Investigating the role of heparin sulfate proteoglycans in hereditary multiple exostoses (HME) tumourigenesis

Introduction Heparin sulfate (HS) has long been implicated in the bone deformity hereditary multiple exostoses (HME), and it is now clear that HME is associated with mutations in the HS biosynthetic genes EXT1 and EXT2. Interestingly, HME is also associated with an increased risk of chondro‐ and osteo‐sarcomas. Methods and results Preliminary analysis of GAG samples purified from fibroblasts of both HME and isolated non‐HME exostoses patients reveal a dramatic shift in the ratio of CS : HS, with the HME and isolated cases having a much higher proportion of CS relative to normal controls. This is true in the case of both shed and cell surface material but is far more extreme in the latter, with the HS reducing from approximately 45% in the controls to less than 10% in HME patients. Initial analysis also reveals shortened chain length within these samples; indeed they often have two populations of chains present. Simple analysis of the total disaccharide composition of these samples demonstrates no significant differences against controls. However, detailed analysis of the subpopulations of chains (as determined by chain length) within these samples as well as cartilaginous samples from exostoses patients may provide further insight into the changes that occur within the biosynthetic pathway following disrupted EXT function. We are also carrying out immunocytochemistry with a variety of HS‐specific antibodies with the aim to further investigate normal HS structure and localization. This is being carried out on human primary chondrocytes isolated from normal patients and also adult mesenchymal stem cells as they undergo differentiation into chondrocytes. HS has been identified in both these cell types, and it is hoped that the manipulation of these cells through RNAi of different enzymes of the HS biosynthetic pathway will provide a suitable model for studying what changes may occur in cellular HS structures over the initial differentiation process in the growth plate. Discussion Together, these investigations should provide a good model to allow us to determine the role of HS in chondrocyte differentiation and maturation in both normal and diseased states.     

Correlations of fibrosis in endomyocardial biopsies from patients with aortic valve disease.

The amount of fibrosis in endomyocardial biopsies from 55 patients with aortic stenosis and 42 patients with aortic regurgitaion was measured. Sixty per cent of the patients with aortic stenosis had some degree of fibrosis; the degree of fibrosis correlated strongly with ejection fraction, peak systolic gradient, symptoms of cardiac failure, and mortality. In patients with aortic regurgitation, fibrosis was found in 40 per cent and was never severe. A correlation was found with symptoms of cardiac failure and mortality at follow-up, but not with ejection fraction or degree of regurgitation.     

Cor triatriatum sinistrum. Diagnostic features on cross sectional echocardiography

M mode and cross sectional echocardiography was carried out in three cases of cor triatriatum sinistrum (two infants and one adult). In two cases a peculiar double arch appearance, not previously reported, was found. All three cases were referred for surgery without cardiac catheterisation, and the diagnosis proved to be correct. The characteristic echocardiographic feature of cor triatriatum is an intra-atrial membrane detected in multiple planes of examination, curving anteroinferiorly and inserting some distance away from the mitral valve ring, proximal to the left atrial appendage. Superiorly the membrane runs parallel to, and a short distance behind, the aortic root creating a superior recess of the distal left atrial chamber. These features differentiate cor triatriatum from a supravalvar mitral ring. During diastole the membrane moves forward towards the mitral valve funnel. This, together with the arching appearance of the membrane on four chamber views and the more superior position of the membrane, makes it possible to distinguish cor triatriatum from total anomalous pulmonary venous drainage to the coronary sinus. From a review of past experience at the Brompton Hospital of the diagnostic accuracy of cardiac catheterisation in this condition, it is concluded that cross sectional echocardiography is superior to angiography as a technique for diagnosing cor triatriatum.     

Echocardiographic demonstration of aortic root abscess after infective endocarditis.

We describe a patient with infective endocarditis in whom the diagnosis was apparent only on two-dimensional echocardiography. There was no clinical or haematological evidence of active endocarditis and the diagnosis was made by the demonstration of an abscess cavity and vegetation posterior and lateral to the aortic root, deforming the left atrial cavity. The findings were confirmed by cardiac catheterisation and operation.     

Use of computed tomographic scanning and aortography in the diagnosis of acute dissection of the thoracic aorta.

Before the introduction of computed tomographic (CT) scanning, aortography was the investigation of choice for acute aortic dissection. Between 1978 and 1982, 24 patients were referred to the Brompton Hospital with suspected acute thoracic aortic dissection; all had aortography with diagnosis confirmed at surgery (n = 12) or necropsy (n = 2) or supported by clinical outcome (n = 8). One patient in whom aortography was negative had type B dissection at necropsy and another patient was lost to follow up. CT scanning became available in this unit in 1983 and between 1983 and 1987 was used as the only imaging investigation in 32 patients with suspected acute dissection of the thoracic aorta while in a further 22 patients aortography was used alone. Results were confirmed at surgery (n = 18), necropsy (n = 3), or supported by clinical outcome (n = 31). Two patients were lost to follow up. In an additional 16 patients both aortography and CT scanning were performed with concordant findings in 10. In six in whom the results were discordant, aortography was normal in three in whom subsequent CT scanning showed type B dissection and CT scanning was normal in three patients in whom aortography showed type A dissection. Both CT scanning and aortography are reliable techniques for assessment of suspected acute dissection of the thoracic aorta. Both techniques misdiagnose occasionally and the frequency of misdiagnosis will be minimised by performing both investigations in patients where the level of clinical suspicion is high and the initial investigation negative. CT scanning tends to miss type A dissection and in view of the success of surgery in this condition this failing has the more serious clinical consequences.     

Left atrial myxoma infected with Streptococcus viridans

A case is described of Streptococcus viridans endocarditis involving a left atrial myxoma. The diagnosis was made by echocardiography and the infected tumour was successfully treated by surgical removal. A review of the published literature about left atrial myxomas underlines the importance of performing echocardiography in all patients with suspected endocarditis.     

The effects of short-term hypertensive left ventricular hypertrophy on intracellular pH and intracellular electrolytes in rats

Experiments were performed to assess the effect of left ventricular hypertrophy (induced by experimental hypertension) on intracellular pH (pHi) and intracellular electrolytes in left ventricular tissue. They were undertaken on: (1) hypertensive rats (hypertension being induced by either: (a) subdiaphragmatic aortic constriction, (b) unilateral renal artery clipping, or (c) unilateral renal artery clipping with contralateral nephrectomy); (2) sham-operated rats for the above 3 subgroups; and (3) control (unoperated) rats. Intracellular pH and intracellular electrolytes were measured in left ventricular, right ventricular and skeletal muscle tissue from these animals. Intracellular pH control was assessed by exposing a number of animals in each group to an acute respiratory acidosis (by varying the concentration of inspired PCO2). In association with left ventricular hypertrophy (secondary to hypertension), left ventricular pHi became significantly alkaline in all experimental hypertensive groups compared with control values; pHi control (in response to an acidosis) was also significantly improved. There was no change in resting levels of pHi or pHi control in right ventricular or skeletal muscle tissue in any hypertensive group. There was no change in resting levels of pHi or pHi control in left ventricular, right ventricular or skeletal muscle tissue from sham-operated animals. This suggests that these changes are the result of hypertrophy per se, rather than due to a generalised mechanism secondary to hypertension and operating on all tissues. There was no change in intracellular electrolyte concentration or content in association with hypertension in any tissue or group studied.     

AMPA receptor potentiation can prevent ethanol-induced intoxication.

We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions in blood oxygenation level dependent (BOLD) in the anesthetized rat brain. A similar attenuation was apparent when measuring local cerebral glucose utilization (LCGU) via C14-2-deoxyglucose autoradiography in freely moving conscious rats. Both LY404187 and LY451395 significantly and dose-dependently reversed ethanol-induced deficits in both motor coordination and disruptions in an operant task where animals were trained to press a lever for food reward. Both prophylactic and acute intervention treatment with LY404187 reversed ethanol-induced deficits in motor coordination. Given that LY451395 and related AMPA receptor potentiators/ampakines are tolerated in both healthy volunteers and elderly patients, these data suggest that such compounds may form a potential management strategy for acute alcohol intoxication.