CO2-dependent component of the neurogenic vascular tone in the cat

Complete vascular isolation of the hindlimbs was performed in vagotomized cats under Sodium Pentobarbital anesthesia. The hindlimbs were perfused at constant flow with blood kept at a constant and physiological , , and pH values by means of a specially designed pump-oxygenator system. The animals were hyperventilated with different CO₂ mixtures (0%, 5%, 7% and 10% in O₂) thereby changing blood gases and pH levels in the upper body but not in the hindlimb vascular bed. At body (mm Hg) of 13.7 ±1.0 (means±SE), 30.6±1.05, 40,4±0,9 and 58.4 ±2.9 the hindlimb perfusion pressure (mm Hg) was, respectively 124±7.6, 138±7.4, 156±11.9 and 187 ±15.1. These changes in perfusion pressure were still present after complete peripheral chemoreceptor denervation but were abolished after section of the spinal cord at the T₅ level. Since hindlimb perfusion pressure fell when body was lowered below physiological levels it is concluded that part of the neurogenic vascular tone of the hindlimbs is maintained by a CO₂ mediated stimulation of supraspinal structures.Supported by Grants of the British Columbia Heart Foundation and the Medical Research Council of Canada.     

The human corpus luteum: reduction in macrophages during simulated maternal recognition of pregnancy

It has been shown that immune cells, particularly macrophages, accumulate in the corpus luteum during luteolysis. This study aimed to investigate the effect of maternal recognition of pregnancy on the localization and numbers of macrophages in the human corpus luteum. Corpora lutea (n = 12) were obtained from normally cycling women at the time of hysterectomy and were dated on the basis of serial urinary luteinizing hormone (LH) estimation. In addition, corpora lutea (n = 4) were collected from women who had received daily doubling doses of human chorionic gonadotrophin (HCG) to mimic the hormonal changes of early pregnancy. Macrophages were localized by immunohistochemistry using an anti-CD68 antibody. Steroidogenic cells, steroidogenic cells of thecal origin and endothelial cells were identified on serial sections by immunohistochemistry for 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase and von Willebrand factor, respectively. The luteal cells capable of responding directly to HCG were identified by isotopic in-situ hybridization for messenger RNA encoding LH/HCG receptors. Macrophages were localized primarily to the vascular connective tissue and theca-lutein areas of the corpus luteum, although some were found in the granulosa-lutein cell layer. Macrophage numbers increased throughout the luteal phase to a maximum in the late- luteal phase (P < 0.05). Luteal 'rescue' with HCG was associated with a marked reduction in the numbers of tissue macrophages when compared with those of the late-luteal phase (P < 0.001). One of the effects of HCG during maternal recognition of pregnancy is to prevent the normal influx of macrophages into the corpus luteum. As LH/HCG receptors localized to the steroidogenic cells, this implies a fundamental role for steroidogenic cell products in the control of macrophage influx into the human corpus luteum.      

Measured haplotype analysis of the angiotensin-I converting enzyme gene

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.      

The role of Epstein-Barr virus in Hodgkin's disease from different geographical areas

Recent studies have suggested that Epstein-Barr virus (EBV) may play a role in the aetiology of Hodgkin's disease. To determine the role of EBV in childhood Hodgkin's disease in different geographical areas, immunohistochemical staining and in situ hybridisation were used to analyse latent membrane protein 1 (LMP 1) and small nuclear non-transcribed RNAs (EBER-1) respectively. Testing for EBV within the Reed-Sternberg and Hodgkin's cells was carried out in childhood Hodgkin's disease from 10 different countries. The proportion of LMP 1 positive cases varied significantly, being 50% of cases from the United Kingdom (38/75), South Africa (9/18), Egypt (7/14), and Jordan (8/16), 60% from the United Arab Emirates (6/10), 70% from Australia (11/16), 81% from Costa Rica (34/42), 88% from Iran (7/8), 90% from Greece (20/22), and 100% of the 56 cases from Kenya. A sensitive polymerase chain reaction based EBV strain typing technique was established using archival tissues. EBV strain type 1 was shown to be predominant in childhood Hodgkin's disease from the United Kingdom, South Africa, Australia, and Greece. Type 2 was predominant in Egypt. EBV strain types 1 and 2 were both detected in some cases of childhood Hodgkin's disease in the United Kingdom, Costa Rica, and Kenya. The high incidence of EBV and the presence especially in developing countries of dual infection with both strain types 1 and 2 may reflect socioeconomic conditions leading to malnutrition induced immunological impairment. The possibility of HIV infection also needs to be explored.     

Renovascular and growth effects of childhood sarcoid

A boy developed early onset sarcoidosis, an extremely rare mimic of juvenile chronic arthritis. Renal granulomas caused severe hypertension and renal impairment, which was controlled by azathioprine and steroids. Severe uveitis caused visual impairment. Impaired growth and delayed puberty, not previously described in childhood sarcoidosis, required growth hormone and testosterone treatment.     

Clinical significance of cough and wheeze in the diagnosis of asthma

OBJECTIVES: (1) To determine the prevalence of cough, wheeze, and breathlessness, both as single symptoms and in combination, in primary schoolchildren and their relation to doctor diagnosed asthma. (2) To identify in areas with different levels of dust pollution whether questionnaire reported 'cough alone' (without wheeze or breathlessness) had similar risk factors to the questionnaire reported triad of 'cough, wheeze, and breathlessness'. SUBJECTS AND METHODS: Two cross sectional community surveys of primary schoolchildren (5-11 years) were performed in 1991 and 1993. Parent completed questionnaires related to socioeconomic and respiratory factors were distributed through 15 schools in three areas of Merseyside, one of which had a relatively high level of dust pollution. Data were analysed to determine the prevalence of different respiratory symptom patterns. Univariate and multiple logistic regressions were used to investigate the associations between respiratory symptom profiles and potential risk factors. RESULTS: The proportions of completed questionnaires that were returned were similarly high in both surveys, 92% in 1991 (1872 of 2035) and 87% in 1993 (3746 of 4288). The proportions of children with different respiratory symptom patterns were similar in the two surveys: in 1991, asymptomatic children 70.1% (1109 of 1583), those with cough alone 8.9% (141 of 1583), and children with the symptom triad of cough, wheeze, and breathlessness 8.3% (132 of 1583); the figures for 1993 were 69.5% (2144 of 3083), 9.2% (284 of 3083), and 7.3% (224 of 3083) respectively. The prevalence of doctor diagnosed asthma increased from 17.4% in 1991 to 22.1% in 1993. The symptom of cough alone was associated with going to school in an area of increased air pollution. The symptom triad of cough, wheeze, and breathlessness was associated with reported allergies, familial history of atopy and preterm birth. In 1991, of children with the symptom of cough alone one in eight were diagnosed asthmatic; twice as many doctors made the diagnosis on this basis in 1993. CONCLUSION: The respiratory symptom of cough alone and cough, wheeze, and breathlessness represent clinical responses to different specific risk factors. Cough alone was associated with the environmental factors of school in the dust exposed zone and dampness in the home, whereas cough, wheeze, and breathlessness related to allergic history and preterm birth, and may be the best surrogate of asthma. Diagnosis of asthma on the basis of cough alone partly explains the increased prevalence of doctor diagnosed asthma, especially in dust polluted areas.     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.