Human beta-mannosidase deficiency.
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Biomedical subjects
Publications and source records attributed to J N Thompson.
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The Sanfilippo A syndrome is characterized by a deficiency in heparin sulfamidase, which removes the N-sulfate groups of heparan sulfate and heparin in the course of normal catabolism of these polysaccharides. [N-35S]Heparin is the most commonly used substrate for the assay of sulfamidase activity but has certain disadvantages which have prompted us to search for alternative substrates. We report here on the use of heparin oligosaccharides for this purpose. The trisaccharide, GlcN-IdoUA-GlcN, and the pentasaccharide, GlcN-GlcUA-GlcN-GlcUA-GlcN, were N-sulfated with [35S]sulfur trioxide-trimethylamine complex; the tetrasaccharide, GlcN-UA-GlcN-UA, and the pentasaccharide, GlcN-IdoUA-GlcN-IdoUA-GlcN, were labeled by reduction with sodium borotritide followed by chemical N-sulfation. When incubated with sonicates of cultured skin fibroblasts from normal individuals, all four oligosaccharides were found to serve as substrates for heparin sulfamidase. Fibroblast sonicates from patients with the Sanfilippo A syndrome had little or no activity toward these substrates. Optimal activity of the enzyme was at pH 4.4-4.5. Comparison of the kinetic parameters showed that heparin had a lower Km than the oligosaccharides, whereas the Vmax values of the latter were higher than for heparin.
Forty patients with obstructive jaundice (bilirubin greater than 100 mumol/l) were entered into a randomized trial of oral ursodeoxycholic acid for 48 h before surgery versus no additional therapy. Pre-operative venous and operative portal total bile salt concentrations were higher in the bile salt treated patients (P less than 0.001). Portal endotoxaemia during operation was reduced in ursodeoxycholic acid treated patients (P less than 0.05). There was no significant difference in systemic venous endotoxaemia, renal function or postoperative morbidity or mortality. This study suggests pre-operative oral bile salt therapy may be of no clinical benefit in patients with obstructive jaundice.
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Gastric mucosal concentrations of histamine and of its metabolic enzyme, histamine methyltransferase activity, were measured in patients with duodenal ulcer disease and patients with an apparently normal stomach and duodenum. Patients with duodenal ulcer had significantly less (p less than 0.05) mucosal histamine (median 204 nmol/g) than control subjects (median 252 nmol/g). There was no significant difference between the two groups in their histamine methyltransferase activity values. Omeprazole therapy did not significantly change mucosal histamine (+23%), histamine methyltransferase activity (+5%), histamine release before (+5%) or during (+7%) pentagastrin infusion. It significantly decreased acid secretion during pentagastrin stimulation (median -73%, p less than 0.001). Omeprazole, like cimetidine, does not stop histamine release during pentagastrin stimulation.
In a prospective study of 65 patients with bile duct obstruction, various radiologic modalities were compared for their capability to demonstrate the level and cause of obstruction and to indicate accurately tumor resectability. Ultrasound (US) was performed in 65 patients, computed tomography (CT) in 51, direct cholangiography (DC) in 57, and angiography in 35. The level of obstruction was correctly indicated by US in 95% of patients and by CT in 90%, and the cause was correctly indicated by US in 88%, by CT in 63%, and by DC in 89%. In predicting tumor resectability, US was correct in 71% of patients, compared with 42% for CT, 58% for DC, and 25% for angiography. US therefore appears to be the single most useful modality in the evaluation bile duct obstruction.
Five patients with stricture of the common hepatic bile duct underwent endoscopic treatment without relief from cholangitis or successful stricture dilation. A Roux-en-Y hepaticojejunostomy was performed upon four patients who are now symptom-free. Endoscopic sphincterotomy leads to bactobilia and increases the risk of cholangitis, particularly in patients with residual obstruction of the bile duct. Although endoscopic treatment may have a role in patients at high risk, there is uncertainty about the long term results and the risk of progressive liver damage. In the majority of patients, the results of operation for benign stricture of the bile duct are such that operative repair is the treatment of choice.
A management plan for patients with suspected focal liver lesions which avoids early biopsy includes routine laboratory investigations, ultrasound scanning, and assessment for evidence of extrahepatic metastases and non-hepatic primary tumours. Angiography and computed tomography may also be indicated, and laparotomy or laparoscopy is undertaken to assess any potentially resectable focal liver lesions. The plan requires modification to suit individual circumstances.
Penetrance frequencies were used to quantify segregating polygenic effects in a natural population of Drosophila melanogaster. When males from a series of 100 isofemale strains were crossed to females from a veinlet (ve) line that had been selected for shortened veins, gaps commonly appeared in the fifth longitudinal (L5) vein in the ve/+ heterozygotes. We were able to assign each strain to one of six significantly different clusters, based upon the pattern of polygenic modifiers of ve dominance segregating in each strain. We conclude that the extensive range of phenotypic variation in vein-forming ability is actually based upon a relatively simple underlying polygenic structure that is consistent with segregation of only a small number of alleles or allele combinations in the wild population.
Gastric secretion was measured in nine patients with duodenal ulcer before, and after treatment for four weeks with omeprazole 20 mg or 40 mg daily. Basal acidity and acid output were affected variably by 20 mg, but inhibited totally by 40 mg daily. Sham feed stimulated acid output was reduced by 20 mg daily and completely inhibited by 40 mg daily. Maximal pentagastrin stimulated acid output was halved by 20 mg omeprazole daily and 84% inhibited by 40 mg daily. The reduction in acidity was always greater than the reduction of volume. Pepsin output after pentagastrin was little altered but with the reduced secretory volume pepsin concentrations were increased by both doses. The major cause of reduced aspirate acid output after omeprazole is decreased secretion of the primary acid component of the parietal cell by the proton pump H+K+ ATPase. Duodenogastric alkaline reflux is, however, markedly increased after omeprazole and is an additional factor in the resultant hypoacidity or even anacidity after this drug.
The records of 37 patients investigated for obscure gastrointestinal haemorrhage originating from the small bowel were reviewed retrospectively. Bleeding was caused by Meckel's diverticula in eight cases, smooth muscle tumours in seven cases, vascular anomalies in 14 cases, and other single lesions in eight cases. The lesions were identified by angiography in 18 patients, operation in 17, and barium follow through examination in two. Only one patient under 50 years of age had a lesion that would not have been found by careful laparotomy. Early laparotomy is advisable in patients aged under 50 with obscure gastrointestinal bleeding; expert selective angiography is recommended before operation in patients aged over 50 and those who have already undergone a laparotomy yielding negative results.
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A case of metastatic adenocarcinoma from the left kidney to the veins of the pampiniform plexus is described following initial presentation with an acute varicocele. It provides further evidence to support the retrograde venous route for intrascrotal secondary malignancy and also for low ligation of the left testicular vein at radical nephrectomy.
Patients with penetrating laryngeal trauma can present a wide spectrum of signs and symptoms. Severe trauma frequently leads to life-threatening airway compromise, whereas lesser injuries are often overlooked because of the subtlety of physical and roentgenographic findings or the severity of vascular and neurologic injuries. Increased suspicion should accompany the examination of patients who have sustained a penetrating neck injury, and such injuries demand examination by an experienced laryngoscopist. Early surgical repair is mandatory to avoid delayed complications, which can permanently impair airway, speech, and deglutition. In a series of 19 patients presented here, diagnosis was delayed in seven (37%). The most relevant factor determining return to normal voice appeared to be the presence or absence of vocal cord paralysis.
Malignant tumors of the nasal septum are rare, probably not more than 300 having been reported. Most of these tumors are epidermoid carcinomas; the second most common histologic type is melanoma. Unless diagnosed and treated early, these tumors are lethal. We report five cases, four carcinomas and one melanoma. We recommend a combined approach with early, wide surgical excision and postoperative irradiation therapy. Surgical considerations must include functional and cosmetic restoration as well as adequate excision of the tumor. Prosthetic appliances can be quite helpful in patients with large resections.
Beadex is a mutation in Drosophila melanogaster that causes premature cell death in the growing wing blade. The extent of cell loss can be modified by environmental conditions and by other genes. By strictly controlling the genotype, therefore, we can use phenotypic variation in the amount of cell death as an in vivo screen of the action that selected drugs have upon cell longevity and replacement in the growing wing. We found that drugs that modify membrane stability or lysosome activity often, but not always, had similar effects upon cell and organism longevity. Thus, the processes important to cell stability in a growing organ are partially separable from those acting upon the organism as a whole. Furthermore, Minute mutations that reduce the efficiency of protein synthesis and extend developmental time allow Beadex -related cell death to be compensated for by additional cell replacement or increased cell lifespan. Both time-span of developmental activity and the stability of cell membranes and organelles are therefore important variables affecting the makeup of the cell populations in an adult organ.