[Interdisciplinary rehabilitation of a patient with associated Bickerstaff brainstem encephalitis and Guillain-Barré syndrome]. / Prise en charge interdisciplinaire en réadaptation d'une encéphalite du tronc cérébral de Bickerstaff associée à un syndrome de Guillain-Barré.

Bickerstaff brainstem encephalitis, Miller-Fisher syndrome and Guillain-Barré syndrome are related conditions and are now considered as part of a continuous clinical spectrum. In this report, we describe the case of a 24-year-old female patient showing paraparesis rapidly evolving into flaccid tetraparesis, areflexia, ophthalmoplegia, drowsiness, cognitive impairment and memory loss leading to the diagnosis of Bickerstaff brainstem encephalitis and Guillain-Barré syndrome overlap. With this example, we emphasize the importance of interdisciplinary rehabilitation care. Indeed such a combination of peripheral and central neurological deficits requests a multimodal approach. We show that early care benefits the autonomy and the quality of life of such patients.

L'encéphalite du tronc cérébral de Bickerstaff, le syndrome de Miller-Fisher et le syndrome de Guillain-Barré sont des pathologies apparentées qui font désormais partie d'un spectre clinique continu. Nous décrivons le cas d'une patiente âgée de 24 ans présentant une paraparésie évoluant rapidement en tétraparésie flasque, une aréflexie, une ophtalmoplégie, de la somnolence, un fléchissement cognitif et des troubles mnésiques, faisant évoquer un chevauchement entre l'encéphalite du tronc cérébral de Bickerstaff et le syndrome de Guillain-Barré. Par cet exemple clinique, nous insistons sur l'importance d'une prise en charge interdisciplinaire en réadaptation. En effet, une approche multimodale est nécessaire pour aborder cette combinaison de symptômes neurologiques périphériques et centraux. Nous montrons l'intérêt que peut avoir une prise en charge précoce sur l'autonomie et la qualité de vie de tels patients.

Gender issues in cardiovascular diseases. Focus on energy metabolism.

It is increasingly recognized that sex and gender differences (S&G) influence cardiovascular diseases (CVD), greatly impacting disease management. In terms of definition, sex refers to biological aspects, gender effects being mainly related to socio-cultural factors. Both sex and gender are interpenetrated in humans and difficult to separate. This is more clearly feasible in animal models where sex effects largely predominate. As alterations in energy metabolism are essential features of cardiovascular diseases, sexual dimorphism of energy metabolism and more specifically mitochondria occupies a place of choice. This review presents the basis of sex and gender differences in the cardiovascular pathophysiology, and how it mainly affects woman diseases, effectiveness of therapies and clinical outcome. These differences rely on complex molecular mechanisms that are still poorly understood because of the under-representation of females/women in experimental and clinical studies. Finally, the differing psychological and biological phases of woman's life are largely underestimated. This review presents an overview of the field with focus on differences in cardiac energy metabolism, which are illustrated with specific examples.

On the use of positron counting for radio-Assay in nuclear pharmaceutical production.

Current techniques for the measurement of radioactivity at various points during PET radiopharmaceutical production and R&D are based on the detection of the annihilation gamma rays from the radionuclide in the labelled compound. The detection systems to measure these gamma rays are usually variations of NaI or CsF scintillation based systems requiring costly and heavy lead shielding to reduce background noise. These detectors inherently suffer from low detection efficiency, high background noise and very poor linearity. They are also unable to provide any reasonably useful position information. A novel positron counting technique is proposed for the radioactivity assay during radiopharmaceutical manufacturing that overcomes these limitations. Detection of positrons instead of gammas offers an unprecedented level of position resolution of the radiation source (down to sub-mm) thanks to the nature of the positron interaction with matter. Counting capability instead of charge integration in the detector brings the sensitivity down to the statistical limits at the same time as offering very high dynamic range and linearity from zero to any arbitrarily high activity. This paper reports on a quantitative comparison between conventional detector systems and the proposed positron counting detector.

Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients.

BACKGROUND: The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. OBJECTIVES: In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. STUDY DESIGN: We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. RESULTS: We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e(-5), thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). CONCLUSIONS: We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis.

Automated production at the curie level of no-carrier-added 6-[(18)F]fluoro-L-dopa and 2-[(18)F]fluoro-L-tyrosine on a FASTlab synthesizer.

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and 2-[(18)F]fluoro-L-tyrosine ([(18)F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18)F]FDOPA and [(18)F]FTYR were produced in 36.3 ± 3.0% (n = 8) and 50.5 ± 2.7% (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95%, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [(18)F]FDOPA and [(18)F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.

Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

Hybrid microPET imaging for dosimetric applications in mice: improvement of activity quantification in dynamic microPET imaging for accelerated dosimetry applied to 6-[18 F]fluoro-L-DOPA and 2-[18 F]fluoro-L-tyrosine.

PURPOSE: Dynamic microPET imaging has advantages over traditional organ harvesting, but is prone to quantification errors in small volumes. Hybrid imaging, where microPET activities are cross-calibrated using post scan harvested organs, can improve quantification. Organ harvesting, dynamic imaging and hybrid imaging were applied to determine the human and mouse radiation dosimetry of 6-[18 F]fluoro-L-DOPA and 2-[18 F]fluoro-L-tyrosine and compared. PROCEDURES: Two-hour dynamic microPET imaging was performed with both tracers in four separate mice for 18 F-FDOPA and three mice for 18 F-FTYR. Organ harvesting was performed at 2, 5, 10, 30, 60 and 120 min post tracer injection with n = 5 at each time point for 18 F-FDOPA and n = 3 at each time point for 18 F-FTYR. Human radiation dosimetry projected from animal data was calculated for the three different approaches for each tracer using OLINDA/EXM. S-factors for the MOBY phantom were used to calculate the animal dosimetry. RESULTS: Correlations between dose estimates based on organ harvesting and imaging was improved from r = 0.997 to r = 0.999 for 18 F-FDOPA and from r = 0.985 to r = 0.996 (p < 0.0001 for all) for 18 F-FTYR by using hybrid imaging. CONCLUSION: Hybrid imaging yields comparable results to traditional organ harvesting while partially overcoming the limitations of pure imaging. It is an advantageous technique in terms of number of animals needed and labour involved.

Relevance of the measure of perceived exertion for the rehabilitation of obese patients.

The most common tool used for measuring effort perception is the rating scale of perceived exertion (RPE) developed by Borg. This scale is also used for various outcomes in the general population. The validity and reliability of this scale have already been reported in obese patients. However, the relevance of measuring perceived exertion in obese patients is still poorly known. This review of the literature presents the Borg RPE scale (i.e., validity, reliability and recommendations) and its main advantages during graded exercise tests (e.g., comparison of physical capacity, predicting physiological variables, verifying exhaustion and exercise safety) and rehabilitation programs (e.g., individualized exercise intensity, evaluation of the impact of a rehabilitation program and even determining the perceptual preference) in obese patients. This review of the literature underlines the relevance and usefulness of the Borg RPE scale, which is still underused in obese patients. However, additional studies are still necessary before using this scale routinely in all obese patients (regardless of the severity of their obesity or associated complications).

Re-irradiation combined with capecitabine in locally recurrent squamous cell carcinoma of the head and neck. A prospective phase II trial.

BACKGROUND: We performed a prospective phase II trial to investigate the safety and efficacy of radiotherapy combined with capecitabine in patients suffering from a recurrence of a squamous cell carcinoma of the head and neck (SCCHN) within a previously irradiated field. PATIENTS AND METHODS: A total of 31 evaluable patients with recurrent SCCHN received re-irradiation with a total dose of 50 Gy (25 fractions over 5 weeks) up to a maximum of 60 Gy combined with 900 mg/m(2)/day capecitabine given on the days of radiotherapy. RESULTS: The median time to relapse after the first course of radiotherapy was 15 months. The overall response rate in our study was 68% including 6 patients with a complete response. The median overall survival was 8.4 months. Grade 3 or 4 mucositis occurred in 4 patients and 1 patient, respectively. No grade 4 hematological toxicities were observed; 1 patient had grade 3 anemia. The cumulative median lifetime dose was 116 Gy. CONCLUSION: Capecitabine combined with re-irradiation is a well-tolerated treatment in patients with recurrent SCCHN. In light of its good tolerability, it appears to be a potential option for patients with a reduced performance status and may also serve as a basis for novel treatment concepts, such as in combination with targeted therapies.

Widespread introgression does not leak into allotopy in a broad sympatric zone.

Species that overlap over a large part of their range and habitat requirements are challenging for the study of speciation and hybridization. In this respect, the study of broadscale introgressive hybridization has raised recent interest. Here we studied hybridization between two closely related amphibians Lissotriton helveticus and Lissotriton vulgaris that reproduce over a wide sympatric zone. We used mitochondrial and microsatellite markers on 1272 individuals in 37 sites over Europe to detect hybrids at the individual-level and to analyse Hardy-Weinberg and linkage disequilibria at the population-level. Morphological traits showed a strong bimodal distribution. Consistently, hybrid frequency was low (1.7%). We found asymmetric introgression with five times more hybrids in L. vulgaris than in L. helveticus, a pattern probably explained by an unequal effective population size in a study part wherein L. helveticus numerically predominates. Strikingly, significant levels of introgression were detected in 73% of sites shared by both species. Our study showed that introgression is widespread but remains confined to the sites where the two species reproduce at the same time. This pattern may explain why these species remain genetically distinct over a broad sympatric zone.

[Effects of intermittent walk program on the body mass and composition in obese women]. / Effets d'un programme de marche intermittente sur la masse et la composition corporelles de femmes obèses.

UNLABELLED: The obese patients adhere weakly to rehabilitation programs; therefore the expected gains are often disappointing. This is possibly linked to the monotony of constant velocity exercises frequently proposed. Consequently, other less monotonous exercises such as the intermittent walk may be more appropriated. OBJECTIVES: The main objectives of this study were to determine if the obese women prefer a constant velocity walk or an intermittent walk, and to analyze the effects of a rehabilitation program based on the intermittent walk. MATERIALS AND METHODS: Twenty obese women were recruited. To determine the preferred walk modality, 10 obese women performed a constant velocity walk and an intermittent walk (with a similar duration and velocity) on a treadmill. The preferred walk modality was determined by lower ratings of perceived exertion. Then, these same 10 women participated in a rehabilitation program of 10 weeks (three days per week) consisting of intermittent walks. The 10 other women did not participate in a training program. RESULTS: The ratings of perceived exertion were not significantly different between the two walk modalities. However, the women who participated in a training program increased their maximal distance during a 6 min walking test and they have stabilized theirs anthropometric data. Meanwhile, the untrained women have increased their body mass, body mass index and percentage of body fat. CONCLUSION: The obese patients preferred similarly the constant velocity walk and the intermittent walk, and a rehabilitation program based on an intermittent walk is effective in avoiding the obesity aggravation.

Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis.

The accumulation of Ca2+ in the mitochondrial matrix can stimulate oxidative phosphorylation, but can also, at high Ca2+ concentrations, transmit and amplify an apoptotic signal. Here, we characterized the capacity of physiological stimuli (for example, histamine and inositol-1,4,5-triphosphate) and inducers of endoplasmic reticulum (ER) stress (for example, A23187, thapsigargin and tunicamycin) to release Ca2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines. Sustained Ca2+ accumulation in the mitochondrial matrix induced by ER stress triggered signs of proapoptotic mitochondrial alteration, namely permeability transition, dissipation of the electrochemical potential, matrix swelling, relocalization of Bax to mitochondria and the release of cytochrome c and apoptosis-inducing factor from mitochondria. In contrast, rapid and transient accumulation of Ca2+ induced by physiological stimuli failed to promote mitochondrial permeability transition and to affect cell viability. The specificity of this apoptosis pathway was validated in cells using a panel of pharmacological agents that chelate Ca2+ (BAPTA-AM) or inhibit inositol-1,4,5-trisphosphate receptor (IP(3)R; 2-aminoethoxydiphenyl borate), voltage-dependent anion channel (VDAC) (4,4'-diisothiocyanatostilbene-2,2'-disulfonate, NADH), the permeability transition pore (cyclosporin A and bongkrekic acid), caspases (z-VAD-fmk) and protein synthesis (cycloheximide). Finally, we designed an original cell-free system in which we confronted purified mitochondria and ER vesicles, and identified IP(3)R, VDAC and the permeability transition pore as key proteins in the ER-triggered proapoptotic mitochondrial membrane permeabilization process.

In-stream and overland dispersal across a river network influences gene flow in a freshwater insect, Calopteryx splendens.

Gene flow in riverine species is constrained by the dendritic (branching) structure of the river network. Spatial genetic structure (SGS) of freshwater insects is particularly influenced by catchment characteristics and land use in the surroundings of the river. Gene flow also depends on the life cycle of organisms. Aquatic larvae mainly drift downstream whereas flying adults can disperse actively overland and along watercourses. In-stream movements can generate isolation by distance (IBD) at a local scale and differentiation between subcatchments. However, these patterns can be disrupted by overland dispersal. We studied SGS across the Loire River in the damselfly Calopteryx splendens which is able to disperse along and between watercourses. Our sampling design allowed us to test for overland dispersal effects on genetic differentiation between watercourses. Amplified fragment length polymorphism markers revealed high genetic differentiation at the catchment scale but the genetic structure did not reflect the geographical structure of sampling sites. We observed IBD patterns when considering the distance following the watercourse but also the Euclidean distance, i.e. the shortest distance, between pairs of sites. Altogether, our results support the hypothesis of overland dispersal between watercourses. From a conservation perspective, attention should be paid to the actual pathways of gene flow across complex landscapes such as river networks.

Inferring gene flow in coral reef fishes from different molecular markers: which loci to trust?

Contrasting results are usually reported in the literature regarding the factors influencing observed structuring of genetic variability. The goals of this study were, for five coral reef fishes in French Polynesia, (1) to infer the theoretical variance of single locus F(ST) estimates expected under neutrality in order to exclude outlier loci before inferring gene flow and (2) to test thereafter whether species laying pelagic eggs effectively disperse more than species laying benthic eggs in this system. For this purpose, a total of 952 individuals from five species belonging to two families (Chaetodontidae and Pomacentridae) were screened among populations sampled within a 60-600 km spatial range for intron length polymorphism at 11 loci in order to illuminate contrasting results previously published on allozymes and mitochondrial DNA (mtDNA) control region polymorphisms. Statistically speaking, among the five species, four loci (three allozymes and one intron) were identified as outliers and discarded before interpretation of genetic differentiation in terms of effective dispersal. Biologically speaking, our results suggest that the observed genetic structure is not significantly related to the reproductive strategy of coral reef fish in the island system we analysed and that observed random genetic differentiation accommodates Wright's island model in all five species surveyed. Overall, our study emphasizes how cautious one has to be when trying to interpret present-day genetic structure in terms of gene flow while using a limited number of loci and/or different sets of loci.

Reproductive efficiency in grazing lactating dairy cows under a programmed reproductive management system.

OBJECTIVE: To evaluate the effectiveness of a reproductive management program consisting of combinations of Ovsynch/TAI and prostaglandin (PG) F(2alpha) treatments in Holstein dairy cows under a pasture-based dairying system. DESIGN: Field trial. PROCEDURE: A total of 1177 cows in 8 commercial dairy farms were randomly allocated to control and treatment groups. Treatment group cows received one of two interventions depending upon the number of days postpartum (DPP) before the planned start of breeding. Cows more than 50 DPP by the planned start of breeding received the Ovsynch/TAI treatment, consisting of gonadotrophin releasing hormone (GnRH) - PGF(2alpha)- GnRH plus timed artificial insemination. Cows between 40 and 50 DPP received a PGF(2alpha) treatment followed by oestrus detection and, if the cow was not seen in oestrus, the cow received a second PGF(2alpha) 14 days later. Control cows were submitted to twice a day heat detection followed by artificial insemination. The experimental period was the start of the breeding season plus 21 days for cows over 50 DPP at the start of breeding, and was 40-61 DPP for cows that calved later and passed their voluntary waiting period after the start of the breeding season. RESULTS: Submission rate was higher for the treated group than for the control group (84.9% vs. 55.1%; P < 0.0001), as was the conception rate (51.0% vs. 46.1%; P < 0.03). Due to farm variations, pregnancy rate was similar in both groups (38.5% vs. 28.2%; P > 0.1). Within the treated group, conception rate and pregnancy rate of the cows inseminated after a PGF(2alpha) were higher than for timed artificial inseminated cows (51.4% vs. 32.6%; P < 0.001), and (37.8% vs. 32.6%; P < 0.001). CONCLUSION: A programmed reproductive management protocol may improve reproductive efficiency in dairy farms with seasonal breeding, by increasing submission and conception rates at the beginning of the breeding season and/or at the end of the voluntary waiting period. Fertility of cows bred after a PGF(2alpha) synchronised heat was greater than after an Ovsynch/TAI protocol.

L-amino acid load to enhance PET differentiation between tumor and inflammation: an in vitro study on (18)F-FET uptake.

Labeled amino acids (AA) are tumor tracers for use in nuclear medecine. O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) is transported by the L-system, known to function as an exchanger. In vitro utilization of FET, after a preload or prior to an afterload of non radioactive L-amino acids, was evaluated in order to measure the potential effects of AA content on the distinction between tumor and inflammatory lesions. Cellular uptake of FET was studied on rat osteosarcoma cells (ROS 17/2.8) and human leukocytes, initially loaded with nonradioactive L-tyrosine or L-methionine. FET efflux was evaluated from cells loaded with nonradioactive L-phenylalanine after tracer uptake. ROS 17/2.8 showed a higher sensitivity to preload and afterload effects on cellular FET content as compared with the leukocytes. We conclude that preload with L-tyrosine, prior to the administration of FET, may be a potential procedure to improve PET differentiation between tumor and inflammatory lesions.

[Duodenocaval fistula: an unusual form of peptic ulcer revelation]. / Fistule duodénocave: mode de révélation inhabituel d'un ulcère duodénal.

The duodenocaval fistula is exceptional. We report the case of a 44-year-old patient with duodenocaval fistula. The patient had no history of peptic ulcer disease. The clinical feature was firstly a septic shock and then an haemorrhagic shock. Only laparotomy confirmed the diagnosis. The treatment was a surgical one with a rapid improvement. The prognosis depends on surgical experience and remains serious.

Maintenance of genetic differentiation across a transition zone in the sea: discordance between nuclear and cytoplasmic markers.

To investigate the origin and maintenance of the genetic discontinuity between Atlantic and Mediterranean populations of the common sea bass (Dicentrarchus labrax) we analysed the genetic variation at a fragment of mitochondrial cytochrome b sequence for 18 population samples. The result were also compared with new or previously published microsatellite data. Seven mitochondrial haplotypes and an average nucleotidic divergence of 0.02 between Atlantic and Mediterranean populations that matches a Pleistocene allopatric isolation were found. The frequency variation at the cytochrome b locus was many times greater between Atlantic and Mediterranean populations (theta(C) = 0.67) than at microsatellite loci (theta(N)= 0.02). The examination of the different evolutionary forces at play suggests that a sex-biased hybrid breakdown is a likely explanation for part of the observed discrepancy between mitochondrial and nuclear loci. In addition, an analysis is made of the correlation between microsatellite loci points towards the possible existence of a hybrid zone in samples from the Alboran Sea.