Neurodevelopmental synaptopathies: Insights from behaviour in rodent models of synapse gene mutations.

The genomic revolution has begun to unveil the enormous complexity and heterogeneity of the genetic basis of neurodevelopmental disorders such as such epilepsy, intellectual disability, autism spectrum disorder and schizophrenia. Increasingly, human mutations in synapse genes are being identified across these disorders. These neurodevelopmental synaptopathies highlight synaptic homeostasis pathways as a convergence point underlying disease mechanisms. Here, we review some of the key pre- and postsynaptic genes in which penetrant human mutations have been identified in neurodevelopmental disorders for which genetic rodent models have been generated. Specifically, we focus on the main behavioural phenotypes that have been documented in these animal models, to consolidate our current understanding of how synapse genes regulate key behavioural and cognitive domains. These studies provide insights into better understanding the basis of the overlapping genetic and cognitive heterogeneity observed in neurodevelopmental disorders.

An approach to the determination of winter chill requirements for different Ribes cultivars.

Winter chilling is critical for flowering and fruiting of many temperate fruits, with evidence that blackcurrant (Ribes nigrum L.) cropping has been adversely affected by warm winters. Accurate models of chill accumulation in blackcurrant are required so that breeding strategies can be formulated for the generation of new cultivars with resilience to future climates. Existing models for chill accumulation have largely been derived from statistical correlation; here we report the derivation of improved models for blackcurrant using controlled environment treatments. Hardwood cuttings from a diverse set of cultivars were exposed to constant or varying chilling temperatures and the effects on bud break after transfer to a warm, permissive environment evaluated. The impact of different combinations of temperature and chilling periods were described in terms of their overall 'Effectiveness' (E). Clear genotypic differences were found, with excessive chilling often inhibiting bud break. There was a significant interaction between observed chilling response and the period of low temperature exposure. A number of chilling models to explain observed interactions between chilling temperature and time of exposure on bud break were compared; the most effective involved an optimal response to increasing chill accumulation. The effects of varying temperatures during chilling on bud break were complex, with warm temperature breaks substantially inhibiting bud development and cooler temperature breaks tending to enhance bud burst. The relevance of these models to generic studies of endodormancy is discussed, together with their potential application to the development of phenotyping screens for future breeding using diverse blackcurrant germplasm.

Multi-environment QTL mapping in blackcurrant (Ribes nigrum L.) using mixed models.

The first genetic linkage map of blackcurrant, published by Brennan et al. (Euphytica 161:19-34, 2008), identified regions where quantitative trait loci (QTLs) for some important traits were located. The analysis was complicated by the fact that the mapping population was found to contain two subgroups, with segregation ratios consistent with these being crossed and selfed offspring. The QTL analysis was based on the trait mean over 3 years and focused on the crossed offspring. Here we proposed a mixed model multi-environment approach for this population. The 3 years are considered as three separate environments, the data from both the selfed and crossed offspring are combined and different residual terms are explored to model the correlation between the years. This permits tests for interactions between the QTLs, the year and the type of offspring (selfed or crossed). This is applied to re-analyse two important traits, anthocyanin concentration and budbreak. Several additional QTLs were identified, some affecting the trait in both the selfed and crossed offspring, others in just one.

All troponins are not created equal.

Troponin measurement is central to the management and risk stratification of acute coronary syndromes. Decisions are made by categorizing troponin as positive or negative. We sought to evaluate categorical agreement between four troponin assays. Sixty blood samples were analysed by three troponin I assays (Centaur, Architect and point-of-care i-STAT) and one troponin T (TnT) assay (Roche Elecys). The upper reference limit was taken as the lowest value with a coefficient of variation of 10% or less. Continuous agreement between assays was good (Pearson's correlation coefficient 0.871-0.995). Categorical agreement assessed by Cohen's kappa varied from poor (between Architect and Centaur kappa = 0.37, and between TnT and Centaur kappa = 0.48) to good (between Architect and i-STAT kappa = 0.68, and between TnT and i-STAT kappa = 0.68). Percentage of positive results varied almost twofold, from 37% for the Centaur to 72% for the Architect. Comparison of four troponin assays showed up to twofold variations in the proportion of positive results. This implies that either a large proportion of troponin-positive diagnoses are missed by some assays or the assays with higher positivity are generating large numbers of false positives. Clinicians should evaluate troponin results in the clinical context and not base decisions solely on the 'normal range' of their local troponin assay.

Recovery of human mesenchymal stem cells following dehydration and rehydration.

As cell therapies advance from research laboratories to clinical application, there is the need to transport cells and tissues across long distances while maintaining cell viability and function. Currently cells are successfully stored and shipped under liquid nitrogen vapor. The ability to store these cells in the desiccated state at ambient temperature would provide tremendous economic and practical advantage. Human mesenchymal stem cells (hMSCs) have broad potential uses in tissue engineering and regeneration since they can differentiate along multiple lineages and support hematopoeisis. The current research applied recent technological advances in the dehydration and storage of human fibroblasts to hMSCs. Three conditions were tested: air-dried, air-dried and stored under vacuum (vacuum only), and incubated with 50 mM trehalose + 3% glycerol and then air-dried and stored under vacuum (vacuum + trehalose). Plates containing dehydrated hMSCs were shipped from San Diego to Baltimore overnight in separate FedEx cardboard boxes. The hMSCs were rehydrated with 3 ml of hMSC medium and were able to regain their spindle-shaped morphology and adhesive capability. In addition, they maintained high viability and proliferation capacity. Rehydrated and passaged cells continued to express the characteristic hMSC surface antigen panel. Additionally, cells showed constitutive levels of mRNA for a stromal factor and, when exposed to reagents known to induce differentiation, demonstrated upregulation of two tissue-specific messages indicative of differentiation potential for fat and bone. While our preliminary findings are encouraging, we still need to address consistency and duration of storage by considering factors such as cell water content, oxygen concentration, and the presence of free radicals.

Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair.

This investigation tested the hypothesis that delivering mesenchymal stem cell-seeded implants to a tendon gap model results in significantly improved repair biomechanics. Cultured, autologous, marrow-derived mesenchymal stem cells were suspended in a collagen gel delivery vehicle; the cell-gel composite was subsequently contracted onto a pretensioned suture. The resulting tissue prosthesis was then implanted into a 1-cm-long gap defect in the rabbit Achilles tendon. Identical procedures were performed on the contralateral tendon, but only the suture material was implanted. The tendon-implant constructs were evaluated 4, 8, and 12 weeks later by biomechanical and histological criteria. Significantly greater load-related structural and material properties were seen at all time intervals in the mesenchymal stem cell-treated tendons than in the contralateral, treated control repairs (p < 0.05), which contained suture alone with natural cell recruitment. The values were typically twice those for the control tissues at each time interval. Load-related material properties for the treated tissues also increased significantly over time (p < 0.05). The treated tissues had a significantly larger cross-sectional area (p < 0.05), and their collagen fibers appeared to be better aligned than those in the matched controls. The results indicate that delivering mesenchymal stem cell-contracted, organized collagen implants to large tendon defects can significantly improve the biomechanics, structure, and probably the function of the tendon after injury.

A review of basic science issues in low back pain.

This review article is based on a workshop, "New Horizons in Low Back Pain" that was held in November 1995 in San Diego, California. The current article follows the 1995 workshop format of a series of three case study models. Three classical clinical profiles were presented for consideration: lumbar radiculopathy, idiopathic (degenerative disk) low back pain, and degenerative stenosis. This article summarizes the basic science perspectives that were presented and discussed on each topic.

Lyme disease in children.

Lyme disease is becoming prevalent throughout the nation. This article will describe the etiology of Lyme disease, discuss ways of preventing the disease, and present methods for diagnosing and treating the disease.

Effects of spaceflight on the musculoskeletal system: NIH and NASA future directions.

Prolonged bed rest, undertaken by volunteers or resulting from injury and disease, can impair bone and muscle function and structure; extended travel in space also induces these effects. Fluid shifts and disrupted fluid balance may also contribute to observed musculoskeletal aberrations in the weightless environment. Some molecular and cellular events involved in the loading and unloading of the musculoskeletal system are under neural and endocrine influence or control, whereas other events are influenced by local growth factors. Studies are in progress to develop interventions that preserve or improve musculoskeletal integrity in 1g. The NIAMS and NASA are interested in basic and clinical studies of the influence of microgravity on the musculoskeletal system. The interagency workshop results form the basis for new collaborative and cooperative research emphases for the biomedical community under a broad agreement between the National Institutes of Health and NASA.

Use and importance of the NIH noncompeting continuation application.

Each year National Institutes of Health (NIH) grant recipients must submit a noncompeting continuation application before receiving continued federal funding. This paper describes the use and value of the application. Investigators benefit by a yearly self-assessment of the research progress and future plans. The noncompeting continuation application is part of the important communication and interaction that should exist between the investigator and NIH staff. NIH staff members use the application to determine important scientific advances that have resulted from supported grants. Many planning activities and required reports are based on information contained in these applications. NIH staff performs scientific and budgetary review to ensure that research progress is satisfactory and that all budgetary and certification issues are in order. Detailed guidance is provided to help the grantee prepare the application. A separate significance section is suggested as a means to document key findings and their importance.

Ingredients of a successful grant application to the National Institutes of Health.

Many factors determine the scientific merit of an NIH research grant application. This paper is intended to help optimize the organization and logical development of investigators' research ideas so that grant applications will be evaluated by the reviewers in as favorable a light as possible. The ingredients of a successful grant application are good ideas, good science, and a good application. The research should be based on a significant hypothesis and, if possible, oriented towards uncovering an important biological mechanism. Specific methods should be directly related to each aim of the project. Likewise, the specific aims should be related to each hypothesis. All aspects of the application should be clear and focused. It is best to define all assumptions, limitations, and alternative approaches. In general, the best philosophy is for the applicant to address all possible problems before the reviewers.

Total hip arthroplasty after renal transplantation. Long-term follow-up study and assessment of metabolic bone status.

Twenty-two patients had 36 total hip arthroplasties for painful osteonecrosis of the femoral head. At a mean of 86 months after operation, a complete follow-up evaluation, including physical examination, was obtained in 24 hips in 15 patients. An additional 12 hips in seven patients were followed by telephone interview and radiographic evaluation. Although most patients experienced improved hip function and symptomatic relief from pain as a result of the operation, 10 hips developed heterotopic bone, 5 hips dislocated after operation, 6 hips failed due to aseptic loosening, and 1 hip developed a deep infection, and one patient died due to pulmonary embolism. Neither sex, preoperative steroid dose, nor postoperative mean alternate-day steroid dose could be related to aseptic loosening. However, histologic examination of transilial bone biopsy specimens (7 patients, 13 hips) revealed steroid-induced osteoporosis, by the presence of hyperosteoidosis (increased unmineralized osteoid) and increased bone resorption. Bilateral hip involvement, osteoporosis, and high turnover skeletal remodelling at the cement-bone interface potentially contributed to a failure rate that was higher in this group than that reported for primary hip arthroplasty for other diagnoses. The existence of steroid-induced metabolic bone disease and preexisting renal osteodystrophy may pose a significant threat to the long-term survival of a total hip implant.

Unicameral bone cyst of the talus.

Unicameral bone cysts are rarely observed in the foot. A histologically proven unicameral bone cyst occurred in the talus of a three-year-old boy. Six additional cases in the world literature are cited to illustrate the therapeutic and diagnostic problems encountered with this lesion.

Scapulothoracic dissociation (closed avulsion of the scapula, subclavian artery, and brachial plexus): a newly recognized variant, a new classification, and a review of the literature and treatment options.

Scapulothoracic (ST) dissociation is a closed complete traumatic forequarter amputation manifested by a flail pulseless arm and well-defined roentgenographic findings. These roentgenographic findings were previously reported to be lateral displacement of the scapula and either acromioclavicular separation (17) or displaced clavicular fracture (20). In this paper we present four patients with ST dissociation who had a previously unreported combination of roentgenographic findings: lateral displacement of the scapula and sternoclavicular separation. Polytrauma was present in all previously reported cases of patients with ST dissociation. We present one patient, however, in whom ST dissociation is an isolated finding. A review of the literature, and a review of treatment options that includes some combination of amputation, shoulder arthrodesis, prosthetic fitting, and reconstructive tendon transfers, are presented.

Management of skeletal giant cell tumors of the phalanges of the hand.

Five cases of unicentric benign giant cell tumors of the phalanges of the hand are reported. Three patients were initially treated with curettage and bone grafting; two had recurrences that necessitated ray resection as the definitive treatment, and one was free of disease at 16 years' follow-up. The two patients who were primarily treated with ray resection were free of disease at follow-up of 2 and 1 years, respectively. Enneking's surgical staging system and Lodwick's x-ray grading of bone tumors were used to evaluate management methods.