Fatal familial cholestatic syndrome in Greenland Eskimo children

Summary We report the first detailed study of hepatic morphlogy in 28 biopsies from 16 Greenland Eskimo children with fatal familial cholestatic syndrome. The changes were categorized as early, intermediate and late. In the early stage, until 5 months of age, changes were restricted to zone 3, consisting of cholestasis and rosette formation without fibrosis. In the intermediate stage, from 5 to 14 months, cholestasis persisted and rosette formation increased, both with further extension into zone 2. Perisinusoidal fibrosis developed, first in zone 3 and later in zone 1. The late stage, from 17 to 60 months, showed a further increase in cholestasis and rosette formation, and fibrosis of zones 3 and 1 in nearly all biopsies. Portal to portal and portal to central fibrosis was evident with resulting cirrhosis in 2 of 7 patients. The morphological features can be summarized as pure cholestasis with prominent rosette formation followed by zone 3 fibrosis, zone 1 fibrosis, and, cirrhosis. Other characteristics are the virtual absence of inflammation and the lack of anatomical abnormalities such as paucity of bile ducts. The changes and their progression resemble those of Byler disease. Clinical and biochemical features are also largely similar, except for the presence of thrombocytosis in many of the Eskimo patients.     

'Vanishing embryo syndrome' in IVF/ICSI

BACKGROUND: In a Danish population-based cohort study assessing the risk of cerebral palsy in children born after IVF, we made some interesting observations regarding 'vanishing co-embryos'. METHODS and RESULTS: All live-born children born in Denmark from 1 January 1995 to 31 December 2000 were included in this analysis. The children conceived by IVF/ICSI (9444) were identified through the IVF Register, the children conceived without IVF/ICSI (395 025) were identified through The Danish Medical Birth Register. Main outcome measure was the incidence of cerebral palsy. Within the IVF/ICSI children we found indications of an increased risk of cerebral palsy in those children resulting from pregnancies, where the number of embryos transferred was higher than the number of children born. CONCLUSIONS: The association between vanishing embryo syndrome and incidence of cerebral palsy following IVF requires further investigation in larger, adequately powered, studies.     

Severe hypertension with cerebral symptoms treated with furosemide, fractionated diazoxide or dihydralazine. Danish Multicenter Study

Emergency treatment of acute, severe hypertension defined as diastolic blood pressure (DBP) greater than or equal to 135 mmHg combined with cerebral symptoms was prospectively monitored in a randomized multicenter study including 64 patients. Treatment was divided into two periods. In the first hour the patients were observed in the supine position after being given 40 mg furosemide intravenously. If DBP remained greater than 125 mmHg (n = 52), the patients were put on fractionated diazoxide administered intravenously (n = 28) or dihydralazine administered intramuscularly (n = 24). Blood pressure (BP) decreased with diazoxide from an average of 241/149 mmHg to 180/111 mmHg after 5 hours and with dihydralazine from 237/149 to 161/101 mmHg. The inter-individual BP response varied considerably. A clear and identical regression in neurological symptoms was observed on both drug regimens. No new neurological symptoms were seen to develop. It is concluded that a gradual fall in BP can be obtained after fractionated dosage of diazoxide (i.v.) as well as after dihydralazine (i.m.). The indication of acute parenteral therapy compared to less aggressive oral treatment is discussed.     

An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and C-terminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method.The method is available at http://www.cbs.dtu.dk/services/NetCTL. Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php.     

Apical and basolateral expression of Aquaporin-1 in transfected MDCK and LLC-PK cells and functional evaluation of their transcellular osmotic water permeabilities

 Aquaporin-1 is present in the apical and basolateral membranes in proximal tubules and descending limbs of Henlé’s loop. In order to be able to study the routing of Aquaporin-1 and the regulation of Aquaporin-1-mediated transcellular water flow, we stably transfected LLC-PK₁ and MDCK-HRS cell lines with an Aquaporin-1 expression construct. LLC-PK₁ clone 7 and MDCK clone K integrated two and one copies, respectively, which was reflected in the amount of Aquaporin-1 mRNA expressed in both clones. The Aquaporin-1 protein levels, however, were similar. In both clones, immuno-electronmicroscopy showed extensive labelling of Aquaporin-1 on the basolateral plasma membrane, endosomal vesicles and the apical plasma membrane, including the microvilli. To measure transcellular water permeation, a simple method was applied using phenol-red as a cell-impermeant marker of concentration. In contrast to the native cell lines, both clones revealed a high transcellular osmotic water permeability, which could not be influenced by forskolin add/3-isobutyl-1-methylxanthine (IBMX) or the phorbol ester 12-O-tetradecanoyl 13-acetate (TPA). After glutaraldehyde fixation, it was inhibitable by HgCl₂. These results indicate that targeting of Aquaporin-1 to the apical and basolateral plasma membrane is independent of cell type and show for the first time that water flow through a cultured epithelium can be blocked by mercurial compounds. Received: 9 October 1996 / Received after revision: 3 January 1997 / Accepted: 8 January 1997     

Circulating immune complexes in ulcerative colitis.--II. Correlation with serum protein concentrations and complement conversion products

Several serum proteins were quantified in twenty-two patients with active ulcerative colitis, and the findings were related to disease activity and occurrence of circulating immune complexes (IC). Conversion of C3 was significantly more frequent in the IC-positive group (eight patients) as compared to the IC-negative group (fourteen patients). Factor B was demonstrable in fifteen out of the twenty-two patients and seven out of the eight IC-positive patients had detectable levels of factor B. There was no difference between the IC-positive and the IC-negative group as regards serum concentrations of the complement factors C3, C4 and factor B, or serum orosomucoid, albumin, IgM and IgG. In contrast, the serum IgA levels tended to be reduced in the IC-positive group. C3 and factor B were significantly elevated in four patients with severe disease activity. In addition, C3, factor B and C4 concentrations showed a positive correlation to the serum orosomucoid levels. The serum concentrations of orosomucoid and albumin were inversely correlated to each other.     

High-dose inhaled steroids in the management of asthma A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function

Svendsen UG, Frølund L, Heinig JH, Madsen F, Nielsen NH, Weeke B. High-dose inhaled steroids in the management of asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function.
The efficacy of budesonide (800 μg b.d.) and beclomethasone dipropionate (750 μg b.d.) in controlling the symptoms of asthma, pulmonary function, bronchial responsiveness to histamine, and adrenal function, was assessed in a double-blind, double-dummy cross-over study of 36 adult chronic asthmatic patients. The patients, the majority of whom were assessed to be affected to a severe degree, were insufficiently controlled in their current regimen of inhaled steroids and/or inhaled and oral bronchodilators. A 2 weeks baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups showed improvements from baseline in clinical assessment of lung function carried out after the first 6 weeks of treatment. No significant differences were seen throughout the entire 12 weeks study, when comparing the effects of the treatments on FEV₁ FVC, PEF or the histamine PC₂₀. Asthma severity, symptom score and inhaled bronchodilator use showed the same results after both treatments. It is concluded that inhalations of budesonide and beclomethasone dipropionate in high doses are equally potent in the treatment of severe asthma. There is no significant influence on the adrenal function and no significant side effects during a period equal to that of the present study.     

Ethylenediaminetetraacetic acid (disodium salt)-labile bovine immunoglobulin M Fc binding to Brucella abortus: a cause of nonspecific agglutination.

It was demonstrated by a radioimmunoassay procedure that Brucella abortus agglutinins from noninfected cattle sera, absorbed to B. abortus antigen and eluted with ethylenediaminetetraacetic acid (EDTA), was immunoglobulin M that bound to that bacterium by its Fc portion. The EDTA-eluted immunoglobulin M agglutinated intact B. abortus cells but not erythrocytes treated with B. abortus lipopolysaccharide. The specificity of the EDTA-eluted immunoglobulin was for B. abortus, although a small titer to Yersinia enterocolitica serotype O:9 was observed. In contrast, immunoglobulin M purified from the serum of a cow injected 7 days previously with heat-killed B. abortus bound to the antigen by its Fab portion, was not labile to EDTA treatment, cross-reacted extensively with Y. enterocolitica serotype O:9, and agglutinated various other bacterial antigens and normal erythrocytes.