Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. METHODS: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. RESULTS: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. CONCLUSIONS: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.

Sex-related and non-sex-related comorbidity subtypes of tic disorders: a latent class approach.

BACKGROUND AND PURPOSE: Recent evidence suggests that there may be more than one Gilles de la Tourette syndrome (GTS)/tic disorder phenotype. However, little is known about the common patterns of these GTS/tic disorder-related comorbidities. In addition, sex-specific phenomenological data of GTS/tic disorder-affected adults are rare. Therefore, this community-based study used latent class analyses (LCA) to investigate sex-related and non-sex-related subtypes of GTS/tic disorders and their most common comorbidities. METHODS: The data were drawn from the PsyCoLaus study (n = 3691), a population-based survey conducted in Lausanne, Switzerland. LCA were performed on the data of 80 subjects manifesting motor/vocal tics during their childhood/adolescence. Comorbid attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depressive, phobia and panic symptoms/syndromes comprised the selected indicators. The resultant classes were characterized by psychosocial correlates. RESULTS: In LCA, four latent classes provided the best fit to the data. We identified two male-related classes. The first class exhibited both ADHD and depression. The second class comprised males with only depression. Class three was a female-related class depicting obsessive thoughts/compulsive acts, phobias and panic attacks. This class manifested high psychosocial impairment. Class four had a balanced sex proportion and comorbid symptoms/syndromes such as phobias and panic attacks. The complementary occurrence of comorbid obsessive thoughts/compulsive acts and ADHD impulsivity was remarkable. CONCLUSIONS: To the best of our knowledge, this is the first study applying LCA to community data of GTS symptoms/tic disorder-affected persons. Our findings support the utility of differentiating GTS/tic disorder subphenotypes on the basis of comorbid syndromes.

Thyroid function and prevalent and incident metabolic syndrome in older adults: the Health, Ageing and Body Composition Study.

OBJECTIVE: Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults. DESIGN: Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults. PARTICIPANTS: Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis. MEASUREMENTS: TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria. RESULTS: At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.01-1.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.03-1.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.0-5.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6-7.5). CONCLUSIONS: Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome.

Strategies of emotion regulation in adolescents and young adults with substance dependence or eating disorders

Some authors argue that both substance dependence and eating disorders should be considered as dependent behaviours. Similarities and differences between these disorders, however, remain unclear. This study compares processes of emotion regulation in adolescents and young adults (15 to 25 years old) with substance dependence (SD) or eating disorders (ED). One hundred and thirteen SD, 50 ED and 86 non-clinical subjects (NC), recruited in four French and Swiss locations, completed a self-report questionnaire of emotion regulation strategies. This questionnaire addresses the subjects' relationships, concerning past and present family, and refers to Main's (1990) concept of primary strategy (balanced activation and deactivation of attachment behaviours), and of secondary strategies (hyperactivation or excessive deactivation of the attachment system). Participants were also questioned in structured interviews, about life events and DSM-IV classification criteria. SD reported more adverse events than ED and NC. SD and ED reported using fewer primary strategies than NC, and SD had secondary strategies that were different from those of ED. Patients with eating disorders reported more hyperactivation, and SD reported more deactivation of the attachment system. It is hypothesized that while subjects with SD and ED have in common poorly regulated strategies, they differ in the way they process emotion or relationship-related information.

Management of refractory status epilepticus in adults: still more questions than answers.

Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug. RSE should be treated promptly to prevent morbidity and mortality; however, scarce evidence is available to support the choice of specific treatments. Major independent outcome predictors are age (not modifiable) and cause (which should be actively targeted). Recent recommendations for adults suggest that the aggressiveness of treatment for RSE should be tailored to the clinical situation. To minimise intensive care unit-related complications, focal RSE without impairment of consciousness might initially be approached conservatively; conversely, early induction of pharmacological coma is advisable in generalised convulsive forms of the disorder. At this stage, midazolam, propofol, or barbiturates are the most commonly used drugs. Several other treatments, such as additional anaesthetics, other antiepileptic or immunomodulatory compounds, or non-pharmacological approaches (eg, electroconvulsive treatment or hypothermia), have been used in protracted RSE. Treatment lasting weeks or months can sometimes result in a good outcome, as in selected patients after encephalitis or autoimmune disorders. Well designed prospective studies of RSE are urgently needed.

A preliminary evaluation of the validity of at-risk criteria for bipolar disorders in help-seeking adolescents and young adults.

INTRODUCTION: We have developed ultra-high risk criteria for bipolar affective disorder (bipolar at-risk - BAR) which include general criteria such as being in the peak age range of the onset of the disorder and a combination of specific criteria including sub-threshold mania, depressive symptoms, cyclothymic features and genetic risk. In the current study, the predictive validity of these criteria were tested in help-seeking adolescents and young adults. METHOD: This medical file-audit study was conducted at ORYGEN Youth Health (OYH), a public mental health program for young people aged between 15 and 24years and living in metropolitan Melbourne, Australia. BAR criteria were applied to the intake assessments of all non-psychotic patients who were being treated in OYH on 31 January, 2008. All entries were then checked for conversion criteria. Hypomania/mania related additions or alterations to existing treatments or initiation of new treatment by the treating psychiatrist served as conversion criteria to mania. RESULTS: The BAR criteria were applied to 173 intake assessments. Of these, 22 patients (12.7%) met BAR criteria. The follow-up period of the sample was 265.5days on average (SD 214.7). There were significantly more cases in the BAR group (22.7%, n=5) than in the non-BAR group (0.7%, n=1) who met conversion criteria (p<.001). CONCLUSIONS: These findings support the notion that people who develop a first episode of mania can be identified during the prodromal phase. The proposed criteria need further evaluation in prospective clinical trials.

Validation d'une version abrégée du TCI (TCI-56) sur un échantillon de jeunes fumeurs et non-fumeurs

Introduction: The psychobiological seven-factor model proposed by Cloninger et al. (1993) takes into account temperament and character dimensions to describe personality. Four of the dimensions are linked with biological, genetic and neuroanatomic structures, whereas the three other dimensions are related to the degree of individual, social and spiritual development. A study conducted by Wills et al. (1994) with adolescents showed that substance abuse was associated with high scores on Novelty Seeking and low scores on Harm Avoidance and Reward Dependence. The aim of the present study was, firstly, to create a short form of Cloninger's (1993) Temperament and Character Inventory (TCI) and, secondly, to study the impact of nicotine dependence as well as demographic variables on a sample of young adults. Method: We created a short form of the TCI containing 56 items (TCI-56), 8 for each scale. Responses are made on a five-point Likert type scale. A Swiss sample (n=211), of 116 women and 95 men, aged from 15 to 30 years, participated in this study. Our population was divided into a group of 81 smokers and another of 130 non-smokers, according to their scores on the Fagerstörm test for nicotine dependence (1999). Results: The structural validation consisted of two separate factor analysis with varimax rotations, one for the temperamental items, and the other, for the character ones. The first factor analysis conducted on the items of the temperament scales allowed to extract 4 factors explaining 40.7% of the variance. The correlations between factors and scales are the following: r=.71 for Novelty Seeking, r=.69 for Persistence, r=.95 for Harm Avoidance, r=.94 for Reward Dependence. The second factor analysis conducted on the items of the character scales allowed to extract 3 factors explaining 41.5% of the variance. The correlations between factors and scales are the following: r=.94 for Self-Directedness, r=.91 for Cooperativeness and r=.99 for Self-Transcendence. The internal consistencies range from α=.65 to α=.75 for the temperament scales, and from α=.71 to α=.83 for the three character scales. Concerning, the impact of the nicotine dependence, we observed that smokers have significantly higher scores for Novelty seeking, than non-smokers (p=.01). We found no difference for Harm Avoidance and Reward Dependence. Nevertheless, smokers seem to have the tendency to score higher on Transcendence (p=.06). Moreover, people having smoked more than 100 cigarettes in their life have significantly higher scores on this scale (p.04) and the correlation between Transcendence and the Fagerstörm test is significant (r=.19). We also found gender differences: the women (N=116) obtain significantly higher scores for Harm Avoidance (p<.001), for Reward Dependence (p<.001) and for Cooperation (p=.01). We further found a significant correlation between age and Self-Directedness, r=.34. We observed no interaction between gender and smoking or age and smoking on the dimensions of the TCI-56. Discussion: The TCI short form (TCI-56) seems to be a valid and useful inventory to assess personality differences. Confirming the results of others about the relation between addiction and personality, we found that smokers have significantly higher scores for Novelty seeking, than non-smokers. But we were not able to find any significant differences for Harm Avoidance and Reward Dependence. This might be due to our sample that was made of young adults. This study also shows that Transcendence could be an interesting dimension for studies on Tobacco smoking to consider. Concerning the impact of demographic variables, we observed that age and gender have specific and coherent influence on personality.

Nemaline myopathy revealed by respiratory failure in adults

Most forms of myopathy may involve the respiratory muscles and progress to respiratory failure. However, the diagnosis of myopathy is seldom considered in an adult patient with no history of muscle disease and presenting with respiratory failure. Nemaline myopathy (NM) is a rare disorder characterized by symmetrical diffuse muscle weakness and rod-like nemaline bodies in muscle fibers. Respiratory muscle involvement is a major determinant of mortality in congenital NM, but is rare in late onset NM. Here, we report that acute or chronic respiratory failure may be caused by NM in subjects with no known history of muscle disease. Adult-onset NM was diagnosed in a 67-year-old woman with chronic respiratory insufficiency. Late onset childhood NM was revealed by respiratory failure in twin sisters aged 31. The diagnosis was established by muscle biopsy and electron microscopy (and mutations in the nebulin gene in the two sisters). Long-term clinical improvement was obtained with non-invasive ventilation (NIV) in the three patients. In conclusion, respiratory failure in an adult patient with no known history may correspond to NM with diaphragm involvement. Long-term outcome may be favorable with NIV.

Assessment of statistical iterative reconstructions to optimize CT examination protocols for children and young adults

La tomodensitométrie (CT) est une technique d'imagerie dont l'intérêt n'a cessé de croître depuis son apparition dans le début des années 70. Dans le domaine médical, son utilisation est incontournable à tel point que ce système d'imagerie pourrait être amené à devenir victime de son succès si son impact au niveau de l'exposition de la population ne fait pas l'objet d'une attention particulière. Bien évidemment, l'augmentation du nombre d'examens CT a permis d'améliorer la prise en charge des patients ou a rendu certaines procédures moins invasives. Toutefois, pour assurer que le compromis risque - bénéfice soit toujours en faveur du patient, il est nécessaire d'éviter de délivrer des doses non utiles au diagnostic.¦Si cette action est importante chez l'adulte elle doit être une priorité lorsque les examens se font chez l'enfant, en particulier lorsque l'on suit des pathologies qui nécessitent plusieurs examens CT au cours de la vie du patient. En effet, les enfants et jeunes adultes sont plus radiosensibles. De plus, leur espérance de vie étant supérieure à celle de l'adulte, ils présentent un risque accru de développer un cancer radio-induit dont la phase de latence peut être supérieure à vingt ans. Partant du principe que chaque examen radiologique est justifié, il devient dès lors nécessaire d'optimiser les protocoles d'acquisitions pour s'assurer que le patient ne soit pas irradié inutilement. L'avancée technologique au niveau du CT est très rapide et depuis 2009, de nouvelles techniques de reconstructions d'images, dites itératives, ont été introduites afin de réduire la dose et améliorer la qualité d'image.¦Le présent travail a pour objectif de déterminer le potentiel des reconstructions itératives statistiques pour réduire au minimum les doses délivrées lors d'examens CT chez l'enfant et le jeune adulte tout en conservant une qualité d'image permettant le diagnostic, ceci afin de proposer des protocoles optimisés.¦L'optimisation d'un protocole d'examen CT nécessite de pouvoir évaluer la dose délivrée et la qualité d'image utile au diagnostic. Alors que la dose est estimée au moyen d'indices CT (CTDIV0| et DLP), ce travail a la particularité d'utiliser deux approches radicalement différentes pour évaluer la qualité d'image. La première approche dite « physique », se base sur le calcul de métriques physiques (SD, MTF, NPS, etc.) mesurées dans des conditions bien définies, le plus souvent sur fantômes. Bien que cette démarche soit limitée car elle n'intègre pas la perception des radiologues, elle permet de caractériser de manière rapide et simple certaines propriétés d'une image. La seconde approche, dite « clinique », est basée sur l'évaluation de structures anatomiques (critères diagnostiques) présentes sur les images de patients. Des radiologues, impliqués dans l'étape d'évaluation, doivent qualifier la qualité des structures d'un point de vue diagnostique en utilisant une échelle de notation simple. Cette approche, lourde à mettre en place, a l'avantage d'être proche du travail du radiologue et peut être considérée comme méthode de référence.¦Parmi les principaux résultats de ce travail, il a été montré que les algorithmes itératifs statistiques étudiés en clinique (ASIR?, VEO?) ont un important potentiel pour réduire la dose au CT (jusqu'à-90%). Cependant, par leur fonctionnement, ils modifient l'apparence de l'image en entraînant un changement de texture qui pourrait affecter la qualité du diagnostic. En comparant les résultats fournis par les approches « clinique » et « physique », il a été montré que ce changement de texture se traduit par une modification du spectre fréquentiel du bruit dont l'analyse permet d'anticiper ou d'éviter une perte diagnostique. Ce travail montre également que l'intégration de ces nouvelles techniques de reconstruction en clinique ne peut se faire de manière simple sur la base de protocoles utilisant des reconstructions classiques. Les conclusions de ce travail ainsi que les outils développés pourront également guider de futures études dans le domaine de la qualité d'image, comme par exemple, l'analyse de textures ou la modélisation d'observateurs pour le CT.¦-¦Computed tomography (CT) is an imaging technique in which interest has been growing since it first began to be used in the early 1970s. In the clinical environment, this imaging system has emerged as the gold standard modality because of its high sensitivity in producing accurate diagnostic images. However, even if a direct benefit to patient healthcare is attributed to CT, the dramatic increase of the number of CT examinations performed has raised concerns about the potential negative effects of ionizing radiation on the population. To insure a benefit - risk that works in favor of a patient, it is important to balance image quality and dose in order to avoid unnecessary patient exposure.¦If this balance is important for adults, it should be an absolute priority for children undergoing CT examinations, especially for patients suffering from diseases requiring several follow-up examinations over the patient's lifetime. Indeed, children and young adults are more sensitive to ionizing radiation and have an extended life span in comparison to adults. For this population, the risk of developing cancer, whose latency period exceeds 20 years, is significantly higher than for adults. Assuming that each patient examination is justified, it then becomes a priority to optimize CT acquisition protocols in order to minimize the delivered dose to the patient. Over the past few years, CT advances have been developing at a rapid pace. Since 2009, new iterative image reconstruction techniques, called statistical iterative reconstructions, have been introduced in order to decrease patient exposure and improve image quality.¦The goal of the present work was to determine the potential of statistical iterative reconstructions to reduce dose as much as possible without compromising image quality and maintain diagnosis of children and young adult examinations.¦The optimization step requires the evaluation of the delivered dose and image quality useful to perform diagnosis. While the dose is estimated using CT indices (CTDIV0| and DLP), the particularity of this research was to use two radically different approaches to evaluate image quality. The first approach, called the "physical approach", computed physical metrics (SD, MTF, NPS, etc.) measured on phantoms in well-known conditions. Although this technique has some limitations because it does not take radiologist perspective into account, it enables the physical characterization of image properties in a simple and timely way. The second approach, called the "clinical approach", was based on the evaluation of anatomical structures (diagnostic criteria) present on patient images. Radiologists, involved in the assessment step, were asked to score image quality of structures for diagnostic purposes using a simple rating scale. This approach is relatively complicated to implement and also time-consuming. Nevertheless, it has the advantage of being very close to the practice of radiologists and is considered as a reference method.¦Primarily, this work revealed that the statistical iterative reconstructions studied in clinic (ASIR? and VECO have a strong potential to reduce CT dose (up to -90%). However, by their mechanisms, they lead to a modification of the image appearance with a change in image texture which may then effect the quality of the diagnosis. By comparing the results of the "clinical" and "physical" approach, it was showed that a change in texture is related to a modification of the noise spectrum bandwidth. The NPS analysis makes possible to anticipate or avoid a decrease in image quality. This project demonstrated that integrating these new statistical iterative reconstruction techniques can be complex and cannot be made on the basis of protocols using conventional reconstructions. The conclusions of this work and the image quality tools developed will be able to guide future studies in the field of image quality as texture analysis or model observers dedicated to CT.

Non-medical prescription drug and illicit street drug use among young Swiss men and associated mental health issues.

Non-medical use of prescription drugs (NMUPD) is increasing among the general population, particularly among teenagers and young adults. Although prescription drugs are considered safer than illicit street drugs, NMUPD can lead to detrimental consequences. The aim of the present study was to investigate the relationship between drug use (NMUPD on the one side, illicit street drugs on the other side) with mental health issues and then compare these associations. A representative sample of 5719 young Swiss men aged around 20 years filled in a questionnaire as part of the ongoing baseline Cohort Study on Substance Use Risk Factors (C-SURF). Drug use (16 illicit street drugs and 5 NMUPDs, including sleeping pills, sedatives, pain killers, antidepressants, stimulants) and mental health issues (depression, SF12) were assessed. Simple and multiple linear regressions were employed. In simple regressions, all illicit and prescription drugs were associated with poorer mental health. In multiple regressions, most of the NMUPDs, except for stimulants, were significantly associated with poorer mental health and with depression. On the contrary, the only associations that remained significant between illicit street drugs and mental health involved cannabis. NMUPD is of growing concern not only because of its increasing occurrence, but also because of its association with depression and mental health problems, which is stronger than the association observed between these problems and illicit street drug use, excepted for cannabis. Therefore, NMUPD must be considered in screening for substance use prevention purposes.

Association of smoking and nicotine dependence with pre-diabetes in young and healthy adults.

INTRODUCTION: Several studies have shown an increased risk of type 2 diabetes among smokers. Therefore, the aim of this analysis was to assess the relationship between smoking, cumulative smoking exposure and nicotine dependence with pre-diabetes. METHODS: We performed a cross-sectional analysis of healthy adults aged 25-41 in the Principality of Liechtenstein. Individuals with known diabetes, Body Mass Index (BMI) >35 kg/m² and prevalent cardiovascular disease were excluded. Smoking behaviour was assessed by self-report. Pre-diabetes was defined as glycosylated haemoglobin between 5.7% and 6.4%. Multivariable logistic regression models were done. RESULTS: Of the 2142 participants (median age 37 years), 499 (23.3%) had pre-diabetes. There were 1,168 (55%) never smokers, 503 (23%) past smokers and 471 (22%) current smokers, with a prevalence of pre-diabetes of 21.2%, 20.9% and 31.2%, respectively (p <0.0001). In multivariable regression models, current smokers had an odds ratio (OR) of pre-diabetes of 1.82 (95% confidential interval (CI) 1.39; 2.38, p <0.0001). Individuals with a smoking exposure of <5, 5-10 and >10 pack-years had an OR (95% CI) for pre-diabetes of 1.34 (0.90; 2.00), 1.80 (1.07; 3.01) and 2.51 (1.80; 3.59) (p linear trend <0.0001) compared with never smokers. A Fagerström score of 2, 3-5 and >5 among current smokers was associated with an OR (95% CI) for pre-diabetes of 1.27 (0.89; 1.82), 2.15 (1.48; 3.13) and 3.35 (1.73; 6.48) (p linear trend <0.0001). DISCUSSION: Smoking is strongly associated with pre-diabetes in young adults with a low burden of smoking exposure. Nicotine dependence could be a potential mechanism of this relationship.

Reproducibility of acute mountain sickness in children and adults : a prospective study

Objectif: Alors qu'un antécédent d' AMS est couramment utilisé pour fournir des conseils et recommander une prophylaxie médicamenteuse pour les expositions ultérieures à la haute altitude, la reproductibilité intra-individuelle de l'AMS au cours d'expositions répétées n'a jamais été examinée dans une étude prospective contrôlée. Méthodes : Chez 27 enfants et 29 adultes non acclimatés, nous avons évalué la présence et la sévérité de l' AMS durant les 48 premières heures après une montée rapide à 3450m, et ceci en deux occasions distantes de 9 à 12 mois. Résultats: 18 adultes (62 %) et 6 enfants (22 %) ont souffert d'AMS durant la première exposition et 14 adultes (48 %) et 4 enfants (15 %) durant la seconde (P=O.Ol, adultes versus enfants). Mais surtout, la reproductibilité intra-individuelle de l'AMS était très différente (P < 0.001) entre les deux groupes; en effet, aucun des 6 enfants ayant souffert d'AMS au cours de la première exposition n'en n'a souffert au cours de la seconde mais 4 enfants sans AMS lors de la première exposition ont été touchés lors de la seconde exposition. Contrairement à cela, 14 des 18 adultes qui ont souffert de 1' AMS lors de la première exposition ont également présenté ce problème au cours de la seconde et aucun nouveau cas ne s'est développé dans ceux qui n'avaient pas souffert de cette affection lors de la première occasion. ConClusion : Si chez 1' adulte, un antécédent d' AMS a une bonne valeur prédictive d'un nouvel épisode durant les expositions futures dans des conditions similaires, il n'en est pas de même chez l'enfant chez lequel il n'a pas de valeur prédictive. Un antécédent d'AMS ne devrait donc pas inciter les praticiens à déconseiller la réexposition ou à prescrire une prophylaxie médicamenteuse chez l'enfant.

Simultaneous detection of aneuploidies for chromosomes 4, 6, 10 and 17 by automated four colour I-FISH in high hyperdiploid acute lymphoblastic leukemia : diagnostic assessment, clonal heterogeneity and chromosomal instability in adults

SummarySimultaneous detection of aneuploidies for chromosomes 4, 6,10 and 17 by automated four color l-FISH in high hyperdiploid acute lymphoblastic leukemia: diagnostic assessment, clonal heterogeneity and chromosomal instability in adultsAnna Talamo BlandinService de Génétique Médicale, Unité de Cytogénétique du Cancer, CHUVAcute lymphoblastic leukemia (ALL) is a malignant hemopathy characterized by the accumulation of the immature lymphoid cells in the bone marrow and, most often, in the peripheral blood. ALL is a heterogeneous disease with distinct biological and prognostic entities. At diagnosis, cytogenetic and molecular findings constitute important and independent prognostic factors. High hyperdiploidy with 51-67 chromosomes (HeH), one of the largest cytogenetic subsets of ALL, in childhood particularly, is generally associated with a relatively favorable outcome. Chromosome gain is nonrandom, extracopies of some chromosome occurring more frequently than those of others. Concurrent presence of trisomy for chromosomes 4, 10 and 17 confers an especially good prognosis. The first aim of our work was to develop an automated four color interphase fluorescence in situ hybridization (l-FISH) methodology and to assess its ability to detect concurrent aneuploidies 4, 6, 10 and 17 in 10 ALL patients. Various combinations of aneuploidies were identified. All clones detected by conventional cytogenetics were also observed by l-FISH. However, in all patients, l-FISH revealed numerous additional abnormal clones, leading to a high level of clonal heterogeneity. Our second aim has been to investigate the nature and origin of this clonal heterogeneity and to test for the presence of chromosome instability (CIN) in HeH ALL at initial presentation. Ten HeH ALL and 10 non-HeH ALL patients were analysed by four colour l-FISH and numerical CIN values were determined for all four chromosomes together and for each chromosome and patient group, an original approach in ALL. CIN values in HeH ALL proved to be much higher than#iose in non-HeH ALL, suggesting that numerical CIN may be at the origin of the high level of clonal heterogeneity revealed by l-FISH. Our third aim has been to study the evolution of these cytogenetic features during the course of the disease in 10 HeH ALL patients. Clonal heterogeneity was also observed again during disease progression, particularly at relapse. Clones detected at initial presentation generally reappeared in relapse, in most cases with newly generated ones. A significant correlation between the number of abnormal clones and CIN suggested that the higher the instability, the larger the number of abnormal clones. Whereas clonal heterogeneity and its evolution most probably result from underlying chromosome instability, operating processes remain conjectural.RésuméLa leucémie lymphoblastique aiguë (LLA) est une hémopathie maligne qui résulte de l'accumulationde cellules lymphoïdes immatures dans la moelle osseuse, et, le plus souvent, dans le sangpériphérique également. La LLA est une affection hétérogène au sein de laquelle se distinguentplusieurs entités biologiques et pronostiques. Les données cytogénétiques et moléculaires font partieintégrante du diagnostic et jouent un rôle essentiel dans l'évaluation du pronostic. L'hyperdiploïdieélevée à 51-­67 chromosomes (HeH), relativement fréquente, en particulier chez l'enfant, s'associe àun pronostic favorable. Le gain de chromosomes ne relève pas du hasard, certains chromosomesétant plus fréquemment impliqués que d'autres. La présence simultanée des trisomies 4, 6, et 17s'associe à un pronostic particulièrement bon. Le premier but du travail a été de développer uneméthode d'analyse automatique par hybridation in situ fluorescente interphasique (I-­FISH) à 4couleurs et de tester sa capacité à identifier la présence simultanée d'aneuploïdies 4, 6, 10 et 17 dans10 cas de LLA. Différentes combinaisons d'aneuploïdies ont été identifiées. Tous les clones détectéspar cytogénétique conventionnelle l'ont été par I-­FISH. Or, chez tous les patients, l'I-­FISH a révélé denombreux clones anormaux additionnels générant un degré élevé d'hétérogénéité clonale. Notredeuxième but a été d'investiguer la nature et l'origine de cette hétérogénéité et de tester la présenced'instabilité chromosomique (CIN) chez les patients avec une LLA HeH en presentation initiale. DixLLA HeH et 10 LLA non-­HeH ont été analysées par I-­FISH et les valeurs de CIN numérique ont étédéterminées pour les 4 chromosomes ensemble et pour chaque chromosome et groupe de patients,approche originale dans la LLA. Ces valeurs étant beaucoup plus élevées dans la LLA HeH que dansla LLA non-­HeH, elles favorisent l'hypothèse selon laquelle la CIN serait à l'origine de l'hétérogénéitéclonale révélée par I-­FISH. Le troisième but de notre travail a été d'étudier l'évolution de cescaractéristiques cytogénétiques au cours de la maladie dans 10 cas de LLA HeH. L'hétérogénéitéclonale a été retrouvée lors de la progression de la maladie, en particulier en rechute, où les clonesanormaux détectés en présentation initiale réapparaissent, généralement accompagnés de clonesnouveaux. La corrélation existant entre nombre de clones anormaux et valeurs de CIN suggère queplus l'instabilité est élevée, plus le nombre de clones anormaux est grand. Bien que l'hétérogénéitéclonale et son évolution résultent très probablement de l'instabilité chromosomique, les processus àl'oeuvre ne sont pas entièrement élucidés.

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.

Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.

Long-term outcome after cognitive and behavioral regression in non-lesional epilepsy with CSWS

Purpose: To present the long-term outcome (LTO) of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to non-lesional focal, mainly frontal epilepsy with continuous spike-waves during slow wave sleep (CSWS). Method: Past medical and EEG data of all patients were reviewed and neuropsychological tests exploring main cognitive functions were administered. Result: After a mean duration of follow-up of 15.6 years (range 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders that were so disturbing during the active period (AP) resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the AP disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. LTO correlated best with duration of CSWS. Conclusion: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence as reported in adults with destructive lesions of the frontal lobes during childhood. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.