LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease.

Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n= 633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR) =0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.

Neuronal in vitro models for the estimation of acute systemic toxicity.

The objective of the EU funded integrated project "ACuteTox" is to develop a strategy in which general cytotoxicity, together with organ-specific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. With regard to the nervous system, the effects of 23 reference chemicals were tested with approximately 50 endpoints, using a neuronal cell line, primary neuronal cell cultures, brain slices and aggregated brain cell cultures. Comparison of the in vitro neurotoxicity data with general cytotoxicity data generated in a non-neuronal cell line and with in vivo data such as acute human lethal blood concentration, revealed that GABA(A) receptor function, acetylcholine esterase activity, cell membrane potential, glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints to use for further testing with 36 additional chemicals. The results of the second analysis showed that no single neuronal endpoint could give a perfect improvement in the in vitro-in vivo correlation, indicating that several specific endpoints need to be analysed and combined with biokinetic data to obtain the best correlation with in vivo acute toxicity.

Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study.

BACKGROUND Little is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the, diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment. METHODS We conducted a multicentre, cohort study in seven hospitals in Spain. Patients' characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients' structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR). RESULTS 470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4 % were physically active. Tumour size was classified as T1 in 41.0 % and as T2 in 40 % of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1 % had low risk cancer according to the D'Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29-2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45-4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026). CONCLUSIONS Most incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently.

The expression level of BAALC-associated microRNA miR-3151 is an independent prognostic factor in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P=0.0025), shorter leukemia-free survival (P=0.026) and higher cumulative incidence of relapse (P=0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P=0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML.

Photoactive sawhorse-type diruthenium tetracarbonyl complexes

Sawhorse-type diruthenium tetracarbonyl complexes incorporating carboxyphenyl porphyrin bridges and pyridine axial ligands have been prepared, characterized and evaluated as potential photosensitizing and chemotherapeutic agents in several human cancer cells (A2780, A549, Me300, HeLa). The mono carboxyphenyl porphyrin derivatives, 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin (HOOCR1-H2) and 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin-Zn (HOOCR1-Zn), after reaction with Ru-3(CO)(12) and pyridine, give the dinuclear complexes [Ru-2(CO)(4)(OOCR1-H2)(2)(NC5H5)(2)] (1) and [Ru-2(CO)(4)-(OOCR1-Zn)(2)(NC5H5)(2)] (2), respectively. Under the same reaction conditions, the di-carboxyphenyl porphyrin derivatives, 5,10-di(4-carboxyphenyl)-15,20-diphenyl-21,23H-porphyrin (HOOCR2-H2COOH) and 5,10-di(4-carboxyphenyl)-15,20-diphenylporphyrin-Zn (HOOCR2-ZnCOOH), give rise to the tetranuclear complexes, [{Ru-2(CO)(4)(NC5H5)(2)}(2)(OOCR2-H2COO)(2)] (3) and [{Ru-2(CO)(4)(NC5H5)(2! )}(2)(OOCR2-ZnCOO)(2)] (4), in which two sawhorse diruthenium tetracarbonyl units are linked by the di-carboxyphenyl porphyrin ligands. When tested in human cancer cell lines, both Zn(II) metallo-porphyrin derivatives 2 and 4 and the tetranuclear derivative 3 show some degree of cytotoxicity in the dark, but seem to present no phototoxicity upon irradiation at 652 nm. These results demonstrate the effect of the Zn(II) ion insertion into the porphyrin core, resulting in increased cytotoxicity and decreased phototoxicity. On the other hand, complex 1, the less cytotoxic derivative with IC50 > 170 mu M in HeLa cervix and A2780 ovarian cancer cell lines, shows an excellent phototoxicity toward these cancer cell lines with LD50 comprised between 4.5 and 7.5 J/cm(2) (irradiance 30 mW/cm(2)) at 5 mu M concentration (incubation time: 24 h). Overall, an excellent ratio between photo-and cytotoxicity has been found for the metal-free porphyrin derivative [Ru-2(CO)(4)(OOCR1-H2)(2)(! NC5H5)(2)] (1).

Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7+/-0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6+/-1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration-response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualizing imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.

Effects of amygdala-hippocampal stimulation on interictal epileptic discharges.

Deep brain stimulation (DBS) of different nuclei is being evaluated as a treatment for epilepsy. While encouraging results have been reported, the effects of changes in stimulation parameters have been poorly studied. Here the effects of changes of pulse waveform in high frequency DBS (130Hz) of the amygdala-hippocampal complex (AH) are presented. These effects were studied on interictal epileptic discharge rates (IEDRs). AH-DBS was implemented with biphasic versus pseudo monophasic charge balanced pulses, in two groups of patients: six with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) and six with non lesional (NLES) temporal epilepsy. In patients with HS, IEDRs were significantly reduced with AH-DBS applied with biphasic pulses in comparison with monophasic pulse. IEDRs were significantly reduced in only two patients with NLES independently to stimulus waveform. Comparison to long-term seizure outcome suggests that IEDRs could be used as a neurophysiological marker of chronic AH-DBS and they suggest that the waveform of the electrical stimuli can play a major role in DBS. We concluded that biphasic stimuli are more efficient than pseudo monophasic pulses in AH-DBS in patients with HS. In patients with NLES epilepsy, other parameters relevant for efficacy of DBS remain to be determined.

Genetic variation in LIN28B is associated with the timing of puberty.

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project)

Background and purpose: Individual rupture risk assessment of intracranial aneurysms is a major issue in the clinical management of asymptomatic aneurysms. Aneurysm rupture occurs when wall tension exceeds the strength limit of the wall tissue. At present, aneurysmal wall mechanics are poorly understood and thus, risk assessment involving mechanical properties is inexistent. Aneurysm computational hemodynamics studies make the assumption of rigid walls, an arguable simplification. We therefore aim to assess mechanical properties of ruptured and unruptured intracranial aneurysms in order to provide the foundation for future patient-specific aneurysmal risk assessment. This work also challenges some of the currently held hypotheses in computational flow hemodynamics research. Methods: A specific conservation protocol was applied to aneurysmal tissues following clipping and resection in order to preserve their mechanical properties. Sixteen intracranial aneurysms (11 female, 5 male) underwent mechanical uniaxial stress tests under physiological conditions, temperature, and saline isotonic solution. These represented 11 unruptured and 5 ruptured aneurysms. Stress/strain curves were then obtained for each sample, and a fitting algorithm was applied following a 3-parameter (C(10), C(01), C(11)) Mooney-Rivlin hyperelastic model. Each aneurysm was classified according to its biomechanical properties and (un)rupture status.Results: Tissue testing demonstrated three main tissue classes: Soft, Rigid, and Intermediate. All unruptured aneurysms presented a more Rigid tissue than ruptured or pre-ruptured aneurysms within each gender subgroup. Wall thickness was not correlated to aneurysmal status (ruptured/unruptured). An Intermediate subgroup of unruptured aneurysms with softer tissue characteristic was identified and correlated with multiple documented risk factors of rupture. Conclusion: There is a significant modification in biomechanical properties between ruptured aneurysm, presenting a soft tissue and unruptured aneurysms, presenting a rigid material. This finding strongly supports the idea that a biomechanical risk factor based assessment should be utilized in the to improve the therapeutic decision making.

Lésions iatrogènes des voies biliaires lors de la cholécystectomie laparoscopique

Objective: Laparoscopic cholecystectomy (LC) has become the gold standard in the treatment of symptomatic cholelithiasis. The aim of this study was to determine the frequency of occurrence and risk factors of iatrogenic bile duct injuries (IBDI) in the LC and study their treatment modalities. Methods: Between January 2000 and December 2011, a series of 13 patients (6 men, 7 women, mean age 66.7 years, mean BMI 27.9 kg/m2) underwent IBDI in our institution for 2'840 LC performed. These patients were identified retrospectively using a wide range of classification codes in our medical center for archiving. Their medical records were examined individually to identify a IBDI. Results: The frequency of IBDI was 0.46% (n=13). The most common indication for surgery was acute cholecystitis (69.2%). The main cause was the confusion of the common bile duct with the cystic duct in 38.5% of cases. Strasberg classification applied to our sample identified the following injuries: A (n=4), D (n=4), E1 (n=3) and E5 (n=2). They were diagnosed intraoperatively in 46.2% of cases and postoperatively in 53.8% of cases. The rate of type D lesions was significantly higher in the group with intraoperative recognition (p= 0.009), while the rate of type A lesions was significantly higher in the group with postoprative recognition (p = 0.026). Intraoperatively, 83.3% of the lesions were treated by primary suture with a biliary drainage and a hepatico-jejunal anastomosis was performed immediately in one case (16.7%). Postoperatively, 85.7% of the lesions were treated by non-surgical techniques in first- line and 4 of them have undergone biliary surgery later. The total number of therapeutic procedures for each IBDI after LC was significantly higher when the diagnosis was made postoperatively (3.4 vs. 1.5, p= 0.040). Conclusion: This study has identified a patient at risk of IBDI, this one is relatively old, overweight and has an inflammatory environment. Misidentification of biliary anatomy remains the main cause. There is a clear relationship between the timing of recognition and the type of injury involved. The primary suture with adequate drainage seems to be the method of choice for intraoperative discovery, while in case of postoperative recognition, the treatment must be adapted after a multidisciplinary consensus by combining interventional radiology, endoscopy and surgery.

Prevalência de lesões por fricção em pacientes hospitalizados com câncer

Esse estudo objetivou identificar a prevalência de lesões por fricção (LF) em pacientes hospitalizados com câncer e avaliar os fatores demográficos e clínicos associados ao seu desenvolvimento. Estudo epidemiológico, de corte transversal, realizado no Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira. Todos os pacientes adultos, internados entre 10 e 18 de abril de 2010, foram avaliados por meio de entrevista e exame físico. Utilizou-se o teste Qui-Quadrado para comparação das variáveis demográficas e clínicas entre pacientes com e sem LF. Foram avaliados 157 pacientes: cinco apresentaram nove LF, acarretando prevalência de 3,3%. Quanto às variáveis demográficas, houve diferença estatisticamente significativa somente para o número de filhos (p=0,027). Clinicamente, pacientes com LF apresentaram menores escores na escala de Karnofsky (p=0,031) e na Escala de Braden (p=0,026), além de comportamento pouco colaborativo (p=0,042). Esse estudo contribui para um melhor conhecimento acerca das LF em pacientes com câncer.

Alimentação da criança no pós-operatório imediato de palatoplastia: comparação entre as técnicas utilizando copo e colher

Estudo prospectivo realizado no Hospital de Reabilitação de Anomalias Craniofaciais, com o objetivo de analisar comparativamente a melhor técnica para alimentar a criança no pós-operatório imediato de palatoplastia: utilizando copo ou colher. Foram acompanhados 44 crianças e seus cuidadores durante a alimentação, em 4 horários consecutivos, gerando 176 avaliações, 88 utilizando copo e 88 a colher. Os testes Exato de Fisher e de Mann-Whitney foram usados para análise estatística, com nível de significância de 5% (p<0,05). O escape de alimento pela comissura labial foi menor (p=0,024; 17%), o volume administrado foi maior (p=0,029; 12%) e a tosse foi menos frequente (p=0,026; 13%) com a técnica que utiliza a colher. Conclui-se que a técnica de administração que utiliza colher para a alimentação pós-palatoplastia é melhor que a que utiliza o copo.

Couples contemporains - Cohésion, régulation et conflits. Une enquête sociologique

Comment peut-on caractériser les relations de couple aujourd'hui ? Sont-elles marquées par l'autonomie des conjoints ou au contraire par la valorisation du « nous-couple » ou du « nous-famille » ? Les couples se replient-ils sur eux-mêmes ou s'ouvrent-ils sur le monde qui les entoure ? Du point de vue des rôles et du pouvoir, l'égalité entre hommes et femmes est-elle désormais pratiquée ou au contraire les arrangements traditionnels perdurent-ils ?Ce livre montre que la situation est caractérisée par une grande diversité de styles d'interactions conjugales plutôt que par un modèle unique. Ces styles répondent à des logiques associées au statut social, à la position dans le parcours de vie et à la participation sociale des couples. De plus, ils génèrent des niveaux de problèmes et de satisfaction très differents.L'intérêt d'une analyse sociologique du fonctionnement des couples contemporains ne tient pas qu'à l'importance d'un groupe que l'on dit essentiel pour la construction de l'individu et pour l'intégration sociale, mais aussi à l'interrogation sociale et politique générée par les mutations familiales des trente dernières années.

Role of Chlamydia trachomatis in miscarriage.

To determine the role of Chlamydia trachomatis in miscarriage, we prospectively collected serum, cervicovaginal swab specimens, and placental samples from 386 women with and without miscarriage. Prevalence of immunoglobulin G against C. trachomatis was higher in the miscarriage group than in the control group (15.2% vs. 7.3%; p = 0.018). Association between C. trachomatis-positive serologic results and miscarriage remained significant after adjustment for age, origin, education, and number of sex partners (odds ratio 2.3, 95% confidence interval 1.1-4.9). C. trachomatis DNA was more frequently amplified from products of conception or placenta from women who had a miscarriage (4%) than from controls (0.7%; p = 0.026). Immunohistochemical analysis confirmed C. trachomatis in placenta from 5 of 7 patients with positive PCR results, whereas results of immunohistochemical analysis were negative in placenta samples from all 8 negative controls tested. Associations between miscarriage and serologic/molecular evidence of C. trachomatis infection support its role in miscarriage.