Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.2 and encodes neurofibromin. NF1 is a "classical" tumor suppressor gene. Congenital disseminated NF1 is rare with just two cases previously reported. We present a deceased baby with congenital disseminated NF1 in whom we performed molecular studies. A germline mutation (R461X) in exon 10a of the NF1 gene was found. A 2 bp deletion (3508delCA) in codon 1170 of exon 21 was identified in DNA derived from some tumor tissue. Loss of heterozygosity in NF1 and TP53 was observed in other tumor samples. No microsatellite instability was observed in the tumor samples. This is the first report of molecular analysis of the NF1 locus in a patient with disseminated congenital neurofibromatosis. This case had a de novo germline mutation in NF1 and three documented somatic mutations in the NF1 and TP53 genes in tumor specimens.

Primary pleural synovial sarcoma presenting as a multiloculated cyst in an adolescent.

Primary pleural synovial sarcoma (PPSS) is a rare pleural malignancy with a grave prognosis. Most cases present as a well-circumscribed mass with foci of haemorrhage and necrosis. We present an unusual case in a Nepalese boy that presented as a multiloculated cyst mimicking hydatid disease. The diagnosis was confirmed by histology and cytogenetic analysis.

Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia - a mechanism for promoting hypertension in obstructive sleep apnoea.

Asphyxia, which occurs during obstructive sleep apnoeic events, alters the baroreceptor reflex and this may lead to hypertension. We have recently reported that breathing an asphyxic gas resets the baroreceptor-vascular resistance reflex towards higher pressures. The present study was designed to determine whether this effect was caused by the reduced oxygen tension, which affects mainly peripheral chemoreceptors, or by the increased carbon dioxide, which acts mainly on central chemoreceptors. We studied 11 healthy volunteer subjects aged between 20 and 55 years old (6 male). The stimulus to the carotid baroreceptors was changed using graded pressures of -40 to +60 mmHg applied to a neck chamber. Responses of vascular resistance were assessed in the forearm from changes in blood pressure (Finapres) divided by brachial blood flow velocity (Doppler) and cardiac responses from the changes in RR interval and heart rate. Stimulus-response curves were defined during (i) air breathing, (ii) hypoxia (12% O(2) in N(2)), and (iii) hypercapnia (5% CO(2) in 95% O(2)). Responses during air breathing were assessed both prior to and after either hypoxia or hypercapnia. We applied a sigmoid function or third order polynomial to the curves and determined the maximal differential (equivalent to peak sensitivity) and the corresponding carotid sinus pressure (equivalent to 'set point'). Hypoxia resulted in an increase in heart rate but no significant change in mean blood pressure or vascular resistance. However, there was an increase in vascular resistance in the post-stimulus period. Hypoxia had no significant effect on baroreflex sensitivity or 'set point' for the control of RR interval, heart rate or mean arterial pressure. Peak sensitivity of the vascular resistance response to baroreceptor stimulation was significantly reduced from -2.5 +/- 0.4 units to -1.4 +/- 0.1 units (P < 0.05) and this was restored in the post-stimulus period to -2.6 +/- 0.5 units. There was no effect on 'set point'. Hypercapnia, on the other hand, resulted in a decrease in heart rate, which remained reduced in the post-stimulus period and significantly increased mean blood pressure. Baseline vascular resistance was significantly increased and then further increased in the post-control period. Like hypoxia, hypercapnia had no effect on baroreflex control of RR interval, heart rate or mean arterial pressure. There was, also no significant change in the sensitivity of the vascular resistance responses, however, 'set point' was significantly increased from 74.7 +/- 4 to 87.0 +/- 2 mmHg (P < 0.02). This was not completely restored to pre-stimulus control levels in the post-stimulus control period (82.2 +/- 3 mmHg). These results suggest that the hypoxic component of asphyxia reduces baroreceptor-vascular resistance reflex sensitivity, whilst the hypercapnic component is responsible for increasing blood pressure and reflex 'set point'. Hypercapnia appears to have a lasting effect after the removal of the stimulus. Thus the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnoea.

Effects of simulated obstructive sleep apnoea on the human carotid baroreceptor-vascular resistance reflex.

Obstructive sleep apnoea (OSA), which is characterized by periodic inspiratory obstruction, is associated with hypertension and possibly with changes in the baroreceptor reflex. In this investigation we induced changes in inspiratory resistance and in inspiratory oxygen and carbon dioxide content, which simulate some of the changes in OSA, to determine whether this caused changes in the gain or setting of the carotid baroreflex. In eight healthy subjects (aged 21-62 years) we changed the stimulus to carotid baroreceptors, using neck chambers and graded pressures of -40 to +60 mmHg, and assessed vascular resistance responses in the brachial artery from changes in blood pressure (Finapres) divided by brachial artery blood flow velocity (Doppler ultrasound). Stimulus-response curves were defined during (a) sham (no additional stimulus), (b) addition of an inspiratory resistance (inspiratory pressure -10 mmHg), (c) breathing asphyxic gas (12% O(2), 5% CO(2)), and (d) combined resistance and asphyxia. Sigmoid or polynomial functions were applied to the curves and maximum differentials (equivalent to peak gain) and the corresponding carotid pressures (equivalent to 'set point') were determined. The sham test had no effect on either gain or 'set point'. Inspiratory resistance alone had no effect on blood pressure and did not displace the curve. However, it reduced gain from -3.0 +/- 0.6 to -2.1 +/- 0.4 units (P < 0.05). Asphyxia alone did increase blood pressure (+7.0 +/- 1.1 mmHg, P < 0.0005) and displaced the curve to higher pressures by +16.8 +/- 2.1 mmHg (P < 0.0005). However, it did not affect gain. The combination of resistance and asphyxia both reduced gain and displaced the curve to higher pressures. These results suggest that inspiratory resistance and asphyxia cause changes in the baroreceptor reflex which could lead to an increase in blood pressure. These changes, if sustained, could provide a mechanism linking hypertension to obstructive sleep apnoea.

Intralobar pulmonary sequestration with congenital cystic adematous malformation and rhabdomyomatous dysplasia.

Pulmonary sequestration and congenital cystic adenomatous malformations (CCAM) are well known but still uncommon anomalies of the lung. Extralobar sequestrations are well described in association with CCAM, but fewer intralobar lesions are found with this association. The existence of striated muscle within CCAM is described, and we have evidence of dysplastic changes within the various cellular components occurring, with rhabdomyomatous dysplasia being one of these. A literature review shows no previous evidence of a reported intralobar sequestration associated with CCAM and rhabdomyomatous dysplastic changes.

Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue.

A second gene for autosomal dominant polycystic kidney disease (ADPKD), PKD2, has been recently identified. Using antisera raised to the human PKD2 protein, polycystin-2, we describe for the first time its distribution in human fetal tissues, as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein, polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1, with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver, lung, bowel, brain, reproductive organs, placenta, and thymus. Of interest, nonepithelial cell types such as vascular smooth muscle, skeletal muscle, myocardial cells, and neurons also express both proteins. In PKD2 cystic kidney and liver, we find polycystin-2 expression in the majority of cysts, although a significant minority are negative, a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts, but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2+/- mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that heterotypic interactions may stabilize these proteins.

Characterisation and expression of the PKD-1 protein, polycystin, in renal and extrarenal tissues.

Studies of the nature and expression of the PKD-1 gene product, polycystin, have been complicated by duplication of the PKD-1 gene, the low expression of the PKD-1 gene in adult tissues and the lack of antibodies to epitopes in the duplicated region of polycystin. Using five monoclonal and polyclonal antibodies to epitopes encompassing the whole of the polycystin molecule, we have studied the biochemical and cellular expression of polycystin, and sought to identify homologues and alternative splice forms of polycystin. We find that polycystin exists as a 400-500 kDa protein in normal kidney and in a range of renal epithelial cell lines by immunoblotting, using antibodies to four different epitopes. No evidence of translated products from the genes (HG) homologous to PKD-1 nor any major splice forms of polycystin was found. In renal cells, polycystin could be detected as a cell surface protein but significant intracellular concentrations were also found by cellular fractionation and immunofluorescence. In normal and PKD-1 fetal tissues, immunoreactive polycystin was detected in many different cell types outside the kidney including vascular smooth muscle cells, endothelium, pancreatic, biliary and respiratory ductal epithelia, thyroidal epithelium, endocardium, myocardium, oocytes and Leydig cells. In the developing mouse kidney, polycystin expression is seen in all nephron segments but expression becomes restricted to mature distal tubules and collecting ducts in adult life. These observations clarify the nature of the PKD-1 protein, provide a molecular basis for understanding the systemic nature of PKD-1 and may explain the known phenotypic difference in the nature of renal cysts between 'early-onset' cases and typical adult-onset disease.

Cardiac and systemic complications in multicentric reticulohistiocytosis.

A 75-year-old man with a short history of cutaneous lesions of multicentric reticulohistiocytosis, preceded by a few months of a symmetrical polyarthritis is described. Within 5 months of onset of symptoms, he developed congestive cardiac failure secondary to pericardial involvement by the disease and succumbed despite therapy with cyclophosphamide and methylprednisolone. Post-mortem revealed the true extent of the disease, with nodules seen in the epiglottis and aryepiglottic folds, duodenal mesentery, pleura, pericardium and myocardium. Although the hallmarks of the disease are the papulonodular skin lesions, together with a severe, sometimes mutilating polyarthropathy, its widespread systemic nature is not often appreciated. We review five other cases in the literature with pericardial involvement and discuss aids to earlier diagnosis by synovial fluid cytology; gallium scanning is discussed as a potentially useful means of detecting the extent of systemic involvement in multicentric reticulohistiocytosis.

Typhoid Vi: a less reactogenic vaccine.

A typhoid vaccine derived from the purified Vi capsular polysaccharide (CPS) antigen of Salmonella typhi was compared with a heat-killed whole-cell typhoid vaccine in 637 healthy male volunteers. The individuals were placed in three groups: group 1 received two doses of heat-killed whole-cell typhoid vaccine, at an interval of 28 days; group 2 received a single dose of typhoid Vi CPS vaccine followed after 28 days by water for injection; and group 3 received water for injection on the first occasion and a single dose of typhoid Vi CPS vaccine 28 days later. Local and systemic adverse reactions were recorded for 5 days following each injection. Subjects receiving the typhoid Vi CPS vaccine complained of fewer local adverse reactions on each of the first 3 days following immunization: on day 1, 18.6% of subjects given typhoid Vi CPS vaccine reported local reactions compared with 59.7% of those receiving heat-killed whole-cell vaccine (P less than 0.001). The percentage of subjects receiving the heat-killed whole-cell vaccine who complained of systemic reactions was more than twice that of subjects receiving the Vi CPS vaccine (7.9% and 3.4%, respectively, on day 1; P less than 0.01).

Reduced peripheral vascular symptoms in elderly patients treated with alpha-methyldopa--a comparison with propranolol.

A multicentre study of 6-10 weeks duration was performed in 60 ambulant hypertensive patients aged over 60 years to compare the efficacy of methyldopa and propranolol with particular reference to the occurrence of cold extremities and sleep disturbances. Blood pressure was effectively controlled by both drugs being reduced from a mean of 180/108 mmHg to 161/93 with methyldopa and 180/108 to 162/94 with propranolol. More patients treated with methyldopa (74%) achieved the target diastolic blood pressure of 95 mmHg or below compared with those treated with propranolol (58%). Side effects were more frequent in the propranolol group necessitating the withdrawal of four patients from the study. Only one patient on methyldopa was withdrawn. The incidence of cold extremities was significantly greater with propranolol. The occurrence of sleep disturbances was similar in both groups. In this group of elderly patients methyldopa was better tolerated than propranolol.

A multicentre open trial indapamide in general practice.

In a multicentre open study, 99 patients were treated with indapamide (2.5 mg daily) by 19 general practitioners. Fourteen patients failed to complete the study and in most cases this was unrelated to active therapy. Fifty patients had not previously received antihypertensive therapy, 25 patients had been on previous antihypertensive therapy with either unsatisfactory blood pressure control of side effects and the remaining 10 patients had indapamide added to their existing therapy. Of the 85 patients who did complete, the mean reduction in blood pressure at the end of 4 months treatment was 26 mmHg systolic and 17 mmHg diastolic. In those patients who were studied for at least 12 months treatment, blood pressure control was maintained in the majority. No severe side effects were reported.

Comparison of antibody responses and virus shedding following administration of trivalent oral poliomyelitis vaccines prepared either in monkey or human diploid cell substrates.

Nineteen (22.9%) of 83 sera collected before vaccination from adult volunteers aged 21-64 years were without neutralizing antibody to poliomyelitis at levels of 0.15 i.u./ml for types I and II and 0.1 i.u./ml for type III. Some correlations were found between the history of previous vaccination and the presence of antibody but these were not well defined. Vaccination with a single dose of trivalent oral polio vaccine elicited fourfold or greater antibody responses to one or more poliomyelitis types in 53 (63.9%) volunteers, the percentage antibody resposnes being inversely related to the titre of antibody present before vaccination. Types I, II or III poliomyelitis virus were recovered from 76.8% of faecal samples collected 1 week after vaccination. The percentage recovery progressively declined thereafter until virus was recovered from 10.5% of samples collected 6 weeks after vaccination. Type for type, the titres and percentages of antibody responses and virus shedding in faeces were similar following trivalent oral poliomyelitis vaccines whether prepared in monkey or human diploid cell substrates. Some change in reproductive capacity temperature (r.c.t./40) marker was found in faecal isolates from volunteers vaccinated with monkey kidney and human diploid grown vaccines but no change in 'd' marker was found.