Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones.

As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).     

Community survey of primary dystonia in the city of Kolkata, India.

An epidemiological study on dystonia has not been reported from India. As part of a major study to find out the prevalence of major neurological disorders in the large urban city of Kolkata, Eastern India, we planned to determine the prevalence of primary dystonia. The study design was a cross-sectional study of a sample population obtained through stratified random selection and conducted in a two-stage procedure of screening by a nonprofessional team followed by confirmation of screened positive cases by the study neurologist. A total population of 52,377 was screened, and 29 subjects with dystonia were diagnosed. Out of them 23 subjects had primary dystonias [crude prevalence rate (CPR), 43.91/100,000; 95% confidence interval (CI), 28.41-64.81; age-standardized rates to world standard population, 49.06 (95% CI,31.74-72.41)] and all cases were focal type and predominantly of limb dystonia variety. Mean onset of dystonias were earlier in women (43.5 years) as compared to men (46.6 years). Thus our study on primary dystonia shows higher prevalence when compared with that of many studies globally, predominantly of focal type, earlier onset among women, and more cases of limb dystonias when compared with more prominent blepharospasm and cervical dystonias in western reports.     

Adverse perinatal factors in the causation of sensorineural hearing impairment in young children

The study involves aetiological evaluation of various adverse perinatal causes leading to bilateral sensorineural hearing impairment in children born during the 5-year period of 1981-1985 (inclusive) in the Greater Manchester area of England, United Kingdom. This group comprised over 12% of the total number of hearing-impaired children in the area. Individual possible adverse factors are discussed in the light of present understanding of the pathogenesis and previous reports.     

The effects of prior exposure to silicone on capsule formation, histology, and pressure

Investigations into the effects of prior silicone exposure on subsequent capsule formation around silicone implants assume particular relevance in light of the exponential increase in the medical application of polymers such as silicone. The inert nature of silicone has been in question with regard to its effects on the immune system, specifically whether or not it may act as a hapten or antigen. The present study analyzes the effects of prior silicone exposure on subsequent capsule formation, histological consistency, and pressures when an animal is reexposed to a silicone implant. Twelve female Lewis rats (body weight 250 g) were randomly divided into two groups. Group 1 (n = 6) rats were subcutaneously injected with 2.5 ml of Freund's Complete Adjuvant, Group 2 (n = 6) rats were injected with an equal volume of adjuvant sonicated with silicone gel. At 4 weeks a gel-filled silicone implant was placed subcutaneously in each animal. Capsule pressures were obtained at 4 months and the capsules from 3 rats from Group 2 were excised and examined microscopically. Pressures were measured again at 8 months and all remaining capsules were excised and examined. No statistically significant differences were noted when comparing two profiles over time between silicone-exposed and nonexposed animals in regard to capsule thickness or capsule pressure. However, capsule pressures were significantly lower at 8 months than at 4 months in both groups (p less than 0.034). In this model, significant reductions in capsule pressure were noted in both groups over time, but prior exposure to silicone did not appear to alter capsule histology, thickness, or pressure.     

Cardiac injuries--a clinical and autopsy profile

One hundred two patients sustaining cardiac injuries over a 4-year period were analysed to highlight the natural history of the cardiac injuries. There were 45 blunt, 36 stab, and 21 gunshot injuries. The injury involved the ventricle in 85, atrium in seven, pulmonary artery in five cases, and resulted in crush injury to the heart in the remaining five cases. Thirty-three patients (32.3%) died on the scene and 58 (56.9%) died during the transportation. Only 11 patients (10.8%) reached the hospital alive, and ten of these patients survived following thoracotomy and repair of the cardiac injury. The factors influencing the natural course of cardiac injury were analysed: 2.2% of patients with blunt cardiac trauma reached the hospital alive compared to 19.4% with stab and 14.3% with gunshot injuries; ventricular injuries had a greater prehospital mortality compared to atrial or pulmonary artery injuries; 11.3% of patients sustaining injury to right ventricle reached the hospital alive compared to 3% of those with left ventricular injuries. These data emphasize the need for rapid transport, immediate recognition, and aggressive surgical management, to make a favourable impact on the natural history of cardiac injuries.     

Reconstruction of the external carotid artery

The external carotid artery (ECA) is an underestimated but important collateral to the cerebral hemisphere and eye in patients with severe disease of the internal carotid artery. Fifteen symptomatic patients with total occlusion of the internal carotid artery underwent ECA reconstruction. Ipsilateral ECA reconstruction was performed upon all patients with no mortality or neurologic deficits. Contralateral disease of the carotid artery was noted in 11 and required correction in seven patients. Follow-up study of the patients ranged from one to 68 months (a mean of 26.8 months) after operation. Vertebrobasilar symptoms persisted in two patients, both with contralateral disease. One of these patients successfully underwent extracranial-intracranial bypass. One ipsilateral and one contralateral stroke occurred during follow-up study, both in patients with contralateral disease. Eleven patients were alive and asymptomatic at last follow-up examination. Symptomatic selected patients with occlusion of the internal carotid artery and ECA stenosis or cul-de-sac formation should be considered for operation. ECA reconstruction is associated with little morbidity and three-fourths of the patients remain asymptomatic. A high incidence of contralateral disease of the carotid artery is present. Extracranial-intracranial bypass should only be considered when symptoms persist after correction of contralateral disease of the carotid artery and any ECA lesions.     

Past exposure and the dynamics of lymphatic filariasis infection in young children.

This study utilizes parallel, longitudinal entomological and parasitological data collected during a 5-year vector control programme in Pondicherry, South India, to quantify Wuchereria bancrofti transmission from the vector to the human population. A simple mathematical model, derived from the standard catalytic model, is used to examine the hypothesis that current infection prevalence in young children is a dynamical function of their cumulative past exposure to infective bites. Maximum likelihood fits of the model to the observed data indicate a constant child infection rate with age, above a threshold representing the pre-patent period, or equivalently, the cumulative biting intensity required to produce patent infections. Extrapolation of the model allows the crude estimation of the equilibrium microfilaria age-prevalence curve due to control. The results suggest that vector control alone may have little impact on the overall age-prevalence of infection even when sustained for long periods. These observations are discussed in terms of the likely impact of density dependent mechanisms, such as acquired immunity, on model predictions.     

Outbreak of Pichia anomala infection in the pediatric service of a tertiary-care center in Northern India

An outbreak of nosocomial fungemia due to the unusual yeast, Pichia anomala occurred in the pediatric wards of our hospital over a period of 23 months (April 1996 to February 1998). A total of 379 neonates and children (4.2% admissions) were infected. The probable index case was admitted to the pediatric emergency ward, with subsequent transmission to the premature nursery, pediatric intensive care units, and other children wards. Carriage on the hands of health care personnel was likely to be responsible for dissemination of the fungus. The outbreak could only be controlled after a health education campaign to improve hand-washing practices was instituted and after nystatin-fluconazole prophylaxis to all premature neonates and high-risk infants was introduced. In a case-control study, we identified a lower gestational age, a very low birth weight (<1,500 g), and a longer duration of hospital stay as significant risk factors associated with P. anomala fungemia in premature neonates. We conducted a culture prevalence survey of 50 consecutive premature neonates and found that 28% were colonized with P. anomala at a skin or mucosal site on the date of delivery and that 20% of these neonates subsequently developed P. anomala fungemia. We performed multilocus enzyme electrophoresis on 40 P. anomala outbreak isolates (including patient and health care workers' hand isolates), and the results suggested that these isolates were identical. Our study highlights the importance of P. anomala as an emerging nosocomial fungal pathogen.