Acute injuries in track and field athletes: A 3-year observational study at the Penn Relays Carnival with epidemiology and medical coverage implications

Background Few studies have examined acute injuries in track and field in both elite and sub-elite athletes. Purpose To observe the absolute and relative rates of injury in track and field athletes across a wide range of competition levels and ages during three years of the Penn Relays Carnival to assist with future medical coverage planning and injury prevention strategies. Study design: Descriptive epidemiology study. Methods Over a 3-year period all injuries treated by the medical staff were recorded on a standardised injury report form. Absolute injury rates (absolute number of injuries) and relative injury rates (number of injuries per 1000 participants) were determined and odds ratios (OR) of injury rates were calculated between sexes, competition levels and events. Injuries were also broken down into major or minor medical or orthopedic injuries. Results Throughout the study period 48,473 competing athletes participated in the Penn Relays Carnival, and 436 injuries were sustained. For medical coverage purposes, the relative rate of injury subtypes was greatest for minor orthopedic injuries (5.71 injuries per 1000 participants), followed by minor medical injuries (3.42 injuries per 1000 participants), major medical injuries (0.69 injuries per 1000 participants) and major orthopedic injuries (0.18 injuries per 1000 participants). College/elite level athletes displayed the lowest relative injury rate (7.99 injuries per 1000 participants), which was significantly less than high school (9.87 injuries per 1000 participants) and masters level athletes (16.33 injuries per 1000 participants). Males displayed a greater likelihood of suffering a minor orthopedic injury compared to females (OR = 1.36, 95% CI = 1.06 to 1.75; χ2 = 5.73, p = 0.017) but were less likely to sustain a major medical injury (OR = 0.33, 95% CI = 0.15 to 0.75; χ2 = 7.75, p = 0.005). Of the three most heavily participated in events, the 4 x 400m relay displayed the greatest relative injury rate (13.6 injuries per 1000 participants) compared to the 4 x 100 and 4 x 200m relay. Conclusions Medical coverage teams for future large scale track and field events need to plan for at least two major orthopedic and seven major medical injuries per 1000 participants. Male track and field athletes, particularly masters level male athletes, are at greater risk of injury compared to other genders and competition levels.

Mechanical filtering for narrow-band hearing in the weta

This paper constitutes a major attempt to associate tympanic deflections with the mechanoreceptor organ location in an acoustic insect. The New Zealand tree weta (Hemideina thoracica) has tympanal ears located on each of the prothoracic tibiae. The tympana exhibit a sclerotized oval plate, membranous processes bulging out from the tibial cuticle and many loosely suspended ripples. We used microscanning laser Doppler vibrometry to determine how such a tympanal membrane vibrates in response to sound and whether the sclerotized region plays a role in hearing. The tympanum displays a single resonance at the calling frequency of the male, an unusual example of an insect tympana acting as a narrow bandpass filter. Both tympana resonate in phase with the stimulus and with each other. Histological sections show that the tympanal area is divided into two distinct regions, as in other ensiferans. An oval plate lies in the middle of a thickened region and is surrounded by a transparent and uniformly thin region. It is hinged dorsally to the tympanal rim and thus resembles the model of a ‘hinged flap’. The thickened region appears to act as a damping mass on the oscillation of the thin region, and vibration displacement is reduced in this area. The thinner area vibrates with higher amplitude, inducing mechanical pressure on the dorsal area adjacent to the crista acustica. We present a new model showing how the thickened region might confer a mechanical gain onto the activation of the crista acustica sensory neurons during the sound-induced oscillations.

Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology

Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models’ initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated.

Age-related changes to adenosine in rat coronary resistance vessels

1. The vasodilator effects of adenosine receptor agonists, isoprenaline and histamine were examined in perfused heart preparations from young (4–6 weeks) and mature (12–20 weeks) rats. 2. Adenosine induced a biphasic concentration-dependent decrease in KCl (35 mM) raised coronary perfusion pressure in hearts from young and mature rats, suggesting the presence of both high- and low-affinity sites for adenosine receptors in the two age groups tested. In heart preparations from mature rats, vasodilator responses to adenosine were significantly reduced compared with responses observed in young rats. 3. Responses to 5′-N-ethylcarboxamidoadenosine (NECA) and 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680) were reduced in preparations from mature rats, whereas the vasodilator actions of N6-cyclopentyladenosine (CPA) and N6-2-(4-aminophenyl)ethyladenosine (APNEA) did not change with age. 4. The results presented in this study suggest that several adenosine receptor subtypes mediate vasodilator responses in the coronary circulation of the rat and that a reduction in response to adenosine with age may be due to changes in the high-affinity receptor site.

Understanding the relationship between interfragmentary movement and callus growth in fracture healing: A novel computational approach

Introduction & Aims Optimising fracture treatments requires a sound understanding of relationships between stability, callus development and healing outcomes. This has been the goal of computational modelling, but discrepancies remain between simulations and experimental results. We compared healing patterns vs fixation stiffness between a novel computational callus growth model and corresponding experimental data. Hypothesis We hypothesised that callus growth is stimulated by diffusible signals, whose production is in turn regulated by mechanical conditions at the fracture site. We proposed that introducing this scheme into computational models would better replicate the observed tissue patterns and the inverse relationship between callus size and fixation stiffness. Method Finite element models of bone healing under stiff and flexible fixation were constructed, based on the parameters of a parallel rat femoral osteotomy study. An iterative procedure was implemented, to simulate the development of callus and its mechanical regulation. Tissue changes were regulated according to published mechano-biological criteria. Predictions of healing patterns were compared between standard models, with a pre-defined domain for callus development, and a novel approach, in which periosteal callus growth is driven by a diffusible signal. Production of this signal was driven by local mechanical conditions. Finally, each model’s predictions were compared to the corresponding histological data. Results Models in which healing progressed within a prescribed callus domain predicted that greater interfragmentary movements would displace early periosteal bone formation further from the fracture. This results from artificially large distortional strains predicted near the fracture edge. While experiments showed increased hard callus size under flexible fixation, this was not reflected in the standard models. Allowing the callus to grow from a thin soft tissue layer, in response to a mechanically stimulated diffusible signal, results in a callus shape and tissue distribution closer to those observed histologically. Importantly, the callus volume increased with increasing interfragmentary movement. Conclusions A novel method to incorporate callus growth into computational models of fracture healing allowed us to successfully capture the relationship between callus size and fixation stability observed in our rat experiments. This approach expands our toolkit for understanding the influence of different fixation strategies on healing outcomes.

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

A Mouse Model of Early-Onset Renal Failure Due to a Xanthine Dehydrogenase Nonsense Mutation

Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. © 2012 Piret et al.

A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways

Background: Changing perspectives on the natural history of celiac disease (CD), new serology and genetic tests, and amended histological criteria for diagnosis cast doubt on past prevalence estimates for CD. We set out to establish a more accurate prevalence estimate for CD using a novel serogenetic approach.Methods: The human leukocyte antigen (HLA)-DQ genotype was determined in 356 patients with 'biopsy-confirmed' CD, and in two age-stratified, randomly selected community cohorts of 1,390 women and 1,158 men. Sera were screened for CD-specific serology.Results: Only five 'biopsy-confirmed' patients with CD did not possess the susceptibility alleles HLA-DQ2.5, DQ8, or DQ2.2, and four of these were misdiagnoses. HLA-DQ2.5, DQ8, or DQ2.2 was present in 56% of all women and men in the community cohorts. Transglutaminase (TG)-2 IgA and composite TG2/deamidated gliadin peptide (DGP) IgA/IgG were abnormal in 4.6% and 5.6%, respectively, of the community women and 6.9% and 6.9%, respectively, of the community men, but in the screen-positive group, only 71% and 75%, respectively, of women and 65% and 63%, respectively, of men possessed HLA-DQ2.5, DQ8, or DQ2.2. Medical review was possible for 41% of seropositive women and 50% of seropositive men, and led to biopsy-confirmed CD in 10 women (0.7%) and 6 men (0.5%), but based on relative risk for HLA-DQ2.5, DQ8, or DQ2.2 in all TG2 IgA or TG2/DGP IgA/IgG screen-positive subjects, CD affected 1.3% or 1.9%, respectively, of females and 1.3% or 1.2%, respectively, of men. Serogenetic data from these community cohorts indicated that testing screen positives for HLA-DQ, or carrying out HLA-DQ and further serology, could have reduced unnecessary gastroscopies due to false-positive serology by at least 40% and by over 70%, respectively.Conclusions: Screening with TG2 IgA serology and requiring biopsy confirmation caused the community prevalence of CD to be substantially underestimated. Testing for HLA-DQ genes and confirmatory serology could reduce the numbers of unnecessary gastroscopies. © 2013 Anderson et al.; licensee BioMed Central Ltd.

HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom

Objective - To investigate the HLA class I associations of ankylosing spondylitis (AS) in the white population, with particular reference to HLA-B27 subtypes. Methods - HLA-B27 and -B60 typing was performed in 284 white patients with AS. Allele frequencies of HLA-B27 and HLA-B60 from 5926 white bone marrow donors were used for comparison. HLA-B27 subtyping was performed by single strand conformation polymorphism (SSCP) in all HLA-B27 positive AS patients, and 154 HLA-B27 positive ethnically matched blood donors. Results - The strong association of HLA-B27 and AS was confirmed (odds ratio (OR) 171, 95% confidence interval (CI) 135 to 218; p < 10-99). The association of HLA-B60 with AS was confirmed in HLA-B27 positive cases (OR 3.6, 95% CI 2.1 to 6.3; p < 5 x 10-5), and a similar association was demonstrated in HLA-B27 negative AS (OR 3.5, 95% CI 1.1 to 11.4; p < 0.05). No significant difference was observed in the frequencies of HLA-B27 allelic subtypes in patients and controls (HLA-B*2702, three of 172 patients v five of 154 controls; HLA-B*2705, 169 of 172 patients v 147 of 154 controls; HkA-B*2708, none of 172 patients v two of 154 controls), and no novel HLA-B27 alleles were detected. Conclusion - HLA-B27 and -B60 are associated with susceptibility to AS, but differences in BLA-B27 subtype do not affect susceptibility to AS in this white population.

The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α-tumor necrosis factor haplotype

Objective. HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes. Methods. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 single-nucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin a (LTA). LTA-TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program. Results. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007). Conclusion. These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.

Genetics of ankylosing spondylitis

Purpose of Review Over the past 3 years, several new genes and gene deserts have been identified that are associated with ankylosing spondylitis (AS). The purpose of this review is to discuss the major findings of these studies, and the answers they provide and questions they raise about the pathogenesis of this common condition. Recent Findings: Five genes/genetic regions have now definitively been associated with AS [the major histocompatibility complex (MHC), IL23R, ERAP1, 2p15 and 21q22]. Strong evidence to support association with the disease has been demonstrated for the genes IL1R2, ANTXR2, TNFSF15, TNFR1 and a region on chromosome 16q including the gene TRADD. There is an overrepresentation of genes involved in Th17 lymphocyte differentiation/activation among genes associated with AS and the related diseases inflammatory bowel disease and psoriasis, pointing strongly to this pathway as playing a major causative role in the disease. Increasing information about differential association of HLA-B27 subtypes with disease suggests a hierarchy of strength of association of those alleles with AS, providing a useful test as to the validity of different potential mechanisms of association of HLA-B27 with AS. The mechanism underlying the association of the gene deserts, 2p15 and 21q22, suggests the involvement of noncoding RNA in AS etiopathogenesis. Summary: The increasing list of genes identified as being definitely involved in AS provides a useful platform for hypothesis-driven research in the field, providing a potential alternative route to determining the underlying mechanisms involved in the disease to research focusing on HLA-B27 alone.

Infection and cellular defense dynamics in a novel 17beta-estradiol murine model of chronic human group B streptococcus genital tract colonization reveal a role for hemolysin in persistence and neutrophil accumulation

Genital tract carriage of group B streptococcus (GBS) is prevalent among adult women; however, the dynamics of chronic GBS genital tract carriage, including how GBS persists in this immunologically active host niche long term, are not well defined. To our knowledge, in this study, we report the first animal model of chronic GBS genital tract colonization using female mice synchronized into estrus by delivery of 17β-estradiol prior to intravaginal challenge with wild-type GBS 874391. Cervicovaginal swabs, which were used to measure bacterial persistence, showed that GBS colonized the vaginal mucosa of mice at high numbers (106–107 CFU/swab) for at least 90 d. Cellular and histological analyses showed that chronic GBS colonization of the murine genital tract caused significant lymphocyte and PMN cell infiltrates, which were localized to the vaginal mucosal surface. Long-term colonization was independent of regular hormone cycling. Immunological analyses of 23 soluble proteins related to chemotaxis and inflammation showed that the host response to GBS in the genital tract comprised markers of innate immune activation including cytokines such as GM-CSF and TNF-α. A nonhemolytic isogenic mutant of GBS 874391, Δcyle9, was impaired for colonization and was associated with amplified local PMN responses. Induction of DNA neutrophil extracellular traps, which was observed in GBS-infected human PMNs in vitro in a hemolysin-dependent manner, appeared to be part of this response. Overall, this study defines key infection dynamics in a novel murine model of chronic GBS genital tract colonization and establishes previously unknown cellular and soluble defense responses to GBS in the female genital tract.

Advanced tissue engineering scaffold design for regeneration of the complex hierarchical periodontal structure

AIM: This study investigated the ability of an osteoconductive biphasic scaffold to simultaneously regenerate alveolar bone, periodontal ligament and cementum. MATERIALS AND METHODS: A biphasic scaffold was built by attaching a fused deposition modelled bone compartment to a melt electrospun periodontal compartment. The bone compartment was coated with a calcium phosphate (CaP) layer for increasing osteoconductivity, seeded with osteoblasts and cultured in vitro for 6 weeks. The resulting constructs were then complemented with the placement of PDL cell sheets on the periodontal compartment, attached to a dentin block and subcutaneously implanted into athymic rats for 8 weeks. Scanning electron microscopy, X-ray diffraction, alkaline phosphatase and DNA content quantification, confocal laser microscopy, micro computerized tomography and histological analysis were employed to evaluate the scaffold's performance. RESULTS: The in vitro study showed that alkaline phosphatase activity was significantly increased in the CaP-coated samples and they also displayed enhanced mineralization. In the in vivo study, significantly more bone formation was observed in the coated scaffolds. Histological analysis revealed that the large pore size of the periodontal compartment permitted vascularization of the cell sheets, and periodontal attachment was achieved at the dentin interface. CONCLUSIONS: This work demonstrates that the combination of cell sheet technology together with an osteoconductive biphasic scaffold could be utilized to address the limitations of current periodontal regeneration techniques.

Laser capture microdissection and multiplex-tandem PCR analysis of proximal tubular epithelial cell signaling in human kidney disease

Interstitial fibrosis, a histological process common to many kidney diseases, is the precursor state to end stage kidney disease, a devastating and costly outcome for the patient and the health system. Fibrosis is historically associated with chronic kidney disease (CKD) but emerging evidence is now linking many forms of acute kidney disease (AKD) with the development of CKD. Indeed, we and others have observed at least some degree of fibrosis in up to 50% of clinically defined cases of AKD. Epithelial cells of the proximal tubule (PTEC) are central in the development of kidney interstitial fibrosis. We combine the novel techniques of laser capture microdissection and multiplex-tandem PCR to identify and quantitate “real time” gene transcription profiles of purified PTEC isolated from human kidney biopsies that describe signaling pathways associated with this pathological fibrotic process. Our results: (i) confirm previous in-vitro and animal model studies; kidney injury molecule-1 is up-regulated in patients with acute tubular injury, inflammation, neutrophil infiltration and a range of chronic disease diagnoses, (ii) provide data to inform treatment; complement component 3 expression correlates with inflammation and acute tubular injury, (iii) identify potential new biomarkers; proline 4-hydroxylase transcription is down-regulated and vimentin is up-regulated across kidney diseases, (iv) describe previously unrecognized feedback mechanisms within PTEC; Smad-3 is down-regulated in many kidney diseases suggesting a possible negative feedback loop for TGF-β in the disease state, whilst tight junction protein-1 is up-regulated in many kidney diseases, suggesting feedback interactions with vimentin expression. These data demonstrate that the combined techniques of laser capture microdissection and multiplex-tandem PCR have the power to study molecular signaling within single cell populations derived from clinically sourced tissue.

Histopathological features of bone regeneration in a canine segmental ulnar defect model

Background Today, finding an ideal biomaterial to treat the large bone defects, delayed unions and non-unions remains a challenge for orthopaedic surgeions and researchers. Several studies have been carried out on the subject of bone regeneration, each having its own advantages. The present study has been designed in vivo to evaluate the effects of cellular auto-transplantation of tail vertebrae on healing of experimental critical bone defect in a dog model. Methods Six indigenous breeds of dog with 32 ± 3.6 kg average weight from both sexes (5 males and 1 female) received bilateral critical-sized ulnar segmental defects. After determining the health condition, divided to 2 groups: The Group I were kept as control I (n = 1) while in Group II (experimental group; n = 5) bioactive bone implants were inserted. The defects were implanted with either autogeneic coccygeal bone grafts in dogs with 3-4 cm diaphyseal defects in the ulna. Defects were stabilized with internal plate fixation, and the control defects were not stabilized. Animals were euthanized at 16 weeks and analyzed by histopathology. Results Histological evaluation of this new bone at sixteen weeks postoperatively revealed primarily lamellar bone, with the formation of new cortices and normal-appearing marrow elements. And also reformation cortical compartment and reconstitution of marrow space were observed at the graft-host interface together with graft resorption and necrosis responses. Finally, our data were consistent with the osteoconducting function of the tail autograft. Conclusions Our results suggested that the tail vertebrae autograft seemed to be a new source of autogenous cortical bone in order to supporting segmental long bone defects in dogs. Furthermore, cellular autotransplantation was found to be a successful replacement for the tail vertebrae allograft bone at 3-4 cm segmental defects in the canine mid- ulna. Clinical application using graft expanders or bone autotransplantation should be used carefully and requires further investigation.