Connexins, diabetes and the metabolic syndrome.

Diabetes and the related metabolic syndrome are multi system disorders that result from improper interactions between various cell types. Even though the underlying mechanism remains to be fully understood, it is most likely that both the long and the short distance range cell interactions, which normally ensure the physiologic functioning of the pancreas, and its relationships with the insulin-targeted organs, are altered. This review focuses on the short-range type of interactions that depend on the contact between adjacent cells and, specifically, on the interactions that are dependent on connexins. The widespread distribution of these membrane proteins, their multiple modes of action, and their interactions with conditions/molecules associated to both the pathogenesis and the treatment of the 2 main forms of diabetes and the metabolic syndrome, make connexins an essential part of the chain of events that leads to metabolic diseases. Here, we review the present state of knowledge about the molecular and cell biology of the connexin genes and proteins, their general mechanisms of action, the roles specific connexin species play in the endocrine pancreas and the major insulin-targeted organs, under physiological and patho-physiological conditions.

A Novel Acute Retroviral Syndrome Severity Score Predicts the Key Surrogate Markers for HIV-1 Disease Progression.

OBJECTIVE: Best long-term practice in primary HIV-1 infection (PHI) remains unknown for the individual. A risk-based scoring system associated with surrogate markers of HIV-1 disease progression could be helpful to stratify patients with PHI at highest risk for HIV-1 disease progression. METHODS: We prospectively enrolled 290 individuals with well-documented PHI in the Zurich Primary HIV-1 Infection Study, an open-label, non-randomized, observational, single-center study. Patients could choose to undergo early antiretroviral treatment (eART) and stop it after one year of undetectable viremia, to go on with treatment indefinitely, or to defer treatment. For each patient we calculated an a priori defined "Acute Retroviral Syndrome Severity Score" (ARSSS), consisting of clinical and basic laboratory variables, ranging from zero to ten points. We used linear regression models to assess the association between ARSSS and log baseline viral load (VL), baseline CD4+ cell count, and log viral setpoint (sVL) (i.e. VL measured ≥90 days after infection or treatment interruption). RESULTS: Mean ARSSS was 2.89. CD4+ cell count at baseline was negatively correlated with ARSSS (p = 0.03, n = 289), whereas HIV-RNA levels at baseline showed a strong positive correlation with ARSSS (p<0.001, n = 290). In the regression models, a 1-point increase in the score corresponded to a 0.10 log increase in baseline VL and a CD4+cell count decline of 12/µl, respectively. In patients with PHI and not undergoing eART, higher ARSSS were significantly associated with higher sVL (p = 0.029, n = 64). In contrast, in patients undergoing eART with subsequent structured treatment interruption, no correlation was found between sVL and ARSSS (p = 0.28, n = 40). CONCLUSION: The ARSSS is a simple clinical score that correlates with the best-validated surrogate markers of HIV-1 disease progression. In regions where ART is not universally available and eART is not standard this score may help identifying patients who will profit the most from early antiretroviral therapy.

Reversal of activity-mediated spine dynamics and learning impairment in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR1 gene coding for a protein implicated in the regulation of protein synthesis at synapses. The lack of functional Fragile X mental retardation protein has been proposed to result in an excessive signaling of synaptic metabotropic glutamate receptors, leading to alterations of synapse maturation and plasticity. It remains, however, unclear how mechanisms of activity-dependent spine dynamics are affected in Fmr knockout (Fmr1-KO) mice and whether they can be reversed. Here we used a repetitive imaging approach in hippocampal slice cultures to investigate properties of structural plasticity and their modulation by signaling pathways. We found that basal spine turnover was significantly reduced in Fmr1-KO mice, but markedly enhanced by activity. Additionally, activity-mediated spine stabilization was lost in Fmr1-KO mice. Application of the metabotropic glutamate receptor antagonist α-Methyl-4-carboxyphenylglycine (MCPG) enhanced basal turnover, improved spine stability, but failed to reinstate activity-mediated spine stabilization. In contrast, enhancing phosphoinositide-3 kinase (PI3K) signaling, a pathway implicated in various aspects of synaptic plasticity, reversed both basal turnover and activity-mediated spine stabilization. It also restored defective long-term potentiation mechanisms in slices and improved reversal learning in Fmr1-KO mice. These results suggest that modulation of PI3K signaling could contribute to improve the cognitive deficits associated with FXS.

Association between foot growth and musculoskeletal loading in children with Prader-Willi syndrome before and during growth hormone treatment

OBJECTIVE: To explore how foot growth relates to musculoskeletal loading in children with Prader-Willi syndrome (PWS). STUDY DESIGN: In 37 children with PWS, foot length (FL) before and after 6 years of growth hormone therapy (GHT) was retrospectively evaluated with parental and sibling's FL, height, and factors reflecting musculoskeletal loading, such as weight for height (WfH), lean body mass (LBM; dual energy X-ray absorptiometry, deuterium labeled water), physical activity (accellerometry), and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, 2 age groups were separated (group 1, >2.5 years; group 2, < or =2.5 years). RESULTS: Children with PWS normalized height, but not FL after 6 years of GHT. Parental FL correlation with PWS's FL was lower than with sibling's FL. In group 1, FL positively correlated with WfH, LBM, and physical activity. In group 2, FL negatively correlated with age at onset of independent ambulation. Foot catch-up growth with GHT was slower in group 2 compared with group 1. CONCLUSION: In PWS, FL is positively associated with musculoskeletal loading. Small feet in children with PWS before and during long-term GHT may be more than just another dysmorphic feature, but may possibly reflect decreased musculoskeletal loading influencing foot growth and genetic and endocrine factors.

Laparoscopic surgery for coeliac artery compression syndrome: current management and technical aspects.

Objectives: The study aims to assess the feasibility and midterm outcome of trans-peritoneal laparoscopy for coeliac artery compression syndrome (CACS).Design: Retrospective chart review involving four European vascular surgery departments and two surgical teams.Materials and methods: charts for patients who underwent laparoscopy for symptomatic CACS between December 2003 and November 2009 were reviewed. Preoperative computed tomography (CT) angiography and postoperative duplex scan and/or CT angiography were performed.Results: Eleven consecutive patients (nine women) with a median age of 52 years (interquartile range: 42.5-59 years) underwent trans-peritoneal laparoscopy for CACS. All patients had a history of postprandial abdominal pain; weight loss exceeded 10% of the body mass in eight cases. Preoperative CT angiography revealed coeliac trunk stenosis >70% in all cases. One patient had additional aortitis and inferior mesenteric artery occlusion, while another patient presented with an occluded superior mesenteric artery. Two conversions occurred (one difficult dissection and one aorto-hepatic bypass needed for incomplete release of CACS). The median blood loss was 195 ml (range: 50-900 ml) and median operative time was 80 min (interquartile range: 65-162.5 years). Symptoms improved immediately in 10/11 patients (no residual stenosis) while one remained unchanged despite a residual stenosis treated by a percutaneous angioplasty. Symptoms reappeared in one patient due to coeliac axis occlusion. The mean follow-up period was 35 +/- 23 months (range: 12-78 months).Conclusion: Our study demonstrates that trans-peritoneal laparoscopy for treating median arcuate ligament syndrome is safe and feasible. Additional patients and a longer follow-up are needed for long-term assessment of this laparoscopic technique. (C) 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Pseudo-pacemaker syndrome in a young woman with first-degree atrio-ventricular block.

First-degree atrio-ventricular (AV) block is defined as a PR interval longer than 200 ms. If too long, it can become clinically relevant and may mimic a pacemaker syndrome. We report the case of a young woman with a long PR interval, probably congenital, with episodes of syncope and dizziness since childhood. Pseudo-pacemaker syndrome is rare and is a Class IIa recommendation for a pacemaker implantation. A dual-chamber pacemaker was implanted and short AV delay was programmed, with rapid clinical improvement.

Primary Sjögren's syndrome (SS) and malignant lymphoma. A retrospective cohort study of 55 patients with SS.

The aim of this study was to assess the prevalence of malignant lymphomas in patients with long-standing primary Sjögren's syndrome (pSS). We retrospectively studied a cohort of 55 patients with pSS over a mean follow-up period of 12 years. Five patients (9%) developed malignant lymphoma. The interval between the diagnoses of SS and lymphoma ranged from four to 12 years (mean = 6.5 years). The lymphoma arose in the lymph nodes in two cases, the parotid gland in one case, the lacrimal gland in one case, and the lung in one case. All five cases were B-cell low-grade lymphomas. Among our SS patients, those with extraglandular manifestations and/or a mixed cryoglobulin were at increased risk for lymphoma development. Secondary lymphoma carried a poor prognosis in our study. Three of the six SS patients who died during the follow-up period had lymphoma.

Congenital high airway obstruction syndrome and airway reconstruction: an evolving paradigm.

OBJECTIVES: To refine the classic definition of, and provide a working definition for, congenital high airway obstruction syndrome (CHAOS) and to discuss the various aspects of long-term airway reconstruction, including the range of laryngeal anomalies and the various techniques for reconstruction. DESIGN: Retrospective chart review. PATIENTS: Four children (age range, 2-8 years) with CHAOS who presented to a single tertiary care children's hospital for pediatric airway reconstruction between 1995 and 2000. CONCLUSIONS: To date, CHAOS remains poorly described in the otolaryngologic literature. We propose the following working definition for pediatric cases of CHAOS: any neonate who needs a surgical airway within 1 hour of birth owing to high upper airway (ie, glottic, subglottic, or upper tracheal) obstruction and who cannot be tracheally intubated other than through a persistent tracheoesophageal fistula. Therefore, CHAOS has 3 possible presentations: (1) complete laryngeal atresia without an esophageal fistula, (2) complete laryngeal atresia with a tracheoesophageal fistula, and (3) near-complete high upper airway obstruction. Management of the airway, particularly in regard to long-term reconstruction, in children with CHAOS is complex and challenging.

Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Role of glutathione deficit in the disconnectivity syndrome in schizophrenia: from pathogenetic mechanisms to therapeutic interventions

In the cerebrospinal fluid of 26 drug-naive schizophrenics (DSM-III- R), we observed that the level of glutathione ([GSH]) and of its metabolite γ-Glu-Gln was decreased by 27% and 16% respectively. Using a new in-vivo method based on magnetic resonance spec- troscopy, [GSH] was measured in the medial prefrontal cortex of 18 schizophrenics and found to be 52 % lower than in controls (n = 20). This is consistent with the recently observed decreased mRNA levels in fibroblasts of patients (n=32) of the two GSH synthesizing en- zymes (glutathione synthetase (GSS), and glutamate-cysteine ligase M (GCLM) the modulatory subunit of glutamate-cysteine ligase). Moreover, the level of GCLM expression in fibroblasts correlates neg- atively with the psychopathology (positive, general and some nega- tive symptoms). Thus, the observed difference in gene expression is not only the cause of low brain [GSH], but is also related to the sever- ity of symptoms, suggesting that fibroblasts are adequate surrogate for brain tissue. A hypothesis was proposed, based on a central role of GSH in the pathophysiology of schizophrenia. GSH is an important endogenous redox regulator and neuroactive substance. GSH is pro- tecting cells from damage by reactive oxygen species generated, among others, by the metabolism of dopamine. A GSH deficit-in- duced oxidative stress would lead to lipid peroxidation and micro-le- sions in the surrounding of catecholamine terminals, affecting the synaptic contacts on dendritic spines of cortical neurones, where ex- citatory glutamatergic terminals converge with dopaminergic ones. This would lead to spines degeneration and abnormal nervous con- nections or structural disconnectivity, possibly responsible for posi- tive, perceptive and cognitive symptoms of schizophrenia. In addi- tion, a GSH deficit could also lead to a functional disconnectivity by depressing NMDA neurotransmission, in analogy to phencyclidine effects. Present experimental biochemical, cell biological and behav- ioral data are consistent with the proposed mechanism: decreasing pharmacologically [GSH] in experimental models, with or without blocking DA uptake (GBR12909), induces morphological and behav- ioral changes similar to those observed in patients. Dendritic spines: (a) In neuronal cultures, low [GSH] and DA induce decreased density of neural processes; (b) In developing rats (p5-p16), [GSH] deficit and GBR induce a decrease in normal spines in prefrontal pyramids and in GABA-parvalbumine but not of -calretinine immunoreactivity in anterior cingulate. NMDA-dependant synaptic plasticity: GSH deple- I/13 tion in hippocampal slices impairs long-term potentiation. Develop- ing rats with low [GSH] and GBR have deficit in olfactory integration and in object recognition which appears earlier in males than fe- males, in analogy to the delay of the psychosis onset between man and woman. In summary, a deficit of GSH and/or GSH-related enzymes during early development could constitute a major vulnerability fac- tor in schizophrenia.

Low immunoglobulin levels in patients with cystic fibrosis: reduced inflammation or sign of common variable immunodeficiency syndrome?

Introduction: In children with cystic fibrosis (CF), low immunoglobulin (IgG) levels have been reported to be associated with significantly less severe lung disease. However, decreased IgG can be a sign for common variable immunodeficiency (CVID) and affect clinical outcome. The aim of this study was to analyze clinical and serological data of patients having low IgG levels in routine blood tests at annual assessment, particularly their antibody response to polysaccharide antigens. Method: Retrospective chart review of demographic data of CF patients followed at the pediatric CF clinic throughout 2009. Clinical parameters (genotype, pancreas sufficiency, FEV1), presence of Pseudomonas aeruginosa (PA) and number of exacerbations per year were correlated with immunoglobulin and vaccination antibodies levels (antibodies to pneumococcal serotypes 14, 19, 23, 1, 5 and 7F measured by enzyme-linked immune-sorbent assay). Results: 4 out of 60 patients (6.7%) had lower IgG-levels for age. Ages ranged from 1 year 8 months to 11 years, 2 boys, 2 girls. Three patients were delF508 homozygotes, one heterozygote composite delF508/G542X. All were pancreatic insufficient. FEV1 ranged from 74 to 108%. One patient never had colonization by PA, 2 had intermittent PA colonization and one was chronically infected. After conjugated vaccination all patients had protective antibodies against serotypes 14, 19, 23F. For serotypes not included in the vaccine, only one patient had protective titers for 1 out of 3 serotypes. None of the patients had received unconjugated pneumococcal vaccine. There was no significant clinical difference in FEV1, PA colonization or number of exacerbations according to IgG and vaccination antibody levels. Conclusion: Cystic Fibrosis patients with low immunoglobulin levels have normal antibody response to protein antigens. However, despite recurrent infections, there seems to be delayed or deficient antibody response to polysaccharide antigens. Prospective studies are needed to evaluate the development of polysaccharide antibody responses in CF-patients to monitor for CVID. With early detection of CF by newborn screening program, long term follow up could be started early in childhood.

Further delineation of the facial 13q14 deletion syndrome in 13 retinoblastoma patients.

Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.

Efficacity of in-hospital multidimensional interventions of secondary prevention after acute coronary syndrome : a systematic review and meta-analysis

RAPPORT DE SYNTHÈSE : Contexte Les programmes de prévention cardiovasculaire secondaire après un événement coronarien aigu ont pu démontrer leur efficacité dans le contexte des soins ambulatoires. L'hospitalisation pour une maladie aiguë peut être considérée comme un «instant charnière», particulièrement adapté à un changement de comportement de santé et où des interventions de prévention secondaire, telle l'éducation du patient, pourraient être particulièrement efficaces. De plus, la prescription de médicaments de prévention cardiovasculaire durant l'hospitalisation semble augmenter la proportion des patients traités selon les recommandations sur le long terme. Récemment, plusieurs études ont évalué l'efficacité de programmes de prévention ayant pour but l'éducation des patients et/ou une augmentation du taux de prescription de médicaments prouvés efficaces par les médecins en charge. L'article faisant l'objet du travail de thèse synthétise la littérature existante concernant l'efficacité en termes de mortalité des interventions multidimensionnelles de prévention cardiovasculaire après un syndrome coronarien aigu, débutées à l'hôpital, centrées sur le patient et ciblant plusieurs facteurs de risque cardiovasculaire. MÉTHODE ET RÉSULTATS : En utilisant une stratégie de recherche définie à l'avance, nous avons inclus des essais cliniques avec groupe contrôle et des études avant-après, débutées à l'hôpital et qui incluaient des résultats cliniques de suivi en terme de mortalité, de taux de réadmission et/ou de récidive de syndrome coronarien aigu. Nous avons catégorisé les études selon qu'elles ciblaient les patients (par exemple une intervention d'éducation aux patients par des infirmières), les soignants (par exemple des cours destinés aux médecins-assistants pour leur enseigner comment prodiguer des interventions éducatives) ou le système de soins (par exemple la mise en place d'itinéraires cliniques au niveau de l'institution). Globalement, les interventions rapportées dans les 14 études répondant aux critères montraient une réduction du risque relatif (RR) de mortalité après un an (RR= 0.79; 95% intervalle de confiance (IC), 0.69-0.92; n=37'585). Cependant, le bénéfice semblait dépendre du type d'étude et du niveau d'intervention. Les études avant-après suggéraient une réduction du risque de mortalité (RR, 0.77; 95% IC, 0.66-0.90; n=3680 décès), tandis que le RR était de 0.96 (95% IC, 0.64-1.44; n=99 décès) pour les études cliniques contrôlées. Seules les études avant-après et les études ciblant les soignants et le système, en plus de cibler les patients, semblaient montrer un bénéfice en termes de mortalité à une année. CONCLUSIONS ET PERSPECTIVES : Les preuves d'efficacité des interventions de prévention secondaires débutées à l'hôpital, ciblant le patient, sont prometteuses, mais pas définitives. En effet, seules les études avant-après montrent un bénéfice en termes de mortalité. Les recherches futures dans ce domaine devraient tester formellement quels éléments des interventions amènent le plus de bénéfices pour les patients.

Body composition phenotypes in pathways to obesity and the metabolic syndrome.

Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height(2) (H(2)), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H(2)) and an FFM index (FFM/H(2)), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome.

Clinical and radiological findings in Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS) is a potentially lethal disorder with facial dysmorphism, pigmentary skin anomalies, developmental delay and major visceral anomalies, such as diaphragmatic hernia, anorectal malformation, and congenital heart disease. PKS is causally associated with mosaic tetrasomy of chromosome 12p. A routine chromosome analysis in peripheral lymphocytes usually fails to detect the mosaic state. A prompt diagnosis rests on clinical awareness and a subsequent chromosome or molecular analysis in fibroblasts, buccal mucosal cells, or bone marrow cells. We report here on three infants with PKS. One infant had aortic dilatation, a previously unreported association in PKS. More importantly, all infants showed a recognizable, though mild, pattern of skeletal changes mainly affecting axial bones, including delayed ossification of the vertebral bodies and pubic bones, flared anterior ribs, and broad metaphyses of the long bones, particularly of the femora. These skeletal changes should be considered as a useful diagnostic sign in PKS. Awareness of the axial skeletal alterations can be helpful in prompting clinicians to search for mosaic tetrasomy 12p and perform chromosomal analysis in appropriate tissue types.