon technique was possible in two (18.2%) patients. In the remaining nine (81.8%) patients, balloon expansion provided only 50% to 80% of commissural split and required instrumental completion with good results. CONCLUSIONS: Balloon mitral commissurotomy, by virtue of its circumferential force, helps to develop a good cleavage and attains good hemodynamic improvement which may be life saving in critical mitral stenosis in selected group of patients with pliable mitral leaflets and minimal subvalvular pathology.

Blood conservation in valve surgery.

Blood utilization in 40 patients undergoing elective valve surgery was prospectively studied. The patients had valvular lesions of rheumatic origin with a mean age of 29.1 years and a mean preoperative hematocrit of 35.23 +/- 4.16. Blood was removed from all patients after induction of anesthesia and reinfused after bypass (mean 365.12 +/- 66.96 ml). Membrane oxygenator was used in all the patients. All discard suction was routed through a regionally heparinised collecting and processing system, and the resulting red cell concentrate was transfused. At the conclusion of bypass, all blood remaining in the pump oxygenator was also processed by cell saver and used for subsequent reinfusion. Normovolemic anemia was accepted in hemodynamically stable patients. Thirty two patients (80%) received no bank blood or blood products during their entire hospital course. A total of twelve units of whole blood was transfused into eight patients.

Surgical management of cardiac myxomas.

Cardiac myxomas are rare cardiac lesions, though they are the commonest tumours of the heart. Seventeen cases of cardiac myxomas have been operated during the last one decade. Exertional dyspnoea, palpitation and chest pain were the main presenting symptoms. Echocardiographic assessment was the only definitive diagnostic investigation required prior to surgery. Early surgical excision was planned in all the cases. Irrespective of the exposure techniques, removal of the tumour with wide excision of its base was practised. There was one early death due to low cardiac output in a patient brought in a shock like state. Follow up study has revealed 14 patients in NYHA class I and two patients are having class II symptoms. Periodic echocardiographic follow up study has not revealed any recurrence till date. It is concluded that an early diagnosis and surgery gives excellent long term results in these cases.

Cultural variation in hemifacial asymmetry of emotion expressions.

Photographs of hemifacial composites (left-left, right-right and normal presentation, right-left) of these cultures (Japanese, Oriental Indian and North American) displaying six emotions (happy, sad, fear, anger, surprise, disgust) and a neutral state were administered successively (one by one) as well as simultaneously (three hemifacial photographs of an expression at a time) to observers for judgment on a 5-point scale in terms of distinctiveness of expression. Observers' judgments were treated with a culture of expressor x sex of expressor x facial presentation x emotion category mixed factorial ANOVA. Cultures did not vary for their distinctiveness of facial expressions, suggesting universality in this respect. Culture-specificity was, however, observed with respect to hemifacial asymmetry and valence of emotion expressions: (1) Japanese showed a right hemifacial bias for positive and left hemifacial bias for negative emotions; Indians and North Americans showed left hemifacial bias for all emotions, and (2) negative emotion expressions were least distinctly identifiable in Japanese faces followed by Indian and North American faces.

Aspergillus colonization in hydatid cyst: Addition of a case.

Aspergillus is a common saprophytic fungus that causes invasive or non-invasive disease in humans. It commonly colonizes pre-existing lung cavities. It has been earlier reported to coexist in previously operated or ruptured hydatid cysts. However there have been only few case reports of its occurrence in previously unoperated cysts in immunocompetent hosts. The present case adds to this category.

Induction of robust de novo centrosome amplification, high-grade spindle multipolarity and metaphase catastrophe: a novel chemotherapeutic approach.

Centrosome amplification (CA) and resultant chromosomal instability have long been associated with tumorigenesis. However, exacerbation of CA and relentless centrosome declustering engender robust spindle multipolarity (SM) during mitosis and may induce cell death. Recently, we demonstrated that a noscapinoid member, reduced bromonoscapine, (S)-3-(R)-9-bromo-5-(4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo-[4,5-g]isoquinoline (Red-Br-nos), induces reactive oxygen species (ROS)-mediated autophagy and caspase-independent death in prostate cancer PC-3 cells. Herein, we show that Red-Br-nos induces ROS-dependent DNA damage that resulted in high-grade CA and SM in PC-3 cells. Unlike doxorubicin, which causes double-stranded DNA breaks and chronic G2 arrest accompanied by 'templated' CA, Red-Br-nos-mediated DNA damage elicits de novo CA during a transient S/G2 stall, followed by checkpoint abrogation and mitotic entry to form aberrant mitotic figures with supernumerary spindle poles. Attenuation of multipolar phenotype in the presence of tiron, a ROS inhibitor, indicated that ROS-mediated DNA damage was partly responsible for driving CA and SM. Although a few cells (∼5%) yielded to aberrant cytokinesis following an 'anaphase catastrophe', most mitotically arrested cells (∼70%) succumbed to 'metaphase catastrophe,' which was caspase-independent. This report is the first documentation of rapid de novo centrosome formation in the presence of parent centrosome by a noscapinoid family member, which triggers death-inducing SM via a unique mechanism that distinguishes it from other ROS-inducers, conventional DNA-damaging agents, as well as other microtubule-binding drugs.

Critical incidents in a multidisciplinary intensive care unit.

We aimed to determine the type and frequency of critical incidents in a multidisciplinary intensive care unit, to determine outcomes consequent to these incidents and to devise corrective strategies. Prospectively collected data on critical incidents during a 33-month period were analysed. In all, 1918 patients were admitted to the unit during the study period. Each incident was analysed in detail. A system-based corrective strategy was sought for and implemented as appropriate. In these patients, 280 critical incidents were reported during the study period, resulting in 3.4 incidents per 100 patient days. Airway-related incidents were the most frequent (32.8%) followed by line-related (21.8%) and drug-related (15%) incidents. Thirty-two incidents (11.4%) led to adverse outcomes. There were four deaths that occurred as a direct consequence of or contributed to by the incident, all due to airway-related incidents. A major physiological change occurred in 3.6% of incidents, while 6.4% of incidents resulted in a minor physiological change. Critical incidents were common in our multidisciplinary ICU, although adverse outcomes were rare.

Reconstruction of alae of the nose and angle of the mouth with naso labial flap.

Naso labial flap is an ideal flap for reconstruction of alae of the nose and angle of the mouth after excision for malignancy. Due to inconspicuous deformity of the donor area it is ideal in old age. We report our experience in 7 cases of basal cell carcinoma of the alae of the nose and 11 cases of carcinoma angle of the mouth.

Pectoralis major rib osteomyo cutaneous flap in primary mandibular reconstruction in floor of the mouth cancer.

We report pectoralis major rib osteo myocutaneous flap in reconstruction of cancer floor of the mouth in 8 cases. We have discussed it's advantages in country like ours over the micro vascular graft. The rib (Vascularised bone graft) incorporated in this flap gives ideal support for mandibular arch reconstruction.

Management of carcinoma anal canal with combination chemotherapy and concurrent radiotherapy.

Results of 21 cases of squamous cell carcinoma of anal canal treated by continuous infusion of 5-fluorouracil 1000 mg/sqm for 4 days and mitomycin-C 15 mg/sqm on 1st day by i.v. route with concurrent external beam radiotherapy of 42 Gy from 1st day of chemotherapy were analysed. Out of 21 patients, 16(76.19%) achieved complete remission, 3 (14.28%) partial remission and 2 (9.52%) cases did not respond at all. On follow-up, 7 (33.33%) histopathological positive cases needed abdominoperineal resection with good recovery. After 2 years of follow-up 14 (66.67%) cases were free from the disease and 3 (14.28%) were alive with the disease. The median duration of follow-up was 36 months.

Leishmanicidal activity of phenylene bridged C2 symmetric glycosyl ureides.

A number of phenylene bridged C2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) and acid (5a-d) functionalities were prepared by addition of glycosyl amino esters with phenyl diisocyanates and their further reaction with LiAlH(4) or hydrolysis with LiOH. All the compounds were screened for their in vitro and in vivo antileishmanial activity. Most of the compounds exhibited good activity while two of the compounds 3e and 3f reduced the clinical dose of standard drug SSG.