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The “living high–training low” model (LHTL), i.e., training in normoxia but sleeping/living in hypoxia, is designed to improve the athletes performance. However, LHTL efficacy still remains controversial and also little is known about the duration of its potential benefit. This study tested whether LHTL enhances aerobic performance in athletes, and if any positive effect may last for up to 2 weeks after LHTL intervention. Eighteen swimmers trained for 13 days at 1,200 m while sleeping/living at 1,200 m in ambient air (control, n=9) or in hypoxic rooms (LHTL, n=9, 5 days at simulated altitude of 2,500 m followed by 8 days at simulated altitude of 3,000 m, 16 h day−1). Measures were done before 1–2 days (POST-1) and 2 weeks after intervention (POST-15). Aerobic performance was assessed from two swimming trials, exploring $$ \ifmmode\expandafter\dot\else\expandafter\.\fi{V}{\text{O}}_{{2\max }} $$ and endurance performance (2,000-m time trial), respectively. Reticulocyte, serum EPO and soluble transferrin receptor responses were not altered by LHTL, whereas reticulocytes decreased in controls. In POST-1 (vs. before): red blood cell volume increased in LHTL only (+8.5%, P=0.03), $$ \ifmmode\expandafter\dot\else\expandafter\.\fi{V}{\text{O}}_{{2\max }} $$ tended to increase more in LHTL (+8.1%, P=0.09) than in controls (+2.5%, P=0.21) without any difference between groups (P=0.42) and 2,000-m performance was unchanged with LHTL. In POST-15, both performance and hematological parameters were similar to initial levels. Our results indicate that LHTL may stimulate red cell production, without any concurrent amelioration of aerobic performance. The absence of any prolonged benefit after LHTL suggests that this LHTL model cannot be recommended for long-term purposes.

International audience; We conducted a prospective controlled study of the clinical and biological determinants of the mental status abnormalities in 139 patients with Guillain-Barr?yndrome (GBS) and 55 patients without GBS placed in the intensive care unit (ICU controls). There were mental status changes in 31% of GBS patients and in 16% of controls (odds ratio = 2.3; P = 0.04). In GBS patients, they included vivid dreams (19%), illusions (30%, including an illusory body tilt), hallucinations (60%, mainly visual) and delusions (70%, mostly paranoid). They appeared a median 9 days after disease onset (range 1-40 days, during the progression or the plateau of the disease), and lasted a median 8 days. Seven (16%) patients experienced the symptoms before their admission to the ICU. Hallucinations were frequently hypnagogic, occurring as soon as the patients closed their eyes. Autonomic dysfunction, assisted ventilation and high CSF protein levels were significant risk factors for abnormal mental status in GBS patients. CSF hypocretin-1 (a hypothalamic neuropeptide deficient in narcolepsy) levels, measured in 20 patients, were lower in GBS patients with hallucinations (555 +/- 132 pg/ml) than in those without (664 +/- 71 pg/ml, P = 0.03). Since the mental status abnormalities had dream-like aspects, we examined their association with rapid eye movement sleep (REM sleep) using continuous sleep monitoring in 13 GBS patients with (n = 7) and without (n = 6) hallucinations and 6 tetraplegic ICU controls without hallucinations. Although sleep was short and fragmented in all groups, REM sleep latency was shorter in GBS patients with hallucinations (56 +/- 115 min) than in GBS patients without hallucinations (153 +/- 130 min) and in controls (207 +/- 179 min, P < 0.05). In addition, sleep structure was highly abnormal in hallucinators, with sleep onset in REM sleep periods (83%), abnormal eye movements during non-REM sleep (57%), high percentages of REM sleep without atonia (92 +/- 22%), REM sleep behaviour disorders and autonomic dysfunction (100%), reminiscent of a status dissociatus. The sleep abnormalities, that were almost absent in non-hallucinated GBS patients, were not exclusively related to ICU conditions, since they also appeared out of ICU, and were reversible, disappearing when the mental status abnormalities vanished while the patients were still in ICU. In conclusion, the mental status abnormalities experienced by GBS patients are different from the ICU delirium, are strongly associated with autonomic dysfunction, severe forms of the disease and possibly with a transitory hypocretin-1 transmission decrease. Sleep studies suggest that mental status abnormalities are wakeful dreams caused by a sleep and dream-associated disorder (status dissociatus).

The Hedgehog (Hh) gene family is known to regulate development of stem cells. In addition, activation is responsible for the induction of GLI1 proto-oncogene and subsequent cellular proliferation. Sonic Hedgehog (SHh), one of the Hh family members promotes carcinogenesis in airway and pancreatic epithelia, is expressed in colonic stem cells. As differentiated colonic cells arise from constant renewal of Hedgehog-expressing colonic stem cells, SHh could be involved in human colonic carcinogenesis.Tissue samples of colorectal adenocarcinoma (T) and adjacent normal colon tissue (NT) were sampled from each of 44 consecutive patients with colorectal cancer. Specific transcription of SHh, GLI1, and the GLI1 downstream target FOXM1 were evaluated using semiquantitative reverse transcriptase polymerase chain reaction. Similar in vitro measurements of mRNA of GLI1 and FOXM1 transcription levels after specific induction by SHh-Np were performed in the HT-29 colorectal tumor cell line to confirm the in vivo results.SHh mRNA was overexpressed in colorectal adenocarcinomas in 38 of 44 (86%) patients. Expression of transcription levels of GLI1 and FOXM1 correlated with SHh expression (SHh vs GLI1, r = 0.77, P.0001; GLI1 vs FOXM1, r = 0.68, P.0001; SHh vs FOXM1, r = 0.79, P.0001). SHh overexpression did not appear to correlate with the patient characteristics evaluated. Similarly, when studied in the HT-29 colorectal cell line, exogenous SHh promoted cell proliferation, while inhibition of SHh expression decreased proliferation. Expression of GLI1 and FOXM1 mRNA increased with exogenous exposure to SHh.We demonstrated increased expression of SHh mRNA in human colonic adenocarcinomas and in a colorectal cell line with downstream increased expression of GLI1 and FOXM1 mRNA known to promote cell proliferation. This upregulation within human colorectal adenocarcinoma tissue confirms the potential role of the Hh pathway in colorectal carcinogenesis and suggests a potential therapeutic target of Hh blockade in colorectal cancer.

Circulating cell detection using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques has been studied as a new prognostic factor in colorectal cancer patients. With the view of enhancing detection sensitivity, we developed a new multiplex RT-PCR assay for circulating cell detection based on the expression of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; formerly CEA) and CEACAM7 (formerly CGM2).Between November 2002 and December 2003, 45 stage III-IV, 39 stage I-II colorectal cancer patients, 32 non-colorectal cancer patients and 41 healthy individuals were included. Positive selection using HEA-125 immunobeads was applied to blood samples before mRNA extraction, cDNA synthesis and a multiplex CEACAM5/CEACAM7 RT-PCR assay. For both CEACAM5 and CEACAM7, the limit of detection was found to be as low as 1 expressing cell in 10The multiplex RT-PCR assay was negative for the 41 healthy individuals and the 32 non-colorectal cancer patients. The test was positive in 53/84 (63%) of the colorectal cancer patients for CEACAM5 and/or CEACAM7, whereas 32/84 (38%) were positive for both markers. Colorectal cancer patients were positive for one of the two markers in 80% of cases (36/45) for stage III-IV patients (CEACAM5 73%, CEACAM7 51%) and in 44% of cases (17/39) for stage I-II patients.This multiplex RT-PCR assay with two markers proved to be more sensitive than use of a single marker in detecting circulating tumour cells. The discrepant expression of CEACAM5 and CEACAM7 may label circulating tumour cells that have different levels of differentiation and subsequent aggressive behaviour.

Background Transthyretin (TTR) familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant neurodegenerative disease characterized by deposition of transthyretin targeting mainly the peripheral nervous system and the heart. Early noninvasive detection of cardiac impairment is of importance for the therapeutic management. Aim Assess if natriuretic peptide (NT-proBNP) or troponin T (cTnT) are reliable biomarkers to predict echocardiographic left ventricle (LV) impairment in a wide variety of TTR patients. Methods 36 asymptomatic carriers and patients with proven FAP genetic mutation had clinical, biological and echocardiography assessment of left ventricle (LV) systolic function (SD), filling pressure (FP) and hypertrophy (LVH) as marker of amyloid deposition Results In the all cohort, the median (IQR) age, NT-proBNP, LV ejection fraction were respectively 59 (41-74), 323pg/ml (58-1960) and 60% (51-66). 64% were men and 12 had an increased in cTnT. TTR gene mutations prevalence was 50% for Val30Met. 4 patients were asymptomatic, 6 had only neurologic clinical signs and 26 had echo-LV abnormalities with or without neurologic disorders. Their median NT-proBNP value were respectively: 33 (19-50), 54 (37-154) and 747 (253;2840). Using received-operator curve, NTproBNP identified significantly patients with echo-LV abnormalities (Area: 0.92;(0.83-0.99), p=0.001) with a threshold above 82pg/ml and a sensitivity of 92% and specificity of 90%. Elevated cTnT (superior to 0.01ng/ml) was only observed in patients combining impairment of LVH and SD or LVH, SD and FP. Conclusion In TTR amyloidosis, NTproBNP and troponin T are associated with LV impairment measured by echocardiography suggesting that NTproBNP could be useful in FAP carriers to start echocardiographic follow-up whereas troponin would identify patients with severe cardiac disease.

Recent technological advances, such as DNA chip devices that allow automated, high-throughput genotyping, promise to considerably improve the detection capability of single-nucleotide polymorphisms (SNPs) in clinically relevant genes. We used the NanoChip(R) Molecular Biology Workstation (Nanogen, www.nanogen.com) and recently introduced microelectronic array technology to develop a detection method for the more frequent mutations involved in familial Mediterranean fever (FMF), an autosomal recessive disease that affects several ethnic groups in the Mediterranean population, whose early diagnosis is crucial if severe complications are to be prevented. We adapted the previously described Nanogen procedures to FMF mutation analysis, introducing modifications that notably improve the technique. First, as the original procedure makes use of costly dye-tagged reporter sequences, we devised a universal reporter strategy, which was first evaluated and validated on the robust, previously established factor V Leiden and factor II (prothrombin) NanoChip diagnostic assays. FMF (MEFV), factor V (F5), and factor II (F2) genotypes identified using this improved system were totally concordant with results of other genotyping methods (denaturing gradient gel electrophoresis [DGGE], SSCP, and RFLP analysis). Second, we showed that the target sequences loaded on the NanoChip cartridges can be rehybridized several times in a highly reproducible manner, allowing sequential analysis of mutations. Thus, we devised a strategy that allows us to monitor the possible interference of additional mutations or SNPs at probe or stabilizer sequences. Finally, a comparative cost per sample analysis demonstrates that the accurate and reproducible FMF mutation detection assay we developed can be readily implemented in the clinical laboratory setting at reasonable expense.

Introduction Meme si dans les modeles experimentaux, les lesions renales d’ischemie-reperfusion (I/R) sont plus importantes chez les souris drepanocytaires comparativement aux souris controle, la survenue de lesions renales liees a des episodes d’I/R au cours des CVO n’a jamais ete demontree chez les patients. Nous avons cherche a determiner si les taux de NGAL urinaires et la micro-albuminurie etaient differents chez un meme patient entre un episode de CVO et l’etat basal. Patients et methodes Il s’agit d’une etude prospective monocentrique portant sur 25 patients adultes drepanocytaires homozygotes. Les donnees cliniques et biologiques incluant en plus des parametres habituels la mesure des taux de NGAL urinaire (ELISA) et l’evaluation du ratio albuminurie/creatininurie ont ete recueillis a l’inclusion (j0 d’une CVO) et a 1 mois apres l’episode aigu. Resultats Vingt-cinq patients (12 hommes, 13 femmes) d’un âge moyen de 34,6 ± 6 ans ont ete inclus. Les taux de CRP et de leucocytes etaient significativement plus eleves pendant la CVO comparativement a l’etat basal alors que l’hemoglobine etait plus basse pendant la crise. Aucun des patients n’a presente durant les 72 premieres heures d’insuffisance renale aigue (IRA) selon les criteres AKIN. A l’etat basal 15 (60 %) patients n’avaient pas d’albuminurie significative, 7 (28 %) et 3 (12 %) patients presentaient respectivement une micro ou macro-albuminurie. Nous n’avons pas observe de difference dans les taux d’albuminurie entre l’etat basal et l’episode de CVO. A l’inverse, les taux de NGAL urinaires etaient significativement plus eleves (76,7 ± 76,7 ng/mL) pendant la CVO comparativement a l’etat basal (28,7 ± 25,7 ng/mL) ( p = 0,007). Cette difference persistait apres normalisation a la creatininurie ( p = 0,004). Discussion et conclusion Nous demontrons pour la premiere fois que les CVO drepanocytaires sont associees a une souffrance tubulaire aigue sur la base de l’augmentation des taux de NGAL urinaires sans traduction clinique du fait de l’absence d’IRA chez ces patients.

Cystatin C (CST3), which belongs to the type II cystatin gene family, is a nonglycosylated 13-kDa protein constitutively secreted shortly after its synthesis (1). Because its low molecular mass and its positive charge at physiologic pH allow it to be freely filtered by kidney glomeruli and because CST3 normally is reabsorbed and then almost completely catabolized by proximal tubular cells (2), CST3 that was not metabolized is eliminated in urine and may represent a useful marker of tubular injury (3) or renal tubular dysfunction (4). The quantitative CST3 assay we developed is highly reliable and may be used as a part of the standard screening panel for renal failure. However, the use of 24-h urine samples is time-consuming and fails to offer clinically relevant data regarding tubular status in emergency cases. To evaluate whether a full 24-h collection is necessary, we analyzed, over a 24-h period, CST3 urinary release to see whether circadian variations were evident. We recruited 11 healthy individuals and collected urine samples every 2 h during a 24-h …

2115 [][1] Introduction VOC, the most common manifestation of SCD, is the first cause of death, particularly when complicated by an acute chest syndrome (ACS) or multiorgan failure.1,2 Vichinsky et al3 found that nearly half their patients included for ACS were initially hospitalized for VOC. However, no data are available on follow-up differences between patients hospitalized for uncomplicated VOC and those who will develop ACS. We report the preliminary analytical results of blood samples drawn on days 1, 2 and 4 of hospitalization for VOC and at steady state from patients enrolled in the more comprehensive PRESEV study. Methods This prospective, monocenter, observational trial included homozygous SCD patients, ≥18 years old with severe VOC requiring admission to our university hospital's Adult Sickle-Cell Referral Center. This study was conducted in accordance with the Declaration of Helsinki principles, Good Clinical Practice guidelines, and local laws and regulations. Severe VOC was defined as pain or tenderness, affecting at least 1 part of the body, e.g. limbs, ribs, sternum, head (skull), spine and/or pelvis, that required opioids and was not attributable to other causes. ACS was defined as the association of 2 criteria among chest pain, radiologic infiltrate and auscultatory abnormality. Patients could be enrolled in the trial more than once if their hospitalizations were separated by ≥1 months. Exclusion criteria were: ACS on day of inclusion, pregnancy, hospitalization for >24 h, chronic blood-exchange transfusion (BET), transfusion impossibility, severe complication requiring transfusion at admission, proven sepsis, surgery

Background Vaso-occlusive crisis (VOC), hallmark of sickle-cell disease (SCD), is the first cause of patients' Emergency-Room admissions and hospitalizations. Acute chest syndrome (ACS), a life-threatening complication, can occur during VOC, be fatal and prolong hospitalization. No predictive factor identifies VOC patients who will develop secondary ACS. Methods This prospective, monocenter, observational study on SS/S-β0thalassemia SCD adults aimed to identify parameters predicting ACS at Emergency-Department arrival. The primary endpoint was ACS onset within 15 days of admission. Secondary endpoints were hospitalization duration, morphine consumption, pain evaluation, blood transfusion(s) (BT(s)), requiring intensive care and mortality. Findings Among 250 VOCs included, 247 were analyzed. Forty-four (17.8%) ACSs occurred within 15 (median [IQR] 3 [2, 3]) days post-admission based on auscultation abnormalities; missing chest radiographs excluded three patients. Comparing ACS to VOC, respectively, median hospital stay was longer 9 [7–11] vs 4 [3–7] days (p, Highlights • Acute chest syndrome is a threatening complication. • Acute chest syndrome often occurs during a vaso occlusive crisis. • Our study provides a predictive score of acute chest syndrome.

Background Huntington's disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntington's disease (HD) and to determine the relationship with weight loss seen in HD Methods and Finding We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex- and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01–5.89) vs. 0.15 (0.005–4.89) ng/ml, p = 0.013 and 0.16±1.02 vs. 0.06±0.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.14±160.5 nmol/L vs. 279.8±130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (β = −0.26, p = 0.001). Conclusion Our data suggest that the thyrotropic and in men gonadotropic axes are altered in HD according to the severity of the disease. The somatotropic axis is overactive even in patients with early disease, and could be related to the weight loss seen in HD patients.