An overview of experimental autogenous vein grafts

Examination of the changes in experimental autogenous vein grafts has presented some important results for both human surgical grafts and also for atherosclerosis. We have developed a microsurgical grafting model in the rat, by anastomosing 4 mm of the iliolumbar vein into the iliac artery. The primary cellular response involves the proliferation and migration of endothelium and smooth muscle cells from the adjacent artery. The majority of this activity is complete within the first 4 weeks after grafting. This development of the new cells in the vein graft is described as intimal (or neointimal) hyperplasia. The revascularization by the vasa vasorum and the reestablishment of sympathetic reinnervation of the graft have both been quantitated in detail. In addition, we are now examining factors that influence the intimal hyperplastic response, specifically nicotine, cholesterol and high blood pressure. These factors, as well as being of clinical importance, also give an indication of the pathogenesis of intimal hyperplasia. In this article we briefly review the work that we have completed over the last 15 years and its relevance to the experimental and clinical research literature on intimal hyperplasia.Biomedical Reviews 1992; 1: 25-32

An overview of the regeneration of skeletal muscle

It has only recently been acknowledged widely that mature skeletal muscle has the ability to regenerate, although reports on this phenomenon have existed in the research literature some 40 years. The regenerative events in skeletal muscle include: phagocytosis of cellular and connective tissue debris; revascularization of the lesion; the proliferation of myogenic precursor cells; their differentiation into myoblasts; myoblasts fusion into myotubes; followed by the reestablishment of the nerve supply, and the maturation of myotubes into muscle fibers. The key cell in skeletal muscle regeneration is the satellite cell, which is a reserve myogenic cell situated in between the muscle fiber sarcolemma and its adjacent external lamina. These cells can only by identified by electron microscopy, which makes them very difficult to investigate in detail or quantitatively. However, there is a substantial body of research literature on satellite cells and relevant aspects of their activity are summarized in this review. Satellite cells provide the source of myogenic precursor cells in the regeneration of skeletal muscle, therefore, any factor which stimulates the proliferative activity of satellite cells is very important in enhancing skeletal muscle regeneration. The cellular events in regenerating skeletal muscle closely resemble those which occur in the process of developmental myogenesis, and references to these similarities and differences are briefly reviewed.Biomedical Reviews 1996; 6: 75-81

Effect of prosthodontic planning on lateral occlusion scheme: a comparison between conventional and digital planning

Recently, digital wax-up is proposed as a tool to aid prosthodontic planning. However, there are no data about the effect of prosthodontic planning on lateral occlusion scheme. Objective : This study aims to evaluate the impact of conventional and digital prosthodontic planning on lateral occlusion scheme. Material and Methods : Dental models of 10 patients were collected. All models had Angle Class I occlusion and were undergoing prosthodontic treatment that would influence the lateral occlusion scheme. Each set of models had received both conventional wax-up and digital wax-up. In relation to the lateral occlusion scheme, the following variables were evaluated: the prevalence of the different lateral occlusion scheme, number of contacting teeth and percentage of each contacting tooth. Four excursive positions on the working side were included: 0.5, 1.0, 2.0 and 3.0 mm from the maximal intercuspation position. Results : The lateral occlusion scheme of the two wax-up models was subjected to alterations following excursion. There was a tendency for the prevalence of canine-guided occlusion to increase and for the prevalence of group function occlusion to decrease with increasing excursion. The number of contacting teeth was decreasing with the increasing magnitude of excursion. For the 0.5 mm and 1.0 mm positions, the two wax-ups had significantly greater contacts than the pre-treatment models, while at the 2.0 mm and 3.0 mm positions, all the models were similar. For all models, canines were the most commonly contacting teeth, followed by the teeth adjacent to them. No difference was observed between the two wax-ups in relation to the number of contacting teeth. Conclusion : Although the prosthodontic planning had influenced the pattern of the lateral occlusion scheme and contacts, there was no difference between the conventional and digital prosthodontic planning

Revascularization of skeletal muscle transplanted into the hamster cheek pouch: Intravital and light microscopy

Small fiber bundles from the extensor digitorum longus (EDL) muscle were transplanted into the hamster cheek pouch to observe the process of revascularization. We tested the hypothesis that blood vessels of a graft degenerate and that revascularization results from the ingrowth of blood vessels from the cheek pouch into the graft. Degeneration and regeneration of muscle fibers followed a pattern similar to that reported for autografts of whole muscles in rats. Blood vessels in the graft that were adjacent to vascularized host tissue survived. At 1 day, surviving blood vessels in the graft had normal structure but erythrocytes were packed tightly in the lumen. At 2 days, sprouts from surviving graft vessels had grown into the cheek pouch. Between 2 and 2.5 days, anastomoses of blood vessels from the graft with those of the cheek pouch reestablished circulation. After circulation was established, the blood vessels contained well-spaced erythrocytes. By 3 days, blood vessels which increased in number and diameter throughout the graft occupied 40-60% of the graft. Over the next 24 hr, blood vessels in the graft regressed toward the control value. We conclude that blood vessels in muscle grafts in the cheek pouch survive transplantation, and that circulation in grafts is reestablished by the anastomoses of blood vessel sprouts from the graft with the blood vessels of the host.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25166/1/0000604.pd

Joint GWAS Analysis: Comparing similar GWAS at different genomic resolutions identifies novel pathway associations with six complex diseases

We show here that combining two existing genome wide association studies (GWAS) yields additional biologically relevant information, beyond that obtained by either GWAS separately. We propose Joint GWAS Analysis, a method that compares a pair of GWAS for similarity among the top SNP associations, top genes identified, gene functional clusters, and top biological pathways. We show that Joint GWAS Analysis identifies additional enriched biological pathways that would be missed by traditional Single-GWAS analysis. Furthermore, we examine the similarities of six complex genetic disorders at the SNP-level, gene-level, gene-cluster-level, and pathway-level. We make concrete hypotheses regarding novel pathway associations for several complex disorders considered, based on the results of Joint GWAS Analysis. Together, these results demonstrate that common complex disorders share substantially more genomic architecture than has been previously realized and that the meta-analysis of GWAS needs not be limited to GWAS of the same phenotype to be informative

Lung function trajectories from pre-school age to adulthood and their associations with early life factors : a retrospective analysis of three population-based birth cohort studies

Funding: MAAS and STELAR cohorts are funded by the The UK Medical Research Council (MRC) Grants G0601361 and MR/K002449/1. The UK Medical Research Council and the Wellcome Trust (Grant ref:102215/2/13/2) and the University of Bristol provide core support for ALSPAC. ALSPAC lung function was funded by MRC grants G0401540 and MR/M022501/1. PIAF was funded by the National Health and Medical Research Council of Australia. DB is supported by the MRC Career Development Award in Biostatistics Grant MR/M015181/1Peer reviewedPostprin

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10-8) and PPP4R4/SERPINA1 (P = 1.0131028) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ~0.6), and accounted for a mean 0.9–1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtyp

Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of Duchenne muscular dystrophy

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles