Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis?

Reperfusion injury can cause liver dysfunction after cold storage and warm ischemia. Recently it has been suggested that more than 50% of hepatocytes and sinusoidal endothelial cells (SEC) are undergoing apoptosis during the first 24 hours of reperfusion. The aim of our study was to quantify apoptotic and necrotic hepatocytes and apoptotic SEC after 60 or 120 minutes of warm, partial no-flow ischemia and 0 to 24 hours reperfusion in male SD rats. Apoptotic cells were identified by TUNEL assay in combination with morphological criteria. After 60 minutes of ischemia and 1 hour of reperfusion there was a significant increase of apoptotic hepatocytes (0.7 +/- 0.1% vs. 0.3 +/- 0.1% in controls) and SEC (1.5 +/- 0.6% vs. 0.3 +/- 0.1% in controls). The number of apoptotic SEC and hepatocytes was not different from controls at 6 hours or 24 hours of reperfusion. In contrast, the number of necrotic hepatocytes was quantified as 12 +/- 2% at 1 hour, 34 +/- 6% at 6 hours, and 57 +/- 11% at 24 hours. These results correlated with the increase in plasma ALT levels at these time points. Longer (120 min) ischemia times did not affect the number of apoptotic cells but increased hepatocellular necrosis to 58 +/- 4% at 6 hours reperfusion. No significant increase in caspase-3 activity and processing was detectable in any of these livers. Moreover, the caspase inhibitor Z-Asp-cmk (2 mg/kg IV) had no significant effect on reperfusion injury. Our results suggest that only a small minority of SEC and hepatocytes undergo apoptosis after 60 to 120 minutes of warm ischemia followed by 0 to 24 hours of reperfusion. Oncotic necrosis appears to be the principal mechanism of cell death for both cell types.

Protection against Fas receptor-mediated apoptosis in hepatocytes and nonparenchymal cells by a caspase-8 inhibitor in vivo: evidence for a postmitochondrial processing of caspase-8.

Lymphocytes can kill target cells including hepatocytes during various inflammatory diseases by Fas receptor-mediated apoptosis. Caspase-8 is activated at the receptor level, thereby initiating the processing of downstream effector caspases. The aim of this study was to investigate the time course of caspase-8 activation and to evaluate the efficacy of the caspase-8 inhibitor IETD-CHO in a model of Fas-induced apoptosis in vivo. C3Heb/FeJ mice were treated with the anti-Fas antibody Jo-2 (0.6 mg/kg). Western blot analysis demonstrated increased cytochrome c in the cytosol (20 min), which was followed by the progressive activation of caspase-3, -9 (40-120 min), and caspase-8 (120 min). At 90 and 120 min, extensive hemorrhage was observed, indicating damage to sinusoidal lining cells. In addition, high plasma ALT levels (997 +/- 316 U/L) and histological evaluation indicated severe parenchymal cell injury. Parenchymal and nonparenchymal cells showed a similar increase in caspase-3 activity and DNA fragmentation. Treatment with IETD-CHO (10 mg/kg) attenuated the increase in caspase-3 activity and DNA fragmentation by 80-90% and completely prevented hemorrhage and parenchymal cell damage. IETD-CHO also prevented the early release of mitochondrial cytochrome c and the processing of caspase-3, -8, and -9. Thus, our data support the hypothesis that Fas-mediated apoptosis is dependent on caspase-8 activation in hepatocytes and nonparenchymal cells. However, the bulk of procaspase-8 is processed late, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor. This initial signal may be amplified by further activation of caspase-8 by effector caspases, i.e., after mitochondrial activation. Caspase-8 is a promising therapeutic target for inhibition of Fas-mediated apoptosis.

Closed mitral valvotomy for mitral restenosis: experience in 113 consecutive cases.

The costs of heart operations and the problems related to anticoagulation after prosthetic valve replacement are among the limitations faced by patients in nonindustrialized countries with mitral stenosis caused by chronic rheumatic heart disease. The young age at which these patients are seen also compels the surgeon to preserve the native valve. The least costly and optimal way to achieve this objective is by closed mitral valvotomy. After closed mitral valvotomy, mitral restenosis is commonly encountered. We report here our 10-year experience with operation on 113 consecutive patients with mitral restenosis. Closed transventricular revalvotomy was performed with Tubbs dilator in 105 of 113 patients. Mean age was 343 years, with a male to female ratio of 1:1.5. Most patients were in New York Heart Association functional classes III and IV (74.3% and 19.4%, respectively). Mean interval between first and second valvotomy was 9.4 years, Hospital mortality rate was 2.8%, trivial postoperative mitral regurgitation occurred in 16.1%, and moderately severe regurgitation occurred in 1.9%. Early postoperative systemic embolism occurred in 3.8% of the cases. Moderate to excellent symptomatic improvement was noted in 89.4% of the cases and poor results were seen in 10.2%. Late follow-up of 76 patients ranged from 2 to 10 years (mean 3.8 years), with 39.4% patients in New York Heart Association class I and 50% in class II. Close mitral revalvotomy is thus an economical, simple, and safe palliative procedure that carries good long-term results.

Respiratory variables during thoracotomy for PDA ligation.

Physiological deadspace fraction of tidal volume (VD/VT), arterial to end-tidal carbon dioxide tension differences [P(a-E')CO2], arterial oxygen tension (PaO2) and respiratory system compliance were studied in twenty patients with patent ductus ateriosus scheduled for multiple ligation and transfixation through posterolateral thoracotomy under general anaesthesia with controlled ventilation. The study period was divided into six stages: stage 1--supine posture under anaesthesia, stage 2--lateral posture before start of surgery, stage 3--after chest opening before lung manipulation, stage 4--after ductus ligation and lung re-expansion before chest closure, stage 5--lateral posture, chest closed, stage 6--supine stage before reversal. There was a significant (P < 0.01) increase of VD/VT on attaining the lateral posture. The fraction decreased significantly (P < 0.05) on opening of the chest (stage 3) and subsequently increased at stage 4. There was no significant change in mean P(a-E')CO2 at various stages of thoracotomy. PaO2 fell significantly on opening of the chest and was lowest before chest closure (stage 4). PaO2 increased following chest closure but was still significantly lower than the pre-surgical supine stage. Respiratory system compliance was lowest at stage 4. Changes in deadspace fraction VD/VT do not correspond favourably to arterial oxygen tensions during posterolateral thoractomy.

Geographical variations in the presentation of ruptured aneurysms of sinuses of valsalva: evaluation of surgical repair.

From 1981 to 1992, 13 male and 7 female patients underwent surgical correction for ruptured aneurysms of sinus of valsalva. A total surgical experience of 22 procedures including 2 reoperations is presented, accounting for 1.37% of open heart surgery for congenital heart disease at PGIMER Chandigarh. Ninety percent were in the 20- to 40-year age group. Forty-five percent of patients had symptoms of > 1-year duration (range 2 months to 20 years) and catastrophic onset of symptoms was noted in four (18%). All patients had localized aneurysms originating either in right coronary sinus (14 pts) or noncoronary sinus (8 pts). Sites of origin and rupture are detailed. Associated congenital abnormalities such as ventricular septal defect (VSD) (13 pts), aortic regurgitation (3 pts), and left superior vena cava and atrial septal defect (ASD) (1 pt each) were noted. The data pertaining to Oriental and Western groups of patients were analyzed, and the differences in age, mode of presentation, site of origin, rupture, and the spectrum of associated abnormalities were elucidated. The majority of the patients (86.4%) were operated by the Bicameral approach. Repair was tailored according to the extent and severity of the defect in the sinus of Valsalva and aortic valve annulus and also the presence and site of VSD.

Childhood-onset diabetes in the white and South Asian population in Leicestershire, UK.

The prevalence of childhood-onset Type 1 diabetes mellitus is important for determining health care provisions. In Leicestershire 13.5% of the childhood population (0-14 years) is of South Asian origin (census 1991). This study determined the prevalence of Type 1 diabetes in Whites and South Asians in Leicestershire, using a capture/recapture method to coincide with the 1991 Census day. Children (0-14 years) with Type 1 diabetes were captured from the central diabetic register. The health visitor and consultant records were used to recapture the cases. Total ascertainment of cases was 95-100%. The prevalence of Type 1 diabetes in White children (107 cases) was 0.75/1000 children (95% CI 0.61-0.89) compared with the South Asian prevalence (18 cases) of 0.77/1000 (95% CI 0.41-1.13). The overall prevalence in White males was 0.82/1000 (0.61-1.03) compared with 0.68/1000 (0.48-0.87) in females. In South Asian males it was 0.59/1000 (0.15-1.03) compared with 0.96/1000 (0.39-1.53) in females. The prevalence of Type 1 diabetes in children of South Asian migrants to the United Kingdom cannot be said to be different from White children.

Midazolam as an induction agent in mitral stenosis patients for closed mitral commissurotomy.

In 30 patients of rheumatic heart disease with mitral stenosis (MS) belonging to NYHA class II and III scheduled for closed mitral commissurotomy anaesthesia was induced with morphine 0.15 mg/kg followed by either thiopentone (group A, n = 15) or midazolam (group B, n = 15) titrated to produce sleep. Patients were intubated with pancuronium bromide in a dose of 0.12 mg/kg. Minimum mean arterial blood pressure following induction was significantly lower in thiopentone group (77 +/- 7 mm Hg) than midazolam group (85 +/- 6 mm Hg; P < 0.05). After intubation blood pressure was significantly higher in thiopentone group (99 +/- 8 mm Hg) than midazolam group patients (89 +/- 7 mm Hg). Heart rate was significantly higher in thiopentone treated patients both before and after endotracheal intubation. During surgery, three patients in group A had hypotensive episodes (mean arterial blood pressure 20% below basal at two successive readings 5 min apart) while one in group B had a hypotensive episode. Average duration of surgery was comparable between the two groups (102 +/- 15 and 95 +/- 18 min) and postoperatively there was no significant difference in sedation score and incidence of nausea and vomiting between the two groups.

Giant congenital left ventricular aneurysm in an adult--a case report.

Congenital cardiac aneurysms are extremely rare. The echocardiographic features of this condition have never been described. The authors report a case of giant congenital left ventricular aneurysm wherein the diagnosis was made by echocardiography and confirmed at cardiac catheterization. The aneurysm was surgically removed. The histologic examination showed that the aneurysmal wall was only 1.5 to 2 mm thick but contained all the layers of the heart.

Ethnic differences in the incidence of lower extremity amputation secondary to diabetes mellitus.

Patients of Asian ethnic origin with diabetes mellitus living in the United Kingdom (UK) have been shown to have a higher prevalence of coronary heart disease and renal disease. Little is known about the incidence of lower extremity amputation in this racial group. The incidence of lower extremity amputation was estimated for patients of Asian ethnic origin and White Caucasians with diabetes mellitus in the county of Leicestershire from 1980 to 1985. The age and sex-adjusted incidence rate of lower extremity amputation for the estimated population of patients with diabetes mellitus in patients of Asian ethnic origin was 3.4 (95% CI, 1.1-10.7) cases per 10,000 patients year-1, compared to 14.2 (12.6-15.9) in White Caucasians. Similarly, a lower incidence rate of lower extremity amputation was recorded in patients of Asian ethnic origin without diabetes mellitus (0.4 (0.2-0.6) vs 1.5 (1.4 to 1.6) cases per 10,000 persons year-1). These findings contrast markedly with the high rates of coronary heart disease and renal disease previously reported in patients of Asian ethnic origin residing in the UK.

Cardio-vascular effects of vecuronium & pancuronium in patients undergoing elective closed mitral valvotomy.

Vecuronium, a monoquaternary analogue of pancuronium, the neuromuscular blocker, was compared with pancuronium in 50 patients undergoing elective closed mitral valvotomy. The patients were randomly divided into two groups of 25 each, and the muscle relaxants were administered in a dose of 0.1 mg/kg body weight. Both the agents produced identical intubating conditions at 3 min. Vecuronium showed a significantly shorter onset of action, as compared to pancuronium. The latter significantly increased the heart rate throughout the period of study whereas vecuronium significantly decreased the heart rate, 25 min after administration. There was significant increase in the mean arterial pressure (MAP) at tracheal intubation in both the groups, which persisted throughout the period of study in pancuronium group. There was a significant fall in MAP at 30 min after relaxant in vecuronium group. The incidence of arrythmias was similar and significant in both the groups. Vecuronium, thus showed a quicker onset of action with minimal haemodynamic effects, as compared to pancuronium in patients undergoing closed mitral valvotomy.

Infective endocarditis at autopsy in northern India. A study of 120 cases.

Pathologic data on 120 autopsied cases of infective endocarditis are presented. They constitute 1.8% of total 6,700 and 6.3% of 1,900 cardiac autopsies over 16 years. Ninety % of patients were below the age of 40 years, 42.5% had no pre-existing heart disease, 33.3% had previous valvular disease, mainly rheumatic, and 24.2% had congenital heart disease. Mitral and aortic valves were each the sites in one third cases, mitral slightly more than aortic, twenty-six point six % of the cases had lesions on the right side of the heart, 16.6% exclusively so. Cardiac complications were infrequent while systemic infarcts were found in over 80% cases. A route of infection was detected only in 24.1% of the cases, puerperal sepsis being the commonest. Staphylococci were the responsible bacteria in 18 out of 28 cases in which microbiologic data were available. There were only 2 cases with infective lesions on prosthetic valves, both fungal. The pattern of infective endocarditis in this and other reports from India and Africa differs from that in the West, in many respects including younger age of our patients, significant rheumatic background disease, absence of narcotic addicts and of "degenerative heart disease" and lower incidence of cardiac complications.

Bronchogenic carcinoma in Northern India.

A study of 336 patients with bronchogenic carcinoma was carried out in Chandigarh, Northern India. The findings suggest that its epidemiology differs in several respects from that in Western countries. Almost a third of all patients and 94.4% of the 54 women had never smoked. The peak frequency of bronchogenic carcinoma occurred between the ages of 51 and 60 years, 14.6% of the patients being aged less than 41 years. Of the 232 smokers and ex-smokers, 48.3% had smoked only cigarettes, 28.4% only bidis (made of naturally cured tobacco), 19.8% both cigarettes and bidis, and 3.4% hukkas. There was a clear association between duration of smoking and frequency of carcinoma. Tumours were classified in 287 (85%) of the patients. Squamous-cell carcinoma was relatively more frequent (32.4%) than any other tumour type and occurred almost exclusively in smokers. Adenocarcinoma was found in 13.2% of patients and was the most frequent tumour in non-smokers. No differences of histological type were found between cigarette smokers and bidi smokers.

Cattle horn injuries.

The successful management of a patient with potentially lethal intrathoracic trauma resulting from bull horn injury and involving the intrapericardial and extrapericardial portions of the right inferior pulmonary vein is described. To the best of our knowledge this particular injury has not previously been reported. Irrespective of the external appearance of the wound, hospitalization and close observation are essential. Exploration if required should be under optimal operative conditions. Popularization of disbudding and dehorning will prove an effective preventive measure.

Myxoma of the tricuspid valve.

Myxomas of the intraventricular cavity are extremely rare, and those of right ventricular origin are the least frequent. Only three cases of myxoma of the tricuspid valve have so far been reported. In this communication a myxoma of the tricuspid valve in a 23-year-old woman is reported because of its unusual and interesting clinical presentation and the extreme rarity of this lesion.