Online control of reaching and pointing to visual, auditory, and multimodal targets: Effects of target modality and method of determining correction latency.

Movements aimed towards objects occasionally have to be adjusted when the object moves. These online adjustments can be very rapid, occurring in as little as 100ms. More is known about the latency and neural basis of online control of movements to visual than to auditory target objects. We examined the latency of online corrections in reaching-to-point movements to visual and auditory targets that could change side and/or modality at movement onset. Visual or auditory targets were presented on the left or right sides, and participants were instructed to reach and point to them as quickly and as accurately as possible. On half of the trials, the targets changed side at movement onset, and participants had to correct their movements to point to the new target location as quickly as possible. Given different published approaches to measuring the latency for initiating movement corrections, we examined several different methods systematically. What we describe here as the optimal methods involved fitting a straight-line model to the velocity of the correction movement, rather than using a statistical criterion to determine correction onset. In the multimodal experiment, these model-fitting methods produced significantly lower latencies for correcting movements away from the auditory targets than away from the visual targets. Our results confirm that rapid online correction is possible for auditory targets, but further work is required to determine whether the underlying control system for reaching and pointing movements is the same for auditory and visual targets.

Pancreatic tumours escape from translational control through 4E-BP1 loss.

The mRNA cap-binding protein eIF4E (eukaryotic translation initiation factor 4E) permits ribosome recruitment to capped mRNAs, and its phosphorylated form has an important role in cell transformation. The oncogenic function of eIF4E is, however, antagonised by the hypophosphorylated forms of the inhibitory eIF4E-binding proteins 1 and 2. eIF4E-binding protein 1 and 2 (4E-BP1 and 2) are two major targets of the protein kinase mTOR, and are essential for the antiproliferative effects of mTOR inhibitors. Herein, we report that pancreas expresses specifically and massively 4E-BP1 (4E-BP2 is nearly undetectable). However, 4E-BP1 expression is extinguished in more than half of the human pancreatic ductal adenocarcinomas (PDAC). 4E-BP1 shutoff is recapitulated in a mouse genetic model of PDAC, which is based on a pancreas-specific mutation of Kras, the more frequently mutated oncogene in human pancreatic tumours. 4E-BP1 downregulation enhances eIF4E phosphorylation and facilitates pancreatic cancer cell proliferation in vitro and tumour development in vivo. Furthermore, 4E-BP1 loss combined with the absence of 4E-BP2 renders eIF4E phosphorylation, protein synthesis and cell proliferation resistant to mTOR inhibition. However, proliferation can be better limited by a recently developed compound that mimics the function of 4E-BP1 and 2 independently of mTOR inhibition.

Useful lower limits to polarization contributions to intermolecular interactions using a minimal basis of localized orthogonal orbitals: theory and analysis of the water dimer.

The problem of describing the energy-lowering associated with polarization of interacting molecules is considered in the overlapping regime for self-consistent field wavefunctions. The existing approach of solving for absolutely localized molecular orbital (ALMO) coefficients that are block-diagonal in the fragments is shown based on formal grounds and practical calculations to often overestimate the strength of polarization effects. A new approach using a minimal basis of polarized orthogonal local MOs (polMOs) is developed as an alternative. The polMO basis is minimal in the sense that one polarization function is provided for each unpolarized orbital that is occupied; such an approach is exact in second-order perturbation theory. Based on formal grounds and practical calculations, the polMO approach is shown to underestimate the strength of polarization effects. In contrast to the ALMO method, however, the polMO approach yields results that are very stable to improvements in the underlying AO basis expansion. Combining the ALMO and polMO approaches allows an estimate of the range of energy-lowering due to polarization. Extensive numerical calculations on the water dimer using a large range of basis sets with Hartree-Fock theory and a variety of different density functionals illustrate the key considerations. Results are also presented for the polarization-dominated Na(+)CH4 complex. Implications for energy decomposition analysis of intermolecular interactions are discussed.

Anti-oncogenic potential of the eIF4E-binding proteins.

The eIF4E-binding proteins (4E-BPs) are inhibitors of protein synthesis that sequester the mRNA cap-binding protein eIF4E and consequently block cell growth and proliferation. In most tumors however, their inhibitory function is compromised by major oncogenic signaling pathways. Recently, thanks to the generation of mouse genetic models, considerable progress has been made in elucidating the involvement of 4E-BPs and their unique target, eIF4E, in the process of carcinogenesis. Increasing evidence indicates that an 'addiction' to protein synthesis emerges in cancer cells, highlighting the potential that 4E-BPs have as targets for therapeutics. In this review, we summarize the biochemical function, regulation and anti-oncogenic activity of the 4E-BPs.

An energy decomposition analysis for intermolecular interactions from an absolutely localized molecular orbital reference at the coupled-cluster singles and doubles level.

We propose a wave function-based method for the decomposition of intermolecular interaction energies into chemically-intuitive components, isolating both mean-field- and explicit correlation-level contributions. We begin by solving the locally-projected self-consistent field for molecular interactions equations for a molecular complex, obtaining an intramolecularly polarized reference of self-consistently optimized, absolutely-localized molecular orbitals (ALMOs), determined with the constraint that each fragment MO be composed only of atomic basis functions belonging to its own fragment. As explicit inter-electronic correlation is integral to an accurate description of weak forces underlying intermolecular interaction potentials, namely, coordinated fluctuations in weakly interacting electronic densities, we add dynamical correlation to the ALMO polarized reference at the coupled-cluster singles and doubles level, accounting for explicit dispersion and charge-transfer effects, which map naturally onto the cluster operator. We demonstrate the stability of energy components with basis set extension, follow the hydrogen bond-breaking coordinate in the C(s)-symmetry water dimer, decompose the interaction energies of dispersion-bound rare gas dimers and other van der Waals complexes, and examine charge transfer-dominated donor-acceptor interactions in borane adducts. We compare our results with high-level calculations and experiment when possible.

Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome.

INTRODUCTION: Gitelman syndrome (GS) is a tubulopathy caused by SLC12A3 gene mutations, which lead to hypokalaemic alkalosis, secondary hyperaldosteronism, hypomagnesaemia and hypocalciuria. AIM: The aim of this study was to assess the prevalence of SLC12A3 gene mutations in adult hypokalaemic patients; to compare the phenotype of homozygous, heterozygous and non-mutated patients; and to determine the efficiency of treatment. METHODS: Clinical, biological and genetic data were recorded in 26 patients. RESULTS: Screening for the SLC12A3 gene detected two mutations in 15 patients (six homozygous and nine compound heterozygous), one mutation in six patients and no mutation in five patients. There was no statistical difference in clinical symptoms at diagnosis between the three groups. Systolic blood pressure tended to be lower in patients with two mutations (P=0.16). Hypertension was unexpectedly detected in four patients. Five patients with two mutated alleles and two with heterozygosity had severe manifestations of GS. Significant differences were observed between the three groups in blood potassium, chloride, magnesium, supine aldosterone, 24 h urine chloride and magnesium levels and in modification of the diet in renal disease. Mean blood potassium levels increased from 2.8 ± 0.3, 3.5 ± 0.5 and 3.2 ± 0.3 before treatment to 3.2 ± 0.5, 3.7 ± 0.6 and 3.7 ± 0.3 mmol/l with treatment in groups with two (P=0.003), one and no mutated alleles respectively. CONCLUSION: In adult patients referred for renal hypokalaemia, we confirmed the presence of mutations of the SLC12A3 gene in 80% of cases. GS was more severe in patients with two mutated alleles than in those with one or no mutated alleles. High blood pressure should not rule out the diagnosis, especially in older patients.

Chronic dialysis-associated anaemia in end-stage renal disease: analysis of management in two French centres.

BACKGROUND: Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients. METHODS: Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other. RESULTS: A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs. CONCLUSION: The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary.

[Heart rate variability alteration in patients on chronic hemodialysis]. / Altération de la variabilité sinusale chez les malades en hémodialyse chronique.

BACKGROUND AND AIM: Decrease in heart rate variability (HRV) is a known risk factor for cardiovascular morbidity and mortality. The aim of our study is to evaluate HRV in chronic hemodialysis patients and to determine factors that might decrease or increase it. METHODS: This is a retrospective study including 51 patients, 23 males and 28 females, with a mean of age of 64.5 years (23-84 years) on chronic hemodialysis for end stage renal disease due to various causes. Twenty-four-hour heart rate monitoring was recorded in all patients to evaluate HRV. HRV of hemodialysis patients was compared to normal patients (control). We also looked for correlation between HRV and a number of clinical and biological factors. RESULTS: All HRV parameters were decreased in chronic hemodialysis patients compared to normal controls with a significant difference (p<0.0005). HRV decreases with age (p=0.012), and is lower in diabetic patients (p=0.026). Interestingly, we found that chronic hemodialysis patients on beta-blockers had higher HRV with p=0.011. CONCLUSION: HRV is reduced in chronic hemodialysis patients mainly in old and diabetic patients, but this decrease is less important in those receiving beta-blockers.

The impact of endoscopic ultrasonography with fine needle aspiration (EUS-FNA) on esophageal cancer staging: a survey of thoracic surgeons and gastroenterologists.

SUMMARY: Accurate staging of esophageal cancer is critical to achieving optimal treatment outcomes. End-oscopic ultrasound with fine needle aspiration (EUS-FNA) has emerged as a valuable tool for locoregional staging. However, it is unclear how different physician specialties perceive the benefit of EUS-FNA for esophageal cancer staging, and thus utilize this modality in clinical practice. A survey regarding utilization of EUS-FNA in esophageal cancer was distributed to 211 thoracic surgeons and 251 EUS-capable gastroenterologists. Seventy-six thoracic surgeons (36%) and 78 gastroenterologists (31%) responded to the survey. Most surgeons (75%) use EUS to stage potentially resectable esophageal cancer 75% of the time. Surgeons using EUS less often are less likely to have access to high-quality EUS services than their peers. Fewer surgeons believe EUS is the most accurate test for T and N-staging (84% and 71%, respectively) as compared with gastroenterologists (97% and 96%, P < 0.01 for both). Most endosonographers (68%) decide whether to dilate a malignant esophageal stricture to complete the staging exam on a case-by-case basis. Surgeons disagree as to whether involvement of celiac lymph nodes should preclude esophagectomy in distal esophageal cancer. While most thoracic surgeons have embraced EUS-FNA as the most accurate locoregional staging modality in esophageal cancer, this attitude is not fully reflected in utilization patterns due to a lack of quality EUS services in some centers. Controversial areas that warrant further study include dilation of malignant strictures to facilitate EUS staging, and the implication of involved celiac lymph nodes on management.

Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1.

The suppressor of translation initiation 4E-BP1 functions as a key regulator in cellular growth, differentiation, apoptosis and survival. While the control of 4E-BP1 activity via phosphorylation has been widely studied, the molecular mechanisms and the signaling pathways that govern 4E-BP1 gene expression are largely unknown. Here we show that inactivation of phosphatidylinositol 3-kinase (PI3K) consequent to stable expression of the antiproliferative somatostatin receptor 2 (sst2) in pancreatic cancer cells leads to transcriptional accumulation of the hypophosphorylated forms of 4E-BP1 protein. In cancer cells, while 4E-BP1 gene promoter is maintained repressed in a PI3K-dependent mechanism, sst2-dependent inactivation of the PI3K/Akt pathway releases 4E-BP1 gene transcription. Furthermore, the use of a pharmacological inhibitor and dominant-negative or -positive mutants of PI3K all affect 4E-BP1 protein expression and promoter activity in different cell lines. These data show that, in addition to inactivation of 4E-BP1 via hyperphosphorylation, signaling through the PI3K pathway silences 4E-BP1 gene transcription.

Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response.

OBJECTIVE: To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA). METHODS: The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated in all subjects. RESULTS: The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged. CONCLUSION: Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.

[Heart rate variability and vasovagal syncope]. / Intérêt de la variabilité sinusale dans la syncope vasovagale.

OBJECTIVE: Tilt Table testing is widely used for the diagnosis and evaluation of vasovagal syncope. By evaluating the fluctuations of the autonomic nervous system that play an important role in syncope genesis, heart rate variability (HRV) can be considered as a tool of added value. METHODS: We evaluated prospectively 123 patients admitted for recurrent syncope with a positive tilt Table testing. A time domain analysis of a 24 hours ambulatory electrocardiography was used in all patients to asses the particularities of their autonomic function. We compared their results with those obtained from a group of 82 healthy volunteers. RESULTS: Statistical analysis of the results showed a significant increase of all HRV parameters in the group of vasovagal syncope compared to the healthy volunteers. SDNNidx (58 vs 42; p < 0.001), rMSSD (40 vs 27; p < 0.001), SDNN (102 vs 83; p < 0.001), SDANN (79 vs 67; p< 0.001), pNN50 (11 vs 4.9; p <0.001). CONCLUSION: Time domain analysis of heart rate variability reveals increased values in patients with vasovagal syncope. It seems to be an interesting, easy and complementary test in the evaluation of syncope of unknown etiology.

[Beneficial effect of sildenafil following surgery for mitral stenosis complicated by pre-capillary pulmonary hypertension: report of two cases]. / Effet bénéfique du sildénafil en postopératoire dans le rétrécissement mitral compliqué d'hypertension artérielle pulmonaire précapillaire: a propos de deux cas.

Pulmonary hypertension is a serious disorder, difficult to treat especially in the severe forms. The treatment consists mainly of calcium channel blockers, anti-coagulation, intravenous epoprostenol, inhaled nitric oxide and recent agents as bosentan and sildenafil. Sildenafil, a phosphodiesterase 5 specific inhibitor, has been largely evaluated in primary pulmonary hypertension, and in some cases of secondary pulmonary hypertension including parenchymal and thromboembolic diseases; it has not yet been evaluated in severe pulmonary hypertension with elevated pre-capillary resistance in operated mitral stenosis. We report the cases of two patients operated from mitral valve replacement for severe mitral stenosis with elevated pre-capillary resistance, where oral sildenafil, introduced empirically immediately after the surgical procedure at the dose of 50 mg/d, permitted a significant decrease in pulmonary pressures and resistances, allowing a rapid withdrawal of nitric oxide and reducing therefore hospitalization time in the intensive care unit. We think that this simple treatment, with or without association to nitric oxide, should be generalized to persistent pulmonary hypertension following cardiac surgery.

[Spontaneously acquired haemophilia: report of a patient with prostatic adenoma]. / Hémophilie A acquise secondaire à un adénome prostatique.

We report the case of a 86-year-old man admitted in a local hospital with spontaneous haematoma, an isolated prolonged activated partial prothrombin time (114/32 seconds; ratio = 3.6), an anemia and a normal platelet count. Two diagnosis were suspected: a coagulation factor defect, or the presence of a lupus anticoagulant or of anti-factor antibodies. An acquired haemophilia A was confirmed with a factor VIII activity level < 1 U/dL associated with the presence of an anti-factor VIII inhibitor. The factor VIII inhibitor titer reached 195 Bethesda U/mL. A prostatic adenocarcinoma was suspected: a 5 cm prostatic tumour was found and the PSA level was 113 ng/mL. The patient was treated with recombinant factor VIIa: Novoseven (90 microg/kg). None immunosuppressive agents were prescribed in this elderly patient. The patient's disease was identified as a spontaneously acquired haemophilia A associated with prostatic adenocarcinoma.

[Sensitization of tilt-table testing for syncope of unknown etiology: which drug to use?]. / Quel agent pharmacologique utiliser pour la sensibilisation du test d'inclinaison dans l'evaluation des syncopes d'origine indéterminée?

OBJECTIVE: The sensitivity of tilt-table testing in the diagnosis of vasovagal syncope is between 30% and 50% only. The most common method currently used to improve the sensitivity of the test is the administration of isoproterenol i.v. However, this method is difficult to perform and time consuming. The objective of our study was to compare sublingual trinitrin administration to i.v. isoproterenol during tilt-table testing. METHODS: We analyzed the results of 257 consecutive patients referred for tilt testing. Patients who had a negative test received either a ten minutes infusion of i.v. isoproterenol at the dose of 4 mcg/kg/min, or 0.4 mg of trinitrin given sublingually. RESULTS: Two hundred (and) fifty-seven patients underwent tilt-table testing. In the first group (isoproterenol group), 42 patients (39%) had a spontaneous positive tilt test, compared to 45 patients (31%) in the trinitrin group (P = NS). After sensitization, 24 additional patients (22%) had a positive test in the isoproterenol group vs 55 patients (37%) in the trinitrin group (P = NS). The total number of positive tests was 66 (61%) in the isoproterenol group compared to 100 (68%) in the trinitrin group (P = NS). CONCLUSION: Sublingual trinitrin is at least as good as IV isoproterenol during tilt-table testing. Because trinitrin is simpler to use and because its administration is much faster than isoproterenol, it should be recommended as the drug of choice to improve the sensitivity of tilt-table testing.

Viscoelasticity modeling of the prostate region using vibro-elastography.

We present an ultrasound vibro-elastography system designed to acquire viscoelastic properties of the prostate and peri-prostatic tissue. An excitation stage imparts low-frequency (<20 Hz), limited amplitude (< +/- 2 mm), broadband vibratory motion to an endorectal transducer, along a radial/transversal direction. The induced tissue motion is estimated from ultrasound radio-frequency data and is used to estimate the mechanical frequency response of tissue to the excitation at different spatial locations. This can be used to determine the spatial distribution of various mechanical parameters of tissue, such as stiffness and viscosity. Phantom and in-vivo images are presented. The results obtained demonstrate high phantom and tissue linearity and high signal-to-noise ratio.

[Thyrotoxic hypokalaemic periodic paralysis in a Caucasian male]. / Paralysie périodique hypokaliémique thyréotoxique chez un Caucasien.

We report the case of a caucasian patient with a presentation of a periodic paralysis associated with hypokalaemia disclosing Graves' disease. Major pathophysiologics hypothesis are discused in order to explain relationships between hyperthyroidism and paralysis through a disturbance of the excitability of the muscle fibres. A genetic predisposition explain the high incidence of this affection in asiatic population while it is uncommon in caucasian race. Potassium supplementation is not needed in order to correct hypokalaemia except in case of cardiac disturbances. Treatment by beta-blockers is advisable with the specific treatment of hyperthyroidism.

Major ketogenesis and the absence of an osmolar gap in an atypical case of alcoholic ketoacidosis.

A new case of alcoholic ketoacidosis (AKA) is presented because of unusual clinical and biochemical features. Although it shares some similarities with typical cases of AKA, it appears as unique because of predominantly neurological, rather than abdominal symptoms, major ketogenesis with normal ketone body ratio, the presence of large amounts of propanediol and the absence of an osmolar gap.

Sensitivity, specificity and accuracy of stress SPECT myocardial perfusion imaging for detection of coronary artery disease in the distribution of first-order branch vessels, using an anatomical matching of angiographic and perfusion data.

We sought to investigate the utility of stress single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for the identification of coronary artery disease (CAD) in the distribution of first-order branch vessels. We evaluated 135 consecutive patients with coronary angiography and stress SPECT MPI. We anatomically matched angiography and SPECT to assess the sensitivity, specificity and accuracy of SPECT MPI for the detection of CAD in the distribution of first-order branches. Subgroup analysis for stress test performance and previous coronary artery bypass grafting (CABG) was also performed. The sensitivity, specificity and accuracy of stress SPECT MPI for the detection of CAD in the distribution of first-order branch vessels were all 67%. For isolated branch vessel CAD, stress SPECT MPI had a sensitivity of 44%. In patients without CABG, the sensitivity, specificity and accuracy for the detection of CAD in the distribution of first-order branch vessels were 71%, 67% and 68%, compared with 60%, 67% and 64% for patients with CABG. The sensitivity for isolated branch vessel CAD was 50% for patients without CABG, but only 29% for patients with CABG. The sensitivity and specificity for CAD in the distribution of branch vessels were similar for all patients for all stress test modalities and heart rate response (sensitivity, 64-69%; specificity, 61-69%). Stress SPECT MPI offers intermediate sensitivity, specificity and accuracy for the detection of CAD in the distribution of first-order coronary artery branch vessels. However, for isolated branch vessel CAD, stress SPECT has a lower sensitivity, particularly in patients with previous CABG.