Molecular mechanism of ultrasound interaction with a blood brain barrier model.

The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.

Variance in the treatment of vertebral haemangiomas.

Vertebral haemangiomas constitute an infrequently encounterd entity in clinical practice. Although x-ray, computerised tomography scan and magnetic resonance Imaging scan provide a pathognomic picture confirming the diagnosis of vertebral haemangiomas, angiography constitutes an important tool for diagnosis and helps in deciding and execution of treatment. Various treatment modalities like surgery, radiotherapy, pre-operative embolisation, percutaneous vertebroplasty and intralesional ethanol have been discussed in the setting of asymptomatic vertebral haemangiomas to those presenting with features of cord compression.

Compensator-based intensity-modulated radiotherapy in head and neck cancer: our experience in achieving dosimetric parameters and their clinical correlation.

AIMS: To review the Batra Hospital and Medical Research Centre experience of using compensator-based intensity-modulated radiotherapy (IMRT) to treat head and neck cancer. MATERIALS AND METHODS: Between October 2003 and August 2004, 18 patients underwent IMRT for head and neck cancer at our institution. IMRT was delivered using partial transmission high-resolution compensator blocks. RESULTS: With a median follow-up of 13.3 months, two patients had residual disease and two failed in the gross tumour volume (GTV). The complete response rate after surgical salvage was 94.5%. Both the locoregional relapse-free and disease-free survival rates were 81.8%. The target coverage in terms of average maximum, mean and minimum dose (in Gy) delivered was 78.6, 73.5 and 58.4 to the GTV-planning target volume, 82.3, 70.9 and 47.3 to clinical target volume 1 (CTV1) and 82.9, 66.2 and 29.6 to CTV2. The dose constraint of 30 Gy to less than 50% of the contralateral parotid volume was achieved in 12 (66.7%) patients. If the dose constraint was revised to 35 Gy, at least 50% of the parotid volume was spared in 17 (94.5%) patients. On average, 75% of the contralateral parotid volume received a dose less than 35 Gy in 13 (72.3%) patients with grade I xerostomia, whereas this was 49.3% in five (27.7%) patients with grade II xerostomia, and the difference was statistically significant (P = 0.001). CONCLUSIONS: In our initial experience, compensator-based IMRT is feasible with regard to target coverage and parotid volume sparing. The parotid volume dose has significant clinical implications on the grade of xerostomia. Our results invoke rethinking into the issues of the parotid volume dose constraint in our subpopulation.

Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species.

We compared the activities of amphotericin B, itraconazole, and voriconazole against clinical Aspergillus (n = 82) and Fusarium (n = 22) isolates by a microdilution method adopted from the National Committee for Clinical Laboratory Standards (NCCLS-M27A). RPMI 1640 (RPMI), RPMI 1640 supplemented to 2% glucose (RPMI-2), and antibiotic medium 3 supplemented to 2% glucose (AM3) were used as test media. MICs were determined after 24, 48, and 72 h. A narrow range of amphotericin B MICs was observed for Aspergillus isolates, with minor variations among species. MICs for Fusarium isolates were higher than those for Aspergillus isolates. MICs of itraconazole were prominently high for two previously defined itraconazole-resistant Aspergillus fumigatus isolates and Fusarium solani. Voriconazole showed good in vitro activity against itraconazole-resistant isolates, but the MICs of voriconazole for F. solani were high. RPMI was the most efficient medium for detection of itraconazole-resistant isolates, followed by RPMI-2. While the significance remains unclear, AM3 lowered the MICs, particularly those of amphotericin B.

A non-randomized comparison of two radiotherapy protocols in inoperable squamous cell carcinoma of the oesophagus.

We report an audit of two different telebrachytherapy schedules in inoperable carcinoma of the oesophagus. Between October 1990 and December 1996, 108 patients with a Karnofsky performance status > or = 50 were selected from our database on the basis of intention to treat by telebrachytherapy. Teletherapy in the low dose group L (55 patients) consisted of 35 Gy in 15 fractions over 3 weeks, while that in the high dose group H (53 patients) consisted of 50 Gy in 25 fractions over 5 weeks. The choice of teletherapy dose was based on physician preference. The high dose rate intraluminal radiotherapy that followed 2 weeks later was identical in both groups and consisted of two applications of 6 Gy, a week apart. The pretreatment disease characteristics of the patients in both arms were similar. Relief of dysphagia was obtained in 49% of the patients in group L and in 75% of those in group H (chi2: P = 0.004). The median dysphagia-free interval was 0 and 7 months in groups L and H respectively (log-rank: P = 0.06), while the median overall survival was identical at 8 months (log-rank: P = 0.21) for both groups. The probability of survival at 1, 2 and 5 years was 34.8% versus 35.8%, 14.5% versus 13.9% and 0% versus 10% for groups L and H respectively. Morbidity in the form of ulcers, strictures and fistulae were observed in 9%, 7% and 5% of patients in group L compared with 8%, 8% and 13% in groups H respectively. This audit suggests that the protocol used in group H, when compared with group L, results in a greater proportion of patients being rendered dysphagia free, with a statistical trend towards a greater sustainment of dysphagia relief on follow-up.

Low fat intake and coronary artery disease in a population with higher prevalence of coronary artery disease: the Indian paradox.

OBJECTIVE: To determine the association between saturated fat intake and prevalence of coronary artery disease (CAD) and coronary risk factors. DESIGN AND SETTING: Total community cross sectional survey of 20 urban streets out of 196 streets, in the city of Moradabad in north India. SUBJECTS AND METHODS: Adult population between 25 to 64 years inclusive comprised of 1806 subjects (904 men, 902 women) were divided into three groups according to level of saturated fat intake as assessed by 7-day dietary intake records (very low < 7%, low 7 to 10%, high > 10% energy (en) per day). RESULTS: We examined the relationship between CAD risk and levels of % en from fat intake. Low (7 to 10% en/day) and high (> 10% en/day) saturated fat were positively and significantly associated with higher prevalence of CAD. The prevalence of coronary risk factors (hypertension, hypercholesterolemia, obesity and sedentary lifestyle) were significantly higher among subjects with low and high saturated fat intake compared to subjects with very low (< 7%) saturated fat intake. Logistic regression analysis with adjustment for age showed that hypercholesterolemia (OR: men 0.89, women 0.68), hypertension (men 0.92, women 0.56), physical activity (men 0.80, women 0.36), obesity (men 0.82, women 0.88) and smoking (0.70 men) were significant risk factors of CAD. Low and high saturated fat intake were associated with more prestigious occupations, higher and middle income status and better educational levels compared to very low saturated fat intake. CONCLUSIONS: The prevalence of CAD and coronary risk factors was higher in urban Indians with low and high saturated fat intake than those with lower saturated fat intake. These findings suggest that the saturated fat intake should be < 7% en/day for prevention of CAD in Indians.

Misuse of oxygen in a neonatal unit.

PIP: Oxygen is the most liberally and often used medication in any neonatal unit. Appropriate oxygen therapy has resulted in improved neonatal survival and a reduction in oxygen-related morbidity over the past 2 decades. However, the degree of arterial oxygenation needs to be continuously and precisely monitored when managing critically ill neonates in order to prevent the adverse effects of both hypoxia and hyperoxia. The authors measured the extent of hyperoxia in spontaneously breathing neonates receiving supplemental oxygen by hood and the utility of pulse oximeters in detecting hyperoxia in newborn infants. The study was conducted during January-April 1996 among 63 preterm and 60 term babies admitted to the Neonatal Unit of Kalawati Saran Children's Hospital, who required supplemental oxygen by hood. All of the infants were independently evaluated by an observer after initial stabilization of temperature and perfusion. 91% of spontaneously breathing infants receiving supplemental oxygen by hood were hyperoxemic, with no relation to the type of morbidity for which oxygen therapy was indicated.^ieng

Neonatal mechanical ventilation--experience at a level II care centre.

One hundred and fifty nine neonates were ventilated over a period of one year of whom 74 (46.54%) survived. This study aims to analyse the indications, complications and outcome of babies requiring mechanical ventilation. The early outcome measures were (i) survival rate with respect to birth weight, gestation and indication of ventilation, and (ii) Complications of assisted ventilation. One hundred and forty seven babies received IPPV and 34 received CPAP. Twenty two out of these 34 required IPPV later. Survival was cent percent on exclusive CPAP mode. HMD was the commonest indication for ventilation followed by Birth asphyxia, Apnea of prematurity, Meconium Aspiration Syndrome and Persistent Pulmonary Hypertension of the New born. Survival rates increased with increasing birth weight and gestational age, changing from 25% for < 1000 gm and 20% for < 28 wks to 53% for > 2500 gms and 50.2% for > 37 wks. Prolonged ventilatory support was needed for HMD (mean 114 hrs) and PPHN (mean 156 hrs). Commonest complication was Sepsis (26%) followed by Pulmonary hemorrhage, Pneumothorax and IVH. Lower success rates in ventilation is due to the poor survival of babies weighing < 1000 gms and those with a gestation of < 28 wks with nosocomial infections as a major complication of assisted ventilation being an additional factor.

Free oxygen radicals--predictors of neonatal outcome following perinatal asphyxia.

The study was undertaken to evaluate the role of free oxygen radicals in asphyxiated neonates. Thirty term neonates appropriate for gestational age and with severe birth asphyxia (Apgar score of 3 or less at 1 minute of life) formed the study subjects. The levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), creatine phosphokinase (CPK) and lipid peroxidase (LPO) in the CSF of these neonates were estimated between 12 and 48 hrs of life. Enzyme estimation was performed by standard methods and the results were analysed statistically using Multivariate Logistic Regression analysis and non parametric tests namely Kruskal Wallis test and Wilcoxon's rank sum test. Out of the thirty babies, 14 were observed to be neurologically normal, 9 had significant morbidity and 7 died. The SOD levels ranged from 12.4 to 140 units/ml, GPx from 128 to 1933 nmol/min/dl, CPK from 2 to 2098 IU/dl and LPO from 5.4 to 30.8 umol/hr/dl. The SOD and GPx levels had an inverse relationship whereas rise in LPO and CPK levels were directly proportional to the extent of neurological damage and ultimate clinical outcome. CPK levels higher than 140 IU/ml were lethal and associated with 100% mortality whereas all normal neonates had CPK below 37 IU/ml. The levels of antioxidant enzymes can reliably and significantly predict mortality and morbidity whereas level of an enzyme cannot confidently confer normalcy. Hence antioxidant enzyme levels with a cut off value can be a useful marker and serve as a prognostic indicator in times to come.

Ventricular fibrillation: one spiral or many?

Ventricular fibrillation is the major cause of sudden cardiac death, the leading cause of death in the industrialized world; however, the mechanisms for its onset are not well understood. To further understand the dynamics of fibrillation at and near its onset, we compared spatial and temporal variability of mean interactivation intervals in a stable canine model for ventricular fibrillation. Temporal variability was very small, suggesting that the relevant physiological parameters remained constant during our experiments. Spatial variability was usually significantly larger and appeared incompatible with the dynamics of a single, meandering spiral wave. This confirmed recent results that a single spiral wave cannot generate ventricular fibrillation. Thus the onset of fibrillation is a multistage process, with spiral-wave breakdown providing a crucial step in the quasi-periodic route to fibrillation.

Epidemiological study of hypertension and its determinants in an urban population of North India.

OBJECTIVES: To determine age-specific prevalence of hypertension and blood pressure (BP) levels in relation to diet and lifestyle factors in North Indians. DESIGN AND SETTING: Cross-sectional survey in 20 randomly selected streets in Moradabad, North India. SUBJECTS AND METHODS: A total of 1806 subjects from North India (904 males and 902 females) age range 25-64 years. The survey methods were as follows: dietary diaries for 7 days food intake record; BP measurements; physician administered questionnaire and anthropometric measurements. Diagnosis of hypertension was based on new World Health Organization/International Society of Hypertension (WHO/ISH) criteria. Risk factors were assessed based on WHO guidelines. RESULTS: The prevalence of hypertension according to WHO/ISH criteria was 23.7% and by old WHO criteria 13.3%. In the WHO/ISH hypertensive group, isolated diastolic hypertension was present in 47.3% males and 40.6% females. Males have a slightly higher prevalence than females in the young age group, however, the prevalence rates are comparable in the older age groups. In both sexes, the prevalence rates and BP level increased with older age. Multivariate analysis revealed that age, higher body mass index, central obesity and higher socioeconomic status were independently and strongly associated with hypertension in both sexes. Higher dietary fat and salt intake and lower physical activity were weakly but significantly associated with hypertension. CONCLUSION: Association of higher socioeconmic status, higher body mass index and central obesity in North Indian adults with higher fat intake, lower physical activity and higher prevalence and level of hypertension indicate that these populations may benefit by decreasing the dietary fat intake and increasing physical activity, with an aim to decrease central obesity for decreasing hypertension in North Indians.

Antioxidant effects of lovastatin and vitamin E on experimental atherosclerosis in rabbits.

The effects of the administration of vitamin E (10 mg/day) plus lovastatin (2 mg/day; group A, n = 10), lovastatin alone (2 mg/day; group B, n = 10), and placebo (group C, n = 10) were compared over 24 weeks in a randomized, single-blind controlled trial. All groups of rabbits received a trans fatty acid (TFA)-rich diet (5-10 g/day) for 36 weeks. Treatment with vitamin E plus lovastatin (group A) and lovastatin (group B) started after 12 weeks of administration of TFA-rich diet was associated with a significant but similar decline in serum cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides in both groups at 36 weeks. Lipid peroxides and diene conjugates showed a significant decline in association with a significant increase in the plasma level of vitamin E in group A rabbits at 36 weeks. However, the lovastatin group B showed a lesser but significant decrease in lipid peroxides and diene conjugates at 36 weeks, indicating that lovastatin may have antioxidant activity. In control group C, the increase in blood lipids and oxidative stress at 36 weeks was much greater than the decrease in groups A and B. After experimental lipid peroxidation at 24 weeks in all of the rabbits, 2 of 10 group B and 3 of 10 group C rabbits died due to coronary thrombosis; there were no deaths in group A. Thus antioxidant therapy with vitamin E can provide protection against death due to free radical stress. Aortic lipids and sudanophilia indicating athorosclorosis were significantly lower in groups A and B than in group C. The atherosclerotic coronary plaque sizes were significantly smaller in group A (18.5 +/- 3.6 microns) than in groups B (41.6 +/- 4.2 microns) and C (85 +/- 6.7 microns). Aortic plaque sizes were also smaller in group A than in group B and C. It is possible that antioxidant therapy with vitamin E, as an adjunct to lipid lowering with lovastatin, can provide additional benefit in the inhibition of oxidative stress and atherosclerosis. The antioxidant activity of lovastatin has not been reported, to our knowledge.

Seroconversion following killed polio vaccine in neonates.

The study was carried out to evaluate the efficacy of IPV in neonates and to study the additive effect of IPV or OPV at birth on seroconversion with three subsequent doses of OPV. Addition of IPV or OPV at birth to the conventional OPV schedule resulted in significantly higher seroconversion rates than in the controls, who received three doses of OPV. Three doses of IPV beginning from birth resulted in significantly better seroconversion rates than in the control group. Children receiving 3 doses of IPV showed significantly greater seroconversion rates against type III polio virus than those receiving IPV/OPV at birth followed by 3 doses of OPV. The difference in the seroconversion rates against the other virus types was not significant. A significantly greater number of children who received some vaccine at birth (IPV or OPV) were protected against poliomyelitis by 6 weeks age as compared to those who received no immunization at birth. The study recommends that seroconversion rates following three doses of IPV are satisfactory. Addition of IPV or OPV at birth to the conventional schedule markedly increases the seroconversion rates. Immunization can be started at birth to ensure early protection against poliomyelitis.

End tidal carbon dioxide monitoring--its reliability in neonates.

End tidal Carbon dioxide monitoring was undertaken prospectively in all Ventilated neonates in our NICU admitted from March 1995 to August 1995 irrespective of the birth weight, gestational age and indication of ventilation. The aim was to determine the correlation between ETCO2 and PaCO2 in various clinical situations. The arterial blood gases were obtained in all ventilated babies with simultaneous and continuous ETCO2 monitoring and were analysed by AVL 995 Hb blood gas analyser. ETCO2 was analysed by side stream technique by Datex Cardiocap II monitor. A total of 152 samples from in-dwelling radial artery catheters were analysed from babies with birth weight from 900 g to 3400 g, gestation age from 28 to 42 wks and were ventilated for various indications like Severe Birth Asphyxia (SBA), Meconium Aspiration Syndrome (MAS), Recurrent Apnoea and Hyaline Membrane Disease (HMD). Statistical analysis was done in 10 groups to see if the ETCO2 correlated with its corresponding PaCO2 value. The study groups comprised three groups based on birth weight being < 1.5-2.5 kg and > 2.5 kg three groups as per the gestational age being 28-31+6 wks, 32-36+6 wks and 37-41+6 wks and four groups as per the need for ventilation being Severe Birth Asphyxia, Meconium Aspiration Syndrome, Apnoea of Prematurity and Hyaline Membrane Disease. Results of the correlation analysis revealed that the correlation coefficient in the study group ranged from 0.55 to 0.96 and was statistically significant in babies > 2.5 kg and 1.5-2.5 kg, in term and preterms 32-36 wks, and in babies with MAS, SBA and Recurrent Apnoea. The correlation coefficient was lowest in babies with HMD, being 0.55. The study showed that ETCO2 correlates closely with PaCO2 in most clinical situations in neonates and we recommend its use in all level III NICUs in ventilated babies.

Immunogenicity and tolerance of H. influenzae type b, tetanus toxoid conjugate vaccine given concurrently or in combination.

The present prospective, open, controlled, randomised comparative trial was undertaken to evaluate the sero response and side effects of PRP-T Conjugate Vaccine (ACT-HIB) in infants and children aged 2 months and 16-24 months. Fifty four babies aged 2 months formed group A, 56 children aged 16-24 months formed group B. Groups A and B were further subdivided into two sub groups each destined to receive either PRP-T vaccine in association with DPT vaccine at different sites (I) or PRP-T and DPT both vaccines at the same site mixed in the same syringe (II). Group A received 3 doses at 2, 3 and 4 months of age and group B received one dose between 16-24 months. The Geometric mean titres of Anti PRP antibodies observed in primary immunisation schedule (A) and single dose vaccination schedule (B) were comparable and significantly higher to prevaccination titres. A serum anti PRP level of > 1.0 mcg/ml after immunisation is believed to correlate with long term protection. Ninety-six percent of infants in Group A and 98% in Group B achieved titres > 1.0 mcg/ml. The side effects were minimal, local and were comparable between the study and control groups, suggesting that PRP-T vaccine is highly immunogenic and well tolerated in Indian infants and children.