Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995.

In six patients suffering from severe early dumping and six patients with late dumping after peptic ulcer surgery, the effect of the somatostatin analogue SMS 201-995 was compared with placebo. In early dumpers subcutaneous administration of 50 micrograms SMS 201-995 prior to meal ingestion induced a strong improvement of dumping symptoms as reflected by a decrease of the Sigstad dumping score from 12 +/- 2 during placebo to 5 +/- 2 (p less than 0.05). Furthermore, the postprandial increase of pulse rate was abolished; maximum pulse rate decreased from 85 +/- 7 beats/min to 67 +/- 7 beats/min (p less than 0.05). SMS 201-995 did not significantly affect postprandial changes in packed cell volume. In late dumpers 50 micrograms SMS 201-995 reduced peak plasma insulin after oral glucose from 173 +/- 16 mU/L during placebo to 35 +/- 9 mU/L during SMS 201-995 (p less than 0.05) and increased individual plasma glucose nadirs from 1.9 +/- 0.3 mmol/L to 7.5 +/- 3.3 mmol/L (p less than 0.01). Both in early and late dumpers SMS 201-995 improved postprandial expiratory breath hydrogen excretion indicating slowing of gastrointestinal hurry. SMS 201-995 is a powerful therapeutic agent for the management of patients suffering from the dumping syndrome after gastric surgery.     

Plasma metallothionein concentration in patients with liver disorders: special emphasis on the relation with primary biliary cirrhosis

The plasma metallothionein concentration was evaluated in healthy subjects and in patients with several types of liver disorders. Plasma metallothionein concentrations in controls varied between 2.4 and 4.8 ng/ml. Patients with disorders associated with increased liver copper concentrations (i.e., primary biliary cirrhosis and primary sclerosing cholangitis) had significantly (both p less than 0.002) elevated plasma metallothionein concentrations (range = 1.8 to 52.2 ng/ml), and a considerable number of these were above the maximum control level (21 of 41 patients). In contrast, patients with liver disorders not associated with increased liver copper concentrations (alcoholic and cryptogenic cirrhosis, and acute viral and chronic active hepatitis) generally had normal plasma metallothionein concentrations and only a few were above the maximum control level (11 of 64 patients, maximum = 8.8 ng/ml). The metallothionein concentrations in plasma samples from patients in stage I or II primary biliary cirrhosis were within or slightly above the control range, whereas most patients in stage III had elevated levels (p less than 0.002), and almost all patients in stage IV had clearly elevated (p less than 0.0001) concentrations. In primary biliary cirrhosis the plasma metallothionein concentration tended to increase during the evolution of the disorder, and the concentration correlated significantly with the serum total bilirubin concentration. In conclusion, the plasma metallothionein concentration is significantly elevated in patients with primary biliary cirrhosis and in patients with primary sclerosing cholangitis. Although related to the histological stage of primary biliary cirrhosis, the measurement of plasma metallothionein concentrations contributes little to the diagnosis or the evaluation of the severity of these disorders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gallbladder sensitivity to cholecystokinin in coeliac disease. Correlation of gallbladder contraction with plasma cholecystokinin-like immunoreactivity during infusion of cerulein.

The present study was undertaken to determine whether alterations in the gallbladder sensitivity to cholecystokinin (CCK), apart from a reduced endogenous CCK secretion, contribute to the abnormally decreased postprandial gallbladder contraction in patients with coeliac disease. Gallbladder emptying, measured by cholescintigraphy, and plasma CCK levels, measured by radioimmunoassay, were studied during infusion of graded doses of the CCK analog cerulein in six coeliac patients with subtotal villous atrophy, six coeliac patients on a gluten-free diet with normal villous architecture, and nine control subjects. Both in the patients and in the controls infusion of stepwise increasing doses of cerulein, in the range of 1-16 ng.kg-1.h-1, induced dose-related changes in plasma CCK-like immunoreactivity (CCK-LI) (r = 0.99; p less than 0.001) and gallbladder emptying (r greater than 0.97; p less than 0.01-p less than 0.001). Plasma CCK-LI and gallbladder responses were not significantly different among untreated coeliac patients, treated coeliac patients, and controls. Gallbladder sensitivity to cerulein in untreated and treated coeliac patients was not significantly different from that in controls. It is concluded that the abnormally decreased gallbladder contraction in coeliac patients is the result of a reduced endogenous CCK secretion and not of a lack of end-organ responsiveness to CCK.     

Expression and biological effects of high levels of serum IgE in epsilon heavy chain transgenic mice

We have generated and examined transgenic mice carrying a rearranged immunoglobulin transgene coding for the heavy chain of an IgE antibody. These mice produce the secreted form of the recombinant epsilon heavy chain. Serum IgE levels were increased at least 100-fold over control values. Transgenic epsilon mRNA was detected in spleen and thymus, not in liver and heart. Transgenic epsilon production in vitro was slightly up-regulated by T cells, but not affected by interleukin 4 in vitro or Nippostrongylus infestation in vivo. The B cell and T cell compartments and antigen-specific IgE, IgG1 and IgM responses as well as the increase in endogenous IgE after Nippostrongylus infestation in transgenic mice were normal. These data indicate that the presence of high levels of transgenic IgE did not induce class-specific suppressive mechanisms. Transgenic IgE bound to Fc epsilon receptor type I and Fc epsilon receptor type II and mediated histamine release from mast cells in vitro and an allergic skin reaction in vivo. It inhibited an ovalbumin-specific skin reaction in ovalbumin-immunized transgenic mice only during the initial phases of the immune response. This result has a bearing on the feasibility of immune therapy of allergic diseases with substances that block binding of IgE to its receptors.     

Mucin profiles and potential for malignancy of human colorectal adenomatous polyps

The mucin histochemical and histologic features of 166 colorectal adenomatous polyps from 124 patients were studied. A majority of the polyps (62%) had a tubular growth pattern whereas 38% showed villous growth. Severe dysplasia was more frequently found in the latter group. A significant correlation (r = 0.27, P less than 0.001) was found between the severity of dysplasia and the size of the polyps. Moreover, the ratio between goblet and columnar cells was also found to decrease (P less than 0.0001) with the severity of dysplasia. Independent of the mucin stain used (periodic acid-Schiff, alcian blue, and high-iron diamine stains), mucin reactive cells were found to be negatively correlated (-0.17 less than r less than -0.44, P less than 0.01) with severity of dysplasia, especially in the tubular adenomas. These findings suggest that evaluation of mucin stain, related to dysplasia, may contribute to the assessment of premalignant and early malignant changes in adenomas of the colon.     

Distribution of the nuclear thyroid-hormone receptor in extraocular and skeletal muscles.

The correlation between the occurrence of Graves' ophthalmopathy and Graves' hyperthyroidism may indicate a role for tri-iodothyronine (T3) hormone in the pathogenesis of Graves' ophthalmopathy. In Graves' ophthalmopathy the recti eye muscles are greatly enlarged whereas skeletal muscles seem unaffected. The distribution of the nuclear T3 receptor was studied in normal human and rat eye and skeletal muscles with immunohistochemistry using mouse (monoclonal) antibodies, and by in-situ hybridization for the detection of mRNA encoding the T3-receptor protein. Nuclear staining with T3-receptor antibodies was found in all types of tissues studied. Cytoplasmic staining occurred predominantly in the muscle fibres of the orbital layer of the eye muscles and was generally absent or very low in skeletal muscle fibres and hepatocytes. Immunostaining could be inhibited by preabsorbing the antibodies with bacterially expressed T3-receptor protein, implying specificity. The presence of nuclear and cytoplasmic hormone-free T3 receptor sites was indicated after preincubation of sections with T3 hormone; T3-receptor immunostaining decreased and T3-hormone staining increased. In-situ hybridization clearly revealed the presence of alpha-1 and beta-1 forms of the T3-receptor mRNA in liver, skeletal muscles, and orbital and intermediate layers of the eye muscles. The data demonstrate the presence of T3 hormone-receptor molecules in the extraocular and skeletal muscles. The different susceptibilities of these muscles to Graves' hyperthyroidism may relate to the quantitative differences in T3 hormone-receptor distribution.     

Individual chaperones required for Yop secretion by Yersinia.

Pathogenic yersiniae secrete anti-host proteins called Yops, by a recently discovered Sec-independent pathway. The Yops do not have a classical signal peptide at their N terminus and they are not processed during membrane translocation. The secretion domain is nevertheless contained in their N-terminal part but these domains do not resemble each other in the different Yops. We have previously shown that YopE secretion requires SycE, a 15-kDa acidic protein acting as a specific cytosolic chaperone. Here we show that the gene downstream from yopH encodes a 16-kDa acidic protein that binds to hybrid proteins made of the N-terminal part of YopH and either the bacterial alkaline phosphatase or the cholera toxin B subunit. Loss of this protein by mutagenesis led to accumulation of YopH in the cytoplasm and to a severe and selective reduction of YopH secretion. This protein thus behaves like the counterpart of SycE and we called it SycH. We also engineered a mutation in lcrH, the gene upstream from yopB and yopD, known to encode a 19-kDa acidic protein. Although this mutation was nonpolar, the mutant no longer secreted YopB and YopD. The product of lcrH could be immunoprecipitated together with cytoplasmic YopD. lcrH therefore seems to encode a YopD-specific chaperone, which we called SycD. Determination of the dependence of YopB on SycD requires further investigation. SycE, SycH, and SycD appear to be members of a new family of cytosolic chaperones required for Yop secretion.     

Walking exercise in patients with intermittent claudication. Experience in routine clinical practice.

BACKGROUND: In patients with intermittent claudication, exercise in the form of walking is effective in reducing pain and maximising achievable walking distance. However, data are lacking on the implementation of walking exercise in these patients. AIMS: To explore the current behaviour and views of patients with intermittent claudication towards taking walking exercise. DESIGN OF STUDY: Postal questionnaire and focus group meetings. SETTING: Two academic general practice networks (Utrecht and Maastricht Universities) in The Netherlands. METHOD: Three hundred and seventy-five patients with intermittent claudication, selected from the files of general practitioners participating in two academic general practice networks, were sent a postal questionnaire; 216 (58%) were returned. Nine of these responders also attended a focus group meeting. RESULTS: Seventy per cent (151/216) of the patients reported having received advice about walking exercise. If specified, the advice given most often recommended walking in the local neighbourhood (56%, 84/151). Fifty-two per cent (113/216) of all patients actually performed walking exercise and only 32%of them received any kind of supervision. Among the barriers for taking walking exercise, 'comorbidity', 'lack of (specific) advice' and 'lack of supervision' were often mentioned. Among the stimuli to start and continue walking, 'following the doctor's advice', 'relief of complaints' and 'a better general condition' were often mentioned by patients. CONCLUSIONS: Walking exercise was not carried out by almost half of patients with intermittent claudication in this study. Lack of specific advice and supervision were found to be important barriers to taking walking exercise.