Hôpital Saint-Julien

BACKGROUND: Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis. METHODS: We conducted a multicenter, randomized, noninferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment. RESULTS: The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval [CI], 2.0 to 7.2) and 9.6% after stenting (95% CI, 6.4 to 14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting. CONCLUSIONS: In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. (ClinicalTrials.gov number, NCT00190398 [ClinicalTrials.gov].).

BACKGROUND: There is no community standard for the treatment of glioblastoma in patients 70 years of age or older. We conducted a randomized trial that compared radiotherapy and supportive care with supportive care alone in such patients. METHODS: Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were randomly assigned to receive supportive care only or supportive care plus radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy). The primary end point was overall survival; secondary end points were progression-free survival, tolerance of radiotherapy, health-related quality of life, and cognition. RESULTS: We randomly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone. The trial was discontinued at the first interim analysis, which showed that with a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone. A final analysis was carried out for the 81 patients with glioblastoma (median age, 73 years; range, 70 to 85). At a median follow-up of 21 weeks, the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, as compared with 16.9 weeks for the 42 patients who received supportive care alone. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29 to 0.76; P=0.002). There were no severe adverse events related to radiotherapy. The results of quality-of-life and cognitive evaluations over time did not differ significantly between the treatment groups. CONCLUSIONS: Radiotherapy results in a modest improvement in survival, without reducing the quality of life or cognition, in elderly patients with glioblastoma. (ClinicalTrials.gov number, NCT00430911 [ClinicalTrials.gov].).

BACKGROUND: The course and prognosis of childhood-onset multiple sclerosis have not been well described. METHODS: We used data from 13 adult neurology departments affiliated with the European Database for Multiple Sclerosis (EDMUS) network to identify a cohort of 394 patients who had multiple sclerosis with an onset at 16 years of age or younger and a comparison group of 1775 patients who had multiple sclerosis with an onset after 16 years of age. We determined the initial clinical features, the dates of disease onset, and the occurrence of outcomes, including relapse, conversion to secondary progression, and irreversible disability as measured by scores of 4 (limited walking ability but ability to walk more than 500 m without aid or rest), 6 (ability to walk with unilateral support no more than 100 m without rest), and 7 (ability to walk no more than 10 m without rest while using a wall or furniture for support) on the Kurtzke Disability Status Scale (range, 0 to 10; higher scores indicate more severe disability). RESULTS: For patients with childhood-onset multiple sclerosis, the estimated median time from onset to secondary progression was 28 years, and the median age at conversion to secondary progression was 41 years. The median times from onset to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and 50.5 years. In comparison with patients with adult-onset disease, those with childhood-onset disease were more likely to be female than male (female:male ratio, 2.8 vs. 1.8), were more likely to have an exacerbating-remitting initial course (98% vs. 84%), took approximately 10 years longer to reach secondary progression and irreversible disability, and reached these landmarks at an age approximately 10 years younger (P<0.001 for all comparisons). CONCLUSIONS: Patients with childhood-onset multiple sclerosis take longer to reach states of irreversible disability but do so at a younger age than patients with adult-onset multiple sclerosis.

In an attempt to reduce the variability in the yields of human islets isolations and to identify donor factors that were potentially deleterious, we retrospectively reviewed 153 human islets isolations in our center over a 3-year period. Isolations were performed using controlled collagenase perfusion via the duct, automated dissociation, and Ficoll purification. Factors leading to successful isolations (recovery of >100,000 islet equivalents at a purity >50%) were analyzed retrospectively using univariate and multivariate analysis. Critical factors in the multiorgan cadaveric donors that were identified using univariate analysis included donor age (P<0.01), body mass index (BMI)(P<0.01), cause of death (P<0.01), and prolonged hypotensive episodes (systolic blood pressure <90 mmHg or mean arterial pressure <60 mmHg for > 15 min) requiring high vasopressors (>15 microgram/kg/min dopamine or >5 microgram/kg/min Levophed) (P>0.01). Independent analysis of 19 donor variables using multivariate logistic stepwise regression showed six factors were statistically significant. Odds ratio (OR) showed that donor age (OR 1.1, P<0.01), local procurement team (OR 10.9, P<0.01), and high BMI (OR 1.4, P<0.01) had a positive correlation with islet recovery. In contrast, hyperglycemia (all blood glucose >10 mmol/L) (OR 0.63, P<0.01), frequency and duration of cardiac arrest (OR 0.7, P<0.01), and increased duration of cold storage before islet isolation (OR 0.83, P<0.01) had negative correlation. Using these combinations of factors, the prediction of success was 85% accurate. By donor age, success was 13% for 2.5- to 18-year-old donors (n=23), 37% for 19- to 28-year-old donors (n=30), 65% for 29- to 50-year-old donors (n=70), and 83% for 51- to 65-year-old (n=29) donors. However, when vitro function was assessed by perifusion, the insulin secretory capabilities of islets isolated from the >50-year-old donor group was significantly reduced as compared with the 2.5- to 18-year-old group (P<0.02). Multiple regression analysis using postdigestion and postpurification islet recovery as outcome variables identified BMI, procurement team, pancreas weight, and collagenase digestion time factors tht can affect the recovery of human islets. Locally procured pancreases and donors with elevated minimum blood glucose levels were identified as factors that affect the insulin secretory capabilities of the isolated islets. This review of parameters suggests an improved approach to the prediction of successful islet isolation from human pancreases. Selection of suitable pancreases for processing may improve consistency in human islet isolation and thereby decrease costs.

Richard S, Campello C, Taillandier L, Parker F, Resche F (Hôpital Necker, Paris, CHU Hôpital Caremeau, Nîmes, CHU Hôpital Saint‐Julien, Nancy, CHU Hôpital de Bic tre, Le Kremlin‐Bic tre, Hôpital Laennec, Nantes, France). Haemangioblastoma of the central nervous system in von Hippel–Lindau disease (Minisymposium: MEN &amp; VHL). J Intern Med 1998; 243 : 547–53. Haemangioblastoma of the central nervous system (CNS) is the most characteristic lesion and the most common presenting manifestation of von Hippel–Lindau (VHL) disease and has a striking tendency to multiple occurrence. Its sites of predilection are the posterior fossa (cerebellum++), and the spinal cord. Haemangioblastoma may cause increased intracranial pressure and/or neurological deficits and remains the main cause of morbidity and mortality in VHL. Treatment of symptomatic haemangioblastoma remains neurosurgical and is often in emergency. Haemangioblastoma appears to be more commonly associated with VHL than previously reported and suggests that all patients with ‘sporadic’ haemangioblastoma should be investigated for evidence of VHL disease. From a fundamental point of view, haemangioblastoma is a benign neoplastic entity with a double, vascular and cellular differentiation. Mutational inactivation of both copies of the VHL gene plays a major role in the pathogenesis of haemangioblastoma. Over‐expression of vascular endothelial growth factor (VEGF) and VEGF‐receptors has been recently demonstrated in these tumours, raising the possibility of angioblastic origin, and is of very great interest in view of the direct implication of the VHL gene in negative regulation of VEGF.

Background and Purpose: The efficiency of prehospital care chain response and the adequacy of hospital resources are challenged amid the coronavirus disease 2019 (COVID-19) outbreak, with suspected consequences for patients with ischemic stroke eligible for mechanical thrombectomy (MT). Methods: We conducted a prospective national-level data collection of patients treated with MT, ranging 45 days across epidemic containment measures instatement, and of patients treated during the same calendar period in 2019. The primary end point was the variation of patients receiving MT during the epidemic period. Secondary end points included care delays between onset, imaging, and groin puncture. To analyze the primary end point, we used a Poisson regression model. We then analyzed the correlation between the number of MTs and the number of COVID-19 cases hospitalizations, using the Pearson correlation coefficient (compared with the null value). Results: A total of 1513 patients were included at 32 centers, in all French administrative regions. There was a 21% significant decrease (0.79; [95%CI, 0.76–0.82]; P &lt;0.001) in MT case volumes during the epidemic period, and a significant increase in delays between imaging and groin puncture, overall (mean 144.9±SD 86.8 minutes versus 126.2±70.9; P &lt;0.001 in 2019) and in transferred patients (mean 182.6±SD 82.0 minutes versus 153.25±67; P &lt;0.001). After the instatement of strict epidemic mitigation measures, there was a significant negative correlation between the number of hospitalizations for COVID and the number of MT cases ( R 2 −0.51; P =0.04). Patients treated during the COVID outbreak were less likely to receive intravenous thrombolysis and to have unwitnessed strokes (both P &lt;0.05). Conclusions: Our study showed a significant decrease in patients treated with MTs during the first stages of the COVID epidemic in France and alarming indicators of lengthened care delays. These findings prompt immediate consideration of local and regional stroke networks preparedness in the varying contexts of COVID-19 pandemic evolution.

Patients who had anterolateral and posterolateral approaches in total hip replacement surgery were compared clinically for limp, dislocation, hospital stay, and discharge disposition. The only statistical difference was that the posterior approach had a statistically higher dislocation rate. Although the number of patients with limp was higher in the anterolateral group, the difference was not statistically different.

PURPOSE: The relationship between seizure frequency and both health care costs and quality of life (QOL) was investigated in a retrospective, cross-sectional, multicenter study in France, Germany, and the United Kingdom. METHODS: Three hundred outpatients with stable partial epilepsy were approximately evenly distributed among five seizure-frequency groups, ranging from seizure-free in the last 3 months (group 1) to daily seizures (group 5). Economic data, obtained through patient interviews and record abstraction, comprised direct medical costs, direct nonmedical costs, and indirect costs for the preceding 3 months. Total societal costs in the three countries were pooled and converted to United States dollar equivalents. QOL was assessed through a self-administered questionnaire, the Functional Status Questionnaire (FSQ). RESULTS: Mean total costs increased from $780 in group 1 to $2,171 in group 5 (p = 0.0001), with significant increases in each cost category as seizure frequency increased. Greater seizure frequency also significantly (p = 0.0270) correlated with lower employment rates, which ranged from 57% in group 1 to 30% in group 5. QOL declined as seizure frequency increased. Particularly affected were basic and intermediate activities of daily living (ADL), mental health, social activity, and feeling about health. CONCLUSIONS: The study results show that higher seizure frequencies are associated with higher direct and indirect costs and with reduced QOL for patients with epilepsy.

BACKGROUND: Factors that could optimize the management of pediatric spinal cord astrocytoma remain unclear and controversial. METHODS: To determine the factors that influence the prognosis of pediatric patients with spinal cord astrocytomas, a series of 73 consecutive patients at 13 French treatment centers with histologically proven spinal cord astrocytomas was retrospectively reviewed. Hospital records, operative records, and results of radiologic investigations were available in all cases. Follow-up was achieved in 94% of cases. RESULTS: Seventy percent of the patients had low grade (1 or 2) tumors. Total or subtotal surgical resection was achieved in 43%. Thirty-six patients were irradiated following surgery. Fifty-one patients were alive at a median follow-up of 54 months. Twenty-three patients relapsed. Univariate analysis showed that good outcome was correlated with male gender, age younger than 7 years, duration of presenting symptoms longer than 2 months, the presence of spinal deformities, and low grade histology, whereas sensory loss was associated with decreased survival. Multivariate analysis using the Cox proportional hazards model confirmed that histology (relative risk [RR] = 7.69) and the interval between first symptoms and diagnosis (RR = 4.93) were significant independent prognostic factors. The extent of surgery or radiotherapy had no clear influence on survival. CONCLUSIONS: This review sheds light on the prognoses of pediatric patients with spinal cord astrocytomas and may help to determine therapeutic strategies based on patients' clinical, radiologic, and pathologic features.

Bacterial microcompartment (MCP) organelles are cytosolic, polyhedral structures consisting of a thin protein shell and a series of encapsulated, sequentially acting enzymes. To date, different microcompartments carrying out three distinct types of metabolic processes have been characterized experimentally in various bacteria. In the present work, we use comparative genomics to explore the existence of yet uncharacterized microcompartments encapsulating a broader set of metabolic pathways. A clustering approach was used to group together enzymes that show a strong tendency to be encoded in chromosomal proximity to each other while also being near genes for microcompartment shell proteins. The results uncover new types of putative microcompartments, including one that appears to encapsulate B(12) -independent, glycyl radical-based degradation of 1,2-propanediol, and another potentially involved in amino alcohol metabolism in mycobacteria. Preliminary experiments show that an unusual shell protein encoded within the glycyl radical-based microcompartment binds an iron-sulfur cluster, hinting at complex mechanisms in this uncharacterized system. In addition, an examination of the computed microcompartment clusters suggests the existence of specific functional variations within certain types of MCPs, including the alpha carboxysome and the glycyl radical-based microcompartment. The findings lead to a deeper understanding of bacterial microcompartments and the pathways they sequester.

BACKGROUND: It is unclear whether symptoms alone can identify patients with caustic ingestion who will benefit from esophagogastroduodenoscopy (EGD). The published data are contradictory. The purpose of the current study was to determine the relationship between initial symptoms and EGD findings in patients with caustic ingestion. METHODS: Chart review of all caustic ingestions who underwent EGD during a 4-year period (December 1993 through November 1997). RESULTS: Twenty-eight patients (15 girls; mean age, 2.7 years (range, 0.92-13.33) underwent EGD after caustic ingestion. Fourteen percent (4/28) of patients were asymptomatic, and findings on endoscopy were normal. Another 57% (16/28) had normal endoscopic findings, although all were symptomatic. Twenty-nine percent (8/28) of patients had esophageal injury on EGD, and all were symptomatic. Esophageal injury was graded as 1 (mucosal erythema), 2 (superficial burns; noncircumferential) or 3 (deep burns; circumferential). The injury was grade 1 in three of eight patients and grade 2 in two; all had one symptom each. Grade 3 injury was found in three of eight patients: two had two symptoms (drooling and vomiting, drooling and stridor), and one had one symptom (dysphagia). All patients with grade 3 injury subsequently underwent esophageal dilations. Follow-up information was secured for two of the three patients with grade 1 injury and both patients with grade 2 injury at 34.3 months (range, 24-50) after the ingestion, and all were asymptomatic. Of the 20 patients with absence of esophageal mucosal damage, follow-up data were available for 15 patients at 37.2 months (range, 7-63) after the event and all were well. CONCLUSIONS: All patients with clinically significant injury (grades 2 and 3) were symptomatic at initial assessment. No single symptom or combination of symptoms could identify all patients with esophageal injury. All asymptomatic patients had normal findings on endoscopic examinations. Esophagogastroduodenoscopy seems unnecessary in asymptomatic patients with alleged caustic ingestion. A larger, prospective study would be necessary to unequivocally answer this clinically important question.

Background and Purpose— Middle cerebral artery M2-segment occlusions represent an important subgroup of patients with acute stroke with large-vessel occlusion. The safety of mechanical thrombectomy, especially contact aspiration (CA), in such distal intracranial occlusions is still under debate. We compared reperfusion, adverse events, neurological recovery, and functional outcome of patients with isolated M2 occlusions according to the first-line strategy mechanical thrombectomy devices (CA versus stent retriever [SR]). Methods— This is a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). The primary outcome was successful reperfusion at the end of all endovascular procedures, defined as modified Thrombolysis in Cerebral Infarction (mTICI) scores 2b/3. Secondary outcomes were mTICI 2c/3 and mTICI 3, 90-day functional outcome, assessed with the modified Rankin Scale score. Safety outcomes included 90-day mortality and any symptomatic intracerebral hemorrhage. Results— Seventy-nine patients were included: 48 were allocated to the CA group and 31 to the SR group. There were no significant differences between CA and SR groups in reperfusion after all endovascular procedures regarding mTICI 2b/3 (89.6% versus 83.9%; P =0.36), mTICI 2c/3 (54.2% versus 54.8%; P =0.90), and mTICI 3 (35.4% versus 41.9%; P =0.36) rates. There were no significant differences between CA and SR groups in 90-day modified Rankin Scale ≤2 rate (54.4% versus 50.0%; P =0.84), 24-hour change in National Institutes of Health Stroke Scale (mean difference, −3.9; 95% confidence interval, −7.9 to 0.01), and Alberta Stroke Program Early Computed Tomography score (mean difference, 0.9; 95% confidence interval, −0.1 to 2.0) scores. Safety parameters were well balanced between the 2 groups except for a higher 90-day mortality rate in the CA group (19.6% versus 3.3%; P =0.078). Conclusions— First-line mechanical thrombectomy with CA compared with SR did not result in an increased successful revascularization rate in patients with acute stroke with isolated M2 occlusion.

Neutrophils acquire lysosomal granules and assembly systems for producing soluble mediators of inflammation during the process of maturation in the bone marrow. Subsequently, they emigrate from the circulation when they become attracted to joint spaces of rheumatoid arthritis patients by chemoattractants such as the complement split product, C5a, and leukotriene B4. Exposure to immune complexes, rheumatoid factor, and cytokines in the synovial fluid results in neutrophil activation with release of granule contents, toxic oxygen metabolites, and proinflammatory products of the arachidonic acid cascade. This process is analogous to a local Arthus reaction in which activation of the complement system is a central event. Some of the inflammatory materials released by this reaction contribute to the cartilage destruction seen in rheumatoid arthritis. Because others are chemoattractants themselves, they perpetuate intraarticular inflammation and permit the predominance of acute inflammatory cells in lesions maintained by chronic inflammation.

Mycophenolate mofetil (MMF) is a new immunosuppressant developed for the prevention and treatment of acute renal rejection after transplantation. Diarrhea is the most frequent side effect observed during treatment with MMF. Its pathogenic mechanisms remain unknown. We describe a case of severe diarrhea due to villous atrophy in a renal transplant recipient during treatment with MMF. The patient was free of symptoms before MMF. Villous atrophy disappeared a few months after MMF withdrawal.

Hip dislocation in children with cerebral palsy is caused by a combination of factors, including spastic muscle imbalance, persistent fetal femoral geometry, acetabular dysplasia, and flexion-adduction contracture. The incidence of dislocation correlates with the severity of the spasticity, and the prevalence is close to 50% in neurologically immature, spastic quadriplegic children. Successful hip reductions improve muscular balance, provide satisfactory reduction of the femoral head, and establish good pelvic coverage. In 31 occurrences of established hip dislocation in 24 patients, the most successful operations used a combined procedure consisting of soft-tissue release, open reduction, femoral varus derotation and shortening osteotomy, and pelvic osteotomy.

A system of surgical treatment of deformities of the ankle and foot in cerebral palsy is presented on the basis of experience with 420 children. The aim of surgery is prevention or correction of deformities. There are three types of deformity (fixed, dynamic, and mixed), each of which is treated differently. Surgery should be delayed as long as there is functional improvement. The most common indication for foot surgery is equinus deformity, which makes it difficult to keep the heel in the shoe. Tendo Achillis lengthening is satisfactory for fixed equinus, and transfer of the medial belly and the tendon of the gastrocnemius to the dorsum of the foot is appropriate for dynamic equinus. Hindfoot valgus in hypertonic cerebral palsy is treated by peroneus brevis elongation when moderate and in combination with subtalar arthrodesis when severe. Hindfoot valgus in hypotonic cerebral palsy is treated by subtalar arthrodesis only. Hindfoot varus is treated by tibialis posterior lengthening, usually in combination with (1) tendo Achillis lengthening, (2) a Steindler plantar release, or (3) valgus calcaneal osteotomy. Dynamic forefoot supination is treated by split-tibialis anterior tendon transfer or, when associated with dorsiflexion of the hallux, by extensor hallucis longus transfer.

The crack healing and strength behavior of an alumina‐silicon carbide (Al 2 O 3 ‐SiC) nanocomposite (Al 2 O 3 + 5 vol% 0.2 μm SiC particles) has been studied, as a function of the crack size and the annealing environment. Results show that annealing treatments can significantly increase the indentation strength. The annealing atmosphere has a profound influence on the extent of crack healing and the degree of strength recovery. Annealing in argon results in a strength increase of 50%, whereas annealing in air yields a three‐fold improvement in the indentation strength. Scanning electron microscopic observation has shown that healing of indentation cracks occurs in both environments, with the greater degree of healing occurring during annealing in air. Implications of the findings to the strengthening mechanism in Al 2 O 3 (SiC) nanocomposites will be discussed.

A retrospective++ review of core decompression of the femoral head for treatment of osteonecrosis was done. Cause of osteonecrosis, radiographic stage and progression, complications, and clinical results were evaluated. The study was based on 54 hips in 45 patients (98.2% followup rate). All patients reported pain preoperatively. Thirty-five hips (30 patients) were considered to have failed. Of these, 26 hips (23 patients) underwent total hip arthroplasty. The remaining 9 hips (7 patients) had little or no relief of pain and no improvement in function, but had not undergone total hip arthroplasty at last followup. The average time to failure was 11.1 months (2-34 months). Nineteen hips (16 patients) were considered successful. Fifteen hips (12 patients) were graded good to excellent and 4 hips (4 patients) were graded fair in terms of clinical results with an average followup of 47.5 months (12.4-95.7 months). The mean preoperative Hospital for Special Surgery hip score improved from 24.6 points (range, 18-38 points) to 34.2 points (range, 20-40 points). There were 2 intertrochanteric femur fractures in this group (5 and 6 weeks postoperatively). The overall success rate of core decompression in this series was 35.2% (19 of 54 hips, 45 patients). The results of core decompression in this study were poor in general and had an unpredictable effect on disease progression.

Summary: Clobazam was compared with placebo as an‐tiepileptic adjunct medication in 129 therapy‐resistant epileptic patients who were mainly suffering from complex partial seizures. The study was performed in five European countries according to a double‐blind crossover design lasting 7 months. Two treatment periods of 3 months (1 month adjustment and 2 months maintenance medication) were separated by one medication switch‐over month. The difference in seizure reduction between clobazam and placebo was significant (p &lt; 0.05). Nineteen percent of patients receiving clobazam became seizure‐free during the maintenance dose period. In contrast, freedom from seizures was not observed in any placebo patient. Electroencephalogram (EEG) signs, mood ratings, and global impressions also indicated therapeutic effects of clobazam in epilepsy. The most frequent adverse reactions to clobazam were drowsiness and dizziness. However, the sedative effects of clobazam seemed to be less pronounced in comparison with other benzodiazepines. The study gives evidence of the therapeutic value of clobazam as adjunct medication in therapy‐resistant partial seizures. The use of clobazam as monotherapy and long‐term treatment, as well as the particular seizure response pattern to clobazam, has to be further investigated. RÉSUMÉ Nous avons comparé le clobazam au placebo comme médicament antiépileptique ajouté au traitement de 129 patients présen‐tant une épilepsie rebelle, le plus souvent avec des crises par‐tielles complexes. l'étude a été menée dans 5 pays d'Europe selon un protocole de croisement en double aveugle sur une pé‐riode de 7 mois. Deux périodes de traitement de 3 mois (1 mois d'ajustement et 2 mois de maintien de la thérapeutique) étaient séparées par un mois de changement du traitement. Les crises ont été significativement réduites par le clobazam par rapport au placebo (p &lt; 0.05). 19% des patients traités par clobazam n'ont plus présenté de crise pendant la période de maintien du traitement. En revanche, nous n'avons pas observé d'arrêt des crises chez les patients sous placebo. l'EEG, les évaluations de l'hu‐meur et l'impression clinique générale sont aussi en faveur d'une action thérapeutique du clobazam dans l'épilepsie. Les effets secondaires les plus fréquents du clobazam furent la somnolence et les sensations vertigineuses. l'effet sédatif du clobazam semble pourtant inférieur à celui des autres benzodiazépines. Cette étude prouve l'intérêt thérapeutique du clobazam comme thérapeutique ajoutée dans le traitement des crises partielles re‐belles. l'utilisation du clobazam en monothérapie, en traitement chronique, et la sensibilityé particulifére au clobazam des dif‐férents types de crises mérite des travaux ultérieurs. RESUMEN El valor del clobazan como medicación complementaria anti‐epiléptica se ha comparado con placebo en 129 enfermos resis‐tentes a terapias previas que padecian epilepsía y fundamental‐mente ataques parciales complejos. El estudio se realizó en 5 países europeos siguiendo un diseño doble‐ciego cruzado que duro 7 meses. Los dos periodos de tratamiento de 3 meses (1 mes de ajuste y 2 meses con medicación) se separaron por un periodo de un mes de cambio de medicaciones. La diferencia de la reducción de ataques entre el clobazan y el placebo fue signi‐ficativa (p &lt; 0.05). El diecinueve por ciento de pacientes que recibían clobazan no presentaron ningún ataque durante el periodo en el que se mantuvo la d6sis. Por el contrario, no se ob‐ servó ningun paciente en placebo en el que se interrumpieran los ataques. Los signos del EEG, los resultados sobre el estado afectivo y la impresión clínica global también indicaron los efectos terapéuticos del clobazan en epilepsía. Las reacciónes adversas más frecuentes tras la administración de clobazan fueron somnolencia y mareos. Sin embargo en los efectos seda‐tivos del clobazan parecen ser menos intensos que otras benzo‐diazepinas. Este estudio proporciona evidencia en favor de la validez terapéutica del clobazan como medicación complemen‐taria en el tratamiento de los ataques parciales resistentes a otro tipo de medicaciones. La utilización del clobazan como mono‐terapia en un tratamiento a largo plazo y el partón de respuesta con respecto a ataques específicos del clobazan necesita una investigation complementaria. ZUSAMMENFASSUNG Bei 129 therapieresistenten epileptischen Patienten mit haupt‐sächlich komplexen PartialAnfällen wurde Clobazepam mit einem Plazebo verglichen als antiepileptische Zusatzmedikation. Die Studie wurde in 5 europäischen Ländern gemaß eines Dop‐pelblind‐Cross‐over‐Designs für 7 Monate durchgeführt. Zwei Behandlungsperioden von jeweils 3 Monaten (1 Monat Einstel‐lungs‐ und 2 Monate Dauermedikation) wurden durch 1 Monat Medikationswechsel getrennt. Der Unterschied der Anfallsre‐duktion war zwischen Clobazepam und Plazebo signifikant (p &lt; 0.05). 19% der Patienten mit Clobazepam wurden während der Dauermedikationsperiode anfallsfrei. Dagegen wurde Anfalls‐freiheit bei keinem Plazebopatienten beobachtet. EEG, Befind‐lichkeit und allgemeiner Eindruck sprach ebenfalls für einen therapeutischen Effekt von Clobazepam auf die Epilepsie, Häu‐figste Nebenreaktion von Clobazepam war Müdigkeit und Schwindel. Andererseits schien der sedative Effekt von Clobazepam weniger deutlich ausgeprägt verglichen mit anderen Benzodiazepinen. Die Studie zeigt, daß Clobazepam einen therapeutischen Wert als Zusatzmedikation bei therapieresistenten partial‐komplexen Anfällen besitzt. Der Einsatz von Clobazepam als Monotherapie und Langzeitmedikation sowie as Ansprechen auf besondere Anfallsmuster bedarf weiterer Unter‐suchungen.

ABSTRACT Climate is a crucial driver of the distributions and activity of multiple biotic and abiotic processes, and thus high‐quality and high–resolution climate data are often prerequisite in various environmental research. However, contemporary gridded climate products suffer critical problems mainly related to sub‐optimal pixel size and lack of local topography‐driven temperature heterogeneity. Here, by integrating meteorological station data, high‐quality terrain information and multivariate modelling, we aim to explicitly demonstrate this deficiency. Monthly average temperatures (1981–2010) from Finland, Sweden and Norway were modelled using generalized additive modelling under (1) a conventional (i.e. considering geographical location, elevation and water cover) and (2) a topoclimatic framework (i.e. also accounting for solar radiation and cold‐air pooling). The performance of the topoclimatic model was significantly higher than the conventional approach for most months, with bootstrapped mean R 2 for the topoclimatic model varying from 0.88 (January) to 0.95 (October). The estimated effect of solar radiation was evident during summer, while cold air pooling was identified to improve local temperature estimates in winter. The topoclimatic modelling exposed a substantial temperature heterogeneity within coarser landscape units (&gt;5 °C/1 km −2 in summer) thus unveiling a wide range of potential microclimatic conditions neglected by the conventional approach. Moreover, the topoclimatic model predictions revealed a pronounced asymmetry in average temperature conditions, causing isotherms during summer to differ several hundreds of metres in altitude between the equator and pole facing slopes. In contrast, cold‐air pooling in sheltered landscapes lowered the winter temperatures ca. 1.1 °C/100 m towards the local minimum altitude. Noteworthy, the analysis implies that conventional models produce biassed predictions of long‐term average temperature conditions, with errors likely to be high at sites associated with complex topography.