The Cannabinoid-Like Compound, VSN16R, Acts on Large Conductance, Ca2+-Activated K+ Channels to Modulate Hippocampal CA1 Pyramidal Neuron Firing.
Large conductance, Ca2+-activated K+ (BKCa) channels are widely expressed in the central nervous system, where they regulate action potential duration, firing frequency and consequential neurotransmitter release. Moreover, drug action on, mutations to, or changes in expression levels of BKCa can modulate neuronal hyperexcitability. Amongst other potential mechanisms of action, cannabinoid compounds have recently been reported to activate BKCa channels. Here, we examined the effects of the cannabinoid-like compound (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl) benzamide (VSN16R) at CA1 pyramidal neurons in hippocampal ex vivo brain slices using current clamp electrophysiology. We also investigated effects of the BKCa channel blockers iberiotoxin (IBTX) and the novel 7-pra-martentoxin (7-Pra-MarTx) on VSN16R action. VSN16R (100 μM) increased first and second fast after-hyperpolarization (fAHP) amplitude, decreased first and second inter spike interval (ISI) and shortened first action potential (AP) width under high frequency stimulation protocols in mouse hippocampal pyramidal neurons. IBTX (100 nM) decreased first fAHP amplitude, increased second ISI and broadened first and second AP width under high frequency stimulation protocols; IBTX also broadened first and second AP width under low frequency stimulation protocols. IBTX blocked effects of VSN16R on fAHP amplitude and ISI. 7-Pra-MarTx (100 nM) had no significant effects on fAHP amplitude and ISI but, unlike IBTX, shortened first and second AP width under high frequency stimulation protocols; 7-Pra-MarTx also shortened second AP width under low frequency stimulation protocols. However, in the presence of 7-Pra-MarTx, VSN16R retained some effects on AP waveform under high frequency stimulation protocols; moreover, VSN16R effects were revealed under low frequency stimulation protocols. These findings demonstrate that VSN16R has effects in native hippocampal neurons consistent with its causing an increase in initial firing frequency via activation of IBTX-sensitive BKCa channels. The differential pharmacological effects described suggest that VSN16R may differentially target BKCa channel subtypes.


Predictors of admission and shunt revision during emergency department visits for shunt-treated adult patients with idiopathic intracranial hypertension.
OBJECTIVE Factors associated with emergency department admission and/or shunt revision for idiopathic intracranial hypertension (IIH) are unclear. In this study, the associations of several factors with emergency department admission and shunt revision for IIH were explored. METHODS The authors performed a retrospective review of 31 patients (169 total emergency department visits) who presented to the emergency department for IIH-related symptoms between 2003 and 2015. Demographics, comorbidities, symptoms, IIH diagnosis and treatment history, ophthalmological examination, diagnostic lumbar puncture (LP), imaging findings, and data regarding admission and management decisions were collected. Multivariable general linear models regression analysis was performed to assess the predictive factors associated with admission and shunt revision. RESULTS Thirty-one adult patients with a history of shunt placement for IIH visited the emergency department a total of 169 times for IIH-related symptoms, with a median of 3 visits (interquartile range 2-7 visits) per patient. Five patients had more than 10 emergency department visits. Baseline factors associated with admission included male sex (OR 10.47, 95% CI 2.13-51.56; p = 0.004) and performance of an LP (OR 3.10, 95% CI 1.31-7.31; p = 0.01). Contrastingly, older age at presentation (OR 0.94, 95% CI 0.90-0.99; p = 0.01), and a greater number of prior emergency department visits (OR 0.94, 95% CI 0.89-0.99; p = 0.02) were slightly protective against admission. The presence of papilledema (OR 11.62, 95% CI 3.20-42.16; p < 0.001), Caucasian race (OR 40.53, 95% CI 2.49-660.09 p = 0.009), and systemic hypertension (OR 7.73, 95% CI 1.11-53.62; p = 0.03) were independent risk factors for shunt revision. In addition, a greater number of prior emergency department visits (OR 0.86, 95% CI 0.77-0.96; p = 0.009) and older age at presentation (OR 0.93, 95% CI 0.87-0.99; p = 0.02) were slightly protective against shunt revision, while there was suggestive evidence that presence of a programmable shunt (OR 0.23, 95% CI 0.05-1.14; p = 0.07) was a protective factor against shunt revision. Of note, location of the proximal catheter in the ventricle or lumbar subarachnoid space was not significantly associated with admission or shunt revision in the multivariable analyses. CONCLUSIONS The decision to admit a shunt-treated patient from the emergency department for symptoms related to IIH is challenging. Knowledge of factors associated with the need for admission and/or shunt revision is required. In this study, factors such as male sex, younger age at presentation, lower number of prior emergency department visits, and performance of a diagnostic LP were independent predictors of admission. In addition, papilledema was strongly predictive of the need for shunt revision, highlighting the importance of an ophthalmological examination for shunt-treated adults with IIH who present to the emergency department.


Effects of centrally applied somatostatin on pituitary adrenocorticotropes in female rats.
Effects of intracerebroventricular (i.c.v.) application of somatostatin (SRIH-14 or SRIH-28) on growth and function of pituitary adrenocorticotropes (ACTH cells) were examined in adult female Wistar rats. Animals were subjected to i.c.v. administration of three 1-microg doses of SRIH-14 or SRIH-28 dissolved in 5 microl saline every second day. Controls were treated in the same way with the same volume of saline only. ACTH-producing cells were studied using the peroxidase-antiperoxidase (PAP) immunohistochemical procedure; blood samples were collected for hormone analyses 5 days after the last injection. SRIH-28 treatment decreased (p < 0.05) all morphometric parameters compared to control rats. Volume of ACTH cells decreased by 10%, nuclei by 36% and volume density by 13%. No significant changes (p > 0.05) in these parameters occurred after SRIH-14 treatment. Plasma concentration of ACTH in SRIH-28-treated rats was significantly lower (p < 0.05) than in control rats by 35%. In SRIH-14-treated rats, plasma concentration of ACTH was slightly, but not significantly (p > 0.05) increased by 13% compared to saline treatment. These observations suggest that centrally administered somatostatin-28, but not somatostatin-14, is specifically involved in the control of growth and secretory activity of ACTH cells in female rats. Thus, selective pharmacological manipulation of SRIH-28 receptors reached from CSF may affect ACTH activity without altering actions usually attributed to receptors sensitive to SRIF-14.


Improving the separability of motor imagery EEG signals using a cross correlation-based least square support vector machine for brain-computer interface.
Although brain-computer interface (BCI) techniques have been developing quickly in recent decades, there still exist a number of unsolved problems, such as improvement of motor imagery (MI) signal classification. In this paper, we propose a hybrid algorithm to improve the classification success rate of MI-based electroencephalogram (EEG) signals in BCIs. The proposed scheme develops a novel cross-correlation based feature extractor, which is aided with a least square support vector machine (LS-SVM) for two-class MI signals recognition. To verify the effectiveness of the proposed classifier, we replace the LS-SVM classifier by a logistic regression classifier and a kernel logistic regression classifier, separately, with the same features extracted from the cross-correlation technique for the classification. The proposed approach is tested on datasets, IVa and IVb of BCI Competition III. The performances of those methods are evaluated with classification accuracy through a 10-fold cross-validation procedure. We also assess the performance of the proposed method by comparing it with eight recently reported algorithms. Experimental results on the two datasets show that the proposed LS-SVM classifier provides an improvement compared to the logistic regression and kernel logistic regression classifiers. The results also indicate that the proposed approach outperforms the most recently reported eight methods and achieves a 7.40% improvement over the best results of the other eight studies.


The Hematopoietic Transcription Factors RUNX1 and ERG Prevent AML1-ETO Oncogene Overexpression and Onset of the Apoptosis Program in t(8;21) AMLs.
The t(8;21) acute myeloid leukemia (AML)-associated oncoprotein AML1-ETO disrupts normal hematopoietic differentiation. Here, we have investigated its effects on the transcriptome and epigenome in t(8,21) patient cells. AML1-ETO binding was found at promoter regions of active genes with high levels of histone acetylation but also at distal elements characterized by low acetylation levels and binding of the hematopoietic transcription factors LYL1 and LMO2. In contrast, ERG, FLI1, TAL1, and RUNX1 bind at all AML1-ETO-occupied regulatory regions, including those of the AML1-ETO gene itself, suggesting their involvement in regulating AML1-ETO expression levels. While expression of AML1-ETO in myeloid differentiated induced pluripotent stem cells (iPSCs) induces leukemic characteristics, overexpression increases cell death. We find that expression of wild-type transcription factors RUNX1 and ERG in AML is required to prevent this oncogene overexpression. Together our results show that the interplay of the epigenome and transcription factors prevents apoptosis in t(8;21) AML cells.


Disability and not osteoarthritis predicts cardiovascular disease: a prospective population-based cohort study.
Previous studies found an association between osteoarthritis (OA) and risk of cardiovascular disease (CVD) and therefore suggested intensive treatment of cardiovascular risk factors in OA patients. However, prospective population-based data is lacking. To investigate the association between OA and CVD longitudinally in a general population and examine the role of disability in this association. This study was embedded in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands that started in 1989. At baseline 4648 persons aged ≥55, free of CVD were classified into those with and those without radiographic or clinical OA. HRs adjusted for traditional cardiovascular risk factors for developing CVD (a composite of fatal and non-fatal coronary heart disease and stroke) were calculated. During a median follow-up of 14.4 years, 1230 cardiovascular events occurred, of which 101 were in participants with clinical OA. Presence of radiographic OA at baseline was not related to future CVD (HR 0.99, 95% CI 0.86 to 1.15), neither was presence of clinical OA (HR 1.09, 95% CI 0.88 to 1.34). However, persons with increasing disability were more likely to suffer a cardiovascular event compared with non-disabled persons (HR 1.26, 95% CI 1.12 to 1.42); this was independent of the presence of OA. In this large population-based study, participants with OA were not at increased risk of CVD. The close relation between disability and osteoarthritis may explain previous findings. Further studies are required in order to clarify whether OA patients need more intensive treatment of their cardiovascular risk factors.


A potential oncogenic role of the commonly observed E2F5 overexpression in hepatocellular carcinoma.
To explore the expression pattern of E2F5 in primary hepatocellular carcinomas (HCCs) and elucidate the roles of E2F5 in hepatocarcinogenesis. E2F5 expression was analyzed in 120 primary HCCs and 29 normal liver tissues by immunohistochemistry analysis. E2F5-small interfering RNA was transfected into HepG2, an E2F5-overexpressed HCC cell line. After E2F5 knockdown, cell growth capacity and migrating potential were examined. E2F5 was significantly overexpressed in primary HCCs compared with normal liver tissues (P = 0.008). The E2F5-silenced cells showed significantly reduced proliferation (P = 0.004). On the colony formation and soft agar assays, the number of colonies was significantly reduced in E2F5-silenced cells (P = 0.004 and P = 0.009, respectively). E2F5 knockdown resulted in the accumulation of G0/G1 phase cells and a reduction of S phase cells. The number of migrating/invading cells was also reduced after E2F5 knockdown (P = 0.021). To our knowledge, this is the first evidence that E2F5 is commonly overexpressed in primary HCC and that E2F5 knockdown significantly repressed the growth of HCC cells.


Differential contextual responses of normal human breast epithelium to ionizing radiation in a mouse xenograft model.
Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed ΔNp63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of γ-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems.


Reaction and movement times in patients with hemiparesis for unilateral and bilateral elbow flexion.
This work was designed to study the effects of bilateral elbow flexion on the reaction and movement times of the impaired upper extremity of patients with hemiparesis. The subjects consisted of an experimental group of patients with hemiparesis (n = 25) and a control group of age-matched healthy volunteers (n = 26). Each subject performed three sets of 16 elbow flexion trials. Two of these sets required unilateral movements, one for each upper extremity. The third set of movements required simultaneous elbow flexions of both upper extremities. In each trial, subjects were instructed to flex their elbows in response to an auditory signal from a supported initial position of 150 degrees through a goal orientation of 120 degrees. "Reaction time" was defined as the time between the auditory signal and movement initiation. "Movement time" was defined as the time between movement initiation and the completion of 30 degrees of elbow flexion. When subjects were asked to bilaterally flex their elbows, the reaction and movement times increased in both extremities. It was speculated that in patients with hemiparesis, movement time of the nonparetic extremity in the bilateral task is limited by the rate of performance of the paretic extremity. The decrease in speed of these performance-determining variables in the bilateral task warrants consideration during physical therapy intervention for patients with hemiparesis.


BRANE Clust: Cluster-Assisted Gene Regulatory Network Inference Refinement.
Discovering meaningful gene interactions is crucial for the identification of novel regulatory processes in cells. Building accurately the related graphs remains challenging due to the large number of possible solutions from available data. Nonetheless, enforcing a priori on the graph structure, such as modularity, may reduce network indeterminacy issues. BRANE Clust (Biologically-Related A priori Network Enhancement with Clustering) refines gene regulatory network (GRN) inference thanks to cluster information. It works as a post-processing tool for inference methods (i.e., CLR, GENIE3). In BRANE Clust, the clustering is based on the inversion of a system of linear equations involving a graph-Laplacian matrix promoting a modular structure. Our approach is validated on DREAM4 and DREAM5 datasets with objective measures, showing significant comparative improvements. We provide additional insights on the discovery of novel regulatory or co-expressed links in the inferred Escherichia coli network evaluated using the STRING database. The comparative pertinence of clustering is discussed computationally (SIMoNe, WGCNA, X-means) and biologically (RegulonDB). BRANE Clust software is available at: http://www-syscom.univ-mlv.fr/~pirayre/Codes-GRN-BRANE-clust.html.


Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.
A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. ClinicalTrials.gov identifier: NCT00707746.


Correlation of Longitudinal Gray Matter Volume Changes and Motor Recovery in Patients After Pontine Infarction.
The mechanisms of motor functional recovery after pontine infarction (PI) remain unclear. Here, we assessed longitudinal changes in gray matter volume (GMV) and examined the relationship between GMV and clinical outcome. Fifteen patients with unilateral PI underwent magnetic resonance imaging and neurological exams five times during a period of 6 months. Another 15 healthy participants were enrolled as the normal control (NC) group and were examined with the same protocol. The MR exam included routine protocol and a 3D T1-weighted magnetization-prepared rapid acquisition gradient echo scan. Changes in GMV were assessed using voxel-based morphometry. Furthermore, the correlations between GMV changes in regions of interest and clinical scores were assessed. Compared with NCs, the decreased GMVs in the contralateral uvula of cerebellum and the ipsilateral tuber of cerebellum were detected at third month after stroke onset. At the sixth month after stroke onset, the decreased GMVs were detected in the contralateral culmen of cerebellum, putamen, as well as in the ipsilateral tuber/tonsil of cerebellum. Compared with NC, the PI group exhibited significant increases in GMV at each follow-up time point relative to stroke onset. Specifically, the significant GMV increase was found in the ipsilateral middle frontal gyrus and ventral anterior nucleus of thalamus at second week after stroke onset. At first month after stroke onset, the increased GMVs in the ipsilateral middle temporal gyrus were detected. The significant GMV increase in the ipsilateral mediodorsal thalamus was noted at third month after stroke onset. At the end of sixth month after stroke onset, the GMV increase was found in the ipsilateral mediodorsal thalamus, superior frontal gyrus, and the contralateral precuneus. Across five times during a period of 6-month, a negative correlation was observed between mean GMV in the contralateral uvula, culmen, putamen, and ipsilateral tuber/tonsil and mean Fugl-Meyer (FM) score. However, mean GMV in the ipsilateral mediodorsal thalamus was positively correlated with mean FM score. Our findings suggest that structural reorganization of the ipsilateral mediodorsal thalamus might contribute to motor functional recovery after PI.


The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial.
beta-Carotene and Retinol Efficacy Trial is a nationwide chemoprevention trial that recruited 18,314 high-risk individuals to test the effect of supplemental beta-carotene and retinol on lung cancer incidence. In this report, we conducted a prospective nested case-control study of the association between serum carotenoids, retinoids, and tocopherols on both lung and prostate cancer incidence. Prerandomization serum samples were selected from 278 lung cancer cases and 205 prostate cancer cases, and 483 controls matched by high-risk population, study center location, age, sex (lung cancer only), smoking status, and year of randomization. Carotenoids, retinoids, and tocopherols were analyzed by high-performance liquid chromatography. Endpoints were confirmed by pathology review (lung cancer) or review of the pathology report (prostate cancer). In the control-only population, there was a significant association between tobacco use and serum micronutrient concentration. Current smokers compared with former smokers had lower mean levels of all of the micronutrients tested with zeaxanthin, beta-cryptoxanthin, alpha-carotene, alpha-tocopherol, retinol, and retinyl palmitate reaching statistical significance at P = 0.05. In the overall population, the mean serum concentrations of all of the micronutrients except gamma-tocopherol were lower for lung cancer cases than controls. Statistically significant trends across quartiles were observed in lutein (P = 0.02), zeaxanthin (P = 0.02), and alpha-tocopherol (P = 0.03). The carotenoid findings in the overall population were because of the strong inverse association between serum micronutrients and lung cancer in females. Statistically significant odds ratios (ORs) comparing 4(th) to 1st quartiles in the female population were seen in lutein [OR, 0.31; confidence interval (CI), 0.13-0.75], zeaxanthin (OR, 0.31; CI, 0.12-0.77), and beta-cryptoxanthin (OR, 0.34; CI, 0.14-0.81). For prostate cancer, mean serum concentrations were lower in cases for all of the nutrients except alpha-carotene. Only for alpha-tocopherol (P(trend) = 0.04) were the findings statistically significant. There was no statistically significant association between serum carotenoids and prostate cancer. Our findings provide additional support for the association between physiological levels of dietary micronutrients and cancer incidence.


Sonography of ventricular size and germinal matrix hemorrhage in premature infants.
Using the anterior fontanelle as an acoustic window, high resolution gray scale sonography brain scans with mobile apparatus were obtained in 35 premature infants. The sonographic technique provided accurate assessment of ventricular size and detected the subependymal germinal matrix and intraventricular hemorrhages. Ventricular size measurements correlated closely with computed tomography (CT) determinations (r = 0.83--0.92) in 29 infants. Sonography imaged the hemorrhages as areas of increased echogenicity with mass effect located characteristically in the region of the caudate nucleus. The size of the hemorrhages could be grossly estimated, but the full extent of hemorrhages was better delineated by CT. Sonography seemed superior in detecting small hemorrhages that were isodense with surrounding brain on CT. Despite its advantages of benignancy, accuracy, ease of examination, and cost, our sonography technique had limitations. False-negative sonograms occurred when the hemorrhage was located only in the posterior aspects of the ventricular system. Small hemorrhages in the caudate could be missed by either CT or sonography because of sampling error. Recognition of other disease processes was limited with sonography. The sonographic brain scan is a good initial test for high risk premature infants suspected of having subependymal germinal matrix and intraventricular hemorrhages. If the sonogram is negative or not typical for subependymal germinal matrix and intraventricular hemorrhages, CT is indicated.


Susceptibility of Cabbage Maggot Larvae (Diptera: Anthomyiidae) to Hypocreales Entomopathogenic Fungi.
The pathogenicity of six Metarhizium spp., four Beauveria bassiana (Balsamo) Vuillemin, and four Tolypocladium cylindrosporum Gams (Ascomycota: Hypocreales) fungal pathogens exposed to third-instar Delia radicum L. was evaluated in laboratory bioassays. The presence of intra- and intergeneric variations concerning the pathogenicity of the isolates was investigated. Results show that all Metarhizium spp. and T. cylindrosporum isolates caused a noteworthy mortality to the third instar and consequently reduced adult eclosion. The well-known standard, F52 strain (identified as Metarhizium brunneum), resulted in up to 79% reduction in D. radicum eclosion. The other Metarhizium isolates including UAMH 9197 (Metarhizium anisopliae) and UAMH 2801 (M. brunneum), as well as T. cylindrosporum DAOM 167325 and DAOM 183952, produced a mean eclosion reduction of >50%. While the pathogenicity of Metarhizium spp. and T. cylindrosporum is similar, the B. bassiana isolates are undoubtedly less pathogenic. Based on the results obtained with the selected isolates, no intrageneric differences relative to the pathogenicity of the isolates appeared to be present. Globally, this study deepened the knowledge about D. radicum susceptibility toward Hypocreales entomopathogenic fungi, chiefly T. cylindrosporum. The implications of this study regarding the development of a biological control agent are discussed.


Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level.
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.


The role of the psoas and iliacus muscles for stability and movement of the lumbar spine, pelvis and hip.
The activation patterns of the psoas and iliacus muscles were investigated in 7 healthy adult subjects (4 men and 3 women) during a variety of motor tasks in standing, sitting and lying. Myoelectric activity was recorded simultaneously from the 2 muscles using thin wire electrodes inserted under guidance of high-resolution ultrasound. In general, both muscles were coactivated, albeit to different relative levels, particularly when hip flexor torque was required. Selective activation of the iliacus could, however, be seen to stabilize the pelvis in contralateral hip extension during standing. Psoas was found to be selectively involved in sitting with a straight back and in contralateral loading situations requiring stabilization of the spine in the frontal plane. During training exercises from a supine position, such as sit-ups, the contribution of the psoas and iliacus muscles could be varied by changing the range of motion as well as the position and support for the legs. Thus, the 2 anatomically different muscles of the iliopsoas complex were shown to have individual and task-specific activation patterns depending on the particular demands for stability and movement at the lumbar spine, pelvis and hip.


Comparison of 24-hour Holter monitoring with 14-day novel adhesive patch electrocardiographic monitoring.
Cardiac arrhythmias are remarkably common and routinely go undiagnosed because they are often transient and asymptomatic. Effective diagnosis and treatment can substantially reduce the morbidity and mortality associated with cardiac arrhythmias. The Zio Patch (iRhythm Technologies, Inc, San Francisco, Calif) is a novel, single-lead electrocardiographic (ECG), lightweight, Food and Drug Administration-cleared, continuously recording ambulatory adhesive patch monitor suitable for detecting cardiac arrhythmias in patients referred for ambulatory ECG monitoring. A total of 146 patients referred for evaluation of cardiac arrhythmia underwent simultaneous ambulatory ECG recording with a conventional 24-hour Holter monitor and a 14-day adhesive patch monitor. The primary outcome of the study was to compare the detection arrhythmia events over total wear time for both devices. Arrhythmia events were defined as detection of any 1 of 6 arrhythmias, including supraventricular tachycardia, atrial fibrillation/flutter, pause greater than 3 seconds, atrioventricular block, ventricular tachycardia, or polymorphic ventricular tachycardia/ventricular fibrillation. McNemar's tests were used to compare the matched pairs of data from the Holter and the adhesive patch monitor. Over the total wear time of both devices, the adhesive patch monitor detected 96 arrhythmia events compared with 61 arrhythmia events by the Holter monitor (P < .001). Over the total wear time of both devices, the adhesive patch monitor detected more events than the Holter monitor. Prolonged duration monitoring for detection of arrhythmia events using single-lead, less-obtrusive, adhesive-patch monitoring platforms could replace conventional Holter monitoring in patients referred for ambulatory ECG monitoring.


Birth of a healthy boy after a double factor PGD in a couple carrying a genetic disease and at risk for aneuploidy: case report.
Preimplantation genetic diagnosis (PGD) for monogenic diseases is widely applied, allowing the transfer to the uterus of healthy embryos. PGD is also employed for the detection of chromosome abnormalities for couples at high risk of producing aneuploid embryos, such as advanced maternal (>35 years). A significant number of patients requesting PGD for monogenic diseases are also indicated for chromosome testing. We optimized and clinically applied a PGD protocol permitting both cytogenetic and molecular genetic analysis. A couple, carriers of two cystic fibrosis (CF) mutations (c.3849 + 10 KbC > T and c.3408C > A) with a maternal age of 38 years and two previously failed IVF-PGD cycles, was enrolled in the study. After ovarian stimulation, six oocytes were obtained. To detect abnormalities for all 23 chromosomes of the oocyte, the first polar body (1PB) was biopsied from five of the oocytes and analyzed using comparative genomic hybridization (CGH). CGH analysis showed that 1PB 1 and 1PB 4 were aneuploid (22X,-9,-13,+19 and 22X,-6, respectively), while 1PB 2, 1PB 3 and 1PB 6 were euploid. Blastomere biopsy was only applicable on embryos formed from Oocyte 3 and Oocyte 6. After whole-genome amplification with multiple displacement amplification, a multiplex PCR, amplifying informative short tandem repeats (D7S1799; D7S1817) and DNA fragments encompassing the mutation sites, was performed. MiniSequencing was applied to directly detect each mutation. Genetic diagnosis showed that Embryo 6 was affected by CF and Embryo 3 carried only the c.3849 + 10 KbC > T mutation. Embryo 3 was transferred achieving pregnancy and a healthy boy was born. This strategy may lead to increased pregnancy rates by allowing preferential transfer of euploid embryos.


Effect of generalised access to early diagnosis and treatment and targeted mass drug administration on Plasmodium falciparum malaria in Eastern Myanmar: an observational study of a regional elimination programme.
Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria. The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether-lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin-piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration. Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8-4·4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76-0·88 per quarter) and in other villages (0·75, 0·73-0·78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13-0·26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631). Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum. The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.


Hematotesticular barrier is altered from early stages of liver cirrhosis: effect of insulin-like growth factor 1.
The pathogenesis of hypogonadism in liver cirrhosis is not well understood. Previous results from our laboratory showed that IGF-1 deficiency might play a pathogenetic role in hypogonadism of cirrhosis. The administration of IGF-1 for a short period of time reverted the testicular atrophy associated with advanced experimental cirrhosis. The aim of this study was to establish the historical progression of the described alterations in the testes, explore testicular morphology, histopathology, cellular proliferation, integrity of testicular barrier and hypophyso-gonadal axis in rats with no ascitic cirrhosis. Male Wistar rats with histologically-proven cirrhosis induced with carbon tetrachloride (CCl4) for 11 wk, were allocated into two groups (n = 12, each) to receive recombinant IGF-1 (2 microg/100 g.d, sc) for two weeks or vehicle. Healthy rats receiving vehicle were used as control group (n = 12). Compared to controls, rats with compensated cirrhosis showed a normal testicular size and weight and very few histopathological testicular abnormalities. However, these animals showed a significant diminution of cellular proliferation and a reduction of testicular transferrin expression. In addition, pituitary-gonadal axis was altered, with significant higher levels of FSH (P<0.001 vs controls) and increased levels of LH in untreated cirrhotic animals. Interestingly, IGF-1 treatment normalized testicular transferrin expression and cellular proliferation and reduced serum levels of LH (P = ns vs controls, and P<0.01 vs untreated cirrhotic group). The testicular barrier is altered from an early stage of cirrhosis, shown by a reduction of transferrin expression in Sertoli cells, a diminished cellular proliferation and an altered gonadal axis. The treatment with IGF-1 could be also useful in this initial stage of testicular disorder associated with compensated cirrhosis.


Prediction of genetic subgroups in adult supra tentorial gliomas by pre- and intraoperative parameters.
Recent progress in neuro-oncology has validated the significance of genetic diagnosis in gliomas. We previously investigated IDH1/2 and TP53 mutations via Sanger sequencing for adult supratentorial gliomas and reported that PCR-based sequence analysis classified gliomas into three genetic subgroups that have a strong association with patient prognosis: IDH mutant gliomas without TP53 mutations, IDH and TP53 mutant gliomas, and IDH wild-type gliomas. Furthermore, this analysis had a strong association with patient prognosis. To predict genetic subgroups prior to initial surgery, we retrospectively investigated preoperative radiological data using CT and MRI, including MR spectroscopy (MRS), and evaluated positive 5-aminolevulinic acid (5-ALA) fluorescence as an intraoperative factor. We subsequently compared these factors to differentiate each genetic subgroup. Multiple factors such as age at diagnosis, tumor location, gadolinium enhancement, 5-ALA fluorescence, and several tumor metabolites according to MRS, such as myo-inositol (myo-inositol/total choline) or lipid20, were statistically significant factors for differentiating IDH mutant and wild-type, suggesting that these two subtypes have totally distinct characteristics. In contrast, only calcification, laterality, and lipid13 (lipid13/total Choline) were statistically significant parameters for differentiating TP53 wild-type and mutant in IDH mutant gliomas. In this study, we detected several pre- and intraoperative factors that enabled us to predict genetic subgroups for adult supratentorial gliomas and clarified that lipid13 quantified by MRS is the key tumor metabolite that differentiates TP53 wild-type and mutant in IDH mutant gliomas. These results suggested that each genetic subtype in gliomas selects the distinct lipid synthesis pathways in the process of tumorigenesis.


Elevated temperature applied during gonadal transformation leads to male bias in zebrafish (Danio rerio).
Temperature effects on sex determination or differentiation exist in many fish species, with high temperatures predominantly producing more males. The present study aimed at elucidating the genetic background of temperature effects on sex differentiation in zebrafish. Experimental fish were generated by matings between 4 or 6 golden females and a normal or a mitotic gynogenetic male, respectively. All the larvae were reared at 28.5°C until they were divided into 3 groups per full-sib family, a control group raised at 28.5°C and 2 treatment groups reared at 35°C from 20 to 30 dpf or 25 to 35 dpf, respectively. Backcross progenies, reared at 28.5°C, were derived from F1 temperature-treated sons (35°C, 25-35 dpf) that were sired by a mitotic gynogenetic male and their corresponding mothers. No significant differences were observed regarding the survival rate between the control and treatment groups. Significant differences in the phenotypic male proportions from the controls were observed in groups treated at 35°C. The sex ratio in zebrafish was influenced by the male spawner, the female spawner, and a significant interaction of genotype by temperature. Backcross experiments point to a continuum of major genetic, minor genetic, and environmental factors in the expression of the phenotypic sex in zebrafish.


Hospital discharge reports: content and design.
The information required by family doctors on initial and final discharge reports from hospitals was specified and 546 such reports from hospitals in Aylesbury, Amersham, Banbury, Oxford, and High Wycombe were reviewed for the availability and accessibility of important information. Several items could have been recorded better, including the name of the hospital, the specialty (or department) concerned, and the name of the consultant in charge of the case. Drug reactions seemed to be under-reported in the initial discharge reports and information about treatment on discharge was inadequate. The recording of the prognosis and information given to the patient was deficient and communication on follow-up needs to be improved. The use of obscure abbreviations was widespread. There is room for improvement in the ease of access to important information, especially the diagnostic assessment, and the time taken for final reports to reach the general practitioner.


Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.
Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Cross-sectional individual participant-level analyses in a global consortium. 17 CKD and 38 general population and high-risk cohorts. Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data were obtained and analyzed between July 2015 and January 2018. We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g). Variations in study era, health care delivery system, typical diet, and laboratory assays. Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.


Chrysophanol Induces Apoptosis of Choriocarcinoma Through Regulation of ROS and the AKT and ERK1/2 Pathways.
Chrysophanol is an anthraquinone compound, mainly isolated from rhubarb, with anti-cancer effects on some types of cancer cells. However, effects of chrysophanol on human choriocarcinoma cells are not known. Therefore, the objective of this study was to determine effects of chrysophanol on choriocarcinoma cells (JAR and JEG-3) and identify signal transduction cascades activated by chrysophanol. Results of present study, showed that chrysophanol decreased cell viability and induced apoptosis of JEG-3, but not JAR cells, in a dose-dependent manner. Chrysophanol also increased oxidative stress in JEG-3 cells by inducing ROS generation followed by mitochondrial dysfunction including depolarization of mitochondrial inner membrane potential. Western blot analysis revealed that ERK1/2, P90RSK, AKT, and P70S6K were increased significantly in JEG-3 cells by chrysophanol. Next, we investigated chrysophanol-mediated effects on proliferation of JEG-3 cells using pharmacological inhibitors of PI3K/AKT (LY294002) and ERK1/2 (U0126). Inhibition of AKT and ERK1/2 prevented chrysophanol-induced stimulation of proliferation of JEG-3 cells. In addition, the phosphorylation of AKT and ERK1/2 was suppressed by LY294002 and U0126 in JEG-3 cells treated with chrysophanol, whereas, the AKT protein was activated by pre-treatment of JEG-3 cells with U0126. Furthermore, we compared therapeutic effects of chrysophanol with cisplatin and paclitaxel which are conventional salvage regimens for choriocarcinoma. Our results verified that chrysophanol has synergistic effects with traditional therapy to increase apoptosis of JEG-3 cells. Collectively, these results indicate that chrysophanol is a potential effective chometherapeutic agent for treatment of choriocarcinoma therapy, and minimizing side effects of conventional treatment regimens. J. Cell. Physiol. 232: 331-339, 2017. © 2016 Wiley Periodicals, Inc.


Mitochondria: Their role in ganglion cell death and survival in primary open angle glaucoma.
Retinal ganglion cell axons within the globe are functionally specialised being richly provided with many mitochondria. Mitochondria produce the high energy that is required for nerve conduction in the unmylenated part of the ganglion cell axons and for the maintenance of optimum neuronal function. We proposed that in the initiation of glaucoma (POAG) an alteration in the quality of blood flow dynamics in the optic nerve head results in sustained or intermittent ischemia of a defined nature. This results in normal mitochondrial function being negatively affected and as a consequence retinal ganglion cell function is compromised. Ganglion cells in this state are now susceptible to secondary insults which they would normally tolerate. One secondary insult to ganglion cell mitochondria in such a state might be light entering the eye. Other insults to the ganglion cells might come from substances such as glutamate, prostaglandins and nitric oxide released from astrocytes and microglia in the optic nerve head region. Such cascades of events initiated by ischemia to the optic nerve head region ultimately cause ganglion cells to die at different rates.


Immediate metabolic consequences of intrauterine growth restriction and low birthweight.
Optimal fetal growth resulting in a 'normally grown' term infant is of paramount importance for assuring a healthy start for postnatal growth and development. Fetal, infant and childhood growth restriction is an important clinical problem for obstetricians, neonatologists, pediatricians and globally, for public health. Worldwide, an estimated 20 million infants are born with low birthweight and a substantial proportion are small for gestational age. Many advances have been made in defining growth restriction by prenatal techniques, thus allowing the recognition of intrauterine growth restriction. Distinguishing infants who are small but have appropriate growth potential from those with growth restriction is important in order to apply obstetric surveillance, anticipate neonatal problems and plan for postneonatal guidance. It is clear that the fetus in growth-restricted pregnancies has limited supply of nutrients and oxygen. The resultant changes, if involving the placenta as well, can lead to circulatory and metabolic changes affecting both short- and long-term survival and development. In this paper, the causes and immediate consequence of being born with low birthweight, intrauterine growth restriction or small for gestational age will be discussed.


A meta-analysis of personality in scientific and artistic creativity.
Theory and research in both personality psychology and creativity share an essential commonality: emphasis on the uniqueness of the individual. Both disciplines also share an emphasis on temporal consistency and have a 50-year history, and yet no quantitative review of the literature on the creative personality has been conducted. The 3 major goals of this article are to present the results of the first meta-analytic review of the literature on personality and creative achievement, to present a conceptual integration of underlying potential psychological mechanisms that personality and creativity have in common, and to show how the topic of creativity has been important to personality psychologists and can be to social psychologists. A common system of personality description was obtained by classifying trait terms or scales onto one of the Five-Factor Model (or Big Five) dimensions: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Effect size was measured using Cohen's d (Cohen, 1988). Comparisons on personality traits were made on 3 sets of samples: scientists versus nonscientists, more creative versus less creative scientists, and artists versus nonartists. In general, creative people are more open to new experiences, less conventional and less conscientious, more self-confident, self-accepting, driven, ambitious, dominant, hostile, and impulsive. Out of these, the largest effect sizes were on openness, conscientiousness, self-acceptance, hostility, and impulsivity. Further, there appears to be temporal stability of these distinguishing personality dimensions of creative people. Dispositions important to creative behavior are parsed into social, cognitive, motivational, and affective dimensions. Creativity like most complex behaviors requires an intra- as well as interdisciplinary view and thereby mitigates the historically disciplinocentric attitudes of personality and social psychologists.


Controlling electron transfer between the two cofactor chains of photosystem I by the redox state of one of their components.
Two functional electron transfer (ET) chains, related by a pseudo-C2 symmetry, are present in the reaction center of photosystem I (PSI). Due to slight differences in the environment around the cofactors of the two branches, there are differences in both the kinetics of ET and the proportion of ET that occurs on the two branches. The strongest evidence that this is indeed the case relied on the observation that the oxidation rates of the reduced phylloquinone (PhQ) cofactor differ by an order of magnitude. Site-directed mutagenesis of residues involved in the respective PhQ-binding sites resulted in a specific alteration of the rates of semiquinone oxidation. Here, we show that the PsaA-F689N mutation results in an ∼100-fold decrease in the observed rate of PhQA(-) oxidation. This is the largest change of PhQA(-) oxidation kinetics observed so far for a single-point mutation, resulting in a lifetime that exceeds that of the terminal electron donor, P700(+). This situation allows a second photochemical charge separation event to be initiated before PhQA(-) has decayed, thereby mimicking in PSI a situation that occurs in type II reaction centers. The results indicate that the presence of PhQA(-) does not impact the overall quantum yield and leads to an almost complete redistribution of the fractional utilization of the two functional ET chains, in favor of the one that does not bear the charged species. The evolutionary implications of these results are also briefly discussed.


Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review.
A systematic review was performed to determine the effectiveness of different approaches for eradicating methicillin-resistant Staphylococcus aureus carriage. Twenty-three clinical trials were selected that evaluated oral antibiotics (7 trials), topically applied antibiotics (12 trials), or both (4 trials). Because of clinical heterogeneity, quantitative analysis of all studies was deemed to be inappropriate, and exploratory subgroup analyses were performed for studies with similar study populations, methods, and targeted bacteria. The estimated pooled relative risk of treatment failure 1 week after short-term nasal mupirocin treatment, compared with placebo, was 0.10 (range, 0.07-0.14). There was low heterogeneity between study outcomes, and effects were similar for patients and healthy subjects, as well as in studies that included only methicillin-susceptible S. aureus carriers or both methicillin-susceptible S. aureus and methicillin-resistant S. aureus carriers. The development of drug resistance during treatment was reported in 1% and 9% of patients receiving mupirocin and oral antibiotics, respectively. Short-term nasal application of mupirocin is the most effective treatment for eradicating methicillin-resistant S. aureus carriage, with an estimated success of rate of 90% 1 week after treatment and approximately 60% after a longer follow-up period.


Hijacking Dorsal Raphe to Improve Metabolism and Depression-Like Behaviors via BDNF Gene Transfer in Mice.
Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders, such as diabetes and obesity, poses a great challenge to treat such conditions. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model (CUMS) of depression and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in db/db mice, BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.


The windowed sound therapy: a new empirical approach for an effectiv personalized treatment of tinnitus.
We auditorily stimulated patients affected by subjective tinnitus with broadband noise containing a notch around their tinnitus frequency. We assessed the long-term effects on tinnitus perception in patients listening to notched noise stimuli (referred to as windowed sound therapy [WST]) by measuring the variation of subjects' tinnitus loudness over a period of 2-12 months. We tested the effectiveness of WST using non-notched broadband noise and noise of water as control sound therapies. We found a significant long-term reduction of tinnitus loudness in subjects treated with notched noise but not in those treated with control stimulations. These results point to the importance of the personalized sound treatment of tinnitus sufferers for the development of an effective tinnitus sound therapy.


Phylogenetic relationships of the genus Kluyvera: transfer of Enterobacter intermedius Izard et al. 1980 to the genus Kluyvera as Kluyvera intermedia comb. nov. and reclassification of Kluyvera cochleae as a later synonym of K. intermedia.
In order to assess the relationship between the genus Kluyvera and other members of the family Enterobacteriaceae, the 16S rRNA genes of type strains of the recognized Kluyvera species, Kluyvera georgiana, Kluyvera cochleae, Kluyvera ascorbata and Kluyvera cryocrescens, were sequenced. A comparative phylogenetic analysis based on these 16S rRNA gene sequences and those available for strains belonging to several genera of the family Enterobacteriaceae showed that members of the genus Kluyvera form a cluster that contains all the known Kluyvera species. However, the type strain of Enterobacter intermedius (ATCC 33110T) was included within this cluster in a very close relationship with the type strain of K. cochleae (ATCC 51609T). In addition to the phylogenetic evidence, biochemical and DNA-DNA hybridization analyses of species within this cluster indicated that the type strain of E. intermedius is in fact a member of the genus Kluyvera and, within it, of the species Kluyvera cochleae. Therefore, following the current rules for bacterial nomenclature and classification, the transfer of E. intermedius to the genus Kluyvera as Kluyvera intermedia comb. nov. is proposed (type strain, ATCC 33110T=CIP 79.27T=LMG 2785T=CCUG 14183T). Biochemical analysis of four E. intermedius strains and one K. cochleae strain independent of the respective type strains further indicated that E. intermedius and K. cochleae represent the same species and are therefore heterotypic synonyms. Nomenclatural priority goes to the oldest legitimate epithet. Consequently, Kluyvera cochleae Muller et al. 1996 is a later synonym of Kluyvera intermedia (Izard et al. 1980) Pavan et al. 2005.


Evaluating rotavirus vaccination in England and Wales. Part II. The potential cost-effectiveness of vaccination.
Rotavirus is the leading cause of acute gastroenteritis in children. Two rotavirus vaccines (RotaTeq and Rotarix) have recently completed clinical trials. We investigated whether routine infant immunisation with either vaccine can be cost effective. We compared costs and outcomes of vaccination using a cohort model, following children over the first 5 years of life. We estimated health provider costs, economic costs and quality adjusted life years (QALYs) lost due to rotavirus-related deaths, hospital admissions, nosocomial infections, accident and emergency attendances, general practice consultations and calls to NHS Direct. Under base case assumptions, a programme using RotaTeq (priced at pound 25 a dose) would cost the health provider pound 79,900 per QALY gained. Using Rotarix (priced at pound 35 a dose) would cost pound 61,000 per QALY gained. Univariate and multivariate sensitivity analysis indicate that at these prices an immunisation programme would be unlikely to be cost-effective for any realistic value of the key parameters. Rotavirus immunisation could reduce the substantial short-term morbidity burden due to rotavirus, but is unlikely to be deemed cost effective unless the vaccine is competitively priced.


Comparison between pulse oximetry and transthoracic impedance alarm traces during home monitoring.
To compare transthoracic impedance (TTI/ECG) and pulse oximetry alarm traces detected during home monitoring in infants at risk of apnoea, bradycardia and hypoxaemia. A retrospective evaluation of the monitor downloads of 67 infants who had undergone either TTI/ECG or pulse oximetry home monitoring using a device which can detect both parameters. The patients were categorised as: apparent life-threatening events (n = 39), preterm infants (n = 21) and miscellaneous (n = 7). TTI/ECG and pulse oximetry alarm traces were scored as either true or false alarms. Classification criteria were based on visual analysis of the impedance and plethysmographic waveforms captured by the memory monitor every time alarm thresholds were violated. 5242 alarms occurred over 3452 days of monitoring: 4562 (87%) were false and 680 (13%) true. The mean duration of monitoring was 51 days (range 5-220 days). There were 2982 TTI/ECG false alarms (65% of the total) and 1580 pulse oximetry false alarms (35%) (p = 0.0042). Of the 680 true alarms, 507 (74%) were desaturations not attributable to central apnoea and 173 (26%) were true TTI/ECG alarms (p = 0.0013). Comparison of pulse oximetry and TTI/ECG alarm traces shows that true events were mostly attributable to desaturations, while false alarms were mainly provoked by TTI/ECG. The total number of false alarms is lower than reported in other studies using TTI/ECG only, thus indicating that monitoring using both pulse oximetry and TTI/ECG is suitable for home use. When the combination of both techniques is not feasible or not required, we recommend the use of motion resistant pulse oximetry alone.


Developing Ethical Practices for Public Health Research Data Sharing in South Africa: The Views and Experiences From a Diverse Sample of Research Stakeholders.
The abundance of South African clinical and public health research data has the potential to unlock important and valuable future advances in biomedical science. Amid increasing calls for more effective sharing of individual-level data, commitment to promote access to research data is evident within South Africa's public research sector, but national guidance and regulation are absent. This qualitative study examined the perceptions, experiences and concerns of 32 research stakeholders about data-sharing practices. There was consensus about the utility of data sharing in publicly funded health research. However, disparate views emerged about the possible harms and benefits of sharing data and how these should be weighed. The relative dearth of policies governing data-sharing practices needs to be addressed and a framework of support developed that incentivizes data-sharing practices for researchers that are both ethical and effective.


Removal of misincorporated ribonucleotides from prokaryotic genomes: an unexpected role for nucleotide excision repair.
Stringent steric exclusion mechanisms limit the misincorporation of ribonucleotides by high-fidelity DNA polymerases into genomic DNA. In contrast, low-fidelity Escherichia coli DNA polymerase V (pol V) has relatively poor sugar discrimination and frequently misincorporates ribonucleotides. Substitution of a steric gate tyrosine residue with alanine (umuC_Y11A) reduces sugar selectivity further and allows pol V to readily misincorporate ribonucleotides as easily as deoxynucleotides, whilst leaving its poor base-substitution fidelity essentially unchanged. However, the mutability of cells expressing the steric gate pol V mutant is very low due to efficient repair mechanisms that are triggered by the misincorporated rNMPs. Comparison of the mutation frequency between strains expressing wild-type and mutant pol V therefore allows us to identify pathways specifically directed at ribonucleotide excision repair (RER). We previously demonstrated that rNMPs incorporated by umuC_Y11A are efficiently removed from DNA in a repair pathway initiated by RNase HII. Using the same approach, we show here that mismatch repair and base excision repair play minimal back-up roles in RER in vivo. In contrast, in the absence of functional RNase HII, umuC_Y11A-dependent mutagenesis increases significantly in ΔuvrA, uvrB5 and ΔuvrC strains, suggesting that rNMPs misincorporated into DNA are actively repaired by nucleotide excision repair (NER) in vivo. Participation of NER in RER was confirmed by reconstituting ribonucleotide-dependent NER in vitro. We show that UvrABC nuclease-catalyzed incisions are readily made on DNA templates containing one, two, or five rNMPs and that the reactions are stimulated by the presence of mispaired bases. Similar to NER of DNA lesions, excision of rNMPs proceeds through dual incisions made at the 8(th) phosphodiester bond 5' and 4(th)-5(th) phosphodiester bonds 3' of the ribonucleotide. Ribonucleotides misinserted into DNA can therefore be added to the broad list of helix-distorting modifications that are substrates for NER.


Transmission of Ebola virus from pigs to non-human primates.
Ebola viruses (EBOV) cause often fatal hemorrhagic fever in several species of simian primates including human. While fruit bats are considered natural reservoir, involvement of other species in EBOV transmission is unclear. In 2009, Reston-EBOV was the first EBOV detected in swine with indicated transmission to humans. In-contact transmission of Zaire-EBOV (ZEBOV) between pigs was demonstrated experimentally. Here we show ZEBOV transmission from pigs to cynomolgus macaques without direct contact. Interestingly, transmission between macaques in similar housing conditions was never observed. Piglets inoculated oro-nasally with ZEBOV were transferred to the room housing macaques in an open inaccessible cage system. All macaques became infected. Infectious virus was detected in oro-nasal swabs of piglets, and in blood, swabs, and tissues of macaques. This is the first report of experimental interspecies virus transmission, with the macaques also used as a human surrogate. Our finding may influence prevention and control measures during EBOV outbreaks.


Mechanical disruption of dentin collagen fibrils during resin-dentin bond testing.
To determine if collagen fibrils on the dentin side of failed resin-dentin interfaces undergo mechanical disruption during microtensile bond testing. Extracted, caries-free human third molars were divided into four groups. The occlusal enamel was removed, leaving a flat dentin surface for bonding. Resin composite buildups were made after the acid-conditioned dentin was bonded with either Single Bond (S) or One-Step (O), and using either moist bonding (M) or air drying for 5 s (D). After storage in water for 24 h, the teeth were vertically sectioned into an array of 0.9 x 0.9 mm resin composite-dentin beams. They were stressed to failure using the nontrimming version of the microtensile bond test. Fractured dentin and resin composite sides of representative beams from each group that exhibited adhesive failures under light microscopy examination were prepared for scanning (SEM) and transmission electron microscopy (TEM). A two-way ANOVA showed that moist bond strengths were significantly higher than those made to dry dentin (M > D; p < 0.001), but that there was no difference between the adhesives (S vs O; p = 0.547). SEM analysis showed the presence of loose collagen fibrils within fractured hybrid layers in the dry groups, but not in the moist groups. TEM examination of the dry-bonded groups revealed collagen fibrils that were thinner and exhibited abnormally wide interfibrillar spaces when hybrid layers were intact. Within dry-bonded fractured hybrid layers, broad mechanical disruption zones could be seen, consisting of fibrils that were devoid of cross banding, defibrillation of the subfibrillar architecture, and gross disaggregation into microfibrils. In the moist-bonded groups, only short mechanical disruption zones were found along the torn edges of the collagen fibrils. The rest of the fibrils beyond the fracture site were intact and retained their periodicity. Mechanical testing of demineralized matrices yielded a maximum modulus of elasticity of 43.9 +/- 6.1 MPa. We speculate that adhesive resin has a protective function for demineralized collagen in well-infiltrated hybrid layers. We propose that both the collagen and resin contribute to load sharing during stress application until the final moment of rupture. On the other hand, collagen fibrils in poorly infiltrated hybrid layers, being unsupported by resin, undergo various degrees of irreversible mechanical disruption depending on how the stress is dissipated. The collagen fibril network has a much lower modulus of elasticity compared to those of resin-infiltrated fibrils or the demineralized dentin.


Chronic subdural hematoma in the elderly: not a benign disease.
Chronic subdural hematoma (CSDH) is perceived to be a "benign," easily treated condition in the elderly, but reported follow-up periods are brief, usually limited to acute hospitalization. The authors conducted a retrospective review of data obtained in a prospectively identified consecutive series of adult patients admitted to their institution between September 2000 and February 2008 and in whom there was a CT diagnosis of CSDH. Survival data were compared to life-table data. Of the 209 cases analyzed, 63% were men and the mean age was 80.6 years (range 65-96 years). Primary surgical interventions performed were bur holes in 21 patients, twist-drill closed-system drainage in 44, and craniotomies in 72. An additional 72 patients were simply observed. Reoperations were recorded in 5 patients-4 who had previously undergone twist-drill drainage and 1 who had previously undergone a bur hole procedure (p = 0.41, chi-square analysis). Thirty-five patients (16.7%) died in hospital, 130 were discharged to rehabilitation or a skilled care facility, and 44 returned home. The follow-up period extended to a maximum of 8.3 years (median 1.45 years). Six-month and 1-year mortality rates were 26.3% and 32%, respectively. In the multivariate analysis (step-wise logistic regression), the sole factor that predicted in-hospital death was neurological status on admission (OR 2.1, p = 0.02, for each step). Following discharge, the median survival in the remaining cohort was 4.4 years. In the Cox proportional hazards model, only age (hazard ratio [HR] 1.06/year, p = 0.02) and discharge to home (HR 0.24, p = 0.01) were related to survival, whereas the type of intervention, whether surgery was performed, size of subdural hematoma, amount of shift, bilateral subdural hematomas, and anticoagulant agent use did not affect the long- or short-term mortality rate. Comparison of postdischarge survival and anticipated actuarial survival demonstrated a markedly increased mortality rate in the CSDH group (median survival 4.4 vs 6 years, respectively; HR 1.94, p = 0.0002, log-rank test). This excess mortality rate was also observed at 6 months postdischarge with evidence of normalization only at 1 year. In this first report of the long-term outcome of elderly patients with CSDH the authors observed persistent excess mortality up to 1 year beyond diagnosis. This belies the notion that CSDH is a benign disease and indicates it is a marker of other underlying chronic diseases similar to hip fracture.


Serological response patterns of melanoma patients immunized with a GM2 ganglioside conjugate vaccine.
Gangliosides, such as GM2, GD2, GD3, and 9-O-acetyl GD3, are receiving attention as targets for antibody-based and vaccine-based therapies of melanoma. GM2 appears to be a particularly immunogenic ganglioside in humans, as indicated by the presence of naturally occurring IgM anti-GM2 antibodies in approximately 5% of humans and the fact that immunization with irradiated GM2-expressing melanoma cells or purified GM2 adherent to bacillus Calmette-Guérin elicits GM2 antibodies of low to moderate titers in a high proportion of vaccinated patients. To develop vaccines that consistently induce high titers of IgM as well as IgG anti-GM2 antibodies, vaccines containing GM2 conjugated to keyhole limpet hemocyanin as the carrier protein and QS-21 as the adjuvant have been constructed. The serological response of vaccinated patients was monitored by ELISA using purified GM2 ganglioside for IgM and IgG anti-GM2 antibodies and for GM2 cell surface-reactive antibodies by immune adherence assays and cytotoxic tests (IgM antibodies) and mixed hemadsorption assays (IgG antibodies). The majority of vaccinated patients developed IgM and IgG antibodies detectable by ELISA. In most cases, the results of IgM ELISA correlated with assays for cell surface-reactive IgM antibodies. This was not true for IgG anti-GM2 antibodies, where strong discrepancies were seen between high titers in ELISA and little or no reactivity in mixed hemadsorption tests for cell surface-reactive antibodies. These IgG antibodies (and the less frequent IgM antibodies that show similar discrepancies) may be directed against GM2 determinants that are buried, hidden, or not present on GM2-expressing target cells. With regard to a major objective of ganglioside vaccines--i.e., generation of cytotoxic antibodies--the GM2-keyhole limpet hemocyanin/QS-21 vaccine is clearly superior to the previously tested GM2/bacillus Calmette-Guérin vaccine. However, variability in patient response and lack of persistence of high-titered IgM cytotoxic antibodies in many patients are problems that remain to be solved.


Release pathways of interferon α2a molecules from lipid twin screw extrudates revealed by single molecule fluorescence microscopy.
The pathways of interferon α2a release from a triglyceride based implant system were studied by single molecule fluorescence microscopy. The protein was labeled with a stable fluorescent dye ATTO647N, freeze-dried and embedded into the lipid matrix via twin-screw extrusion. The implant system consisted of a pore-forming agent (water soluble PEG 6000) and two types of triglycerides with different melting ranges which allowed the production of the implants at moderate temperatures and without the use of organic solvents. Single molecule microscopy and single particle tracking of labeled proteins contained in these implants revealed that two populations of diffusing proteins were present. Moreover, proteins were not only released via water-filled pores (created by dissolution of the pore-former), but surprisingly also through diffusion in a phase of molten lipid. Diffusion coefficients of IFNα 2a derived by tracking of individual protein molecules within the implant system were similar to diffusion coefficients obtained from control measurements in pure molten lipid and highly concentrated solutions of PEG 6000. In conclusion, tracking of individual protein molecules was successfully used to elucidate the release pathways of proteins from a relevant lipid based implant system.


Rho-kinase inhibitor coupled to peptide-modified albumin carrier reduces portal pressure and increases renal perfusion in cirrhotic rats.
Rho-kinase (ROCK) activation in hepatic stellate cells (HSC) is a key mechanism promoting liver fibrosis and portal hypertension (PTH). Specific delivery of ROCK-inhibitor Y-27632 (Y27) to HSC targeting mannose-6-phosphate-receptors reduces portal pressure and fibrogenesis. In decompensated cirrhosis, presence of ascites is associated with reduced renal perfusion. Since in cirrhosis, platelet-derived growth factor receptor beta (PDGFRβ) is upregulated in the liver as well as the kidney, this study coupled Y27 to human serum albumin (HSA) substituted with PDGFRβ-recognizing peptides (pPB), and investigated its effect on PTH in cirrhotic rats. In vitro collagen contraction assays tested biological activity on LX2 cells. Hemodynamics were analyzed in BDL and CCl4 cirrhotic rats 3 h, 6 h and 24 h after i.v. administration of Y27pPBHSA (0.5/1 mg/kg b.w). Phosphorylation of moesin and myosin light chain (MLC) assessed ROCK activity in liver, femoral muscle, mesenteric artery, kidney and heart. Three Y27 molecules were coupled to pPBHSA as confirmed by HPLC/MS, which was sufficient to relax LX2 cells. In vivo, Y27pPBHSA-treated rats exhibited lower portal pressure, hepatic vascular resistance without effect on systemic vascular resistance, but a tendency towards lower cardiac output compared to non-treated cirrhotic rats. Y27pPBHSA reduced intrahepatic resistance by reduction of phosphorylation of moesin and MLC in Y27pPBHSA-treated cirrhotic rats. Y27pPBHSA was found in the liver of rats up to 6 hours after its injection, in the HSC demonstrated by double-immunostainings. Interestingly, Y27pPBHSA increased renal arterial flow over time combined with an antifibrotic effect as shown by decreased renal acta2 and col1a1 mRNA expression. Therefore, targeting the ROCK inhibitor Y27 to PDGFRβ decreases portal pressure with potential beneficial effects in the kidney. This unique approach should be tested in human cirrhosis.


Vascular cell adhesion molecule-1: a viable therapeutic target for atherosclerosis?
Atherosclerosis is now well recognised as a chronic inflammatory process which may ultimately lead to myocardial infarction, stroke and peripheral vascular disease. The role of inflammation in the pathogenesis of atherosclerosis has lead to interest in developing therapies that target vascular inflammation. Leucocytes play a key role during atherosclerotic plaque development. Activated vascular endothelium expresses vascular cell adhesion cell molecule-1 (VCAM-1), a member of the adhesion molecule superfamily, to which monocytes and lymphocytes can bind. These inflammatory cells can then move through the endothelium by diapedesis and release cytokines and enzymes, important components in the progression of the lesion. Researchers have demonstrated that the extent of atherosclerotic lesions is significantly reduced in animal models with decreased VCAM-1 expression. VCAM-1 has therefore been identified as a potential anti-inflammatory therapeutic target, the hypothesis being that reduced expression of VCAM-1 will slow the development of atherosclerosis. Succinobucol (AGI-1067), an anti-oxidant compound also capable of inhibiting VCAM-1 gene expression, is an example of such an agent and is currently being investigated in a phase III cardiovascular end-point trial due to report in 2007. If the results are positive, further investigations should derive to what extent blockade of VCAM-1 by succinobucol, rather than its other effects, accounts for the reduction in vascular events.


School performance after experiencing trauma: a longitudinal study of school functioning in survivors of the Utøya shootings in 2011.
The psychological impact on survivors of terrorism has been well documented. However, studies on adolescent survivors and the academic performance of high school students following a terrorist attack are lacking. This study investigated academic performance, absenteeism, and school support amongst survivors of a terrorist attack in Norway. Data from a longitudinal interview study were linked to officially registered grades of students (N=64) who successfully completed their 3-year senior high school program. Statistical tests of mean differences and linear regression were used to compare the survivors' registered grades with the national grade point average, before and after the event, as well as to assess absenteeism, self-reported grades and to test the association with school support. The students' grades were lower the year after the event than they had been the year before, and they were also lower than the national grade point average (p<0.001). However, their grades improved in the last year of high school, indicating possible recovery. Absence from school increased after the event, compared to the previous year. However, students reported high satisfaction with school support. The results indicate that academic functioning was reduced in the year after the traumatic event, but for students who successfully completed high school, the school situation improved 2 years after the event. The findings underscore the importance of keeping trauma-exposed students in school and providing support over time. A more defined educational approach to maintaining school attendance and educational measures which compensate for learning loss are needed in trauma-sensitive teaching.


Posttraumatic stress disorder in veterans and military personnel: epidemiology, screening, and case recognition.
Posttraumatic stress disorder (PTSD) is a psychiatric disorder that affects 7-8% of the general U.S. population at some point during their lifetime; however, the prevalence is much higher among certain subgroups, including active duty military personnel and veterans. In this article, we review the empirical literature on the epidemiology and screening of PTSD in military and veteran populations, including the availability of sensitive and reliable screening tools. Although estimates vary across studies, evidence suggests that the prevalence of PTSD in deployed U.S. military personnel may be as high as 14-16%. Prior studies have identified trauma characteristics and pre- and posttrauma factors that increase risk of PTSD among veterans and military personnel. This information may help to inform prevention and screening efforts, as screening programs could be targeted to high-risk populations. Large-scale screening efforts have recently been implemented by the U.S. Departments of Defense and Veterans Affairs. Given the prevalence and potential consequences of PTSD among veterans and active duty military personnel, development and continued evaluation of effective screening methods is an important public health need.


Moderate alcohol consumption and stroke. The epidemiologic evidence.
An extensive search of the English-language literature identified 62 epidemiologic studies that examined the relation between moderate alcohol consumption and risk of stroke. Moderate drinking (less than 60 g ethanol/day) and ischemic stroke have a complex association that might be explained by interaction with race; a J-shaped association has been found in predominantly white populations, while little (if any) association has been found among Japanese. By contrast, moderate drinking increases risk of both intracerebral and subarachnoid hemorrhage in diverse populations. There is insufficient epidemiologic evidence to conclude whether recent alcohol use affects risk of either ischemic or hemorrhagic stroke. These distinctive associations help explain contradictory reports on the relation between moderate alcohol consumption and risk of "stroke." The high prevalence of alcohol use throughout the world suggests opportunities for primary prevention and the importance of continued research in this area.


Hyperuniformity in amorphous silicon based on the measurement of the infinite-wavelength limit of the structure factor.
We report the results of highly sensitive transmission X-ray scattering measurements performed at the Advanced Photon Source, Argonne National Laboratory, on nearly fully dense high-purity amorphous-silicon (a-Si) samples for the purpose of determining their degree of hyperuniformity. A perfectly hyperuniform structure has complete suppression of infinite-wavelength density fluctuations, or, equivalently, the structure factor S(q→0) = 0; the smaller the value of S(0), the higher the degree of hyperuniformity. Annealing was observed to increase the degree of hyperuniformity in a-Si where we found S(0) = 0.0075 (±0.0005), which is significantly below the computationally determined lower bound recently suggested by de Graff and Thorpe [de Graff AMR, Thorpe MF (2010) Acta Crystallogr A 66(Pt 1):22-31] based on studies of continuous random network models, but consistent with the recently proposed nearly hyperuniform network picture of a-Si. Increasing hyperuniformity is correlated with narrowing of the first diffraction peak and extension of the range of oscillations in the pair distribution function.


Cold ischemia time and allograft outcomes in live donor renal transplantation: is live donor organ transport feasible?
One of the greatest obstacles to the implementation of regional or national kidney paired donation programs (KPD) is the need for the donor to travel to their matched recipient's hospital. While transport of the kidney is an attractive alternative, there is concern that prolonged cold ischemia time (CIT) would diminish the benefits of live donor transplantation (LDTx). To examine the impact of increased CIT in LDTx, 1-year serum creatinine (SCr), delayed graft function (DGF), acute rejection (AR) and allograft survival (AS) were analyzed in 38 467 patients by 2 h CIT groups (0-2, 2-4, 4-6 and 6-8 h) using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN). Adjusted probabilities of DGF and AR were estimated in multivariate logistic regression models and AS was examined in multivariate Cox proportional hazards models. Although some increase in DGF was observed between the 0-2 h (4.7%) and 4-6 h (8.3%) groups, prolonged CIT did not result in inferior SCr, increased AR or compromised AS in any group with >2 h CIT compared with the 0-2 h group. Comparable long-term outcomes for these grafts suggests that transport of live donor organs may be a feasible alternative to donor travel in KPD regions where CIT can be limited to 8 h.


Alterations in the neurotrophic factors BDNF, GDNF and CNTF in the regenerating olfactory system.
Neurogenesis, axonal outgrowth and synapse formation are usually restricted to specific stages during central nervous system development, but the mature olfactory system maintains these capacities. The cycle of neuronal turnover can be experimentally induced by surgical ablation of the olfactory bulb (OB). We are interested in the growth factor regulation of these processes and the trophic role played by the target tissue, the OB. We studied the immunohistochemical expression of three neurotrophic factors, brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the rat olfactory neuroepithelium (ON) and OB and in target-deprived ON at 1, 3 and 12 weeks post unilateral bulbectomy. We found BDNF immunoreactivity (IR) was restricted to the basal cells and did not alter postbulbectomy. GDNF-IR was expressed by mature olfactory receptor neurons (ORNs), their axons and target cells in the OB in controls, but was absent from the ON postbulbectomy. Hence, the expression of GDNF by ORNs was found to be target-dependent. CNTF-IR was present in ORNs and their target cells in the OB, in basal cells and in some immature ORNs. Postbulbectomy, CNTF-IR was unaltered in the basal cells, and very low levels were detectable in maturing ORNs in the ON. Our results indicate that these three factors may contribute to the trophic regulation of this neuronal pathway in a coordinated fashion. Previous work has shown that BDNF promotes survival of ORNs in vitro, and TrkB expression has been found in both immature and mature ORNs. Hence, BDNF produced by basal cells may be acting locally on neurons expressing TrkB. Expression of CNTF by both the basal cells and the ORNs suggests that it may play an integral role in this neuronal differentiation pathway. Finally, the expression of GDNF exclusively by mature ORNs in the ON, its presence in the target cells in the OB and abolition of expression by bulbectomy, suggests that it may be target-derived. This provides a major mechanism by which the bulb could exert trophic influences on ORNs.


Basal bodies and associated structures are not required for normal flagellar motion or phototaxis in the green alga Chlorogonium elongatum.
The interphase flagellar apparatus of the green alga Chlorogonium elongatum resembles that of Chlamydomonas reinhardtii in the possession of microtubular rootlets and striated fibers. However, Chlorogonium, unlike Chlamydomonas, retains functional flagella during cell division. In dividing cells, the basal bodies and associated structures are no longer present at the flagellar bases, but have apparently detached and migrated towards the cell equator before the first mitosis. The transition regions remain with the flagella, which are now attached to a large apical mitochondrion by cross-striated filamentous components. Both dividing and nondividing cells of Chlorogonium propagate asymmetrical ciliary-type waveforms during forward swimming and symmetrical flagellar-type waveforms during reverse swimming. High-speed cinephotomicrographic analysis indicates that waveforms, beat frequency, and flagellar coordination are similar in both cell types. This indicates that basal bodies, striated fibers, and microtubular rootlets are not required for the initiation of flagellar beat, coordination of the two flagella, or determination of flagellar waveform. Dividing cells display a strong net negative phototaxis comparable to that of nondividing cells; hence, none of these structures are required for the transmission or processing of the signals involved in phototaxis, or for the changes in flagellar beat that lead to phototactic turning. Therefore, all of the machinery directly involved in the control of flagellar motion is contained within the axoneme and/or transition region. The timing of formation and the positioning of the newly formed basal structures in each of the daughter cells suggests that they play a significant role in cellular morphogenesis.


The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts.
Anecdotal evidence suggests that birds have smaller intestines than mammals. In the present analysis, we show that small birds and bats have significantly shorter small intestines and less small intestine nominal (smooth bore tube) surface area than similarly sized nonflying mammals. The corresponding >50% reduction in intestinal volume and hence mass of digesta carried is advantageous because the energetic costs of flight increase with load carried. But, a central dilemma is how birds and bats satisfy relatively high energy needs with less absorptive surface area. Here, we further show that an enhanced paracellular pathway for intestinal absorption of water-soluble nutrients such as glucose and amino acids may compensate for reduced small intestines in volant vertebrates. The evidence is that l-rhamnose and other similarly sized, metabolically inert, nonactively transported monosaccharides are absorbed significantly more in small birds and bats than in nonflying mammals. To broaden our comparison and test the veracity of our finding we surveyed the literature for other similar studies of paracellular absorption. The patterns found in our focal species held up when we included other species surveyed in our analysis. Significantly greater amplification of digestive surface area by villi in small birds, also uncovered by our analysis, may provide one mechanistic explanation for the observation of higher paracellular absorption relative to nonflying mammals. It appears that reduced intestinal size and relatively enhanced intestinal paracellular absorption can be added to the suite of adaptations that have evolved in actively flying vertebrates.


The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone.
The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity. A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years. Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia. These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.


[Overweight, obesity and chronic mal nutrition in 6 to 9 year-old children in Peru, 2009-2010].
To determine the prevalence of overweight, obesity and chronic malnutrition in 6- to 9-year-old children in Peru. A cross-cutting study based on the 2009-2010 National Household Survey. The size/age ratio was analyzed with references of the National Center for Health Statistic (NCSH) and the World Health Organization (WHO), considering less than two standard deviations for chronic malnutrition (CM); and the Must and WHO reference tables to measure the body mass index with 85 to 95 percentile values for overweight and above 95 for obesity. With Must as reference, overweight was 12.1% and obesity 9.4%, and according to WHO overweight and obesity were 10.2 and 11.3% respectively. The prevalence of CM according to NCSH and WHO is 15.4 and 17.8% respectively. The highest prevalence of CM is in the north (25.2%), center (22.9%) and south of (19%) the Highland, while obesity is more present in the south coast (28%), Metropolitan Lima (22.8%) and the central Coast (22.5%). Of all the children with CM, 6.5% has overweight and 1.2% obesity. CM is decreasing because size averages have improved, however obesity has doubled. The presence of CM and obesity in children aged 6 to 9 years old in different regions of Peru poses a challenge in the planning of food and nutrition policies.


[Adiposity and psychological well-being: effects of physical activity on university students in Valencia, Spain].
To determine, through the use of a structural equation model, the relationships that exist between physical activity, body fat, perceived physical ability, and three indicators of psychological well-being, in a sample of Spanish university students. A descriptive cross-sectional study of 639 students 18-29 years of age representative of the universities of Valencia, Spain, during the 2005-2006 term. Physical exercise was rated by taking an inventory of healthy behaviors among students. The following scales were applied: self-perceived physical ability, self-esteem, satisfaction with life, and subjective vitality. Body fat was expressed as the percentage of fat mass (PFM). A theoretical model was devised using six measured variables. The participants' level of physical activity was moderate; they perceived themselves to be physically competent; had high self-esteem; were satisfied with life; and had high vitality. Physical activity was negatively correlated with PFM in men and women alike; and negatively associated with perceived physical ability; while perceived physical ability was positively associated with self-esteem, life satisfaction, and subjective vitality. The effect of physical activity on perceived competence was mediated in part by PFM in men. In women, exercise was directly correlated to PFM, as well as perceived ability, without PFM mediation. Increased physical activity is of great value to public health because, in addition to helping to reduce body fat, it improves psychological well-being and self-image.