SLC30A8 (ZnT8) Polymorphism is Associated with Young Age at Type 1 Diabetes Onset

It was recently shown that the major allele of the SLC30A8 (zinc transporter 8, ZnT8) single nucleotide polymorphism (SNP) rs13266634 was associated with type 2 diabetes and with reduced insulin secretion in non-diabetic relatives. Because of its role in beta-cell function, we hypothesized that this candidate SNP may confer increased susceptibility for beta-cell destruction in type 1 diabetes. We analyzed SLC30A8 genotypes in 874 patients with type 1 diabetes and 1021 control subjects. No difference in allele and genotype frequencies of the SLC30A8 SNP rs13266634 was found between patients and controls. Analysis with respect to age at type 1 diabetes onset, however, showed that patients with a diabetes onset before age 5 years had an increased prevalence of the cytosine (C) allele (risk allele, 82%) and the homozygous CC genotype (65%) compared to patients who developed type 1 diabetes after age 5 years (67% and 49%; p < 0.01) and compared to controls (69% and 48%; p < 0.03). These data suggest that genetic susceptibility for beta-cell dysfunction in the presence of autoimmunity may lead to accelerated progression and early manifestation of the disease.     

CXCR5‐ and CCR7‐dependent lymphoid neogenesis in a murine model of chronic antigen‐induced arthritis

Objective

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process.

Methods

We developed a modified model of chronic antigen‐induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild‐type, CXCR5‐deficient, and CCR7‐deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints.

Results

In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild‐type, CXCR5^−/−, and CCR7^−/− mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5^−/− mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5‐deficient and CCR7‐deficient mice.

Conclusion

Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.

     

Radiation dosimetry and biodistribution of 11C-ABP688 measured in healthy volunteers

Introduction In this study, we assessed the whole-body biodistribution and radiation dosimetry of the new glutamatergic ligand ¹¹C-ABP688. This ligand binds specifically to the metabotropic glutamatergic receptor of subtype 5 (mGluR5). Materials and methods The study included five healthy male volunteers aged 20–29 years. After intravenous injection of 240–260 MBq, a series of four to ten whole-body positron emission tomography/computed tomography scans were initiated, yielding 60–80 min of data. Residence times were then calculated in the relevant organs, and the software packages Mirdose and Olinda were used to calculate the absorbed radiation dose and the effective dose equivalent. Results Of the excreted ¹¹C activity at 1 hour, approximately 80% were eliminated via the hepato-biliary pathway and 20% through the urinary tract. The absorbed dose (mGy/MBq) was highest in the liver (1.64 E -2 ± 5.08 E -3), gallbladder (8.13 E -3 ± 5.6 E -3), and kidneys (7.27 E -3 ± 2.79 E -3). The effective dose equivalent was 3.68 ± 0.84 microSv/MBq. Brain uptake in the areas with high mGluR5 density was 2–3 (SUV). The agreement between the values obtained from Mirdose and the Olinda was excellent. Conclusion ¹¹C-ABP688 is a very promising ligand for the investigation of mGluR5 receptors in humans. Brain uptake is high and the effective dose equivalent so low that serial examinations in the same subject seem feasible.     

Microarray analysis of Ewing's sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy

In Ewing's sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer.     

The overexpression of c-met as a prognostic indicator for gastric carcinoma compared to p53 and p21 nuclear accumulation

The purpose of this study was to clarify the relationship of the immunohistochemical expression of c-met, p53 and p21 with clinicopathological parameters and prognosis in gastric carcinomas. We analyzed specimens from 114 gastric cancer patients (median age 64 years, range: 33-86) who underwent gastrectomy with lymphadenectomy. Specimens were categorized according to the tumor differentiation, based on UICC, WHO, Laurén, Ming and Goseki classifications. Specimens were examined immunohistochemically with antibodies against c-met, p53 and p21. The expression was evaluated semiquantitatively and correlated with the clinicopathological parameters. The c-met staining pattern was positive in 73.7%. P53 and p21 were positive in 86.8 and 67.5%, respectively. No significant correlation between c-met or p21 expression and the clinicopathological parameters was seen. A significant increase of p53 expression was observed in stage pT3 and -4. The overexpression of c-met and p53 was significantly associated with a poor prognosis in the univariate survival analysis. In the multivariate analysis this impact was maintained for c-met. P21 proved to be a significant prognostic factor in the multivariate analysis. Our data suggest that the overexpression of c-met and p21 may represent independent prognostic factors in gastric carcinoma.     

Multiple-needle insertion method in percutaneous ethanol injection therapy for liver neoplasms

One of the shortcomings of percutaneous ethanol injection therapy (PEIT) is that many sessions are necessary to accomplish the treatment. In order to reduce the number of treatment sessions, we inserted two or three needles before injection of ethanol was begun. Using the multiple-needle insertion method, we markedly reduced the number of treatment sessions. Histopathologic examination, imaging techniques, and serum alpha-fetoprotein levels showed efficacy of PEIT using the multiple-needle insertion method. No serious complication occurred. Levels of transient pain, fever, and the feeling of intoxication did not seem to be different from those occurring with the conventional method. Multiple-needle insertion method may be valuable as a method for reducing the number of treatment sessions necessary and thus shortening the treatment period.     

Assignment of the human gene for muscle-type phosphofructokinase (PFKM) to chromosome 1 (region cen→q32) using somatic cell hybrids and monoclonal anti-M antibody

Human phosphofructokinase (PFK; EC 2.7.1.11) is under the control of three structural loci which encode muscle-type (M), liver-type (L), and platelet-type (P) subunits; human diploid fibroblasts and leukocytes express all three loci. In order to assign human PFKMlocus to a specific chromosome we have analyzed human × Chinese hamster somatic cell hybrids for the expression of human M subunits, using an anti-human M subunit-specific mouse monoclonal antibody. In 18 of 19 hybrids studied, the expression of the PFKMlocus segregated concordantly with the presence of chromosome 1 (discordancy rate 0.05) as indicated by chromosome and isozyme marker analysis. The discordancy rates for all the other chromosomes were 0.32 or greater, indicating that the PFKMlocus is on chromosome 1. For the regional mapping of PFKM,eight hybrids were studied that contained one of five distinct regions of chromosome 1. These results further localize the human PFKMlocus to region cenq32 of chromosome 1.     

Actinic superficial folliculitis

Actinic superficial folliculitis was first described in 1985, and since then only three reports have been published. Clinically and histopathologically this disease is very particular and has been suggested to be considered as an entity. We report on a 30-year-old man who presented with an extensive superficial follicular pustulosis on his back, shoulders and upper chest after exposure to intense heat and subsequent sweating on a sunny day. The pustules arose within 24-36 h afterwards. Histology and immunohistochemistry revealed subcorneal pustules, suppurative folliculitis and an infiltrate consisting of T cells, macrophages and neutrophils around the hair follicle, sebaceous glands and small vessels. To the best of our knowledge this is the fourth report on actinic superficial folliculitis and the first on which a characterization of the inflammatory infiltrate has been performed. Because of the impressive, unique symptoms and the characteristic histology we agree with those who have suggested that actinic superficial folliculitis is a new entity.