Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations

We evaluated the influence of several DNA repair gene polymorphisms on the frequency of chromosomal aberrations (CAs) analyzed in peripheral lymphocytes, using the fluorescence in situ hybridization technique. The CA data were obtained from an earlier study of 84 healthy nonsmokers (48 women and 36 men) carefully characterized for indoor radon exposure. The frequency of translocations showed a wide interindividual variability, which was only partly explained by age. To investigate the potential role of DNA repair polymorphisms in this variation, genotypes of DNA repair genes OGG1 (codon 326), XPD (codon 751), XRCC1 (X-ray repair cross-complementing group 1) (codons 194, 280, and 399), and XRCC3 (X-ray repair cross-complementing group 3) (codon 241) were determined from leukocyte DNA using polymerase chain reaction-based methods. Negative binomial regression models were applied to evaluate the effect of the polymorphisms and other factors (age, gender, radon exposure, and medical exposure) on the frequency of CAs. No interactions between genotypes and radon, medical exposure, or gender were found. Carriers of the XRCC1 codon 280His variant allele had a two-fold increase (frequency ratio [FR] = 2.01, 95% confidence interval [CI] = 1.01-3.98; P = 0.046) in unstable exchanges (dicentrics and ring chromosomes). In addition, the XRCC3 codon 241 homozygous variant genotype (Met/Met) was associated with an increase (FR = 1.70, 95% CI = 1.06-2.74; P = 0.028) in two-way translocations when age was taken into account in the analysis. Our data suggest that the XRCC1 280His and XRCC3 241Met alleles affect individual CA levels, most probably via influencing the DNA repair phenotype.     

Current Total Knee Designs: Does Baseplate Roughness or Locking Mechanism Design Affect Polyethylene Backside Wear?

Clinical Orthopaedics and Related Research® - Tibial baseplate roughness and polyethylene-insert micromotion resulting from locking-mechanism loosening can lead to polyethylene backside wear...     

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

Aims/hypothesis

This case–control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland.

Methods

Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing.

Results

Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%).

Conclusions/interpretation

The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.

     

COX-2 is widely expressed in metaplastic epithelium in pulmonary fibrous disorders

Idiopathic usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) and asbestosis represent progressive and often fatal pulmonary fibrous disorders, whereas cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis-interstitial lung disease (RB-ILD) usually are reversible or nonprogressive conditions. Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and myofibroblast transition, its production depending on cyclooxygenase-2 (COX-2). In patients with UIP/IPF, levels of PGE2 and COX-2 are reduced in fibroblasts, and levels of PGE2 in bronchioalveolar lavage fluid may be lowered. We analyzed the immunohistochemical expression of COX-2 in UIP/IPF, asbestosis, COP, DIP, and RB-ILD. Our results show that the metaplastic epithelium in UIP/IPF, asbestosis, and COP is widely COX-2+, whereas COX-2 positivity is scant in DIP and RB-ILD. The mesenchymal cells remained negative. Our results suggest that irrespective of the underlying disease, lung injury that causes extensive fibrosis induces wide expression of COX-2 in the regenerating metaplastic epithelium.     

Enteroviruses in the pathogenesis of type 1 diabetes

The question if enteroviruses could cause beta-cell damage and type 1 diabetes has become more and more relevant when recent studies have provided new evidence supporting this scenario. One important observation is the recent discovery of IFIH1 as a risk gene for type 1 diabetes. This gene is an innate immune system receptor for enteroviruses offering one possible mechanism for the diabetogenic effect of enteroviruses. This is further emphasized by the observations suggesting that the innate immune system is activated in the pancreatic islets of type 1 diabetic patients and that the innate immune system is important for the defense against the virus and for the regulation of adaptive immune system. Important progress has also been gained in studies analyzing pancreas tissue for possible presence of enteroviruses. Several studies have found enteroviruses in the pancreatic islets of type 1 diabetic patients using various methods. The virus seems to be located in the islets while exocrine pancreas is mostly uninfected. One recent study found the virus in the intestinal mucosa in the majority of diabetic patients. Enteroviruses can also infect cultured human pancreatic islets causing either rapid cell destruction or a persistent-like noncytolytic infection. Combined with all previous, epidemiological findings indicating the risk effect of enteroviruses in cross-sectional and prospective studies, these observations fit to a scenario where certain diabetogenic enterovirus variants establish persistent infection in gut mucosa and in the pancreatic islets. This in turn could lead to a local inflammation and the breakdown of tolerance in genetically susceptible individuals. This is also supported by mouse experiments showing that enteroviruses can establish prolonged infection in the pancreas and intestine, and some virus strains cause beta-cell damage and diabetes. In conclusion, recent studies have strengthened the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes. These findings open also new opportunities to explore the underlying mechanism and get closer to causal relationship.     

Differences in Trochlear Surface Damage and Wear Between Three Different Total Knee Arthroplasty Designs

Introduction

Trochlear design plays a role in patellofemoral kinematics. Little is known regarding differences in the contact properties between modern designs. The purpose of the present study was to analyze patellofemoral joint contact by identifying areas of joint surface damage and wear in retrieved femoral components of 3 modern designs.

Determination of concept technology – the ontology of the concept as a component of the knowledge development in caring science

The purpose of this study is to determine the ontology of the concept of technology from the perspective of caring science. The aim is to increase knowledge of the concept in caring science and to answer the research question concerning what the concept of technology is in caring science. In literature, the concept of technology is used diversely referring it to caring technology, nursing technology, wellbeing technology, information technology, telenursing and technology in care named by a specific device or an area of nursing or medicine. The definition of the concept of technology and its ontology has not been determined from the viewpoint of caring science. Eriksson's model of concept determination provides a method to explore the ontology of the concept. This includes an etymological and semantic analysis as well as a determination of essence and basic category of the concept. The results showed that the concept of technology is multidimensional. It has evolved and altered over the centuries. The origin of the concept formulated from the Greek word ‘techne’, which has wider ontological dimensions. It is universal, it can be taught and it depends on the substance. Subsequently, the concept was introduced an ethical dimension, and it also developed more to the direction of engineering, mechanics and technical know‐how. The semantic analysis revealed synonyms of the concept: art, equipment and knowledge. These introduced concepts such as craft, skill, treatment, engineering, science, study method and way. The nuances of the concept framed its nature. On the one hand, it stands out as practical and advanced, but on the other hand, it is difficult and conventional. The knowledge gained in this study will help to understand the phenomenon of technology in caring science.     

Spindle cell tumours of the pleura: a clinical, histological and comparative genomic hybridization analysis of 14 cases

We examined 14 spindle cell tumours of the pleura that were sent to a Mesothelioma Panel for re-evaluation after a primary suspicion of mesothelioma. The clinical, histological, immunohistochemical and CGH findings were investigated. Final diagnoses were eight sarcomatoid mesotheliomas (SM) and six non-mesotheliomas: two pulmonary sarcomatoid carcinomas, an epithelioid hemangioendothelioma, a malignant solitary fibrous tumour, a malignant pleural smooth muscle tumour and an extraskeletal osteosarcoma. Seven of the eight SM and two of the other six tumours presented with unilateral pleural effusion, dyspnoea, and chest pain, which are characteristic clinical findings in malignant mesothelioma. No single antibody used in the immunohistochemistry separated SM from other tumour types. The most frequently observed chromosomal losses in SM were 4q, 4p11-p13/p15, 6q and 13. Losses of 4p11-p13/p15 and 4q occurred in combination in four out of five SM with detectable chromosomal changes, but neither was found in any of the other tumours. Gain or high-level amplification of 5p was also common in SM. According to our results and literature, losses at 4p, 4q and 9p and gain at 5p are the chromosomal changes that best differentiate SM from pleural sarcomas and lung carcinomas. CGH analysis may help distinguish a cytokeratin-positive SM from a sarcomatoid carcinoma. Similarly, in the case of a cytokeratin-negative tumour, CGH analysis may disclose chromosomal changes characteristic of sarcomas or mesotheliomas.     

Molecular analysis of an echovirus 3 strain isolated from an individual concurrently with appearance of islet cell and IA-2 autoantibodies

Growing evidence has implicated members of the genus Enterovirus of the family Picornaviridae in the etiology of some cases of type 1 diabetes (T1D). To contribute to an understanding of the molecular determinants underlying this association, we determined the complete nucleotide sequence of a strain of echovirus 3 (E3), Human enterovirus B (HEV-B) species, isolated from an individual who soon after virus isolation developed autoantibodies characteristic of T1D. The individual has remained positive for over 6 years for tyrosine phosphatase-related IA-2 protein autoantibodies and islet cell autoantibodies, indicating an ongoing autoimmune process, although he has not yet developed clinical T1D. The sequence obtained adds weight to the observation that recent enterovirus isolates differ significantly from prototype strains and provides further evidence of a role for recombination in enterovirus evolution. In common with most HEV-B species members, the isolate exhibits 2C and VP1 sequences suggested as triggers of autoimmunity through molecular mimicry. However, comparisons with the E3 prototype strain and previously reported diabetogenic and nondiabetogenic HEV-B strains do not reveal clear candidates for sequence features of PicoBank/DM1/E3 that could be associated with autoantibody appearance. This is the first time a virus strain isolated at the time of commencement of beta-cell damage has been analyzed and is an invaluable addition to enterovirus strains isolated previously at the onset of T1D in the search for specific molecular features which could be associated with diabetes induction.