MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice.

Peroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: alpha, beta (or delta) and gamma. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPARalpha and PPARbeta in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild-type, PPARalpha-null mice and PPARbeta-null mice. T(2)-weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild-type and PPAR-null mice for both alpha and beta isotypes. These data validate high-resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPARalpha and PPARbeta in the brain.

Linkage disequilibrium between a melanin-based colour polymorphism and tail length in the barn owl

A linkage disequilibrium between sexually selected and life history traits can be explained by three mutually non-exclusive mechanisms. Genes coding for two traits may be located close on the same chromosome, genes responsible for variation in one of the trait may pleiotropically alter the other, and non-random pairing with respect to two traits may generate a non-physical linkage disequilibrium between their genes. Knowledge of which of these three mechanisms is responsible for a covariation between two traits is of interest to understand why differently ornamented individuals differ in several phenotypic aspects. In Switzerland, barn owls Tyto alba mate randomly with respect to a colour polymorphism generating a large range of variants between reddish-brown and white, males being lighter coloured than females. Several studies have shown that plumage coloration is not neutral with respect to some life history components. To test whether coloration is genetically associated with body size, partial cross-fostering experiments were performed by exchanging some hatchlings between nests. These experiments showed that darker biological fathers produce longer-tailed offspring. This sex-specific pattern is consistent with the hypothesis of non-physical linkage disequilibrium. In line with this hypothesis, darker coloured males were mated with longer-tailed females, whereas female coloration was not associated with tail length of their mate. The finding that dark nestlings had a longer tail than their pale siblings also supports the physical linkage and pleiotropy hypotheses. Therefore, non-random pairing can generate or strengthen a genetic covariation between a secondary sexual character and a morphological trait.

Endocytosis, autophagy and JNK inhibition in neuroprotection against excitotoxicity and neonatal cerebral ischemia

Abstract : Neonatal stroke occurs in 1 out of 4000 live births and usually leads to serious motor and cognitive disabilities. Ischemic brain injury results from a complex of pathophysiological events that evolve over space and time making it difficult to devise successful therapy. To date, there are no effective treatments for perinatal brain damage. Most clinical trials of neuroprotectaot drugs have failed because of their side-effects. For this reason it is important to find ways to target drugs specifically into the stressed cells. In this study we plan to contribute to the development of an efficient neuroprotective strategy against excitotoxic cell death in the neonate. In order to achieve this goal, several strategies were followed. A recently described phenomenon of induced endocytosis associated with excitotoxicity was more deeply investigated. As a simplified model we used dissociated cortical neurons exposed to an excitotoxic dose of NMDA, and we showed that this phenomenon depends on clathrin and dynamin. Using a model of neonatal focal cerebral ischemia, we demonstrated that the excitotoxicity-related endocytosis targets molecules such as TAT peptides into stressed neurons. These appear to be viable, raising the possibility of using this phenomenon as a doorway for neuroprotection. One part of the project was devoted to the study of the TAT-conjugated JNK inhibitory peptide, D-JNKI1. Adose-response study showed strong neuroprotection over a wide dose-range in the case of delayed administration (either intravenous or intraperitoneal). Since D-JNKI1 is aTAT-linked peptide, we investigated the role of its own NMDA-induced endocytosis in its neuroprotective efficacy. Furthermore, we showed that this endocytosis is JNK dependent, and that D-JNKI1 regulates its own uptake. We additionally studied the different types of cell death involved in a model of neonatal focal cerebral ischemia. Necrosis occurred rapidly in the center of the lesion whereas apoptosis and autophagic cell death occurred late at the lesion border. Inhibiting apoptosis was not protective, but use of autophagy inhibitor 3methyladenine provided a strong neuroprotection. Finally, combining two neuroprotectants that target different intracellular pathways was neuroprotective in a severe model of cerebral ischemia where neither of the drugs was efficient when administered individually. Résumé : L'ischémie néonatale connaît une incidence de 1 naissance sur 4000, entraînant généralement de sérieux dysfonctionnements moteurs et cognitifs. L'ischémie cérébrale résulte d'évènements physiopathologiques complexes qui évoluent dans l'espace et le temps rendant difficile la conception de thérapies efficaces. A l'heure actuelle, aucun traitement n'existe pour lutter contre les accidents vasculaires cérébraux qui se produisent autour de la naissance. La plupart des essais cliniques concernant des molécules neuroprotectrices ont échoué du fait de leurs effets secondaires néfastes. Pour cette raison, il est important de trouver des moyens de cibler les drogues dans les cellules stressées spécifiquement. Dans cette étude nous visons à participer au développement d'une stratégie neuroprotectrice efficace contre l'ischémie cérébrale chez le nouveau-né. Dans ce but, plusieurs stratégies ont été poursuivies. Un nouveau phénomène d'endocytose induite par un stimulus excitotoxique a été récemment décrit. Une partie de cette étude va consister à mieux comprendre ce phénomène. Pour céla, nous avons utilisé comme modèle d'étude simplifié des cultures dissociées de neurones corticaux exposées à une dose excitotoxique de NMDA. Nous avons ainsi montré que cette endocytose associée à l'excitotoxicité dépend de la clathrine et de la dynamine. A l'aide d'un modèle d'ischémie cérébrale focale chez le raton de 12 jours, nous avons démontré que cette endocytose induite par l'excitotoxicité permet de cibler des molécules diverses et en particulier les peptides TAT dans les neurones stressés. Ces neurones fortement endocytiques apparaissent comme étant encore viables, ouvrant la possibilité d'utiliser cette endocytose comme moyen d'entrée pour des molécules thérapeutiques. Une partie du projet a été consacrée à l'étude d'un inhibiteur de la voie JNK, couplé au TAT, appelé D-JNKI1. Des études de dose réponse du D-JNKI1 ont été réalisées chez l'animal, testant les effets d'une administration retardée en injection intraveineuse ou intra péritonéale. Ces études démontrent qu'une large gamme de dose permet d'obCenir une réduction de la taille de la lésion. Comme D-JNK11 est couplé au peptide TAT, nous avons étudié la contribution que sa propre endocytose lors de l'excitotoxicité apporte à ses effets protecteurs. Par ailleurs, nous avons montré que cette endocytose induite par l'excitotoxicité dépend de la voie de signalisation JNK et que D-JNK11 est donc capable de réguler sa propre entrée. Nous avons en parallèle étudié les différents types de mort cellulaires impliqués dans le développement de la lésion dans un modèle sévère d'ischémie cérébrale chez le raton nouveau-né. La mort cellulaire par nécrose se développe rapidement dans le centre de la lésion alors que les morts cellulaires par apoptose et autophagique vont apparaître plus tard et au bord de la lésion. Inhiber l'apoptose n'a pas permis de réduire la taille de la lésion alors que l'utilisation d'un inhibiteur d'autophagie, la 3-méthyladénine, procure une forte neuroprotection. Finalement, la combinaison de deux peptides qui ciblent différentes voies de signalisation intracellulaire permet d'obtenir une bonne protection dans le modèle d'ischémie sévère dans lequel aucun des deux peptides administré séparément n'a donné d'effets bénéfiques.

Premature epiphyseal closure in an adolescent treated by retinoids for acne: An unusual cause of anterior knee pain

Introduction.- Retinoids are effective and widely used for the treatment of severe acne. Their use can be, however, associated with numerous side effects. For example, some rare cases of premature epiphyseal closure were reported.Observation.- A sixteen-year-old soccer player consulted for bilateral progressive anterior knee pain, since two months, evoking a femoro-patellar origin. After physiotherapy, the pain decreases on the right but remained on the left. The history taking brought out the use of isotretinoin for more than 6 months (0.5 mg/kg). Magnetic resonance imaging (MRI) findings showed an irregularity of the growth plate and an important metaphyso-epiphyseal oedema, more marked on the left. The diagnosis of retinoid induced premature ephysieal closure was retained. The treatment was stopped, with a resolution of symptoms within two months. The control MRI of the left knee present persisting small sequelar thumbprint-like growth plate lesion. Eighteen months later, neither limb-length discrepancy nor static disorder was noticed.Discussion.- Premature epiphyseal closure is a rare complication of retinoid treatment of acne. Retinoids induce an invasion of the growth plate by osteoclasts and a decrease in proteoglycans synthesis. The knee seems the most involved joint. The clinical presentation is aspecific, sometimes lightly symptomatic. A careful pharmacological history and an appropriate imaging are necessary. MRI is now the gold standard. It shows an irregularity of the growth plate with an oedema on both sides. In chronic phase, a thumbprint-like image may persist. The symptoms resolution arises in few weeks after the treatment interruption. A single case of static disorder was reported until now. The small size of the growth plate interruptions, insufficient to lead to a growth disorder if the medicament is stopped early enough, explains probably it. This complication being rare, a radiological follow-up of the young patients treated by retinoids is not proposed.

Prise en charge des patients avec des problèmes d'alcool: quelle efficacité? Quelques éléments de réponse à partir d'une revue de la littérature [Management of patients with alcohol problems: how effective? Several response factors based on a review of the literature]

What do we know about the effectiveness of various treatments of alcoholism? This review of literature shows that lack--or weaknesses--of published studies make it impossible to draw definite conclusions. Rigorous controlled studies show high rates of spontaneous remission and important uncertainties about specialised treatments of alcoholism. However, except for severe dependence that may well require a different approach, brief interventions conducted by non-specialists have proved highly effective for at-risk alcohol drinkers: based on minimal medical advice, they increase the chances of lowering alcohol consumption. General practitioners may thus represent on important link in the therapeutic chain.

Population demography of an endangered lizard, the Blue Mountains Water Skink.

BACKGROUND: Information on the age structure within populations of an endangered species can facilitate effective management. The Blue Mountains Water Skink (Eulamprus leuraensis) is a viviparous scincid lizard that is restricted to < 40 isolated montane swamps in south-eastern Australia. We used skeletochronology of phalanges (corroborated by mark-recapture data) to estimate ages of 222 individuals from 13 populations. RESULTS: These lizards grow rapidly, from neonatal size (30 mm snout-vent length) to adult size (about 70 mm SVL) within two to three years. Fecundity is low (mean 2.9 offspring per litter) and is affected by maternal body length and age. Offspring quality may decline with maternal age, based upon captive-born neonates (older females gave birth to slower offspring). In contrast to its broadly sympatric (and abundant) congener E. tympanum, E. leuraensis is short-lived (maximum 6 years, vs 15 years for E. tympanum). Litter size and offspring size are similar in the two species, but female E. leuraensis reproduce annually whereas many E. tympanum produce litters biennially. Thus, a low survival rate (rather than delayed maturation or low annual fecundity) is the key reason why E. leuraensis is endangered. Our 13 populations exhibited similar growth rates and population age structures despite substantial variation in elevation, geographic location and swamp size. However, larger populations (based on a genetic estimate of effective population size) contained older lizards, and thus a wider variance in ages. CONCLUSION: Our study suggests that low adult survival rates, as well as specialisation on a rare and fragmented habitat type (montane swamps) contribute to the endangered status of the Blue Mountains Water Skink.

CT dose optimization when changing to CT multi-detector row technology

The purpose of this article was to review the strategies to control patient dose in adult and pediatric computed tomography (CT), taking into account the change of technology from single-detector row CT to multi-detector row CT. First the relationships between computed tomography dose index, dose length product, and effective dose in adult and pediatric CT are revised, along with the diagnostic reference level concept. Then the effect of image noise as a function of volume computed tomography dose index, reconstructed slice thickness, and the size of the patient are described. Finally, the potential of tube current modulation CT is discussed.

Cost-effectiveness analysis of a European primary-care physician training in smoking cessation counseling.

BACKGROUND: Physician training in smoking cessation counseling has been shown to be effective as a means to increase quit success. We assessed the cost-effectiveness ratio of a smoking cessation counseling training programme. Its effectiveness was previously demonstrated in a cluster randomized, control trial performed in two Swiss university outpatients clinics, in which residents were randomized to receive training in smoking interventions or a control educational intervention. DESIGN AND METHODS: We used a Markov simulation model for effectiveness analysis. This model incorporates the intervention efficacy, the natural quit rate, and the lifetime probability of relapse after 1-year abstinence. We used previously published results in addition to hospital service and outpatient clinic cost data. The time horizon was 1 year, and we opted for a third-party payer perspective. RESULTS: The incremental cost of the intervention amounted to US$2.58 per consultation by a smoker, translating into a cost per life-year saved of US$25.4 for men and 35.2 for women. One-way sensitivity analyses yielded a range of US$4.0-107.1 in men and US$9.7-148.6 in women. Variations in the quit rate of the control intervention, the length of training effectiveness, and the discount rate yielded moderately large effects on the outcome. Variations in the natural cessation rate, the lifetime probability of relapse, the cost of physician training, the counseling time, the cost per hour of physician time, and the cost of the booklets had little effect on the cost-effectiveness ratio. CONCLUSIONS: Training residents in smoking cessation counseling is a very cost-effective intervention and may be more efficient than currently accepted tobacco control interventions.

Nonspecific PCR amplification by high-fidelity polymerases: implications for next-generation sequencing of AFLP markers.

High-fidelity 'proofreading' polymerases are often used in library construction for next-generation sequencing projects, in an effort to minimize errors in the resulting sequence data. The increased template fidelity of these polymerases can come at the cost of reduced template specificity, and library preparation methods based on the AFLP technique may be particularly susceptible. Here, we compare AFLP profiles generated with standard Taq and two versions of a high-fidelity polymerase. We find that Taq produces fewer and brighter peaks than high-fidelity polymerase, suggesting that Taq performs better at selectively amplifying templates that exactly match the primer sequences. Because the higher accuracy of proofreading polymerases remains important for sequencing applications, we suggest that it may be more effective to use alternative library preparation methods.

Immediate hip spica is as effective as, but more efficient than, flexible intramedullary nailing for femoral shaft fractures in pre-school children.

Flexible intramedullary nailing (FIN) is the gold standard treatment for femur fracture in school-aged children. It has been performed successfully in younger children, although Spica cast immobilisation (SCI) has been the most widely used strategy to date. METHOD: A retrospective analysis was performed between two comparable groups of children aged 1-4 years with a femoral shaft fracture. Two University hospitals, each using specific treatment guidelines, participated in the study: SCI in Group I (Basel, Switzerland) and FIN in Group II (Lausanne, Switzerland). RESULTS: Group I included 19 children with a median age of 26 months (range 12-46 months). Median hospital stay was 1 day (range 0-5 days) and casts were retained for a median duration of 21 days (range 12-29 days). General anaesthesia was used in six children and sedation in four. Skin breakdown secondary to cast irritation occurred in two children (10.5%). The median follow-up was 114 months (range 37-171 months). No significant malunion was noted. Group II included 27 children with a median age of 38.4 months (range 18.7-46.7 months). Median hospital stay was 4 days (range 1-13 days). All children required general anaesthesia for insertion and removal of the nails. Free mobilisation and full weight bearing were allowed at a median of 2 days (range 1-10 days) and 7 days (range 1-30 days), respectively, postoperatively. Nail exteriorisation was noted in three children (11%). The median follow-up was 16.5 months (range 8-172 months). No significant malunion was reported. CONCLUSIONS: Young children with a femoral shaft fracture treated by SCI or FIN had similarly favourable outcomes and complication rates. FIN allowed earlier mobilisation and full weight bearing. Compared to SCI, a greater number of children required general anaesthesia. In a pre-school child with a femoral shaft fracture, immediate SCI applied by a paediatric orthopaedic team following specific guidelines allowed early discharge from hospital with few complications.