PKCθ/β and CYLD are antagonistic partners in the NFκB and NFAT transactivation pathways in primary mouse CD3+ T lymphocytes.

In T cells PKCθ mediates the activation of critical signals downstream of TCR/CD28 stimulation. We investigated the molecular mechanisms by which PKCθ regulates NFκB transactivation by examining PKCθ/β single and double knockout mice and observed a redundant involvement of PKCθ and PKCβ in this signaling pathway. Mechanistically, we define a PKCθ-CYLD protein complex and an interaction between the positive PKCθ/β and the negative CYLD signaling pathways that both converge at the level of TAK1/IKK/I-κBα/NFκB and NFAT transactivation. In Jurkat leukemic T cells, CYLD is endoproteolytically processed in the initial minutes of stimulation by the paracaspase MALT1 in a PKC-dependent fashion, which is required for robust IL-2 transcription. However, in primary T cells, CYLD processing occurs with different kinetics and an altered dependence on PKC. The formation of a direct PKCθ/CYLD complex appears to regulate the short-term spatial distribution of CYLD, subsequently affecting NFκB and NFAT repressional activity of CYLD prior to its MALT1-dependent inactivation. Taken together, our study establishes CYLD as a new and critical PKCθ interactor in T cells and reveals that antagonistic PKCθ/β-CYLD crosstalk is crucial for the adjustment of immune thresholds in primary mouse CD3(+) T cells.

AT-RISK ALCOHOL USE IN YOUNG ADULTS - EFFECTIVENESS AND MECHANISMS OF BRIEF MOTIVATIONAL INTERVENTION AS A PRIMARY AND SECONDARY PREVENTION MEASURE

SummaryThe alcohol use of adolescents and young adults is one of the world's most important and costliest health problems. Particularly, binge drinking (i.e. drinking an important amount of alcohol in one occasion) among young people increase the risk of detrimental consequences such as blackouts, injuries, at-risk sexual behaviors, involvement in violent acts, academic failure, and suicide attempts. In countries with mandatory conscription mechanisms, such as Switzerland, the army provides a unique opportunity to reach a large portion of this high risk population. We used this sample to evaluate the prevalence of binge drinking among young men, to test the efficacy of brief motivational interventions (BMI) as a primary and secondary preventive measure, and to examine the mechanisms underlying BMI in this age group.We showed that binge drinking among young French-speaking Swiss men is less of an exception than it is the norm. Of those using alcohol, 75.5% had a binge drinking episode at least monthly, and 69.3% of all consumption reported in a one-week diary was due to binge drinking days.We used two different inclusion modes to evaluate the success of alcohol BMI. In the first randomized controlled trial, inclusion relied on a random selection of conscripts. BMI efficacy was evaluated in a sample of conscripts who visited the army recruitment centre that is potentially generalizable to the entire population. In the second randomized controlled trial, we included subjects voluntarily participating in BMI. This venue might be more realistic for young adults; it is more akin to the MI spirit, in which it is crucial for individuals to control their own decisions.Regarding BMI efficacy as a secondary prevention measure (i.e. to help decrease alcohol use among at-risk drinkers, defined here as those having a binge drinking episode at least monthly), it was effective among randomly selected at-risk drinkers, whereas it was not effective among at-risk drinkers who voluntarily showed up. Individuals who showed interest in BMI had more severe patterns of alcohol use, which may have made change more difficult and calls for treatment that is more intensive. BMI demonstrated a 20% reduction in weekly alcohol use among randomly selected participants, indicating potential interest in BMI implementation within similar community settings.Regarding BMI efficacy as a primary prevention measure (i.e. to help maintain low levels of use among low-risk drinkers), it had significant protective effects among low-risk drinkers voluntarily showing up whereas it was not effective among low-risk drinkers randomly selected. This suggests that BMI might help young individuals keep their drinking at low levels, especially when they are interested in discussing their alcohol use. Therefore, BMI has potentially promising uses in primary prevention efforts. The content of these interventions for low-risk drinkers who do not seek BMI on their own should be further evaluated.BMI mechanisms were addressed since little is known about exactly which elements of it work, or which of the counselor and subject communication behaviors are most effective in triggering behavior changes. The causal chain hypothesis developed in the motivational interviewing (MI) theory was followed, and it was found that counselor behaviors consistent with the MI approach (MICO) were significantly more likely to be followed by participant language in favor of change (change talk, CT), while behaviors inconsistent with MI (MIIN) were significantly less likely to do so. Several CT dimensions measured during BMI (particularly Ability, Desire, and Need to change) were predictive of change in alcohol use. Our findings lend strong support for the use of MICO behaviors and the avoidance of MIIN behaviors in eliciting CT, and point out that particular attention should be paid to the utterances in several sub-dimensions of CT and to the strength of expression, since these are good indicators of potential actual behavior change in future.RésuméLa consommation d'alcool chez les adolescents et les jeunes adultes est un des problèmes de santé les plus importants et les plus coûteux dans le monde. En particulier, les consommations importantes d'alcool en une occasion (binge drinking) parmi les jeunes adultes ont été liées à des conséquences telles que pertes de connaissance, accidents et blessures, comportements sexuels à risque, violences, difficultés scolaires et tentatives de suicide. Les pays qui, comme la Suisse, connaissent un processus de recrutement obligatoire pour l'armée offrent une opportunité unique d'atteindre une large portion de cette population à hauts risques. Nous avons utilisé cet échantillon pour évaluer la prévalence du binge drinking parmi les jeunes hommes, pour tester l'efficacité de l'intervention brève motivationnelle (IBM) comme mesure de prévention primaire et secondaire, et pour examiner les mécanismes sous-tendant ce type d'interventions.La première partie de cette étude montre que le binge drinking est moins une exception que la norme parmi les jeunes hommes suisses francophones. 75.5% des personnes consommant de l'alcool avaient au moins un épisode de binge drinking par mois et 69.3% du total des boissons alcoolisées reportées comme consommation de la semaine précédant le questionnaire avaient été consommées lors d'épisodes de binge drinking.Pour évaluer l'efficacité de l'IBM dans ce cadre, nous avons utilisé deux modes d'inclusion. Dans une première étude randomisée contrôlée, nous avons inclus des personnes sélectionnées au hasard parmi toutes celles se présentant au centre de recrutement, créant ainsi un groupe potentiellement représentatif de l'ensemble du collectif. Dans la deuxième étude randomisée contrôlée, nous avons inclus des sujets se présentant volontairement pour recevoir une IBM, prendre des volontaires pouvant être plus proche de la réalité et plus proche de l'esprit motivationnel dans lequel il est crucial que l'individu contrôle ses décisions.En regardant l'IBM comme mesure de prévention secondaire (c'est-à-dire aider à diminuer la consommation d'alcool chez les consommateurs à risque, définis ici comme au moins un épisode de binge drinking par mois), l'IBM était efficace lorsque les participants étaient inclus au hasard et inefficace lorsqu'ils étaient volontaires. Les jeunes hommes volontaires pour un IBM avaient un mode de consommation particulièrement sévère qui pourrait être plus difficile à changer et nécessiter un traitement plus intensif. Parmi les personnes sélectionnées au hasard, l'IBM permettait une diminution de 20% de la consommation hebdomadaire d'alcool, montrant l'intérêt potentiel d'une implémentation de ce type de mesures dans des contextes communautaires similaires.En ce qui concerne l'IBM comme mesure de prévention primaire (c'est-à-dire aider à maintenir une consommation à bas risque chez les consommateurs à bas risque), l'IBM avaient un effet protectif significatif parmi les jeunes hommes volontaires pour une IBM, mais pas d'effet chez ceux sélectionnés au hasard. Ces résultats suggèrent que l'IBM pourrait aider de jeunes personnes à maintenir un niveau de consommation à bas risque si celles-ci s'intéressent à discuter cette consommation et aurait ainsi un potentiel intéressant comme mesure de prévention primaire. Le contenu de l'IBM pour des consommateurs à bas risque non-volontaires pour une IBM devra encore être évalué.Nous avons ensuite examiné les mécanismes de l'IBM car son fonctionnement est encore peu expliqué et les comportements de l'intervenant et du sujet les plus à même de provoquer le changement ne sont pas bien définis. En suivant l'hypothèse d'une chaine causale développée dans la littérature de l'entretien motivationnel (EM), nous avons pu montrer qu'un discours en faveur du changement chez le sujet était plus probable après des comportements de l'intervenant recommandés dans l'EM et moins probable après des comportements à éviter dans l'EM ; et que plusieurs dimensions de ce discours en faveur du changement (notamment la capacité, le désir et le besoin de changer) prédisaient un changement effectif dans la consommation d'alcool. Ces résultats encouragent donc à utiliser des comportements recommandés dans l'EM pour favoriser un discours en faveur du changement. Ils montrent aussi qu'une attention particulière doit être portée à la fréquence et à la force avec laquelle sont exprimées certaines dimensions de ce discours car ceux-ci indiquent un potentiel changement effectif de comportement.Résumé vulgariséLa consommation d'alcool chez les adolescents et les jeunes adultes est un des problèmes de santé les plus importants et les plus coûteux dans le monde. En particulier, les consommations importantes d'alcool en une occasion (binge drinking) parmi les jeunes adultes augmentent fortement les risques de conséquences telles que pertes de connaissance, accidents et blessures, comportements sexuels à risque, violences, difficultés scolaires et tentatives de suicide. Les pays qui, comme la Suisse, connaissent un processus de recrutement obligatoire pour l'armée offrent une opportunité unique d'atteindre une large portion de cette population à hauts risques. Nous avons utilisé cet échantillon pour évaluer l'importance du phénomène de binge drinking, pour tester l'efficacité de l'intervention brève motivationnelle (IBM) comme mesure de prévention de la consommation à risque d'alcool, et pour examiner comment fonctionne ce type d'interventions.La première partie de cette étude montre que le binge drinking est moins une exception que la norme parmi les jeunes hommes suisses francophones. Trois quart des personnes consommant de l'alcool avaient au moins un épisode de binge drinking par mois. Presque 70% du total des boissons alcoolisées consommées durant la semaine précédant le questionnaire avaient été consommées lors d'épisodes de binge drinking.Nous avons ensuite mené deux études pour évaluer l'efficacité de l'IBM dans ce cadre. Dans une première étude, nous avons sélectionné des personnes au hasard parmi toutes celles se présentant au centre de recrutement, créant ainsi un groupe potentiellement représentatif de l'ensemble du collectif. Dans la deuxième étude, nous avons inclus toutes les personnes se présentant volontairement pour recevoir une IBM, prendre des volontaires pouvant être plus proche de la réalité et plus proche de l'approche motivationnelle dans laquelle il est crucial que l'individu contrôle ses décisions. Dans les deux études, nous testions l'efficacité de l'IBM comme mesure de prévention primaire et secondaire (voir ci-dessous).En regardant l'IBM comme mesure de prévention secondaire (c'est-à-dire aider à diminuer la consommation d'alcool chez les consommateurs à risque, définis ici comme au moins un épisode de binge drinking par mois), l'IBM était efficace lorsque les participants étaient inclus au hasard et inefficace lorsqu'ils étaient volontaires. Les jeunes hommes volontaires pour un IBM avaient un mode de consommation particulièrement sévère qui pourrait être plus difficile à changer et nécessiter un traitement plus intensif. Parmi les personnes sélectionnées au hasard, l'IBM permettait une diminution de 20% de la consommation hebdomadaire d'alcool, montrant l'intérêt potentiel de la mise en place de ce type de mesures dans des contextes communautaires similaires.En ce qui concerne l'IBM comme mesure de prévention primaire (c'est-à-dire aider à maintenir une consommation à bas risque chez les consommateurs à bas risque), l'IBM avaient un effet protectif parmi les jeunes hommes volontaires pour une IBM, mais pas d'effet chez ceux sélectionnés au hasard. Ces résultats suggèrent que l'IBM pourrait aider de jeunes personnes à maintenir un niveau de consommation à bas risque si celles-ci s'intéressent à discuter de cette consommation. Le contenu de l'IBM pour des consommateurs à bas risque non-volontaires pour une IBM devra encore être évalué.Nous avons ensuite examiné le fonctionnement de l'IBM et cherché quels comportements de l'intervenant et du jeune homme pouvaient être les plus à même d'amener à un changement dans la consommation. Nous avons pu montrer que 1) un discours en faveur du changement chez le jeune homme était plus probable après des comportements de l'intervenant recommandés dans l'approche motivationnelle et moins probable après des comportements non-recommandés ; et 2) plusieurs dimensions de ce discours en faveur du changement (notamment la capacité, le désir et le besoin de changer) prédisaient un changement effectif dans la consommation d'alcool. Ces résultats encouragent donc à utiliser des comportements recommandés dans l'EM pour favoriser un discours en faveur du changement. Ils montrent aussi qu'une attention particulière doit être portée à certaines dimensions de ce discours car celles-ci indiquent un potentiel changement effectif de comportement.

The habenula encodes negative motivational value associated with primary punishment in humans.

Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.

Expression of dual angiogenic/neurogenic growth factors in human primary brain tumors.

Brain tumors, benign or malignant, are characterized by a very high degree of vascularization. Recent accumulating evidence suggests that during development the neuronal wiring follows the same routes as the vasculature and that these two systems may share some of the same factors for guidance. Thus, expression of dual angiogenic/neurogenic growth factors was evaluated by in situ hybridization in human primary brain tumors of three different types, i.e., astrocytomas, oligodendrogliomas, and ependymomas, of increasing grades, in relation with the grade and type of the tumor. For this evaluation we selected vascular endothelial growth factor (VEGF-A) and its receptors VEGF-R1 and VEGF-R2 and the neuropilins 1 and 2 (NRP-1 and NRP-2), which have proangiogenic properties, platelet-derived growth factor (PDGF) receptor-beta (PDGF-Rβ), which is required for the functional maturation of blood vessels, the ephrins and their Eph receptors, angiotensinogen (AGT) and thrombospondin-2 (TSP-2), which have potential antiangiogenic properties, and netrin-1 (Net-1), which regulates vascular architecture. We show that the expression of the VEGF-NRP system, PDGF-Rβ, TSP-2, AGT, and Net-1 are differentially regulated, either increased or decreased, in relation with the type and grade of the tumor, whereas regulation of the ephrinB system does not seem to be relevant in these human brain tumors.

Tuning In to Sound: Frequency-Selective Attentional Filter in Human Primary Auditory Cortex.

Cocktail parties, busy streets, and other noisy environments pose a difficult challenge to the auditory system: how to focus attention on selected sounds while ignoring others? Neurons of primary auditory cortex, many of which are sharply tuned to sound frequency, could help solve this problem by filtering selected sound information based on frequency-content. To investigate whether this occurs, we used high-resolution fMRI at 7 tesla to map the fine-scale frequency-tuning (1.5 mm isotropic resolution) of primary auditory areas A1 and R in six human participants. Then, in a selective attention experiment, participants heard low (250 Hz)- and high (4000 Hz)-frequency streams of tones presented at the same time (dual-stream) and were instructed to focus attention onto one stream versus the other, switching back and forth every 30 s. Attention to low-frequency tones enhanced neural responses within low-frequency-tuned voxels relative to high, and when attention switched the pattern quickly reversed. Thus, like a radio, human primary auditory cortex is able to tune into attended frequency channels and can switch channels on demand.

Development and validation of a clinical prediction rule for chest wall syndrome in primary care.

ABSTRACT: BACKGROUND: Chest wall syndrome (CWS), the main cause of chest pain in primary care practice, is most often an exclusion diagnosis. We developed and evaluated a clinical prediction rule for CWS. METHODS: Data from a multicenter clinical cohort of consecutive primary care patients with chest pain were used (59 general practitioners, 672 patients). A final diagnosis was determined after 12 months of follow-up. We used the literature and bivariate analyses to identify candidate predictors, and multivariate logistic regression was used to develop a clinical prediction rule for CWS. We used data from a German cohort (n = 1212) for external validation. RESULTS: From bivariate analyses, we identified six variables characterizing CWS: thoracic pain (neither retrosternal nor oppressive), stabbing, well localized pain, no history of coronary heart disease, absence of general practitioner's concern, and pain reproducible by palpation. This last variable accounted for 2 points in the clinical prediction rule, the others for 1 point each; the total score ranged from 0 to 7 points. The area under the receiver operating characteristic (ROC) curve was 0.80 (95% confidence interval 0.76-0.83) in the derivation cohort (specificity: 89%; sensitivity: 45%; cut-off set at 6 points). Among all patients presenting CWS (n = 284), 71% (n = 201) had a pain reproducible by palpation and 45% (n = 127) were correctly diagnosed. For a subset (n = 43) of these correctly classified CWS patients, 65 additional investigations (30 electrocardiograms, 16 thoracic radiographies, 10 laboratory tests, eight specialist referrals, one thoracic computed tomography) had been performed to achieve diagnosis. False positives (n = 41) included three patients with stable angina (1.8% of all positives). External validation revealed the ROC curve to be 0.76 (95% confidence interval 0.73-0.79) with a sensitivity of 22% and a specificity of 93%. CONCLUSIONS: This CWS score offers a useful complement to the usual CWS exclusion diagnosing process. Indeed, for the 127 patients presenting CWS and correctly classified by our clinical prediction rule, 65 additional tests and exams could have been avoided. However, the reproduction of chest pain by palpation, the most important characteristic to diagnose CWS, is not pathognomonic.

Nouveau programme de formation en médecine interne générale: implications pour les médecins de premier recours [The new postgraduate training program in general internal medicine: implications for the primary care physician].

The Swiss postgraduate training program in general internal medicine is now designed as a competency-based curriculum. In other words, by the end of their training, the residents should demonstrate a set of predefined competences. Many of those competences have to be learnt in outpatient settings. Thus, the primary care physicians have more than ever an important role to play in educating tomorrows doctors. A competency-based model of training requires a regular assessment of the residents. The mini-CEX (mini-Clinical Evaluation eXercise) is the assessment tool proposed by the Swiss institute for postgraduate and continuing education. The mini-CEX is based on the direct observation of the trainees performing a specific task, as well as on the ensuing feedback. This article aims at introducing our colleagues in charge of residents to the mini-CEX, which is a useful tool promoting the culture of feedback in medical education.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans.

Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) (5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS (Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training.

Comparisons of Preoperative Three-Dimensional Planning and Surgical Reconstruction in Primary Cementless Total Hip Arthroplasty

La planification scanographique (3D) a démontré son utilité pour une reconstruction anatomique plus précise de la hanche (longueur du fémur, centre de rotation, offset, antéversion et rétroversion). Des études ont montré que lors de la planification 2D 50% seulement correspondaient à l'implant définitif du fémur alors que dans une autre étude ce taux s'élevait à 94% pour une planification 3D. Les erreurs étaient liées à l'agrandissement des radiographies. L'erreur sur la taille de la tige est liée à l'estimation inadéquate de la morphologie osseuse ainsi qu'à la densité osseuse. L'erreur de l'antéversion, augmentée par l'inclinaison du bassin, a pu être éliminée par la planification 3D et l'offset restauré dans 98%. Cette étude est basée sur une nouvelle technique de planification scanographique en trois dimensions pour une meilleure précision de la reconstruction de la hanche. Le but de cette étude est de comparer l'anatomie post-opératoire à celle préopératoire en comparant les tailles d'implant prévu lors de la planification 3D à celle réellement utilisée lors de l'opération afin de déterminer l'exactitude de la restauration anatomique avec étude des différents paramètres (centre de rotation, densité osseuse, L'offset fémoral, rotations des implants, longueur du membre) à l'aide du Logiciel HIP-PLAN (Symbios) avec évaluation de la reproductibilité de notre planification 3D dans une série prospective de 50 patients subissant une prothèse totale de hanche non cimentée primaire par voie antérieure. La planification pré-opératoire a été comparée à un CTscan postopératoire par fusion d'images. CONCLUSION ET PRESPECTIVE Les résultats obtenus sont les suivants : La taille de l'implant a été prédit correctement dans 100% des tiges, 94% des cupules et 88% des têtes (longueur). La différence entre le prévu et la longueur de la jambe postopératoire était de 0,3+2,3 mm. Les valeurs de décalage global, antéversion fémorale, inclinaison et antéversion de la cupule étaient 1,4 mm ± 3,1, 0,6 ± 3,3 0 -0,4 0 ± 5 et 6,9 ° ± 11,4, respectivement. Cette planification permet de prévoir la taille de l'implant précis. Position de la tige et de l'inclinaison de la cupule sont exactement reproductible. La planification scanographique préopératoire 3D permet une évaluation précise de l'anatomie individuelle des patients subissant une prothèse totale de hanche. La prédiction de la taille de l'implant est fiable et la précision du positionnement de la tige est excellente. Toutefois, aucun avantage n'est observée en termes d'orientation de la cupule par rapport aux études impliquant une planification 2D ou la navigation. De plus amples recherches comparant les différentes techniques de planification pré-opératoire à la navigation sont nécessaire.

High constant incidence rates of second primary neoplasms

The incidence of contralateral breast cancer is high and constant with age, around five per 1000 women who had a primary breast cancer. For other neoplasms, the pattern of incidence of second primary neoplasms with age is less known, particularly as for only a few neoplasms the site of origin is not totally removed, and hence remains at risk of a second primary. Using the dataset from the Cancer Registry of the Swiss Canton of Vaud, we show that the incidence of second neoplasms is constant with age also after oral and pharyngeal, colorectal cancers, cutaneous malignant melanoma (CMM) and basal cell carcinoma. The incidence of first primary oral and pharyngeal cancer increased 20-fold between age 30-39 and 70-89 years, whereas the incidence of second neoplasms did not increase with age. Rates of second colorectal cancer remained relatively constant with age, between 2.5 per 1000 at age 40-59 years and 3.8 per 1000 at 70 years and above. Likewise, for CMM, the age-specific incidence rates of second primary CMM did not vary, ranging between 1 and 2.5 per 1000 in various subsequent age groups. The pattern of incidence for second basal cell carcinoma was similar, with no clear rise with age. These patterns are compatible with the occurrence of a single mutational event in a population of susceptible individuals. A possible implication of these observations is that a variable, but potentially large, proportion of cancers arise in very high-risk individuals and the incidence, on average, increases at a high constant level at a predetermined age.

SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant.

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.

High constant incidence of second primary colorectal cancer.

Patients who had a colorectal cancer have a 1.5- to 2-fold excess risk of a second colorectal cancer as compared to the general population, the excess being higher at younger age at diagnosis. To further investigate the risk and the age-relation of the incidence of second primary colorectal cancer, we considered 9,389 first colon and rectal cancers registered in the Vaud Cancer Registry, Switzerland, between 1974 and 2008, and followed-up to the end of 2008 for a total of 44,113 person-years. There were 136 second colorectal cancers versus 90.5 expected, corresponding to a standardized incidence ratio (SIR) of 1.5 (95% confidence interval, CI, 1.3-1.8). The SIRs were not heterogeneous between men and women, and in strata of calendar year at diagnosis, duration of follow-up, and subsite. However, the SIR was 7.5 (95% CI 4.2-12.4) for subjects diagnosed below age 50 and declined thereafter to reach 1.0 (95% CI 0.6-1.6) at age 80 or over. Consequently, the incidence of second primary colorectal cancer was stable, and exceedingly high, around 300-400/100,000 between age 30-39 and 70 or over. This age pattern is consistent with the existence of a single mutational event in a population of highly susceptible individuals.