Prophylactic effect of cimetidine in gastric ulcer patients.

Nineteen patients entered a double-blind randomized trial of the prophylactic effect of cimetidine in gastric ulcer disease. The diagnosis of gastric ulcer had been established endoscopically prior to the trial, but at the time of entry the patients were symptom-free and their ulcers had healed. The patients received either cimetidine, 400 mg twice daily or inactive tablets. Ten cimetidine-treated patients completed 12 months' treatment without suffering a recurrence of symptoms, whereas 5 of 9 placebo-treated patients suffered a symptomatic relapse after 7 to 18 weeks (P less than 0.025). In 4 of the 5 patients an ulcer was found at gastroscopy. It is concluded that maintenance treatment with cimetidine helps to prevent symptomatic relapses in gastric ulcer patients.     

Functional Studies of Tyrosine Hydroxylase Missense Variants Reveal Distinct Patterns of Molecular Defects in Dopa‐Responsive Dystonia

Congenital tyrosine hydroxylase deficiency (THD) is found in autosomal‐recessive Dopa‐responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early‐onset lethal disease to mild Parkinson disease‐like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease‐related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (TH) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser, and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and Dopa, whereas p.Cys359Phe had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients.     

Structural basis for activation of the complement system by component C4 cleavage

An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.     

Treatment of hepatitis C virus infection in adults and children: updated Swedish consensus recommendations

Swedish recommendations for the treatment of hepatitis C virus (HCV) infection were updated at a recent expert meeting. Therapy for acute HCV infection should be initiated if spontaneous resolution does not occur within 12 weeks. The recommended standard-of-care therapy for chronic HCV genotype 1 infection is an HCV protease inhibitor in combination with peginterferon (peg-IFN) and ribavirin. Treatment is strongly recommended in patients with bridging fibrosis and cirrhosis, whereas in patients with less advanced fibrosis, deferring therapy may be preferential in light of likely therapeutic improvements in the near future. Patients with chronic genotype 2/3 infection should generally be treated with peg-IFN and ribavirin for 24 weeks. In patients with a very rapid viral response (i.e. HCV RNA below 1000 IU/ml on day 7), or favourable baseline characteristics and undetectable HCV RNA week 4, treatment can be shortened to 12-16 weeks, provided that no dose reductions are needed.     

Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells

CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs), but the mechanism by which they do so remains incompletely understood. In the present study, we assessed CTLA-4 protein function in both Tregs and conventional (Tconv) CD4(+) T cells. We report that CTLA-4 proteins are responsible for all 3 characteristic Treg functions of suppression, TCR hyposignaling, and anergy. However, Treg suppression and anergy only required the external domain of CTLA-4, whereas TCR hyposignaling required its internal domain. Surprisingly, TCR hyposignaling was neither required for Treg suppression nor anergy because costimulatory blockade by the external domain of CTLA-4 was sufficient for both functions. We also report that CTLA-4 proteins were localized in Tregs in submembrane vesicles that rapidly recycled to/from the cell surface, whereas CTLA-4 proteins in naive Tconv cells were retained in Golgi vesicles away from the cell membrane and had no effect on Tconv cell function. However, TCR signaling of Tconv cells released CTLA-4 proteins from Golgi retention and caused activated Tconv cells to acquire suppressor function. Therefore, the results of this study demonstrate the importance of intracellular localization for CTLA-4 protein function and reveal that CTLA-4 protein externalization imparts suppressor function to both regulatory and conventional CD4(+) T cells.     

Visuoconstructional Abilities in Cognitively Healthy Illiterate Turkish Immigrants: A Quantitative and Qualitative Investigation

Assessment of visuospatial function is an integral part of most neuropsychological assessments and is frequently assessed by visuoconstructional tests. A significant impact of limited schooling and illiteracy has been found on numerous neuropsychological tests and it can be difficult to interpret test results from illiterate individuals. In this study, quantitative and qualitative aspects of performance of elderly cognitively healthy illiterate and literate Turkish immigrants were compared on five commonly used visuoconstructional tests. Significantly poorer performances of illiterate compared to literate subjects were found in copying of two- and three-dimensional geometric designs, and in Clock Drawing Test performance. A systematic qualitative analysis found lacking three-dimensionality, “curved angles”, omissions, distorted relation between elements, and spatial disorganization to be common error types in illiterate subjects. Performances were not found to be influenced by duration of residence in Denmark or level of acculturation. The results warrant caution in the interpretation of visuoconstructional test performances in illiterate subjects, as they can easily be misinterpreted as signs of cognitive dysfunction.     

Laminarthrectomy as a surgical approach for decompressing the spinal canal: assessment of preoperative versus postoperative dural sac cross-sectional areal (DSCSA)

Introduction

Surgery for lumbar spinal stenosis (LSS) is today the most frequently performed procedure in the adult lumbar spine. Long-term benefit of surgery for LSS is well documented both in randomized and in non-randomized trials. In this paper, we present the results from laminarthrectomy as an alternative surgical approach, which have theoretical advantages over other approaches. In this study, we wanted to study the clinical and radiological results of laminarthrectomy. Dural sac cross-sectional areal (DSCSA) is an objective method to quantify the degree of central stenosis in the spinal canal, and was used to measure whether we were able to achieve an adequate decompression of the spinal canal with laminarthrectomy as a surgical approach.

Materials and methods

All patients operated on with this approach consecutively in the period 1 January 2008 to 31 March 2009 were included in the study. All perioperative complications were noted. Clinical results were measured by means of a questionnaire. The patients that agreed to attend the study had an MRI taken of the operated level. DSCSA before and after surgery of the actual level were measured by three observers. We then performed a correlation test between increase of area and clinical results. We also tested for inter- and intra-observer reability.

Results

Fifty-six laminarthrectomy were performed. There were 17 % complications, none of them were life-threatening or disabling. 46 patients attended the study and answered the questionnaire. Thirty-four patients (83 %) reported clinical improvement, whereas six (13 %) patients reported no improvement, and two (4 %) patients reported that they were worse. Mean ODI was 23.0. Mean EQ-5D was 0.77. Mean VAS-score for back-pain was 3.1 and mean VAS-score for leg-pain was 2.8. Mean DSCSA were measured to 80 mm² before surgery and 161 mm² after surgery. That gave an increase of DSCSA of 81 mm² (101 %). We found a significant positive correlation between increase of area and clinical results. We also found consistent inter- and intra-observer reability.

Discussion

In this study, the clinical results of laminarthrectomy were good, and comparable with other reports for LSS. The rates of complications are also comparable with other reports in spinal surgery. A significant increase in the spinal canal diameter was achieved. Within the limitations a retrospective study gives, we conclude that laminarthrectomy seems to be a safe and effective surgical approach for significant decompressing the adult central spinal canal, and measurement of DSCSA, before and after surgery seems to be a good way to quantify the degree of decompression.