Fragile X-syndrome: literature review and report of two cases

Fragile X-syndrome is caused by a mutation in chromosome X. It is one of the most frequent causes of learning disability. The most frequent manifestations of fragile X-syndrome are learning disability, different orofacial morphological alterations and an increase in testicle size. The disease is associated with cardiac malformations, joint hyperextension and behavioural alterations. We present two male patients aged 17 and 10 years, treated in our Service due to severe gingivitis. Both showed the typical facial and dental characteristics of the syndrome. In addition, we detected the presence of root anomalies such as taurodontism and root bifurcation, which had not been associated with fragile X-syndrome in the literature. In some cases these root malformations have been associated with other sex-linked congenital syndromes, though in none of the studies published in the literature have they been related with fragile X-syndrome. This syndrome is relevant due to its high prevalence, the presentation of certain oral and facial characteristics that can facilitate the diagnosis, and the few cases published to date

Myofascial pain associated to trigger points: A literature review. Part 2: Differential diagnosis and treatment

During the last decades the advance in knowledge of myofascial pain has been constant in the medical and dental community. However, although several aspects have been clarified in relation to its epidemiology, clinical characteristics and etiopathogenesis, many uncertainties remain. Many clinical conditions are included in the differential diagnosis of myofascial pain associated to trigger points. A good anamnesis and clinical exploration is thus required in order to ensure correct diagnosis and treatment. Among the numerous treatments used in application to trigger points, the spray-and-stretch technique and direct injection targeted to such trigger points have been found to be the most effective options. In chronic cases, psychosocial intervention is required, due to the high incidence of mood disorders and/or anxiety observed in these patients, who in turn present a poorer prognosis. This underscores the importance of early diagnosis and treatment.

Allosteric conversation in the androgen receptor ligand-binding domain surfaces

Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design.

Cardiopathie congénitale: de l'enfance à l'âge adulte [Congenital heart disease: from childhood to adulthood].

Grâce à l'amélioration de la chirurgie cardiaque, les enfants avec une malformation cardiaque congénitale atteignent actuellement en grande majorité l'âge adulte avec une bonne qualité de vie. Un suivi cardiaque régulier est toutefois recommandé. La période de l'adolescence coïncide souvent avec la survenue de complications à moyen et long termes et la nécessité d'une reprise chirurgicale ou par cathétérisme interventionnel, en particulier chez les patients avec cardiopathie complexe. Par conséquent, il est primordial de débuter le processus de transition assez tôt et de la poursuivre jusqu'à l'âge adulte. Nous avons élaboré un programme de transition formel, adapté aux patients avec cardiopathie congénitale. With the improvement of congenital heart surgery, most children with congenital heart disease will survive into adulthood with a good quality of life. Regular cardiac follow-up is recommended for all patients. The adolescent period coincides often with medium and long term consequences and complications and repeat surgery or catheter interventions might be needed. It is therefore of prime importance to begin the transition process early and to pursue it well into adulthood. We have elaborated a formal transition program adapted to youngsters with congenital heart disease.

Outcome of patients admitted with acute coronary syndrome on palliative treatment: insights from the nationwide AMIS Plus Registry 1997-2014.

OBJECTIVE: Compliance with guidelines is increasingly used to benchmark the quality of hospital care, however, very little is known on patients admitted with acute coronary syndromes (ACS) and treated palliatively. This study aimed to evaluate the baseline characteristics and outcomes of these patients. DESIGN: Prospective cohort study. SETTING: Eighty-two Swiss hospitals enrolled patients from 1997 to 2014. PARTICIPANTS: All patients with ACS enrolled in the AMIS Plus registry (n=45,091) were analysed according to three treatment groups: palliative treatment, defined as use of aspirin and analgesics only and no reperfusion; conservative treatment, defined as any treatment including antithrombotics or anticoagulants, heparins, P2Y12 inhibitors, GPIIb/IIIa but no pharmacological or mechanical reperfusion; and reperfusion treatment (thrombolysis and/or percutaneous coronary intervention during initial hospitalisation). The primary outcome measure was in-hospital mortality and the secondary measure was 1-year mortality. RESULTS: Of the patients, 1485 (3.3%) were palliatively treated, 11,119 (24.7%) were conservatively treated and 32,487 (72.0%) underwent reperfusion therapy. In 1997, 6% of all patients were treated palliatively and this continuously decreased to 2% in 2013. Baseline characteristics of palliative patients differed in comparison with conservatively treated and reperfusion patients in age, gender and comorbidities (all p<0.001). These patients had more in-hospital complications such as postadmission onset of cardiogenic shock (15.6% vs 5.2%; p<0.001), stroke (1.8% vs 0.8%; p=0.001) and a higher in-hospital mortality (25.8% vs 5.6%; p<0.001).The subgroup of patients followed 1 year after discharge (n=8316) had a higher rate of reinfarction (9.2% vs 3.4%; p=0.003) and mortality (14.0% vs 3.5%; p<0.001). CONCLUSIONS: Patients with ACS treated palliatively were older, sicker, with more heart failure at admission and very high in-hospital mortality. While refraining from more active therapy may often constitute the most humane and appropriate approach, we think it is important to also evaluate these patients and include them in registries and outcome evaluations. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT01 305 785.

Use of amitriptyline for the treatment of chronic tension-type headache. Review of the literature

Amitriptyline is a tricyclic antidepressant, considered the treatment of choice for different types of chronic pain, including chronic myofascial pain. Its antinociceptive property is independent of its antidepressant effect. Although its analgesic mechanism is not precisely known, it is believed that the serotonin reuptake inhibition in the central nervous system plays a fundamental role in pain control. Although this medication is widely used in the prevention of chronic tension-type headache, few studies have investigated the efficacy of this treatment and the published results are contradictory. The objective of this article was to review the literature published on the use of amitriptyline in the prophylactic treatment of chronic tension-type headache, considering the level of scientific evidence of the different studies using the SORT criteria. From this review, 5 articles of evidence level 1, and another 5 articles of evidence level 2 were selected. Following analysis of the 10 studies, and in function of their scientific quality, a level A recommendation was made in favor of using amitriptyline in the treatment of chronic tension-type headache.

Retrospective study of 145 supernumerary teeth

Objective: The goal of the present retrospective study is to describe the distribution of the supernumerary teeth in a population of patients that have been attended at the Public Clinic of the Department of Oral Surgery. Background: Supernumerary teeth and multiple hyperdontia are usually associated with different syndromes, such as Gardner syndrome, or with facial fissures; however, they can appear in patients without any pathology. Their prevalence oscillates to 0.5-3.8% in patients with permanent teeth and to 0.35-0.6% in patients with primary teeth. Patients and Methods: A total of 36,057 clinical histories of patients that were admitted at the clinic between September of 1991 and March of 2003 were revised. The following data were extrapolated: age, sex, number of extracted supernumerary teeth, localization, morphology and type of supernumerary teeth. Consequently, 102 patients were included into the present study. Results: Of the 147 supernumerary teeth identified in the oral cavities of patients 145 were extracted. The most frequent supernumerary teeth identified were mesiodens (46.9%), followed by premolars (24.1%) and fourth molars or distal molars (18%). As for location, 74.5% of the supernumerary teeth were found in the superior maxillary bone and 46.9% of the supernumerary teeth were present in the palatine/lingual area. Heteromorphology was found in two thirds of the supernumerary teeth, with conical shape being the most frequent. Finally, 29.7% of the supernumerary teeth had occlusion with permanent teeth, and mesiodens were the predominating type of supernumerary teeth that showed this feature. Conclusions: Mesiodens very frequently cause retention of permanent incisors, which erupt spontaneously after the extraction of supernumerary teeth, if there is sufficient space in the dental arch and if they conserve the eruptive force. Generally, supernumerary premolars are eumorphic and are casually discovered during radiological exam, if not producing any symptomology.

Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood.

BACKGROUND: Since recombinant human growth hormone (rhGH) became available in 1985, the spectrum of indications has broadened and the number of treated patients increased. However, long-term health-related quality of life (HRQoL) after childhood rhGH treatment has rarely been documented. We assessed HRQoL and its determinants in young adults treated with rhGH during childhood. METHODOLOGY/PRINCIPAL FINDINGS: For this study, we retrospectively identified former rhGH patients in 11 centers of paediatric endocrinology, including university hospitals and private practices. We sent a questionnaire to all patients treated with rhGH for any diagnosis, who were older than 18 years, and who resided in Switzerland at time of the survey. Three hundred participants (58% of 514 eligible) returned the questionnaire. Mean age was 23 years; 56% were women; 43% had isolated growth hormone deficiency, or idiopathic short stature; 43% had associated diseases or syndromes, and 14% had growth hormone deficiency after childhood cancer. Swiss siblings of childhood cancer survivors and the German norm population served as comparison groups. HRQoL was assessed using the Short Form-36. We found that the Physical Component Summary of healthy patients with isolated growth hormone deficiency or idiopathic short stature resembled that of the control group (53.8 vs. 54.9). Patients with associated diseases or syndromes scored slightly lower (52.5), and former cancer patients scored lowest (42.6). The Mental Component Summary was similar for all groups. Lower Physical Component Summary was associated with lower educational level (coeff. -1.9). Final height was not associated with HRQoL. CONCLUSIONS/SIGNIFICANCE: In conclusion, HRQoL after treatment with rhGH in childhood depended mainly on the underlying indication for rhGH treatment. Patients with isolated growth hormone deficiency/idiopathic short stature or patients with associated diseases or syndromes had HRQoL comparable to peers. Patients with growth hormone deficiency after childhood cancer were at high risk for lower HRQoL. This reflects the general impaired health of this vulnerable group, which needs long-term follow-up.

Creatine deficiency syndomes : a new model of partial GAMT deficiency affecting brain cell development

Les syndromes de déficiences cérébrales en créatine (CCDS) sont dus à des mutations dans les gènes GATM et G AMT (codant pour les enzymes AGAT et G AMT de la voie de synthèse de créatine) ainsi que SLC6A8 (transporteur de créatine), et génèrent une absence ou une très forte baisse de créatine (Cr) dans le cerveau, mesurée par spectroscopic de résonance magnétique. Les patients CCDS développent des handicaps neurologiques sévères. Les patients AGAT et GAMT peuvent être traités avec des doses importantes de Cr, mais gardent dans la plupart des cas des séquelles neurologiques irréversibles. Aucun traitement efficace n'existe à ce jour pour la déficience en SLC6A8. Bien que de nombreux modèles aient été développés pour comprendre la Cr cérébrale en conditions physiologiques, les pathomécanismes des CCDS ne sont pas encore compris. Des souris transgéniques pour les gènes Gatm, Gamt et Slc6a8 ont été générées, mais elles ne miment que partiellement la pathologie humaine. Parmi les CCDS, la déficience en GAMT est la plus sévère, en raison de l'accumulation cérébrale de l'intermédiaire guanidinoacétate (GAA). Alors que la toxicité cérébrale du GAA a été étudiée par exposition directe au GAA d'animaux adultes sains, les mécanismes de la toxicité du GAA en condition de déficience en GAMT dans le cerveau en développement sont encore inconnus. Le but de ce projet était donc de développer un modèle de déficience en GAMT dans des cultures 3D primaires de cellules nerveuses de rat en agrégats par knock-down du gène GAMT, en utilisant un virus adéno-associé (AAV) induisant le mécanisme d'interférence à l'ARN (RNAi). Le virus scAAV2, à la multiplicité d'infection de 1000, s'est révélé le plus efficace pour transduire tous les types de cellules nerveuses des cultures (neurones, astrocytes, oligodendrocytes), et générer un knock-down maximal de la protéine GAMT de 85% (jour in vitro 18). Cette déficience partielle en GAMT s'est révélée insuffisante pour générer une déficience en Cr, mais a causé l'accumulation attendue de GAA, à des doses comparables aux niveaux observés dans le LCR des patients GAMT. Le GAA a induit une croissance axonale anarchique accompagnée d'une baisse de l'apoptose naturelle, suivis par une induction tardive de mort cellulaire non-apoptotique. Le co-traitement par la Cr a prévenu tous les effets toxiques du GAA. Ce travail montre que l'accumulation de GAA en absence de déficience en Cr est suffisante pour affecter le développement du tissu nerveux, et suggère que des formes de déficiences en GAMT supplémentaires, ne présentant pas de déficiences en Cr, pourraient être découvertes par mesure du GAA, en particulier à travers les programmes récemment proposés de dépistage néonatal de la déficience en GAMT. -- Cerebral creatine deficiency syndromes (CCDS) are caused by mutations in the genes GATM and GAMT (respectively coding for the two enzymes of the creatine synthetic pathway, AGAT and GAMT) as well as SLC6A8 (creatine transporter), and lead to the absence or very strong decrease of creatine (Cr) in the brain when measured by magnetic resonance spectroscopy. Affected patients show severe neurological impairments. While AGAT and GAMT deficient patients can be treated with high dosages of Cr, most remain with irreversible brain sequelae. No treatment has been successful so far for SLC6A8 deficiency. While many models have helped understanding the cerebral Cr pathways in physiological conditions, the pathomechanisms underlying CCDS are yet to be elucidated. Transgenic mice carrying mutations in the Gatm, Gamt and Slc6a8 genes have been developed, but only partially mimic the human pathology. Among CCDS, GAMT deficiency is the most severe, due to the CNS accumulation of the guanidinoacetate (GAA) intermediate. While brain toxicity of GAA has been explored through direct GAA exposure of adult healthy animals, the mechanisms underlying GAA toxicity in GAMT deficiency conditions on the developing CNS are yet unknown. The aim of this project was thus to develop and characterize a GAMT deficiency model in developing brain cells by gene knockdown, by adeno-associated virus (AAV)-driven RNA interference (RNAi) in rat 3D organotypic primary brain cell cultures in aggregates. scAAV2 with a multiplicity of infection of 1000 was shown as the most efficient serotype, was able to transduce all brain cell types (neurons, astrocytes, oligodendrocytes) and to induce a maximal GAMT protein knockdown of 85% (day in vitro 18). Metabolite analysis showed that partial GAMT knockdown was insufficient to induce Cr deficiency but generated the awaited GAA accumulation at concentrations comparable to the levels observed in cerebrospinal fluid of GAMT-deficient patients. Accumulated GAA induced axonal hypersprouting paralleled with inhibition of natural apoptosis, followed by a later induction in non-apoptotic cell death. Cr supplementation led to the prevention of all GAA-induced toxic effects. This work shows that GAA accumulation without Cr deficiency is sufficient to affect CNS development, and suggests that additional partial GAMT deficiencies, which may not show the classical brain Cr deficiency, may be discovered through GAA measurement including by recently proposed neonatal screening programs for GAMT deficiency.

Epidemiology of hypospadias in Europe: a registry-based study.

BACKGROUND: Hypospadias is a common congenital malformation. The prevalence of hypospadias has a large geographical variation, and recent studies have reported both increasing and decreasing temporal trends. It is unclear whether hypospadias prevalence is associated with maternal age. AIM: To analyze the prevalence and trends of total hypospadias, isolated hypospadias, hypospadias with multiple congenital anomalies, hypospadias with a known cause, and hypospadias severity subtypes in Europe over a 10-year period and to investigate whether maternal age is associated with hypospadias. METHODS: We included all children with hypospadias born from 2001 to 2010 who were registered in 23 EUROCAT registries. Information on the total number of births and maternal age distribution for the registry population was also provided. We analyzed the total prevalence of hypospadias and relative risks by maternal age. RESULTS: From 2001 to 2010, 10,929 hypospadias cases were registered in 5,871,855 births, yielding a total prevalence of 18.61 per 10,000 births. Prevalence varied considerably between different registries, probably due to differences in ascertainment of hypospadias cases. No significant temporal trends were observed with the exceptions of an increasing trend for anterior and posterior hypospadias and a decreasing trend for unspecified hypospadias. After adjusting for registry effects, maternal age was not significantly associated with hypospadias. CONCLUSIONS: Total hypospadias prevalence was stable in 23 EUROCAT registries from 2001 to 2010 and was not significantly influenced by maternal age.

Association between frailty and delirium in older adult patients discharged from hospital.

BACKGROUND: Delirium and frailty - both potentially reversible geriatric syndromes - are seldom studied together, although they often occur jointly in older patients discharged from hospitals. This study aimed to explore the relationship between delirium and frailty in older adults discharged from hospitals. METHODS: Of the 221 patients aged >65 years, who were invited to participate, only 114 gave their consent to participate in this study. Delirium was assessed using the confusion assessment method, in which patients were classified dichotomously as delirious or nondelirious according to its algorithm. Frailty was assessed using the Edmonton Frailty Scale, which classifies patients dichotomously as frail or nonfrail. In addition to the sociodemographic characteristics, covariates such as scores from the Mini-Mental State Examination, Instrumental Activities of Daily Living scale, and Cumulative Illness Rating Scale for Geriatrics and details regarding polymedication were collected. A multidimensional linear regression model was used for analysis. RESULTS: Almost 20% of participants had delirium (n=22), and 76.3% were classified as frail (n=87); 31.5% of the variance in the delirium score was explained by frailty (R (2)=0.315). Age; polymedication; scores of the Confusion Assessment Method (CAM), instrumental activities of daily living, and Cumulative Illness Rating Scale for Geriatrics; and frailty increased the predictability of the variance of delirium by 32% to 64% (R (2)=0.64). CONCLUSION: Frailty is strongly related to delirium in older patients after discharge from the hospital.

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Although approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management.

OBJECTIVE: To develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA). METHODS: The EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached. RESULTS: Twenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed. DISCUSSION: These recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research.

Why evolution matters for species conservation: perspectives from three case studies of plant metapopulations

We advocate the advantage of an evolutionary approach to conservation biology that considers evolutionary history at various levels of biological organization. We review work on three separate plant taxa, spanning from one to multiple decades, illustrating extremes in metapopulation functioning. We show how the rare endemics Centaurea corymbosa (Clape Massif, France) and Brassica insularis in Corsica (France) may be caught in an evolutionary trap: disruption of metapopulation functioning due to lack of colonization of new sites may have counterselected traits such as dispersal ability or self-compatibility, making these species particularly vulnerable to any disturbance. The third case study concerns the evolution of life history strategies in the highly diverse genus Leucadendron of the South African fynbos. There, fire disturbance and the recolonization phase after fires are so integral to the functioning of populations that recruitment of new individuals is conditioned by fire. We show how past adaptation to different fire regimes and climatic constraints make species with different life history syndromes more or less vulnerable to global changes. These different case studies suggest that management strategies should promote evolutionary potential and evolutionary processes to better protect extant biodiversity and biodiversification.

Intoxication aiguë au baclofène. Particularités et principes thérapeutiques

En raison de sa prescription croissante pour des indications d'aide à la réduction des consommations ou au maintien de l'abstinence à l'alcool, le risque d'intoxication volontaire ou accidentelle au baclofène s'accroît et favorise l'admission aux urgences ou en réanimation de comas profonds. La difficulté diagnostique repose sur une relative méconnaissance de cette substance et sur le fait que le baclofène ne fait pas partie des substances mises en évidence par les examens toxicologiques de dépistage habituels. La modification de la pharmaco- cinétique du baclofène en cas de surdosage expose le patient à un coma prolongé, nécessitant dès lors un soutien ventilatoire de longue durée. De manière paradoxale, le baclofène expose également à un risque potentiel de convulsions. En cas de prise en charge adéquate, le pronostic est excellent dans la majorité des cas. En partant d'un cas clinique illustratif et d'une revue de littérature, nous proposons une synthèse des principes de prise en charge d'une intoxication aiguë au baclofène. Baclofen is widely used for the treatment of neurological spastic syndromes and has been recently proposed for the treatment of alcohol dependence. The risk of accidental or self- intoxication with baclofen may therefore increase in the future. Baclofen overdose affects the autonomic nervous system and produces an inhibitory effect on the central nervous system. The classic clinical presentation involves prolonged impaired consciousness or coma and neurovegetative symptoms. Paradoxically, baclofen overdose may also promote the occurrence of seizures. The emergency management is mainly supportive and, in the majority of cases, the prognosis appears excellent. Herein we report a case of baclofen self-intoxication and review the literature regarding the toxicity of baclofen, the clinical presentation of an acute baclofen poisoning and the related principles of management.