Descriptive epidemiology of Cornelia de Lange syndrome in Europe.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed <or=2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males.

Success of a general school-based physical activity intervention on bone mineral content depends on pubertal stage but not on gender

Aims: We performed a randomised controlled trial in children of both gender and different pubertal stages to determine whether a school-based physical activity (PA) program during a full schoolyear influences bone mineral content (BMC) and whether there are differences in response for boys and girls before and during puberty. Methods: Twenty-eight 1st and 5th grade classes were cluster randomised to an intervention (INT, 16 classes, n=297) and control (CON; 12 classes, n=205) group. The intervention consisted of a multi-component PA intervention including daily physical education during a full school year. Each lesson was predetermined, included about ten minutes of jumping or strength training exercises of various intensity and was the same for all children. Measurements included anthropometry (height and weight), tanner stages (by self-assessment), PA (by accelerometry) and BMC for total body, femoral neck, total hip and lumbar spine using dualenergy X-ray absorptiometry (DXA). Bone parameters were normalized for gender and tanner stage (pre- vs. puberty). Analyses were performed by a regression model adjusted for gender, baseline height, baseline weight, baseline PA, post-intervention tanner stage, baseline BMC, and cluster. Researchers were blinded to group allocation. Children in the control group did not know about the intervention arm. Results: 217 (57%) of 380 children who initially agreed to have DXA measurements had also post-intervention DXA and PA data. Mean age of prepubertal and pubertal children at baseline was 9.0±2.1 and 11.2±0.6 years, respectively. 47/114 girls and 68/103 boys were prepubertal at the end of the intervention. Compared to CON, children in INT showed statistically significant increases in BMC of total body (adjusted z-score differences: 0.123; 95%>CI 0.035 to 0.212), femoral neck (0.155; 95%>CI 0.007 to 0.302), and lumbar spine (0.127; 95%>CI 0.026 to 0.228). Importantly, there was no gender*group, but a tanner*group interaction consistently favoring prepubertal children. Conclusions: Our findings show that a general, but stringent school-based PA intervention can improve BMC in elementary school children. Pubertal stage, but not gender seems to determine bone sensitivity to physical activity loading.

Entropy change of martensitic transformations in Cu-based shape-memory alloys

We have investigated the different contributions to the entropy change at the martensitic transition of different families of Cu-based shape-memory alloys. The total entropy change has been obtained through calorimetric measurements. By measuring the evolution of the magnetic susceptibility with temperature, the entropy change associated with conduction electrons has been evaluated. The contribution of the anharmonic vibrations of the lattice has also been estimated using various parameters associated with the anharmonic behavior of these alloys, collected from the literature. The results found in the present work have been compared to values published for the martensitic transition of group-IV metals. For Cu-based alloys, both electron and anharmonic contributions have been shown to be much smaller than the overall entropy change. This finding demonstrates that the harmonic vibrations of the lattice are the most relevant contribution to the stability of the bcc phase in Cu-based alloys.

Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial.

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

A quasi-randomized group trial of a brief alcohol intervention on risky single occasion drinking among secondary school students.

OBJECTIVES: To show the effectiveness of a brief group alcohol intervention. Aims of the intervention were to reduce the frequency of heavy drinking occasions, maximum number of drinks on an occasion and overall weekly consumption. METHODS: A cluster quasi-randomized control trial (intervention n = 338; control n = 330) among 16- to 18-year-old secondary school students in the Swiss Canton of Zürich. Groups homogeneous for heavy drinking occasions (5+/4+ drinks for men/women) consisted of those having medium risk (3-4) or high risk (5+) occasions in the past 30 days. Groups of 8-10 individuals received two 45-min sessions based on motivational interviewing techniques. RESULTS: Borderline significant beneficial effects (p < 0.10) on heavy drinking occasions and alcohol volume were found 6 months later for the medium-risk group only, but not for the high-risk group. None of the effects remained significant after Bonferroni corrections. CONCLUSIONS: Group intervention was ineffective for all at-risk users. The heaviest drinkers may need more intensive treatment. Alternative explanations were iatrogenic effects among the heaviest drinkers, assessment reactivity, or reduction of social desirability bias at follow-up through peer feedback.

A test of Jessor's problem behavior theory in a Eurasian and a Western European developmental context.

PURPOSE: The current study tested the applicability of Jessor's problem behavior theory (PBT) in national probability samples from Georgia and Switzerland. Comparisons focused on (1) the applicability of the problem behavior syndrome (PBS) in both developmental contexts, and (2) on the applicability of employing a set of theory-driven risk and protective factors in the prediction of problem behaviors. METHODS: School-based questionnaire data were collected from n = 18,239 adolescents in Georgia (n = 9499) and Switzerland (n = 8740) following the same protocol. Participants rated five measures of problem behaviors (alcohol and drug use, problems because of alcohol and drug use, and deviance), three risk factors (future uncertainty, depression, and stress), and three protective factors (family, peer, and school attachment). Final study samples included n = 9043 Georgian youth (mean age = 15.57; 58.8% females) and n = 8348 Swiss youth (mean age = 17.95; 48.5% females). Data analyses were completed using structural equation modeling, path analyses, and post hoc z-tests for comparisons of regression coefficients. RESULTS: Findings indicated that the PBS replicated in both samples, and that theory-driven risk and protective factors accounted for 13% and 10% in Georgian and Swiss samples, respectively in the PBS, net the effects by demographic variables. Follow-up z-tests provided evidence of some differences in the magnitude, but not direction, in five of six individual paths by country. CONCLUSION: PBT and the PBS find empirical support in these Eurasian and Western European samples; thus, Jessor's theory holds value and promise in understanding the etiology of adolescent problem behaviors outside of the United States.

Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.

BACKGROUND & AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Indicateurs sécurité en obstétrique : une étude Delphi [Patient safety indicators for obstetrics: a Delphi based study]

OBJECTIVE: Clinical indicators are increasingly used to assess safety of patient care. In obstetrics, only a few indicators have been validated to date and none is used across specialties. The purpose of this study was to identify and assess for face and content validity a group of safety indicators that could be used by anaesthetists, obstetricians and neonatologists involved in labour and delivery units. MATERIALS AND METHODS: We first conducted a systematic review of the literature to identify potential measures. Indicators were then validated by a panel of 30 experts representing all specialties working in labour and delivery units. We used the Delphi method, an iterative questionnaire-based consensus seeking technique. Experts determined on a 7-point Likert scale (1=most representative/7=less representative) the soundness of each indicator as a measure of safety and their possible association with errors and complications caused by medical management. RESULTS: We identified 44 potential clinical indicators from the literature. Following the Delphi process, 13 indicators were considered as highly representative of safety during obstetrical care (mean score</=2.3). Experts ranked 6 of these indicators as being strongly associated to potential errors and complications. CONCLUSIONS: We identified and validated for face and content, a group of six clinical indicators to measure potentially preventable iatrogenic complications in labour and delivery units.

Genetic and karyotypic structure in the shrews of the Sorex araneus group: are they independent?

The species of the common shrew (Sorex araneus) group are morphologically very similar but exhibit high levels of karyotypic variation. Here we used genetic variation at 10 microsatellite markers in a data set of 212 individuals mostly sampled in the western Alps and composed of five karyotypic taxa (Sorex coronatus, Sorex antinorii and the S. araneus chromosome races Cordon, Bretolet and Vaud) to investigate the concordance between genetic and karyotypic structure. Bayesian analysis confirmed the taxonomic status of the three sampled species since individuals consistently grouped according to their taxonomical status. However, introgression can still be detected between S. antinorii and the race Cordon of S. araneus. This observation is consistent with the expected low karyotypic complexity of hybrids between these two taxa. Geographically based cryptic substructure was discovered within S. antinorii, a pattern consistent with the different postglaciation recolonization routes of this species. Additionally, we detected two genetic groups within S. araneus notwithstanding the presence of three chromosome races. This pattern can be explained by the probable hybrid status of the Bretolet race but also suggests a relatively low impact of chromosomal differences on genetic structure compared to historical factors. Finally, we propose that the current data set (available at http://www.unil.ch/dee/page7010_en.html#1) could be used as a reference by those wanting to identify Sorex individuals sampled in the western Alps.

Early dyadic patterns of mother-infant interactions and outcomes of prematurity at 18 months.

OBJECTIVE: With the increased survival of very preterm infants, there is a growing concern for their developmental and socioemotional outcomes. The quality of the early mother-infant relationship has been noted as 1 of the factors that may exacerbate or soften the potentially adverse impact of preterm birth, particularly concerning the infant's later competencies and development. The first purpose of the study was to identify at 6 months of corrected age whether there were specific dyadic mother-infant patterns of interaction in preterm as compared with term mother-infant dyads. The second purpose was to examine the potential impact of these dyadic patterns on the infant's behavioral and developmental outcomes at 18 months of corrected age. METHODS: During a 12-month period (January-December 1998), all preterm infants who were <34 weeks of gestational age and hospitalized at the NICU of the Lausanne University Hospital were considered for inclusion in this longitudinal prospective follow-up study. Control healthy term infants were recruited during the same period from the maternity ward of our hospital. Mother-infant dyads with preterm infants (n = 47) and term infants (n = 25) were assessed at 6 months of corrected age during a mother-infant play interaction and coded according to the Care Index. This instrument evaluates the mother's interactional behavior according to 3 scales (sensitivity, control, and unresponsiveness) and the child's interactional behavior according to 4 scales (cooperation, compliance, difficult, and passivity). At 18 months, behavioral outcomes of the children were assessed on the basis of a semistructured interview of the mother, the Symptom Check List. The Symptom Check List explores 4 groups of behavioral symptoms: sleeping problems, eating problems, psychosomatic symptoms, and behavioral and emotional disorders. At the same age, developmental outcomes were evaluated using the Griffiths Developmental Scales. Five areas were evaluated: locomotor, personal-social, hearing and speech, eye-hand coordination, and performance. RESULTS: Among the possible dyadic patterns of interaction, 2 patterns emerge recurrently in mother-infant preterm dyads: a "cooperative pattern" with a sensitive mother and a cooperative-responsive infant (28%) and a "controlling pattern" with a controlling mother and a compulsive-compliant infant (28%). The remaining 44% form a heterogeneous group that gathers all of the other preterm dyads and is composed of 1 sensitive mother-passive infant; 10 controlling mothers with a cooperative, difficult, or passive infant; and 10 unresponsive mothers with a cooperative, difficult, or passive infant. Among the term control subjects, 68% of the dyads are categorized as cooperative pattern dyads, 12% as controlling pattern dyads, and the 20% remaining as heterogeneous dyads. At 18 months, preterm infants of cooperative pattern dyads have similar outcomes as the term control infants. Preterm infants of controlling pattern dyads have significantly fewer positive outcomes as compared with preterm infants of cooperative pattern dyads, as well as compared with term control infants. They display significantly more behavioral symptoms than term infants, including more eating problems than term infants as well as infants from cooperative preterm dyads. Infants of the controlling preterm dyads do not differ significantly for the total development quotient but have worse personal-social development than term infants and worse hearing-speech development than infants from cooperative preterm dyads. The preterm infants of the heterogeneous group have outcomes that can be considered as intermediate with no significant differences compared with preterm infants from the cooperative pattern or the controlling pattern dyads. CONCLUSION: Among mother-preterm infant dyads, we identified 2 specific patterns of interaction that could play either a protective (cooperative pattern) or a risk-precipitating (controlling pattern) role on developmental and behavioral outcome, independent of perinatal risk factors and of the family's socioeconomic background. The controlling pattern is much more prevalent among preterm than term dyads and is related to a less favorable infant outcome. However, the cooperative pattern still represents almost 30% of the preterm dyads, with infants' outcome comparable to the ones of term infants. These results point out the impact of the quality of mother-infant relationship on the infant's outcome. The most important clinical implication should be to support a healthy parent-infant relationship already in the NICU but also in the first months of the infant's life. Early individualized family-based interventions during neonatal hospitalization and transition to home have been shown to reduce maternal stress and depression and increase maternal self-esteem and to improve positive early parent-preterm infant interactions.

Genetic removal of tri-unsaturated fatty acids suppresses developmental and molecular phenotypes of an Arabidopsis tocopherol-deficient mutant. Whole-body mapping of malondialdehyde pools in a complex eukaryote.

Malondialdehyde (MDA) is a small, ubiquitous, and potentially toxic aldehyde that is produced in vivo by lipid oxidation and that is able to affect gene expression. Tocopherol deficiency in the vitamin E2 mutant vte2-1 of Arabidopsis thaliana leads to massive lipid oxidation and MDA accumulation shortly after germination. MDA accumulation correlates with a strong visual phenotype (growth reduction, cotyledon bleaching) and aberrant GST1 (glutathione S-transferase 1) expression. We suppressed MDA accumulation in the vte2-1 background by genetically removing tri-unsaturated fatty acids. The resulting quadruple mutant, fad3-2 fad7-2 fad8 vte2-1, did not display the visual phenotype or the aberrant GST1 expression observed in vte2-1. Moreover, cotyledon bleaching in vte2-1 was chemically phenocopied by treatment of wild-type plants with MDA. These data suggest that products of tri-unsaturated fatty acid oxidation underlie the vte2-1 seedling phenotype, including cellular toxicity and gene regulation properties. Generation of the quadruple mutant facilitated the development of an in situ fluorescence assay based on the formation of adducts of MDA with 2-thiobarbituric acid at 37 degrees C. Specificity was verified by measuring pentafluorophenylhydrazine derivatives of MDA and by liquid chromatography analysis of MDA-2-thiobarbituric acid adducts. Potentially applicable to other organisms, this method allowed the localization of MDA pools throughout the body of Arabidopsis and revealed an undiscovered pool of the compound unlikely to be derived from trienoic fatty acids in the vicinity of the root tip quiescent center.

Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

Urinary Sphincter Based on Electronics and Artificial Muscles

Objectives: The AMS 800 is the current artifi cial urinary sphincter (AUS) forincontinence due to intrinsic sphincter defi ciency. Despite good clinical results,technical failures inherent to the hydraulic mechanism or urethral ischemicinjury contribute to revisions up to 60%. We are developing an electronic AUS,called ARTUS to overcome the rigors of AMS. The objective of this study wasto evaluate the technical effi cacy and tissue tolerance of the ARTUS systemin an animal model.Methods: The ARTUS is composed by three parts: thecontractile unit, a series of rings and an integrated microprocessor. The contractileunit is made of Nitinol fi bers. The rings are placed around the urethrato control the fl ow of urine by squeezing the urethra. They work in a sequentialalternative mode and are controlled by a microprocessor. In the fi rst phase athree-rings device was used while in the second phase a two-rings ARTUS wasused. The device was implanted in 14 sheep divided in two groups of six andeight animals for study purpose. The fi rst group aimed at bladder leak pointpressure (BLPP) measurement and validation of the animal model; the secondgroup aimed at verifying midterm tissue tolerance by explants at twelve weeks.General animal tolerance was also evaluated.Results: The ARTUS systemimplantation was uneventful. When the system was activated, the BLPP wasmeasured at 1.038 ± 0.044 bar (mean ± SD). Urethral tissue analysis did notshow signifi cant morphological changes. No infection and no sign of discomfortwere noted in animals at 12 weeks.Conclusions: The ARTUS proved to beeffective in continence achievement in this study. Histological results supportour idea that a sequential alternative mode can avoid urethral atrophy andischemia. Further technical developments are needed to verify long-termoutcome and permit human use.

A clinical pattern-based etiological diagnostic strategy for sensory neuronopathies: a French collaborative study.

Sensory neuronopathies (SNNs) encompass paraneoplastic, infectious, dysimmune, toxic, inherited, and idiopathic disorders. Recently described diagnostic criteria allow SNN to be differentiated from other forms of sensory neuropathy, but there is no validated strategy based on routine clinical investigations for the etiological diagnosis of SNN. In a multicenter study, the clinical, biological, and electrophysiological characteristics of 148 patients with SNN were analyzed. Multiple correspondence analysis and logistic regression were used to identify patterns differentiating between forms of SNNs with different etiologies. Models were constructed using a study population of 88 patients and checked using a test population of 60 cases. Four patterns were identified. Pattern A, with an acute or subacute onset in the four limbs or arms, early pain, and frequently affecting males over 60 years of age, identified mainly paraneoplastic, toxic, and infectious SNN. Pattern B identified patients with progressive SNN and was divided into patterns C and D, the former corresponding to patients with inherited or slowly progressive idiopathic SNN with severe ataxia and electrophysiological abnormalities and the latter to patients with idiopathic, dysimmune, and sometimes paraneoplastic SNN with a more rapid course than in pattern C. The diagnostic strategy based on these patterns correctly identified 84/88 and 58/60 patients in the study and test populations, respectively.

Mentally Ill Offenders in Community-Based Corrections, Research in Brief, Iowa Department of Corrections, April 2008

A survey of offenders supervised by the eight district departments of correctional services. This report was commissioned by the Iowa Department of Corrections Focus Group on Mental Health in Community-Based Corrections.