On the influence of cell shape on dynamic reaction-diffusion polarization patterns.

The distribution of signaling molecules following mechanical or chemical stimulation of a cell defines cell polarization, with regions of high active Cdc42 at the front and low active Cdc42 at the rear. As reaction-diffusion phenomena between signaling molecules, such as Rho GTPases, define the gradient dynamics, we hypothesize that the cell shape influences the maintenance of the "front-to-back" cell polarization patterns. We investigated the influence of cell shape on the Cdc42 patterns using an established computational polarization model. Our simulation results showed that not only cell shape but also Cdc42 and Rho-related (in)activation parameter values affected the distribution of active Cdc42. Despite an initial Cdc42 gradient, the in silico results showed that the maximal Cdc42 concentration shifts in the opposite direction, a phenomenon we propose to call "reverse polarization". Additional in silico analyses indicated that "reverse polarization" only occurred in a particular parameter value space that resulted in a balance between inactivation and activation of Rho GTPases. Future work should focus on a mathematical description of the underpinnings of reverse polarization, in combination with experimental validation using, for example, dedicated FRET-probes to spatiotemporally track Rho GTPase patterns in migrating cells. In summary, the findings of this study enhance our understanding of the role of cell shape in intracellular signaling.

Five-year mortality in patients with diabetic foot ulcer during 2009-2010 was lower than expected.

AIM: Mortality rates are decreasing in patients with diabetes. However, as this observation also concerns patients with diabetic foot ulcer (DFU), additional data are needed. For this reason, our study evaluated the 5-year mortality rate in patients with DFU during 2009-2010 and identified risk factors associated with mortality. METHODS: Consecutive patients who attended a clinic for new DFU during 2009-2010 were followed until healing and at 1 year. Data on mortality were collected at year 5. Multivariate Cox proportional-hazards model was used to identify mortality risk factors. RESULTS: A total of 347 patients were included: mean age was 65±12 years, diabetes duration was 16 [10; 27] years; 13% were on dialysis; and 7% had an organ transplant. At 5 years, 49 patients (14%) were considered lost to follow-up. Total mortality rate at 5 years was 35%, and 16% in patients with neuropathy. On multivariate analyses, mortality was positively associated with: age [hazard ratio (HR): 1.05 (1.03-1.07), P<0.0001]; duration of diabetes [HR: 1.02 (1.001-1.03], P=0.03]; PEDIS perfusion grade 2 vs. 1 [HR: 2.35 (1.28-4.29), P=0.006)]; PEDIS perfusion grade 3 vs. 1 [HR: 3.14 (1.58-6.24), P=0.001); and ulcer duration at year 1 [HR 2.09 (1.35-3.22), P=0.0009]. CONCLUSION: Mortality rates were not as high as expected despite the large number of comorbidities, suggesting that progress has been made in the health management of these patients. In particular, patients with neuropathic foot ulcer had a survival rate of 84% at 5 years.

Mini wing osteotomy: A variant of chin wing osteotomy.

The mini wing is a variant of the chin wing osteotomy. Its design extends from the chin region to the horizontal branch of the mandible as in a traditional chin wing. However, the posterior most cut ends on the upper part of the mandibular notch. It corresponds to a shortened chin wing that respects the basilar edge of the mandible. Its advantage is the capacity to associate it with a bilateral sagittal split osteotomy (BSSO) in the global management of dento-skeletal deformity. There is no contraindication to the realization of a mini wing. Contrarily to the traditional chin wing, a very low positioned inferior alveolar nerve (IAN) is not a contraindication to the mini wing.

Orthodontic - Surgical management in a Class II case with idiopathic root resorption.

Patients with root resorption and malocclusion can benefit from orthodontic treatment with or without surgery. However, orthodontics has a risk of inducing or aggravating root resorption, therefore the duration of the treatment is of utmost importance. In this paper, a surgery-first protocol with lower jaw advancement and precise interdental alveolar osteotomies was conducted to accelerate the treatment of a 14-year-old female patient who presented with a Class II division 2 malocclusion, anterior dental crowding and idiopathic root resorption. One week after the surgery, the patient received postoperative orthodontic treatment for 6 months with weekly activation the first month. The clinical outcome was satisfactory with complete clinical resolution and no tooth loss. This surgery approach allowed an 'en bloc' tooth movement and induced an increased bone remodelling, which resulted in an accelerated tooth movement. The reduction of treatment time was beneficial and no aggravation of the root resorption was seen.

The course of apathy in late-life depression treated with electroconvulsive therapy; a prospective cohort study.

OBJECTIVES: Apathy, a lack of motivation, is frequently seen in older individuals, with and without depression, with substantial impact on quality of life. This prospective cohort study of patients with severe late-life depression treated with electroconvulsive therapy (ECT) aims to study the course of apathy and the predictive value of vascular burden and in particular white matter hyperintensities on apathy course. METHODS: Information on apathy (defined by a score of >13 on the Apathy Scale), depression severity, vascular burden, and other putative confounders was collected in at 2 psychiatric hospitals on patients with late-life depression (aged 55 to 87 years, N = 73). MRI data on white matter hyperintensities were available in 52 patients. Possible risk factors for apathy post-ECT were determined using regression analyses. RESULTS: After treatment with ECT, 52.0% (26/50) of the depression remitters still suffered from clinically relevant apathy symptoms. In the entire cohort, more patients remained apathetic (58.9%) than depressed (31.5%). Presence of apathy post-ECT was not associated with higher age, use of benzodiazepines, or severity of apathy and depression at baseline. Less response in depressive symptomatology after ECT predicted post-treatment apathy. The presence of vascular disease, diabetes mellitus and smoking, and white matter hyperintensities in the brain was not associated with post-treatment apathy. CONCLUSIONS: Apathy may perpetuate in individual patients, despite remission of depressive symptoms. In this cohort of patients with late-life depression, post-ECT apathy is not associated with white matter hyperintensities.

In silico clinical trials for pediatric orphan diseases.

To date poor treatment options are available for patients with congenital pseudarthrosis of the tibia (CPT), a pediatric orphan disease. In this study we have performed an in silico clinical trial on 200 virtual subjects, generated from a previously established model of murine bone regeneration, to tackle the challenges associated with the small, pediatric patient population. Each virtual subject was simulated to receive no treatment and bone morphogenetic protein (BMP) treatment. We have shown that the degree of severity of CPT is significantly reduced with BMP treatment, although the effect is highly subject-specific. Using machine learning techniques we were also able to stratify the virtual subject population in adverse responders, non-responders, responders and asymptomatic. In summary, this study shows the potential of in silico medicine technologies as well as their implications for other orphan diseases.

Erratum: Capturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study.

This corrects the article DOI: 10.1038/srep20010.

Capturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study.

Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40-80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by "Design of Experiments" identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT.

Quality of life and satisfaction after multilevel surgery in cerebral palsy: confronting the experience of children and their parents.

OBJECTIVES: If the benefits of single-event multilevel surgery (SEMS) in ambulatory children with cerebral palsy have already been validated, especially in terms of functional outcomes, fewer studies have evaluated SEMS in terms of quality of life and satisfaction with surgical outcomes, especially pertaining to the opinions of children and their family. The objectives of this study were to confront the perceptions of parents and the experience of their operated children in terms of quality of life and surgical outcomes. MATERIALS AND METHODS: This was an observational, descriptive, single-center study conducted in a regional Pediatric Physical Medicine and Rehabilitation (PM&R) center, which is considered a reference center in this region of France. The subjects recruited were ambulatory children with cerebral palsy (CP) who had SEMS between 2009 and 2011, and one of their parents. The specific "child" and "parent" CP-related modules of the DISABKIDS questionnaire were used to assess these children's quality of life post-surgery. Perceptions of parents and children regarding gait evolution and satisfaction with surgical outcomes were analyzed via a questionnaire developed by the author. Regarding quality of life and surgical outcomes, the correlation between the perception of parents and experience of children was estimated using the intraclass correlation coefficient (ICC) or prevalence-adjusted bias-adjusted kappa values (PABAK). RESULTS: Twelve children (83% of them boys) and their parents participated in the study. For the DISABKIDS questionnaire, a moderate correlation was found regarding functional impact (ICC=0.58; P<0.0178) but a high correlation was reported for the communication item of the questionnaire (ICC=0.73; P=0.0025). Regarding satisfaction with surgical outcomes, results showed a good correlation (PABAK=0.64). CONCLUSION: Concerning quality of life and satisfaction with surgical outcomes, our study showed a good or even high correlation between parents' perceptions and their child's experience. It is however essential to privilege the child's opinion whenever possible.

[Macro replantation of upper extremity. Update and review of the long-term functional results]. / Macro-réimplantation de membre supérieur. Mise au point et résultat fonctionnel a très long-terme.

Confronted with increasing problems of financing in health care, some question the relevance of certain interventions of high technicality. Today, the limiting factor for practitioners is not any longer situated at the technical and technological level (the survival of macro replantations is assured in 85-90%) but moves slowly and surely towards the economic level. It is true that medicine has a price and that if a technique is expensive, it should at least be justified at the human level and superior to other less expensive therapeutic options which are available. In this article, we will first focus on the long-term outcome of patients and also on the functional benefit which brings them replantation compared to patients who underwent a regularization of their stump and possibly a reconstruction enabling them to be correctly fitted with a prosthesis.

Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies.

Calcium phosphate (CaP) has traditionally been used for the repair of bone defects because of its strong resemblance to the inorganic phase of bone matrix. Nowadays, a variety of natural or synthetic CaP-based biomaterials are produced and have been extensively used for dental and orthopaedic applications. This is justified by their biocompatibility, osteoconductivity and osteoinductivity (i.e. the intrinsic material property that initiates de novo bone formation), which are attributed to the chemical composition, surface topography, macro/microporosity and the dissolution kinetics. However, the exact molecular mechanism of action is unknown. This review paper first summarizes the most important aspects of bone biology in relation to CaP and the mechanisms of bone matrix mineralization. This is followed by the research findings on the effects of calcium (Ca²âº) and phosphate (PO4³â») ions on the migration, proliferation and differentiation of osteoblasts during in vivo bone formation and in vitro culture conditions. Further, the rationale of using CaP for bone regeneration is explained, focusing thereby specifically on the material's osteoinductive properties. Examples of different material forms and production techniques are given, with the emphasis on the state-of-the art in fine-tuning the physicochemical properties of CaP-based biomaterials for improved bone induction and the use of CaP as a delivery system for bone morphogenetic proteins. The use of computational models to simulate the CaP-driven osteogenesis is introduced as part of a bone tissue engineering strategy in order to facilitate the understanding of cell-material interactions and to gain further insight into the design and optimization of CaP-based bone reparative units. Finally, limitations and possible solutions related to current experimental and computational techniques are discussed.

Exposing the third chromosome of Burkholderia cepacia complex strains as a virulence plasmid.

The Burkholderia cepacia complex (Bcc) consists of 17 closely related species of opportunistic bacterial pathogens, which are particularly problematic for cystic fibrosis patients and immunocompromised individuals. Bcc genomes consist of multiple replicons, and each strain sequenced to date has three chromosomes. In addition to genes thought to be essential for survival, each chromosome carries at least one rRNA operon. We isolated three mutants during a transposon mutagenesis screen that were non-pathogenic in a Caenorhabditis elegans infection model. It was demonstrated that these mutants had lost chromosome 3 (c3), and that the observed attenuation of virulence was a consequence of this. We constructed a c3 mini-replicon and used it to cure c3 from strains of several Bcc species by plasmid incompatibility, resulting in nine c3-null strains covering seven Bcc species. Phenotypic characterization of c3-null mutants revealed that they were attenuated in virulence in multiple infection hosts (rat, zebrafish, C. elegans, Galleria mellonella and Drosophila melanogaster), that they exhibited greatly diminished antifungal activity, and that c3 was required for d-xylose, fatty acid and pyrimidine utilization, as well as for exopolysaccharide production and proteolytic activity in some strains. In conclusion, we show that c3 is not an essential chromosomal element, rather a large plasmid that encodes virulence, secondary metabolism and other accessory functions in Bcc bacteria.

Designing optimal calcium phosphate scaffold-cell combinations using an integrative model-based approach.

Bone formation is a very complex physiological process, involving the participation of many different cell types and regulated by countless biochemical, physical and mechanical factors, including naturally occurring or synthetic biomaterials. For the latter, calcium phosphate (CaP)-based scaffolds have proven to stimulate bone formation, but at present still result in a wide range of in vivo outcomes, which is partly related to the suboptimal use and combination with osteogenic cells. To optimize CaP scaffold selection and make their use in combination with cells more clinically relevant, this study uses an integrative approach in which mathematical modeling is combined with experimental research. This paper describes the development and implementation of an experimentally informed bioregulatory model of the effect of calcium ions released from CaP-based biomaterials on the activity of osteogenic cells and mesenchymal stem cell driven ectopic bone formation. The amount of bone formation predicted by the mathematical model corresponds to the amount measured experimentally under similar conditions. Moreover, the model is also able to qualitatively predict the experimentally observed impaired bone formation under conditions such as insufficient cell seeding and scaffold decalcification. A strategy was designed in silico to overcome the negative influence of a low initial cell density on the bone formation process. Finally, the model was applied to design optimal combinations of calcium-based biomaterials and cell culture conditions with the aim of maximizing the amount of bone formation. This work illustrates the potential of mathematical models as research tools to design more efficient and cell-customized CaP scaffolds for bone tissue engineering applications.

[Patient complaints in a hospital emergency department in Belgium]. / Typologie des plaintes déposée dans un service d'urgences en Belgique.

Patients express their dissatisfaction through complaints. This study analyzed the frequency and chief complaints of patients presenting to the emergency department (ED). The end point was find ways to improve patient satisfaction after their ED visit. In this retrospective, seven years study, we reviewed 155 chief complaints of patients presenting to the ED of a university hospital. The chief complaints were either from the patients or a family member. One hundred and fifty five chief complaints collected from 496.816 patients presenting to the ED were reviewed over a period of seven years. Complaints case rate was 3.1 per 10.000 visits. Complaints came from patients between the age of 20 to 60 years old (75.0 percent). Complains involved a physician (79.0 percent). The complaints were related a lack of communication (39.0 percent), long waiting time (14.0 percent), wrong diagnosis (22.0 percent), wrong treatment (13.0 percent) and ED disposition of the patient (12.0 percent). Two types of pathology represented more than 15 percent of the complaints: the traumatology (22.0 percent) and the psychiatry (17.0 percent). The traumatology and psychiatry represented respectively 30.0 percent and 10.0 percent of ED visits. Most complaints were addressed and resolved through a hospital mediator, Chief of service or Chief of staff. The rate of complains is low. Most complaints can be prevented if the physician improves communication with patients.

A 24-year-old patient with paraplegia and acquired urethral diverticulum: a case report.

Urethral diverticulum is a rare pathology in male patients. It is most often encountered in patients with paraplegia due to iterative catheterizations. The diagnosis of a large diverticulum is easy to make when faced with clinical symptoms, such as: repeated urinary tract infections, perineal pain and especially when there is penile swelling. We report the case of a 24-year-old patient with paraplegia and urethral diverticulum. In this case, the issue lies in the therapeutic possibilities.

[The anatomical laboratory: a tool for the trial of the new therapeutic procedures]. / Le laboratoire d'anatomie: un banc d'essai des nouvelles technologies.

Since September 2009, the new anatomical department is located on the CHU building. This modern anatomical laboratory is an effective tool to design the new therapeutic procedures and to teach these procedures to practitioners.