Impact of recommendation updates in well-controlled patients on nonrecommended antiretroviral therapies: the Swiss HIV cohort study.

BACKGROUND: HIV treatment recommendations are updated as clinical trials are published. Whether recommendations drive clinicians to change antiretroviral therapy in well-controlled patients is unexplored. METHODS: We selected patients with undetectable viral loads (VLs) on nonrecommended regimens containing double-boosted protease inhibitors (DBPIs), triple-nucleoside reverse transcriptase inhibitors (NRTIs), or didanosine (ddI) plus stavudine (d4T) at publication of the 2006 International AIDS Society recommendations. We compared demographic and clinical characteristics with those of control patients with undetectable VL not on these regimens and examined clinical outcome and reasons for treatment modification. RESULTS: At inclusion, 104 patients were in the DBPI group, 436 in the triple-NRTI group, and 19 in the ddI/d4T group. By 2010, 28 (29%), 204 (52%), and 1 (5%) patient were still on DBPIs, triple-NRTIs, and ddI plus d4T, respectively. 'Physician decision,' excluding toxicity/virological failure, drove 30% of treatment changes. Predictors of recommendation nonobservance included female sex [adjusted odds ratio (aOR) 2.69, 95% confidence interval (CI) 1 to 7.26; P = 0.01] for DPBIs, and undetectable VL (aOR 3.53, 95% CI 1.6 to 7.8; P = 0.002) and lack of cardiovascular events (aOR 2.93, 95% CI 1.23 to 6.97; P = 0.02) for triple-NRTIs. All patients on DBPIs with documented diabetes or a cardiovascular event changed treatment. Recommendation observance resulted in lower cholesterol values in the DBPI group (P = 0.06), and more patients having undetectable VL (P = 0.02) in the triple-NRTI group. CONCLUSION: The physician's decision is the main factor driving change from nonrecommended to recommended regimens, whereas virological suppression is associated with not switching. Positive clinical outcomes observed postswitch underline the importance of observing recommendations, even in well-controlled patients.

Complete Maxillo-Mandibular Syngnathia in a Newborn with Multiple Congenital Malformations.

Syngnathia is an extremely rare condition involving congenital fusion of the maxilla with the mandible. Clinical presentations vary from simple mucosal bands (synechiae) to complete bony fusion (synostosis). Most cases are unilateral incomplete fusions. We report the case of a severely growth-retarded newborn infant with complete synostosis of the mandible with the maxilla and the zygoma associated with cleft palate, choanal atresia, deafness, delayed cerebral white matter development, and genital and limb malformations. Extensive genetic analysis did not reveal any mutations. This association of multiple congenital malformations may represent an entity distinct from previously described syndromes associated with syngnathia.

Experimental evidence that adult antipredator behaviour is heritable and not influenced by behavioural copying in a wild bird.

Knowledge of the relative importance of genetics and behavioural copying is crucial to appraise the evolvability of behavioural consistencies. Yet, genetic and non-genetic factors are often deeply intertwined, and experiments are required to address this issue. We investigated the sources of variation of adult antipredator behaviour in the Alpine swift (Apus melba) by making use of long-term behavioural observations on parents and cross-fostered offspring. By applying an 'animal model' approach to observational data, we show that antipredator behaviour of adult Alpine swifts was significantly repeatable over lifetime (r = 0.273) and heritable (h(2) = 0.146). Regression models also show that antipredator behaviours differed between colonies and sexes (females were more tame), and varied with the hour and year of capture. By applying a parent-offspring regression approach to 59 offspring that were exchanged as eggs or hatchlings between pairs of nests, we demonstrate that offspring behaved like their biological parents rather than like their foster parents when they were adults themselves. Those findings provide strong evidence that antipredator behaviour of adult Alpine swifts is shaped by genetics and/or pre-hatching maternal effects taking place at conception but not by behavioural copying.

Phacomatoses et tumeurs génétiquement déterminées: la transition enfant-adulte [Phacomatosis and genetically determined tumors: the transition from childhood to adulthood]

Les phacomatoses regroupent des maladies du développement du neurectoderme, engendrant des manifestations cutanées ou du système nerveux central. Les symptômes de ces maladies peuvent affecter les individus atteints à différents moments de leur vie. Il s'agit de maladies, héréditaires ou congénitales, qui sont transmises de façon variable. Effectivement, certaines, telles que la neurofibromatose, la sclérose tubéreuse ou la maladie de von Hippel-Lindau sont autosomiques dominantes, alors que d'autres, telles que la maladie de Sturge-Weber sont sporadiques. Des transmissions autosomiques récessives liées à X ou des formes mosaïques existent également. Une revue de la littérature, comprenant les cinq phacomatoses les plus fréquemment vues par un neurochirurgien (neurofibromatose de type I et II, sclérose tubéreuse de Bourneville, maladie de Sturge-Weber-Krabbe, maladie de von Hippel-Lindau) a été effectuée en se centrant sur le diagnostic, la variabilité de la symptomatologie selon l'âge du patient et son traitement. Les cas de patients adultes et pédiatriques vus aux consultations de neurologie et neurochirurgie de l'hôpital de Lille (France) et Lausanne (Suisse), de 1961 à nos jours, ont été revus pour illustrer les différentes pathologies rencontrées, selon l'âge des patients atteints. Le phénotype de ces maladies se modifie avec l'âge, car les gènes incriminés sont des gènes impliqués dans la différentiation tissulaire et sont activés à des âges différents suivant les tissus. Le rôle du neurochirurgien sera variable selon l'âge et le syndrome du patient. Il importe de connaître les variations du phénotype de ces maladies avec l'âge ainsi que les conséquences à long terme des traitements pour proposer au patient un suivi neurochirurgical personnalisé. Phacomatoses, or neurocutaneous disorders, are a group of congenital and hereditary diseases characterized by developmental lesions of the neuroectoderm, leading to pathologies affecting the skin and the central nervous system. There is a wide range of pathologies affecting individuals at different moments of life. The genetics is variable: while neurofibromatosis 1 and 2, tuberous sclerosis and von Hippel-Lindau disease are all inherited as autosomal dominant traits, Sturge-Weber syndrome is sporadic. Other neurocutaneous disorders can be inherited as autosomal recessive traits (i.e., ataxia-telangiectasia), X-linked (i.e., incontinentia pigmenti) or explained by mosaicism (i.e., hypomelanosis of Ito, McCune-Albright syndrome). In this review, we discuss the major types of neurocutaneous disorders most frequently encountered by the neurosurgeon and followed beyond childhood. They include neurofibromatosis types 1 and 2, tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. In each case, a review of the literature, including diagnosis, genetics and treatment will be presented. The lifespan of the disease with the implications for neurosurgeons will be emphasized. A review of cases, including both pediatric and adult patients, seen in neurosurgical practices in the Lille, France and Lausanne, Switzerland hospitals between 1961 and 2007 is presented to illustrate the pathologies seen in different age-groups. Because the genes mutated in most phacomatoses are involved in development and are activated following a timed schedule, the phenotype of these diseases evolves with age. The implication of the neurosurgeon varies depending on the patient's age and pathology. While neurosurgeons tend to see pediatric patients affected with neurofibromatosis type 1, tuberous sclerosis and Sturge-Weber syndrome, there will be a majority of adult patients with von Hippel-Lindau disease or neurofibromatosis type 2

Importance clinique du caryotype en hématologie. [Clinical importance of karyotype in hematology.]

Cytogenic analysis of leukemic cells has proven to be a mandatory part of the diagnosis of malignant hemopathies. Recurring clonal cytogenetic abnormalities may be divided into those exclusively associated with myeloid disorders, those uniquely observed in lymphoid diseases, and those detected in both myeloid and lymphoid hemopathies. Several of the common defects are characteristic of specific FAB types or subtypes and are associated with specific clinico pathologic syndromes and clinical complications. Cytogenetic abnormalities have served to define relatively homogeneous subsets of malignant hemopathies which are not evident from morphological and other available markers. Cytogenetic findings have been demonstrated to be powerful indicators in predicting clinical course and outcome in patients and in guiding their management. Given the significant progress made in the treatment of malignant hemopathies, it is very important to identify parameters which may be used to predict whether patients will respond favorably to standard therapies or if they are unlikely to do so and require alternative strategies, such as bone marrow transplantation. Cytogenetic studies have also provided important insights into the understanding of malignant transformation processes. In a number of recurring chromosome translocations characteristic of leukemias and lymphomas the genes that are located at the breakpoints have been identified. Molecular analysis has revealed that alteration in expression of these genes or in the properties of the encoded proteins resulting from the rearrangements plays an integral part in malignant transformation. Studies of clonality have suggested that several chromosome abnormalities may arise in pluripotent hemopoietic stem cells, whereas others may originate in cells of more restricted lineage. The author focuses first on the implications of the karyotype in the diagnosis and the prognosis of myeloproliferative syndromes, acute leukemias and myelodysplastic syndromes, then on the interest of describing new clinical-cytogenetic associations. Finally, some of the recent results obtained in a cytogenetic study of myelodysplastic syndromes are discussed.

Troubles du sommeil chez des patients présentant une insuffisance rénale chronique [Sleep disorders in patients with chronic renal insufficiency].

Sleep disorders, especially insomnia, daytime sleepiness, sleep apnea syndrome and restless legs syndrome are very frequently encountered in patients with chronic renal failure whether or not they undergo renal replacement therapy. The causes of sleep disorders are multifactorial and not only linked to the renal disease itself, but also to its treatment and its associated psychosocial factors. This article discusses the prevalence and physiopathology of the most frequently encountered sleep disorders in chronic renal failure patients, and highlights the actually available therapeutic options.

Anorectal Malformations: Finding the Pathway out of the Labyrinth.

Anorectal malformations (ARMs) are a complex group of congenital anomalies involving the distal anus and rectum, as well as the urinary and genital tracts in a significant number of cases. Most ARMs result from abnormal development of the urorectal septum in early fetal life. In most cases, the anus is not perforated and the distal enteric component ends blindly (atresia) or as a fistula into the urinary tract, genital tract, or perineum. ARMs are also present in a great number of syndromes and associations of congenital anomalies. The classification of ARMs is mainly based on the position of the rectal pouch relative to the puborectal sling, the presence or absence of fistulas, and the types and locations of the fistulas. All of this information is crucial in determining the most appropriate surgical approach for each case. Imaging studies play a key role in evaluation and classification of ARMs. In neonates, clinical and radiologic examinations in the first 3 days of life help determine the type of ARM and the need for early colostomy. In older children, preoperative pelvic magnetic resonance imaging is the most efficient diagnostic method for evaluating the size, morphology, and grade of development of the sphincteric musculature.

Enclouage verrouillé du tibia [Interlocking nailing of the tibia]

Centromedullary nailing is a well-established method of treatment for diaphyseal long bone fractures. The indications have been broadened greatly since the introduction in 1974 of interlocking centromedullary nailing. The purpose of this paper is to review our first results with locked intramedullary nailing of the tibia. We report our experience with the first 19 cases of interlocking tibia nails (15 fractures, 1 delayed union, 2 pseudarthrosis, 1 osteotomy). On the extension table, the insertion of the nail and the placement of the interlocking screws did not cause any problem. In 3 cases, a proximal screw had to be removed within two weeks because of spontaneous displacement. Complications have been noticed in three patients (15.8%) (pulmonary embolism on day 1, and compartment syndrome two days later in one case, sciatic nerve neuroapraxia in the other two). The other patients have been mobilized 24 to 48 hours after surgery. 94% of the fractures were consolidated 4 months post-operatively, with no major deformation. Interlocking tibia nailing seems to be an attractive method in the treatment of certain fractures of the tibia. Early mobilisation and weight-bearing are provided. The indications, the technical aspects as well as the dangers of the method must be carefully respected in order to avoid complications and poor results.

In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease.

Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis, Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC-MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a bicompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED.

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome.

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.

Influence of the primary cleft palate closure on the future need for orthognathic surgery in unilateral cleft lip and palate patients

RESUME : Introduction : L'objectif de cette étude est de déterminer l'influence de la dissection du palais lors de la chirurgie primaire et le type de chirurgie orthognathique requise chez les patients porteurs d'une séquelle de fente labio-maxillo-palatine unilatérale complète Méthode : Cette revue porte sur 58 enfants nés avec une fente labio-maxillo-palatine complète unilatérale et traités entre 1994 et 2008 à Page approprié pour une chirurgie orthognathique. C'est une étude rétrospective longitudinale mixte. Les patients avec des syndromes ou anomalies associées ont été exclus. Tous les patients ont été traités parle même orthodontiste et par la même équipe chirurgicale. Les enfants sont divisés en deux groupes; le premier comprend les patients avec une chirurgie primaire du palais conventionnelle, avec un décollement extensif de la fibro-muqueuse palatine. Le deuxième groupe comprend les patients opérés selon le protocole de Malek. Le palais mou est fermé a |'âge de trois mois, le palais dur à |'âge de six mois, avec un décollement minimal de la tibro-muqueuse palatine. Les radiographies du crâne de profil ainsi que les données chirurgicales ont été comparées. Résultats: La nécessité d'une chirurgie orthognathique est plus élevée dans le premier groupe par rapport au deuxième (60% versus 47,8%). Concernant le type de chirurgie orthognathique réalisé, des ostéotomies Lefort I en deux ou trois pièces ou des ostéotomies bi-maxillaires ont aussi été plus fréquentes dans le premier groupe Conclusion : La chirurgie primaire du palais selon le protocole de Malek améliore le pronostic des patients avec une fente labio-maxillo-palatine. Avec un décollement minimal de la fibro-muqueuse palatine, le nombre d'interventions de chirurgie orthognathique a été diminué. Lorsque ces opérations étaient néanmoins indiquées, elles étaient simplifiées.

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L'association entre haut potentiel (HP) et Trouble Déficit de l'Attention/Hyperactivité (TDA/H), couple mythique ou infernal, représente un vrai défi diagnostique et thérapeutique, du fait de similitudes sémiologiques entre les deux syndromes d'une part, mais aussi de leur possible coexistence d'autre part. Identifier, poser un diagnostic puis traiter deviennent un challenge complexe, à la hauteur de ces enfants à besoins particuliers. Nombre d'enfants sont amenés en consultation car ils souffrent d'isolement, de difficultés scolaires, voire sont poursuivis par la réputation d'être ingérables ou mal éduqués. La question d'un HP ou d'un TDA/H est alors évoquée. Mais si l'enfant HP peut être pris pour un TDA/H et inversement, l'un peut-il masquer l'autre, en cas de co-morbidité? Comment éviter alors de se fourvoyer en traitant des faux positifs tout en négligeant les faux négatifs ?

Lymphatic vascular morphogenesis in development, physiology, and disease.

The lymphatic vasculature constitutes a highly specialized part of the vascular system that is essential for the maintenance of interstitial fluid balance, uptake of dietary fat, and immune response. Recently, there has been an increased awareness of the importance of lymphatic vessels in many common pathological conditions, such as tumor cell dissemination and chronic inflammation. Studies of embryonic development and genetically engineered animal models coupled with the discovery of mutations underlying human lymphedema syndromes have contributed to our understanding of mechanisms regulating normal and pathological lymphatic morphogenesis. It is now crucial to use this knowledge for the development of novel therapies for human diseases.

Role of surgery in pediatric epilepsy.

Twenty five percent of patients with intractable epilepsy have surgically remediable epilepsy syndromes. This article reviews the treatment paradigm for pediatric epilepsy and also the indications, methods, and surgical options for the subgroup of patients with surgically remediable epileptic disorders based on our experience in the management of these children. The article also discusses the rationale for offering surgery and the timing of surgery in these patients. The study of surgically remediable epilepsy can best be divided into focal, sub hemispheric, hemispheric and multifocal epileptic syndromes. These syndromes have both acquired and congenital etiologies and can be treated by resective or disconnective surgery. The surgical management of these conditions (with the exception of multifocal epilepsy) provides Engel's Class 1 outcome(complete seizure freedom) in approximately 80% of children. The consequences of seizure freedom leads to a marked improvement in the quality of life of these children. The benefits to society, of allowing a child to grow to adulthood with normal cognition to earn a livelihood and contribute actively to society, cannot be understated.