The role of dietary lipid in the regulation of unconjugated hyperbilirubinaemia in Gunn rats.
1. The purpose of this study was to characterize the mechanisms of diet-induced hyperbilirubinaemia in Gunn rats with emphasis on the role of lipids, and to examine their relationship with regard to fasting hyperbilirubinaemia. 2. A lipid-free normocaloric diet produced a threefold increase in plasma bilirubin concentration (baseline 109.4 mumol/l), which was maximal by 10 days and thereafter remained constant. The level of hyperbilirubinaemia attained was not influenced by fasting or phenobarbitone, and returned to baseline concentration within 10 days of resuming a normal diet. 3. Determination of hepatic bilirubin showed that the magnitude of the hepatic bilirubin pool was increased by the lipid-free diet but was unchanged by fasting. Hepatic ligandin concentrations were comparable in fasted Gunn rats and those fed normal or lipid-free diets, although total hepatic ligandin was reduced in the fasted animals. 4. The hyperbilirubinaemic effect of the lipid-free diet was largely reversed by the inclusion of 10% lipid in the diet and was affected to a lesser extent by 5% lipid. Similar reductions in plasma bilirubin concentration were observed with a variety of other lipids (10%), regardless of their fatty acid chain length or degree of saturation. 5. In fasting animals a direct correlation was observed between plasma bilirubin and free fatty acid concentrations and insulin levels were greatly depressed, whereas in those fed on the lipid-free diet no significant changes were evident in plasma concentrations of free fatty acids or insulin. 6. Plasma bilirubin concentration was unrelated to alterations in plasma triglycerides produced by the administration of clofibrate. However, an unexplained decrease in plasma bilirubin (40%) without a significant change in triglycerides was noted when clofibrate was added to the lipid-free diet. 7. Analysis of kinetic data obtained from [14C]bilirubin clearance studies revealed that hyperbilirubinaemia associated with the lipid-free diet reflected a marked reduction (60%) in plasma clearance with no change in bilirubin turnover. This was accompanied by a relative redistribution of bilirubin from the extravascular pool to the plasma pool. 8. Although these studies indicate that fasting and the withdrawal of dietary lipid have some similar effects on bilirubin metabolism, it seems likely that different mechanisms are responsible for the hyperbilirubinaemia.


Surgery increases survival in patients with gastrinoma.
To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery. The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival. Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies. The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8-12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002). These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.


An evaluation of the relevance of routine DNA typing of fingernail clippings for forensic casework.
DNA extracted from fingernail clippings of victims in forensic cases is a possible source of DNA from the perpetrator in cases where victims struggled or defended themselves. The source of this DNA on a victim's fingernails could possibly originate from contact with the suspect's blood, saliva, semen or scratched skin. In this technical note we evaluate the relevance of routine DNA typing of fingernail clippings in the forensic biology laboratory when, in real casework, normally only small quantities of nail material is sent. This was carried out by extracting DNA from fingernail clippings from a number of volunteers, before and after aggressively scratching other volunteers. No blood was drawn from the scratching, but skin flakes were observed under the nails before cutting and subsequent DNA typing. The DNA extracted was then typed using the STR systems: HUMTHO1, HUMTPOX and HUMCSF1PO (CTT triplex) and the system of D1S80. These profiles were compared with profiles achieved by similar typing of buccal swabs as a reference from each volunteer. In this study, the profile detected from each volunteer's clippings was the same before and after scratching, and matched the profile of the corresponding volunteer as defined by typing each volunteer's reference buccal swab. Fingernail clippings that are sent to our lab in actual casework are usually so small that additional treatment by swabbing or removing debris from below the clipping is not possible. For this reason, in this simulation the entire clippings were used for DNA extraction, to maximize the possibility of finding an additional profile. In conclusion, the findings from this study show that although the profiles obtained when typing fingernail clippings are those of the donors themselves, we suggest that typing of fingernail clippings should be carried out in forensic cases only when relevant. We would suggest that fingernail clippings not be routinely sent to the biology laboratory as items of evidence to be tested.


Rabbit-immunoglobulin G levels in patients receiving thymoglobulin as part of conditioning before unrelated donor stem cell transplantation.
The role of serum concentrations of rabbit antithymoglobulin (ATG) in the development of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) with unrelated donors is unknown. We determined the serum concentration of rabbit immunoglobulin-G (IgG) using an enzyme linked immunosorbent assay in 61 patients after unrelated donor HSCT. The doses of ATG ranged between 4 and 10 mg/kg. The conditioning consisted mainly of cyclophosphamide and total body irradiation or busulfan. Most patients received GVHD prophylaxis with cyclosporine and methotrexate. The rabbit IgG levels varied widely in each dose group. The levels of rabbit IgG gradually declined and could still be detected up to five weeks after HSCT. We found a correlation between the grade of acute GVHD and the concentration of rabbit IgG in serum before the transplantation (p=0.017). Patients with serum levels of rabbit IgG >70 mg/mL before HSCT ran a very low risk of developing acute GVHD grades II-IV, as compared to those with levels <70 mg/mL (11% vs. 48%, p=0.006). The measurement of rabbit IgG levels in patients receiving ATG as prophylaxis against GVHD after HSCT may be of value in lowering the risk of severe GVHD.


Telecentric 3D profilometry based on phase-shifting fringe projection.
Three dimensional shape measurement in the microscopic range becomes increasingly important with the development of micro manufacturing technology. Microscopic fringe projection techniques offer a fast, robust, and full-field measurement for field sizes from approximately 1 mm2 to several cm2. However, the depth of field is very small due to the imaging of non-telecentric microscope, which is often not sufficient to measure the complete depth of a 3D-object. And the calibration of phase-to-depth conversion is complicated which need a precision translation stage and a reference plane. In this paper, we propose a novel telecentric phase-shifting projected fringe profilometry for small and thick objects. Telecentric imaging extends the depth of field approximately to millimeter order, which is much larger than that of microscopy. To avoid the complicated phase-to-depth conversion in microscopic fringe projection, we develop a new system calibration method of camera and projector based on telecentric imaging model. Based on these, a 3D reconstruction of telecentric imaging is presented with stereovision aided by fringe phase maps. Experiments demonstrated the feasibility and high measurement accuracy of the proposed system for thick object.


Effect of adenovirus infection on expression of human histone genes.
The influence of adenovirus type 2 infection of HeLa cells upon expression of human histone genes was examined as a function of the period of infection. Histone RNA synthesis was assayed after run-off transcription in nuclei isolated from mock-infected cells and after various periods of adenovirus infection. Histone protein synthesis was measured by [3H]leucine labeling of intact cells and fluorography of electrophoretically fractionated nuclear and cytoplasmic proteins. The cellular representation of RNA species complementary to more than 13 different human histone genes was determined by RNA blot analysis of total cellular, nuclear or cytoplasmic RNA by using a series of 32P-labeled cloned human histone genes as hybridization probes and also by analysis of 3H-labeled histone mRNA species synthesized in intact cells. By 18 h after infection, HeLa cell DNA synthesis and all parameters of histone gene expression, including transcription and the nuclear and cytoplasmic concentrations of core and H1 mRNA species, were reduced to less than 5 to 10% of the control values. By contrast, transcription and processing of other cellular mRNA sequences have been shown to continue throughout this period of infection. The early period of adenovirus infection was marked by an inhibition of transcription of histone genes that accompanied the reduction in rate of HeLa cell DNA synthesis. These results suggest that the adenovirus-induced inhibition of histone gene expression is mediated in part at the transcriptional level. However, the persistence of histone mRNA species at concentrations comparable to those of mock-infected control cells during the early phase of the infection, despite a reduction in histone gene transcription and histone protein synthesis, implies that histone gene expression is also regulated post-transcriptionally in adenovirus-infected cells. These results suggest that the tight coupling between histone mRNA concentrations and the rate of cellular DNA synthesis, observed when DNA replication is inhibited by a variety of drugs, is not maintained after adenovirus infection.


How regularity representations of short sound patterns that are based on relative or absolute pitch information establish over time: An EEG study.
The recognition of sound patterns in speech or music (e.g., a melody that is played in different keys) requires knowledge about pitch relations between successive sounds. We investigated the formation of regularity representations for sound patterns in an event-related potential (ERP) study. A pattern, which consisted of six concatenated 50 ms tone segments differing in fundamental frequency, was presented 1, 2, 3, 6, or 12 times and then replaced by another pattern by randomly changing the pitch of the tonal segments (roving standard paradigm). In an absolute repetition condition, patterns were repeated identically, whereas in a transposed condition, only the pitch relations of the tonal segments of the patterns were repeated, while the entire patterns were shifted up or down in pitch. During ERP measurement participants were not informed about the pattern repetition rule, but were instructed to discriminate rarely occurring targets of lower or higher sound intensity. EPRs for pattern changes (mismatch negativity, MMN; and P3a) and for pattern repetitions (repetition positivity, RP) revealed that the auditory system is able to rapidly extract regularities from unfamiliar complex sound patterns even when absolute pitch varies. Yet, enhanced RP and P3a amplitudes, and improved behavioral performance measured in a post-hoc test, in the absolute as compared with the transposed condition suggest that it is more difficult to encode patterns without absolute pitch information. This is explained by dissociable processing of standards and deviants as well as a back propagation mechanism to early sensory processing stages, which is effective after less repetitions of a standard stimulus for absolute pitch.


A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517.
We performed a phase II study of oral vorinostat (200 mg twice daily, days 1-14 of a 21-day cycle), a histone and protein deacetylase inhibitor, to examine efficacy and tolerability in patients with relapsed/refractory Hodgkin lymphoma (HL) with ≤ 5 prior therapies. The primary endpoint was the objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), safety and tolerability. A two-stage design was used for patient accrual. Twenty-five eligible patients were accrued in the first stage. Median time on treatment was 3.8 months. The ORR was 4% (one partial response). Median PFS was 4.8 months. The drug was well tolerated. The second stage of accrual was not opened due to few objective responses. Oral vorinostat has limited single-agent activity in relapsed/refractory HL. There was one partial response, while seven other patients had stable disease for > 1 year, including two with stable disease for nearly 3 years, suggesting that further studies in combination with other active agents in this setting may be warranted.


Retrosigmoid craniotomy for clipping of two vertebrobasilar junction aneurysms.
In this operative video, we demonstrate the approach to a 10-mm distal left vertebral artery and proximal basilar artery blister aneurysm in a 62-year-old male presenting with subarachnoid hemorrhage. He initially underwent clipping of the ruptured ACoA aneurysm and two incidental right MCA aneurysms. Ten days later, the posterior circulation aneurysms were clipped through an extended retrosigmoid approach, working between cranial nerves 9-11 inferiorly and 7-8 superiorly. The vertebral artery was accessible from its dural entry site to the vertebrobasilar junction with the rostral limit of the exposure at the level of the tentorium. He underwent uneventful clipping of all aneurysms without postoperative morbidity. The video can be found here: http://youtu.be/PaZM7ecBCB0 .


Year in school and physical activity stage of change as discriminators of variation in the physical activity correlate profile of adolescent females.
Knowledge of the physical activity correlate profile of adolescent females will provide insight into decreasing physical activity patterns among adolescent females. Correlates of physical activity and physical activity stage of change were assessed during 2007-2008 among 871 Irish adolescent females in years 1-6 in secondary schools (15.28 ± 1.8 years). Multivariate Analysis of Variance was used to identify whether differences in correlates of physical activity could be detected across year in school and physical activity stages of change. Significant differences (P < .01) were found in 11 of the 16 measured correlates across year in school and in 14 of the 16 correlates across stage of change. Effect size estimates and regression analysis revealed perceived competence, peer social support and intention to be physically active (partial eta range (ηp2) .21-.25) to be the most important predictors of physical activity stage of change. Females in more senior years in school and in earlier physical activity stages of change reported a significantly less positive physical activity correlate profile than females in junior years and in later physical activity stages of change. This finding supports the construct validity of the physical activity stages of change.


Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells.
Anergic CD4+ Th cells do not produce IL-2 when challenged with Ag-pulsed accessory cells because of a transcriptional defect. In this work, we report that these anergic T cells are defective in their ability to up-regulate protein binding and transactivation at two critical IL-2 DNA enhancer elements: NF-AT (nuclear factor of activated T cells; a sequence that binds a heterotrimeric NFATp, Fos, and Jun protein complex) and Activator Protein-1 (AP-1) (that binds Fos and Jun heterodimers). Western blot analysis of nuclear extracts showed that the impaired DNA-protein interactions in anergic T cells were associated with poor expression of the inducible AP-1 family members c-Fos, FosB, and JunB. However, the reduced expression of these proteins was not the result of a global TCR/CD3-signaling defect because CD3 cross-linking induced an equivalent increase in intracellular-free calcium ions, as well as NFATp dephosphorylation, translocation to the nucleus, and DNA binding in both normal and anergic T cells. Thus, defective IL-2 gene transcription appears to be due, at least in part, to a selective block in the expression of the AP-1 Fos and Jun family members in anergic T cells.


Complications and outcomes after spinal deformity surgery in the elderly: review of the existing literature and future directions.
The elderly population (age > 60 years) is the fastest-growing age group in the US. Spinal deformity is a major problem affecting the elderly and, therefore, the demand for surgery for spinal deformity is becoming increasingly prevalent in elderly patients. Much of the literature on surgery for adult deformity focuses on patients who are younger than 60 years, and therefore there is limited information about the complications and outcomes of surgery in the elderly population. In this study, the authors undertook a review of the literature on spinal deformity surgery in patients older than 60 years. The authors discuss their analysis with a focus on outcomes, complications, discrepancies between individual studies, and strategies for complication avoidance. A systematic review of the MEDLINE and PubMed databases was performed to identify articles published from 1950 to the present using the following key words: "adult scoliosis surgery" and "adult spine deformity surgery." Exclusion criteria included patient age younger than 60 years. Data on major Oswestry Disability Index (ODI) scores, visual analog scale (VAS) scores, patient-reported outcomes, and complications were recorded. Twenty-two articles were obtained and are included in this review. The mean age was 74.2 years, and the mean follow-up period was 3 years. The mean preoperative ODI was 48.6, and the mean postoperative reduction in ODI was 24.1. The mean preoperative VAS score was 7.7 with a mean postoperative decrease of 5.2. There were 311 reported complications for 815 patients (38%) and 5 deaths for 659 patients (< 1%). Elderly patient outcomes were inconsistent in the published studies. Overall, most elderly patients obtained favorable outcomes with low operative mortality following surgery for adult spinal deformity.


Lack of Sarcocystis neurona antibody response in Virginia opossums (Didelphis virginiana) fed Sarcocystis neurona-infected muscle tissue.
Serum was collected from laboratory-reared Virginia opossums (Didelphis virginiana) to determine whether experimentally infected opossums shedding Sarcocystis neurona sporocysts develop serum antibodies to S. neurona merozoite antigens. Three opossums were fed muscles from nine-banded armadillos (Dasypus novemcinctus), and 5 were fed muscles from striped skunks (Mephitis mephitis). Serum was also collected from 26 automobile-killed opossums to determine whether antibodies to S. neurona were present in these opossums. Serum was analyzed using the S. neurona direct agglutination test (SAT). The SAT was modified for use with a filter paper collection system. Antibodies to S. neurona were not detected in any of the serum samples from opossums, indicating that infection in the opossum is localized in the small intestine. Antibodies to S. neurona were detected in filter-paper-processed serum samples from 2 armadillos naturally infected with S. neurona.


Modulation of Phosphorene for Optimal Hydrogen Evolution Reaction.
Economical and highly effective catalysts are crucial to the electrocatalytic hydrogen evolution reaction (HER), and few-layer black phosphorus (phosphorene) is a promising candidate because of the high carrier mobility, large specific surface area, and tunable physicochemical characteristics. However, the HER activity of phosphorene is limited by the weak hydrogen adsorption ability on the basal plane. In this work, optimal active sites are created to modulate the electronic structure of phosphorene to improve the HER activity and the effectiveness is investigated theoretically by density-functional theory calculation and verified experimentally. The edges and defects affect the electronic density of states, and a linear relationship between the HER activity and lowest unoccupied states (εLUS) is discovered. The medium εLUS value corresponds to the suitable hydrogen adsorption strength. Experiments are designed and performed to verify the prediction, and our results show that a smaller phosphorene moiety with more edges and defects exhibits better HER activity and surface doping with metal adatoms improves the catalytic performance. The results suggest that modified phosphorene has large potential in efficient HER and provides a convenient standard to explore ideal electrocatalysts.


Glucocorticoids act on glutamatergic pathways to affect memory processes.
Glucocorticoids can acutely affect memory processes, with both facilitating and impairing effects having been described. Recent work has revealed that glucocorticoids may affect learning and memory processes by interacting with glutamatergic mechanisms. In this opinion article I describe different glutamatergic pathways that glucocorticoids can affect to modulate memory processes. Furthermore, glucocorticoid-glutamatergic interactions during information processing are proposed as a potential model to explain many of the diverse actions of glucocorticoids on cognition. The model suggests that direct modulation of glutamatergic pathways by glucocorticoids could serve as an important mechanism for these hormones to directly alter cognitive functions.


The allele-specific synthetic lethality of prlA-prlG double mutants predicts interactive domains of SecY and SecE.
The secretion of proteins from the cytoplasm of Escherichia coli requires the interaction of two integral inner membrane components, SecY and SecE. We have devised a genetic approach to probe the molecular nature of the SecY-SecE interaction. Suppressor alleles of secY and secE, termed prlA and prlG, respectively, were analyzed in pair-wise combinations for synthetic phenotypes. From a total of 115 combinations, we found only seven pairs of alleles that exhibit a synthetic defect when present in combination with one another. The phenotypes observed are not the result of additive defects caused by the prl alleles, nor are they the consequence of multiple suppressors functioning within the same strain. In all cases, the synthetic defect is recessive to wild-type secY or secE provided in trans. The recessive nature argues for a defective interaction between the Prl suppressors. The extreme allele specificity and topological coincidence of the mutations represented by these seven pairs of alleles identify domains of interaction between SecY/PrlA and SecE/PrlG.


Driver drowsiness detection based on non-intrusive metrics considering individual specifics.
Drowsy driving is a serious highway safety problem. If drivers could be warned before they became too drowsy to drive safely, some drowsiness-related crashes could be prevented. The presentation of timely warnings, however, depends on reliable detection. To date, the effectiveness of drowsiness detection methods has been limited by their failure to consider individual differences. The present study sought to develop a drowsiness detection model that accommodates the varying individual effects of drowsiness on driving performance. Nineteen driving behavior variables and four eye feature variables were measured as participants drove a fixed road course in a high fidelity motion-based driving simulator after having worked an 8-h night shift. During the test, participants were asked to report their drowsiness level using the Karolinska Sleepiness Scale at the midpoint of each of the six rounds through the road course. A multilevel ordered logit (MOL) model, an ordered logit model, and an artificial neural network model were used to determine drowsiness. The MOL had the highest drowsiness detection accuracy, which shows that consideration of individual differences improves the models' ability to detect drowsiness. According to the results, percentage of eyelid closure, average pupil diameter, standard deviation of lateral position and steering wheel reversals was the most important of the 23 variables. The consideration of individual differences on a drowsiness detection model would increase the accuracy of the model's detection accuracy.


Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue.
Hepatocytes derived from human pluripotent stem cells (hPSC-HEP) have the potential to replace presently used hepatocyte sources applied in liver disease treatment and models of drug discovery and development. Established hepatocyte differentiation protocols are effective and generate hepatocytes, which recapitulate some key features of their in vivo counterparts. However, generating mature hPSC-HEP remains a challenge. In this study, we applied transcriptomics to investigate the progress of in vitro hepatic differentiation of hPSCs at the developmental stages, definitive endoderm, hepatoblasts, early hPSC-HEP, and mature hPSC-HEP, to identify functional targets that enhance efficient hepatocyte differentiation. Using functional annotation, pathway and protein interaction network analyses, we observed the grouping of differentially expressed genes in specific clusters representing typical developmental stages of hepatic differentiation. In addition, we identified hub proteins and modules that were involved in the cell cycle process at early differentiation stages. We also identified hub proteins that differed in expression levels between hPSC-HEP and the liver tissue controls. Moreover, we identified a module of genes that were expressed at higher levels in the liver tissue samples than in the hPSC-HEP. Considering that hub proteins and modules generally are essential and have important roles in the protein-protein interactions, further investigation of these genes and their regulators may contribute to a better understanding of the differentiation process. This may suggest novel target pathways and molecules for improvement of hPSC-HEP functionality, having the potential to finally bring this technology to a wider use.


High retention in care among HIV-infected patients entering care with CD4 levels >350 cells/μL under routine program conditions in Uganda.
In Africa, human immunodeficiency virus (HIV)-infected patients who present to care with CD4 levels >350 cells/µL (ie, current antiretroviral treatment thresholds) are often thought to be poorly retained in care, but most estimates do not account for outcomes among patients lost to follow-up. We evaluated HIV-infected adults who had made a visit in the last 2.5 years in a program in Uganda. We identified a random sample of patients lost to follow-up (9 months without a visit). Ascertainers sought patients in the community in this sample and outcomes were incorporated into revised survival estimates of mortality and retention for the clinic population using a probability weight. Of 6473 patients, (29% male, median age 29 years, median CD4 count 550 cells/µL), 1294 (20%) became lost to follow-up over 2.5 years. Two hundred seven (16%) randomly selected lost patients were sought, and in 175 (85%) vital status was ascertained. In 19 of 175 (11%), the patient had died. Of the 156 (89%) alive, 74 (47%) were interviewed in person, and 38 of 74 (51%) reported HIV care elsewhere, whereas 36 of 74 (49%) were not in care. Application of weights derived from sampling found that at 2.5 years, retention among patients who enrolled with CD4 levels >350 cells/µL was 88.2% and mortality was 2.5%. Lower income, unemployment, and rural residence were associated with failure to be retained. Retention in patients entering care with high CD4 counts under routine program conditions in Africa is high in a Ugandan care program and may be systematically underestimated in many other settings.


Time and spatial dependence of the concentration of less than 105 microelectrode-generated molecules.
The time and spatial dependence of the concentration of as few as 40,000 electrogenerated, redox-active molecules has been determined. The distance between generator and detector microelectrodes in an array used in the study could be varied from 0.8 to 28 micrometers. Measurements of a sufficiently small ensemble of molecules allowed the experimental results to be compared with a quantitative simulation of the random movement of each member of the ensemble. The transit time of an electrogenerated species from the generator to a collector microelectrode was measured as a function of viscosity, diffusivity, and distance.


Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia.
The beneficial effects of cardiac resynchronization therapy (CRT) are thought to result from favorable left ventricular (LV) reverse remodeling, however CRT is only successful in about 70% of patients. Whether response to CRT is associated with a decrease in ventricular arrhythmias (VA) is still discussed controversially. Therefore, we investigated the incidence of VA in CRT responders in comparison with non-responders. In this nonrandomized, two-center, observational study patients with moderate-to-severe heart failure, LV ejection fraction (LVEF) ≤35%, and QRS duration >120 ms undergoing CRT were included. After 6 months patients were classified as CRT responders or non-responders. Incidence of VA was compared between both groups by Kaplan-Meier analysis and Cox regression analysis. ROC analysis was performed to determine the aptitude of LVEF cut-off values to predict VA. In total 126 consecutive patients (64±11 years; 67%male) were included, 74 were classified as responders and 52 as non-responders. While the mean LVEF at baseline was comparable in both groups (25±7% vs. 24±8%; P = 0.4583) only the responder group showed an improvement of LVEF (36±6% vs. 24±7; p<0.0001) under CRT. In total in 56 patients VA were observed during a mean follow-up of 28±14 months, with CRT responders experiencing fewer VA than non-responders (35% vs. 58%, p<0.0061). Secondary preventive CRT implantation was associated with a higher likelihood of VA. As determined by ROC analysis an increase of LVEF by >7% was found to be a predictor of a significantly lower incidence of VA (AUC = 0.606). Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia.


Time trends (1998-2007) in brain cancer incidence rates in relation to mobile phone use in England.
Mobile phone use in the United Kingdom and other countries has risen steeply since the early 1990's when the first digital mobile phones were introduced. There is an ongoing controversy about whether radio frequency (RF) exposure from mobile phones increases the risk of brain cancer. However, given the widespread use and nearly two decades elapsing since mobile phones were introduced, an association should have produced a noticeable increase in the incidence of brain cancer by now. Trends in rates of newly diagnosed brain cancer cases in England between 1998 and 2007 were examined. There were no time trends in overall incidence of brain cancers for either gender, or any specific age group. Systematic increases in rates for cancers of the temporal lobe in men (0.04 new cases/year) and women (0.02/year) were observed, along with decreases in the rates of cancers of the parietal lobe (-0.03/year), cerebrum (-0.02/year) and cerebellum (-0.01/year) in men only. The increased use of mobile phones between 1985 and 2003 has not led to a noticeable change in the incidence of brain cancer in England between 1998 and 2007. The observed increase in the rate of cancers in the temporal lobe, if caused by mobile phone use, would constitute <1 additional case per 100,000 people in that period. These data do not indicate a pressing need to implement a precautionary principle by means of population-wide interventions to reduce RF exposure from mobile phones.


Nutritional support practices in hematopoietic stem cell transplantation centers: A nationwide comparison.
In 2009, international nutritional societies published practice guidelines on screening and nutritional support for patients undergoing stem cell transplantation. Little is known about how these guidelines are implemented in clinical practice. We performed a nationwide survey with the aim of understanding current practice patterns, differences between clinical practice, and international recommendations as well as barriers to the use of nutritional therapy. We performed a qualitative survey including all centers across Switzerland offering allogeneic (n = 3) or autologous (n = 7) stem cell transplantation. We focused on in-house protocols pertaining to malnutrition screening, indications for nutritional support, types of nutritional therapy available and provided, and recommendations regarding neutropenic diets. All centers offering allogeneic, and most of the centers offering autologous transplantation, had a malnutrition screening tool, mainly the nutritional risk score (NRS 2002) method. Only one center does not provide nutritional support. There is wide variation regarding start and stop of nutritional therapy as well as route of delivery, with five centers recommending parenteral nutrition and five centers recommending enteral nutrition as a first step. Although all centers offering allogeneic transplantation, and approximately every other autologous transplant center, used a neutropenic diet, specific recommendations regarding the type of food and food handling showed significant variation. This Swiss survey found wide variation in the use of nutritional therapy in patients undergoing stem cell transplantation, with low adherence overall to current practice guidelines. Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. Close collaboration of centers will facilitate future research needed to improve current practice and ensure high quality of treatment.


Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark.
The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.


Exploring the innate immunological response of an alternative nonhuman primate model of infectious disease; the common marmoset.
The common marmoset (Callithrix jacchus) is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease.


Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.
Rotavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca²⁺ concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP₃), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT₃ receptor antagonists.


The first Neanderthal specimen from Serbia: Maxillary first molar from the Late Pleistocene of Pešturina Cave.
Neanderthals were the only human group in Europe throughout the Late Pleistocene until the arrival of modern humans, and while their presence has been confirmed in the surrounding regions, no Neanderthal fossils are known to date from the Central Balkans. Systematic excavations of Pešturina Cave (Serbia) resulted in the discovery of a permanent right M1 (Pes-3). The specimen was recovered from stratigraphic Layer 4b with an estimated age of 102.4 ± 3.2 ka, associated with Mousterian artifacts. The exceptional state of preservation and minimal wear of the molar enabled a detailed description and comparative analysis of the inner and outer dental structure, including non-metric dental traits and morphometric features of the crown, roots, and dental tissues. The results of this study strongly support the identification of Pes-3 as Neanderthal. Non-metric traits of the occlusal surface of the crown, enamel-dentine junction, and roots are consistent with Neanderthal morphology. The crown shows morphometric features typical for Neanderthal M1, such as a buccolingually skewed crown shape, internally compressed cusps, and a relatively large hypocone. The specimen also shows Neanderthal-like dental tissue proportions, characterized by relatively thin enamel and large coronal dentine and coronal pulp volumes. The discovery of the Pes-3 molar therefore confirms the presence of Neanderthals in the territory of Serbia and the Central Balkans at the end of Marine Isotope Stage (MIS) 5c.


Cardiovascular risk in women with non-specific chest pain (from the Women's Health Initiative Hormone Trials).
Women discharged with diagnoses of nonspecific chest pain (NSCP) may be at increased risk for subsequent coronary artery disease (CAD) events. The influence of hormone therapy on NSCP is unknown. The Women's Health Initiative (WHI) enrolled postmenopausal women aged 50 to 79 years. The duration of follow-up was 7.1 years in the WHI Estrogen-Alone trial (E-Alone) and 5.6 years in the WHI Estrogen Plus Progestin trial (E+P). After excluding women with previous cardiovascular disease, 9,427 women in E-Alone and 15,105 women in E+P were included in this analysis. NSCP, defined as having a primary hospital discharge diagnosis of NSCP by International Classification of Diseases, Ninth Revision, code, was reported in 322 women in E-Alone and 249 in E+P. Risks for subsequent CAD events were estimated using intent-to-treat Cox proportional-hazards models stratified by clinic and adjusted for age and other risk factors. In the fully adjusted models of the combined trials, women with NSCP had a twofold greater risk for subsequent nonfatal CAD events, including nonfatal myocardial infarction (2.3% vs 1.7%, hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.11 to 3.98), revascularization (3.5% vs 2.6%, HR 1.99, 95% CI 1.20 to 3.30), and hospitalized angina (3.7% vs 2.3%, HR 2.39, 95% CI 1.46 to 3.92). Hormone therapy did not appear to have a significant effect on either the incidence of NSCP hospitalizations (E-Alone: HR 1.04, 95% CI 0.81 to 1.32; E+P: HR 0.78, 95% CI 0.59 to 1.02) or the risk for a subsequent CAD event. In conclusion, a hospitalization for NSCP doubles the risk for a subsequent CAD event in postmenopausal women over the next 5 to 7 years and identifies them as candidates for aggressive risk factor treatment.


Extending Ripley's K-Function to Quantify Aggregation in 2-D Grayscale Images.
In this work, we describe the extension of Ripley's K-function to allow for overlapping events at very high event densities. We show that problematic edge effects introduce significant bias to the function at very high densities and small radii, and propose a simple correction method that successfully restores the function's centralization. Using simulations of homogeneous Poisson distributions of events, as well as simulations of event clustering under different conditions, we investigate various aspects of the function, including its shape-dependence and correspondence between true cluster radius and radius at which the K-function is maximized. Furthermore, we validate the utility of the function in quantifying clustering in 2-D grayscale images using three modalities: (i) Simulations of particle clustering; (ii) Experimental co-expression of soluble and diffuse protein at varying ratios; (iii) Quantifying chromatin clustering in the nuclei of wt and crwn1 crwn2 mutant Arabidopsis plant cells, using a previously-published image dataset. Overall, our work shows that Ripley's K-function is a valid abstract statistical measure whose utility extends beyond the quantification of clustering of non-overlapping events. Potential benefits of this work include the quantification of protein and chromatin aggregation in fluorescent microscopic images. Furthermore, this function has the potential to become one of various abstract texture descriptors that are utilized in computer-assisted diagnostics in anatomic pathology and diagnostic radiology.


Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort.
Evidence is growing that indoor pesticide exposure is of considerable magnitude in the United States and that pesticide concentrations may be especially high in urban areas. Of particular concern is exposure of pregnant women because animal data suggest that exposure to pesticides during pregnancy and early life may impair neurodevelopment in the offspring. To investigate the relationship between prenatal exposure to indoor pesticides and infant growth and development, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. This article provides data on pesticide exposure based on questionnaire items and analysis of maternal urinary metabolite levels among 386 women. Both the questionnaire and laboratory data revealed that exposure to indoor pesticides was considerable. The proportion of women estimated from questionnaire data as having been exposed during pregnancy to indoor pesticides (approximately 70%) was somewhat lower than the 80-90% of American households who reportedly used pesticides in previous surveys, but some of the latter surveys included both indoor and outdoor pesticide use. Urinary metabolite levels of 3,5,6-trichloro-2-pyridinol (TCPy; median = 11.3 micro g/g creatinine), phenoxybenzoic acid (PBA; median =19.3 micro g/g creatinine), and pentachlorophenol (PCP; median =7.3 micro g/g creatinine) were higher than those reported in other studies of adults in the United States. Furthermore, no associations were evident between the pesticide questionnaire data and the urinary metabolites. Assessments of sociodemographic and building characteristics with questionnaire data and the metabolite levels revealed no consistent trends. Significant temporal variations were observed for urinary PBA but not TCPy or PCP. The temporal variations for PBA were consistent with seasonal spraying of pyrethroid pesticides. These data underscore the need to assess the potentially adverse effects of pesticide exposure on fetuses and infants and the importance of finding alternative methods for pest management to reduce pesticide exposures.


Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol.
Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial cancer cells. Our findings suggest that about 95% of [125I]IGF-I is bound to membrane-associated IGFBPs rather than to IGF-I receptors. Specifically, [125I]IGF-I binding to cell membranes could be completely displaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [125I]des-(1-3)IGF-I as the ligand. Des-(1-3) IGF-I binds with high affinity to IGF-I receptors, but with markedly lower affinity to IGFBPs. [125I]Des-(1-3)IGF-I bound to Ishikawa cells was displaced by IGF-I, IGF-II, and insulin. These results suggest that measuring IGF-I receptor levels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [125I]IGF-I and [125I]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikawa cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferation, but at low concentrations, and this stimulation is largely dependent on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP levels, presumably increasing the availability of IGFs for their receptors. This elevation in IGF-I receptor levels and the decrease in IGFBP levels were accompanied by a 3.5-fold increase in IGF-I receptor messenger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experiments suggest that estradiol sensitizes endometrial cancer cells to the effects of IGFs by simultaneously elevating receptor levels and decreasing (potentially inhibitory) IGFBP levels.


Cancer-specific mortality, cure fraction, and noncancer causes of death among diffuse large B-cell lymphoma patients in the immunochemotherapy era.
Survival after the diagnosis of diffuse large B-cell lymphoma (DLBCL) has been increasing since 2002 because of improved therapies; however, long-term outcomes for these patients in the modern treatment era are still unknown. Using Surveillance, Epidemiology, and End Results data, this study first assessed factors associated with DLBCL-specific mortality during 2002-2012. An epidemiologic risk profile, based on clinical and demographic characteristics, was used to stratify DLBCL cases into low-, medium-, and high-risk groups. The proportions of DLBCL cases that might be considered cured in these 3 risk groups was estimated. Risks of death due to various noncancer causes among DLBCL cases versus the general population were also calculated with standardized mortality ratios (SMRs). Overall, 8274 deaths were recorded among 18,047 DLBCL cases; 76% of the total deaths were attributed to DLBCL, and 24% were attributed to noncancer causes. The 10-year survival rates for the low-, medium-, and high-risk groups were 80%, 60%, and 36%, respectively. The estimated cure proportions for the low-, medium-, and high-risk groups were 73%, 49%, and 27%, respectively; however, these cure estimates were uncertain because of the need to extrapolate the survival curves beyond the follow-up time. Mortality risks calculated with SMRs were elevated for conditions including vascular diseases (SMR, 1.3), infections (SMR, 3.1), gastrointestinal diseases (SMR, 2.5), and blood diseases (SMR, 4.6). These mortality risks were especially high within the initial 5 years after the diagnosis and declined after 5 years. Some DLBCL patients may be cured of their cancer, but they continue to experience excess mortality from lymphoma and other noncancer causes. Cancer 2017;123:3326-34. © 2017 American Cancer Society.


Potential effects of dams on migratory fish in the Mekong River: lessons from salmon in the Fraser and Columbia Rivers.
We compared the effects of water resource development on migratory fish in two North American rivers using a descriptive approach based on four high-level indicators: (1) trends in abundance of Pacific salmon, (2) reliance on artificial production to maintain fisheries, (3) proportion of adult salmon that are wild- versus hatchery-origin, and (4) number of salmon populations needing federal protection to avoid extinction. The two rivers had similar biological and physical features but radically different levels of water resource development: the Fraser River has few dams and all are located in tributaries, whereas the Columbia River has more than 130 large mainstem and tributary dams. Not surprisingly, we found substantial effects of development on salmon in the Columbia River. We related the results to potential effects on migratory fish in the Mekong River where nearly 200 mainstem and tributary dams are installed, under construction, or planned and could have profound effects on its 135 migratory fish species. Impacts will vary with dam location due to differential fish production within the basin, with overall effects likely being greatest from 11 proposed mainstem dams. Minimizing impacts will require decades to design specialized fish passage facilities, dam operations, and artificial production, and is complicated by the Mekong's high diversity and productivity. Prompt action is needed by governments and fisheries managers to plan Mekong water resource development wisely to prevent impacts to the world's most productive inland fisheries, and food security and employment opportunities for millions of people in the region.


Septal-lateral annular cinching abolishes acute ischemic mitral regurgitation.
Ring annuloplasty prevents acute ischemic mitral regurgitation in sheep, but it also abolishes normal mitral annular and posterior leaflet dynamics. We investigated a novel surgical approach of simple septal-lateral annular cinching with sutures to treat acute ischemic mitral regurgitation. Nine adult sheep underwent implantation of multiple radiopaque markers on the left ventricle, mitral anulus, and mitral leaflets. A septal-lateral transannular suture was anchored to the midseptal mitral anulus and externalized to a tourniquet through the midlateral mitral anulus and left ventricular wall. Open-chest animals were studied immediately postoperatively. Acute ischemic mitral regurgitation was induced by means of proximal left circumflex artery snare occlusion, and 3 progressive steps of septal-lateral annular cinching (each 2-3 mm suture tightening for 5 seconds) were performed with the transannular suture. Biplane videofluoroscopy for 3-dimensional marker coordinates and transesophageal echocardiography were performed continuously before and during left circumflex ischemia and septal-lateral annular cinching. Acute left circumflex ischemia caused ischemic mitral regurgitation (+0.5 +/- 0.4 [baseline] vs +2.0 +/- 0.7 [ischemia]; P =.005; scale, +0-4), which decreased progressively with each step of septal-lateral annular cinching and was eliminated during the third step (ischemic mitral regurgitation, +0.6 +/- 0.5; P = not significant vs baseline). The third step of septal-lateral annular cinching decreased the septal-lateral diameter by 6.0 +/- 2.6 mm (P =.005); however, mitral anulus area reduction (8.5% +/- 1.0% and 6.9% +/- 1.9% for ischemic mitral regurgitation and septal-lateral annular cinching step 3, respectively; P =.006) and posterior leaflet excursion (50 degrees +/- 9 degrees and 44 degrees +/- 11 degrees for regurgitation and annular cinching step 3, respectively; P =.002) throughout the cardiac cycle were affected only mildly. Normal mitral annular 3-dimensional shape was maintained with septal-lateral annular cinching. Isolated 22% +/- 10% reduction in mitral annular septal-lateral dimension abolished acute ischemic mitral regurgitation in normal sheep hearts while allowing near-normal mitral annular and posterior leaflet dynamic motion. Septal-lateral annular cinching may represent a simple method for the surgical treatment of ischemic mitral regurgitation, either as an adjunctive technique or alone, which helps preserve physiologic annular and leaflet function.


In Vivo Estimation of Oncolytic Virus Populations within Tumors.
The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of in vivo data has made difficult parametrization of these models. To tackle this problem, we studied the in vitro and in vivo spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship in vitro between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. In vivo radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression in vitro and in vivo implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive in vivo relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution in vivo These data suggest that methods that enable quantitation of in vivo anisotropies are required for continuing development of oncolytic virotherapy.Significance: These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses in vivo Cancer Res; 78(20); 5992-6000. ©2018 AACR.


Preparation and in vitro evaluation of bFGF-loaded chitosan nanoparticles.
The objective of our study was to prepare and characterize basic fibroblast growth factor (bFGF)-loaded nanoparticles. Protein-loaded chitosan nanoparticles were obtained by ionotropic gelation process based on the interaction between chitosan and tripolyphosphate (TPP). The protein-loading capacity and encapsulation efficiency were 0.021% and 27.388%, respectively. The bFGF-loaded nanoparticles have a mean diameter of 424 nm, a narrow size distribution, spherical shape and positive surface charges. In vitro release showed that the extent of release was 68% at 24 hr. The protein integrity was investigated by SDS-PAGE analysis that confirmed protein integrity was not affected by the encapsulation procedure and release conditions.


Connexin40 controls endothelial activation by dampening NFκB activation.
Connexins are proteins forming gap junction channels for intercellular communication. Connexin40 (Cx40) is highly expressed by endothelial cells (ECs) of healthy arteries but this expression is lost in ECs overlying atherosclerotic plaques. Low/oscillatory shear stress observed in bends and bifurcations of arteries is atherogenic partly through activation of the pro-inflammatory NFκB pathway in ECs. In this study, we investigated the relation between shear stress, Cx40 and NFκB. Shear stress-modifying casts were placed around carotid arteries of mice expressing eGFP under the Cx40 promoter (Cx40+/eGFP ). We found that Cx40 expression is decreased in carotid regions of oscillatory shear stress but conserved in high and low laminar shear stress regions. These results were confirmed in vitro. Using phage display, we retrieved a binding motif for the intracellular regulatory Cx40 C-terminus (Cx40CT), i.e. HS[I, L, V][K, R]. One of the retrieved peptides (HSLRPEWRMPGP) showed a 58.3% homology with amino acids 5-to-16 of IκBα, a member of the protein complex inhibiting NFκB activation. Binding of IκBα (peptide) and Cx40 was confirmed by crosslinking and en face proximity ligation assay on carotid arteries. TNFα-induced nuclear translocation of NFκB in ECs was enhanced after reducing Cx40 with siRNA. Transfection of HeLa cells with either full-length Cx40 or Cx40CT demonstrated that Cx40CT was sufficient for inhibition of TNFα-induced NFκB phosphorylation. Finally, Tie2CreTgCx40fl/flApoe-/- mice showed exaggerated shear stress-induced atherosclerosis and enhanced NFκB nuclear translocation. Our data show a novel functional IκBα-Cx40 interaction that may be relevant for the control of NFκB activation by shear stress in atherogenesis.


Factors Controlling Soil Microbial Biomass and Bacterial Diversity and Community Composition in a Cold Desert Ecosystem: Role of Geographic Scale.
Understanding controls over the distribution of soil bacteria is a fundamental step toward describing soil ecosystems, understanding their functional capabilities, and predicting their responses to environmental change. This study investigated the controls on the biomass, species richness, and community structure and composition of soil bacterial communities in the McMurdo Dry Valleys, Antarctica, at local and regional scales. The goals of the study were to describe the relationships between abiotic characteristics and soil bacteria in this unique, microbially dominated environment, and to test the scale dependence of these relationships in a low complexity ecosystem. Samples were collected from dry mineral soils associated with snow patches, which are a significant source of water in this desert environment, at six sites located in the major basins of the Taylor and Wright Valleys. Samples were analyzed for a suite of characteristics including soil moisture, pH, electrical conductivity, soil organic matter, major nutrients and ions, microbial biomass, 16 S rRNA gene richness, and bacterial community structure and composition. Snow patches created local biogeochemical gradients while inter-basin comparisons encompassed landscape scale gradients enabling comparisons of microbial controls at two distinct spatial scales. At the organic carbon rich, mesic, low elevation sites Acidobacteria and Actinobacteria were prevalent, while Firmicutes and Proteobacteria were dominant at the high elevation, low moisture and biomass sites. Microbial parameters were significantly related with soil water content and edaphic characteristics including soil pH, organic matter, and sulfate. However, the magnitude and even the direction of these relationships varied across basins and the application of mixed effects models revealed evidence of significant contextual effects at local and regional scales. The results highlight the importance of the geographic scale of sampling when determining the controls on soil microbial community characteristics.


The longitudinal BELLA study: design, methods and first results on the course of mental health problems.
The high prevalence of mental health problems (MHP) in childhood and adolescence is a global health challenge of the 21st century. Information about age of onset, persistence and development of MHP in young people is necessary to implement effective prevention and intervention strategies. We describe the design and methods of the longitudinal BELLA study, which investigates developmental trajectories of MHP from childhood into adulthood, their determinants, and the utilisation of mental health services. First results on the developmental course of MHP in children and adolescents are reported over a 6-year period. The BELLA study is the mental health module of the German National Health Interview and Examination Survey for children and adolescents (KiGGS). BELLA examines the mental health and well-being of children and adolescents aged 7-17 years (a representative subsample of KiGGS, n = 2,863 at baseline). Standardised screening measures served to identify MHP at baseline and at follow-ups (1, 2, and 6 years later). Among children and adolescents participating at all measurement points (n = 1,255), 10 % showed clinically significant MHP at baseline (n = 130). Over the 6-year period, 74.3 % showed no signs of MHP (n = 933), 15.5 % had remitted (n = 194), 2.9 % showed persistent (n = 36) and 7.3 % acute or recurrent MHP (n = 92). Overall, MHP were more likely to occur between the age of 7 and 12 and after the age of 19 years. Regarding mental health service use, 33 % of the participants with acute or recurrent MHP (n = 30) and 63.9 % with persistent MHP used mental health services (n = 23). Mental health problems in children and adolescents have a high risk to persist into adulthood. In children and adolescents a low rate of mental health service use was observed, even among those with mental health problems.


Association of genetic polymorphisms related to Johne's disease with estimated breeding values of Holstein sires for milk ELISA test scores.
Johne's disease (JD) is a chronic intestinal inflammatory disease caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection in ruminants. Since there are currently no effective vaccine or treatment options available to control JD, genetic selection may be an alternative strategy to enhance JD resistance. Numerous Single Nucleotide Polymorphisms (SNPs) have been reported to be associated with MAP infection status based on published genome-wide association and candidate gene studies. The main objective of this study was to validate these SNPs that were previously identified to be associated with JD by testing their effect on Holstein bulls' estimated breeding values (EBVs) for milk ELISA test scores, an indirect indicator of MAP infection status in cattle. Three SNPs, rs41810662, rs41617133 and rs110225854, located on Bos taurus autosomes (BTA) 16, 23 and 26, respectively, were confirmed as significantly associated with Holstein bulls' EBVs for milk ELISA test score (FDR < 0.01) based on General Quasi Likelihood Scoring analysis (GQLS) analysis. Single-SNP regression analysis identified four SNPs that were associated with sire EBVs (FDR < 0.05). This includes two SNPs that were common with GQLS (rs41810662 and rs41617133), with the other two SNPs being rs110494981 and rs136182707, located on BTA9 and BTA16, respectively. The findings of this study validate the association of SNPs with JD MAP infection status and highlight the need to further investigate the genomic regions harboring these SNPs.


Micropatterned Hydrogel Surface with High-Aspect-Ratio Features for Cell Guidance and Tissue Growth.
Surface topography has been introduced as a new tool to coordinate cell selection, growth, morphology, and differentiation. The materials explored so far for making such structural surfaces are mostly rigid and impermeable. Hydrogel, on the other hand, was proved a better synthetic media for cell culture because of its biocompatibility, softness, and high permeability. Herein, we fabricated a poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel substrate with high-aspect-ratio surface microfeatures. Such structural surface could effectively guide the orientation and shape of human mesenchymal stem cells (HMSCs). Notably, on the flat hydrogel surface, cells rounded up, whereas on the microplate patterned hydrogel surface, cells elongated and aligned along the direction parallel to the plates. The microplates were 2 μm thick, 20 μm tall, and 10-50 μm wide. The interplate spacing was 5-15 μm, and the intercolumn spacing was 5 μm. The elongation of cell body was more pronounced on the patterns with narrower interplate spacing and wider plates. The cells behaved like soft solid. The competition between surface energy and elastic energy defined the shape of the cells on the structured surfaces. The soft permeable hydrogel scaffold with surface structures was also demonstrated as being viable for long-term cell culture, and could be used to generate interconnected tissues with finely tuned cell morphology and alignment across a few centimeter sizes.


VEGFR-2 Inhibitor Apatinib Hinders Endothelial Cells Progression Triggered by Irradiated Gastric Cancer Cells-derived Exosomes.
Background: Radiotherapy is a standard treatment for a significant fraction of cancer patients. Nonetheless, to this day radiation resistance is a key impediment in gastric cancer (GC) treatment. Moreover, GC is characterized by its substantial neo-angiogenesis, driven by high levels of vascular endothelial growth factor (VEGF) correlated with the presence of stomach cancer. The aim of our study was to address if VEGFR inhibitors treatments impact the negative effect of radiotherapy regiments of gastric cancer. Materials and methods: Isolation of exosomes released by SGC-7901 and BGC-823 lines after irradiation at 0 Gy or 6 Gy was performed by differential ultra-centrifugation. Incubation of Human Umbilical Vein Endothelial Cells (HUVEC) was carried out with different concentrations of exosomes from non- or irradiated GC cells to address their proliferation and survival fraction (SF) by MTS. 6 Gy irradiated cells exosomes at concentration of 20 µg/ml were compared to EC incubated with the same exosome concentration from non-irradiated human GC cells over 72-hour time course. Wound-healing and Transwell assays were performed in a migration buffer consisting of exosomes released by non- or irradiated SGC-7901 and BGC-823 cells over 24-hour time course. HUVEC cells stained with DAPI that have passed through a gluten gel were counted in order to monitor their invasion capacity. Employing IC50, 60 µg/ml was determined as the optimal Apatinib (YN968D1) concentration for the half-life of HUVEC, and incubated with exosomes from irradiated GC cells. The aforementioned assays were performed in the background of the same conditions in order to analyse the effect of Apatinib on HUVEC progression. Results: We show that proliferation, motility and invasive capacity of HUVEC are enhanced upon incubation with exosomes released by irradiated GC cell lines. Importantly, the latter is counteracted by the VEGFR-2 inhibitor Apatinib which hinders ECs progression. Conclusion / Significance: Combining radiotherapy and VEGFR inhibitors treatment can provide potentially a substantial impact in decreasing cancer death rates by averting the negative effect of radiotherapy regiments and provide better standard for cancer patients.


Oxidative UO2 dissolution induced by soluble Mn(III).
The stability of UO2 is critical to the success of reductive bioremediation of uranium. When reducing conditions are no longer maintained, Mn redox cycling may catalytically mediate the oxidation of UO2 and remobilization of uranium. Ligand-stabilized soluble Mn(III) was recently recognized as an important redox-active intermediate in Mn biogeochemical cycling. This study evaluated the kinetics of oxidative UO2 dissolution by soluble Mn(III) stabilized by pyrophosphate (PP) and desferrioxamine B (DFOB). The Mn(III)-PP complex was a potent oxidant that induced rapid UO2 dissolution at a rate higher than that by a comparable concentration of dissolved O2. However, the Mn(III)-DFOB complex was not able to induce oxidative dissolution of UO2. The ability of Mn(III) complexes to oxidize UO2 was probably determined by whether the coordination of Mn(III) with ligands allowed the attachment of the complexes to the UO2 surface to facilitate electron transfer. Systematic investigation into the kinetics of UO2 oxidative dissolution by the Mn(III)-PP complex suggested that Mn(III) could directly oxidize UO2 without involving particulate Mn species (e.g., MnO2). The expected 2:1 reaction stoichiometry between Mn(III) and UO2 was observed. The reactivity of soluble Mn(III) in oxidizing UO2 was higher at lower ratios of pyrophosphate to Mn(III) and lower pH, which is probably related to differences in the ligand-to-metal ratio and/or protonation states of the Mn(III)-pyrophosphate complexes. Disproportionation of Mn(III)-PP occurred at pH 9.0, and the oxidation of UO2 was then driven by both MnO2 and soluble Mn(III). Kinetic models were derived that provided excellent fits of the experimental results.


Sources of regional variation in Medicare Part D drug spending.
Sources of regional variation in spending for prescription drugs under Medicare Part D are poorly understood, and such variation may reflect differences in health status, use of effective treatments, or selection of branded drugs over lower-cost generics. We analyzed 2008 Medicare data for 4.7 million beneficiaries for prescription-drug use and expenditures overall and in three drug categories: angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), and selective serotonin-reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Differences in per capita expenditures across hospital-referral regions (HRRs) were decomposed into annual prescription volume and cost per prescription. The ratio of prescriptions filled as branded drugs to all prescriptions filled was calculated. We adjusted all measures for demographic, socioeconomic, and health-status differences. Mean adjusted per capita pharmaceutical spending ranged from $2,413 in the lowest to $3,008 in the highest quintile of HRRs. Most (75.9%) of that difference was attributable to the cost per prescription ($53 vs. $63). Regional differences in cost per prescription explained 87.5% of expenditure variation for ACE inhibitors and ARBs and 56.3% for statins but only 36.1% for SSRIs and SNRIs. The ratio of branded-drug to total prescriptions, which correlated highly with cost per prescription, ranged across HRRs from 0.24 to 0.45 overall and from 0.24 to 0.55 for ACE inhibitors and ARBs, 0.29 to 0.60 for statins, and 0.15 to 0.51 for SSRIs and SNRIs. Regional variation in Medicare Part D spending results largely from differences in the cost of drugs selected rather than prescription volume. A reduction in branded-drug use in some regions through modification of Part D plan benefits might lower costs without reducing quality of care. (Funded by the National Institute on Aging and others.).


IMG/M-HMP: a metagenome comparative analysis system for the Human Microbiome Project.
The Integrated Microbial Genomes and Metagenomes (IMG/M) resource is a data management system that supports the analysis of sequence data from microbial communities in the integrated context of all publicly available draft and complete genomes from the three domains of life as well as a large number of plasmids and viruses. IMG/M currently contains thousands of genomes and metagenome samples with billions of genes. IMG/M-HMP is an IMG/M data mart serving the US National Institutes of Health (NIH) Human Microbiome Project (HMP), focussed on HMP generated metagenome datasets, and is one of the central resources provided from the HMP Data Analysis and Coordination Center (DACC). IMG/M-HMP is available at http://www.hmpdacc-resources.org/imgm_hmp/.


Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol.
The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.


Long-term risks of bladder augmentation in pediatric patients.
Bladder augmentation is still a commonly performed reconstructive procedure for pediatric patients with severe bladder dysfunction. Recent developments in the long-term risks associated with this procedure are reviewed. There are metabolic changes in these patients after incorporation of bowel into the urinary tract. Linear growth and bone mineral density are more affected by the primary disorder rather than bladder augmentation. There is a high rate of reoperation in patients after bladder augmentation for perforation, bladder stones, and bowel obstruction. Bladder cancer has been reported in patients after bladder augmentation but also in patients without augmentation. Bladder augmentation is associated with a number of potential long-term risks, including a high risk of needing further surgery and development of serious complications such as bowel obstruction or bladder perforation. Bladder stones continue to be common in patients after bladder augmentation. Multiple cases of bladder cancer have been reported recently in young adults with a history of bladder augmentation in childhood and reinforce the need for lifelong follow up for these patients. Future studies will hopefully define the benefits and role of cancer surveillance for these patients.


Cigarette smoking and Parkinson's disease: a meta-analysis.
Many but not all studies have indicated that smoking is inversely associated with Parkinson's disease (PD). Meta-analysis of epidemiological studies on smoking and PD was performed to summarize data from published studies. Fifty-four epidemiological studies (48 case-control and 6 cohort studies, 53 publications) were identified for potential inclusion in meta-analysis. The summary risk estimates for current smokers, former smokers, and ever (current and former) smokers were 0.31 (95% confidence interval (CI) = 0.25-0.38), 0.72 (95% CI = 0.63-0.83) and 0.55 (95% CI = 0.51-0.59), respectively. In stratified analysis by study design, smoking had a somewhat greater impact on PD risk in cohort studies than in case-control studies. However, meta-regression indicated that the study design did not significantly contribute to heterogeneity. Additional analyses were restricted to case-control studies because of the sufficient number of studies. Stratified analysis by ethnicity indicated that the summary OR for ever-smokers was nonsignificantly smaller in Asian populations than in Caucasian populations. In stratified analysis by source of controls, former smoking was significantly associated with a decreased risk of PD in hospital-based case-control studies but was marginally associated with a decreased risk in population-based case-control studies. The source of controls did not contribute significantly to heterogeneity. PD risk associated with ever-smoking was significantly lower for a hospital-based approach than a population-based approach. Among current smokers, the association held true to the same extent for both approaches. This meta-analysis indicated that smokers have a lower risk of PD. As PD is a multifactorial disease, further investigation of the smoking-gene interaction on PD risk may lead to a better understanding of the pathogenesis of PD.


Is vasopressin an important hypertensive hormone?
To generate quantitative data relating to the potential hypertensive activity of arginine vasopressin (AVP), 140 and 560 microunits AVP/kg/min were infused chronically in both normotensive dogs and dogs made hypertensive by chronic infusion of either angiotensin II (AII) or aldosterone. The lower rate of AVP infusion increased plasma AVP concentration from 0.4 +/- 0.1 microunits/ml. Mean arterial pressure (MAP) was recorded 24 hours per day, and all dogs were infused continuously with 800 ml of isotonic saline per day. During the initial days of AVP infusion in normotensive dogs, natriuresis, kaliuresis, and water retention were prominent and MAP increased progressively to a peak on Day 6 (30 mm Hg above control). Subsequently, diuresis ensued, net water retention decreased, and MAP fell progressively to only 13 mm Hg above control by Day 12 of AVP infusion. In contrast, in AII or aldosterone hypertensive dogs during AVP infusion, the natriuresis was greatly attenuated, water balance was unchanged or even negative, and MAP either did not increase or increased only transiently. When AVP infusion was terminated in dogs given only AVP, diuresis occurred, and MAP fell gradually over a period of hours to hypertensive levels. In marked contrast, cessation of AVP infusion in dogs with either AII or aldosterone hypertension was associated with a precipitous fall in MAP of 35 to 40 mm Hg within 1 hour: however, this reduction was only transient - over the subsequent hours, both salt and water retention occurred, and MAP returned to previous hypertensive levels. Thus, in the hypertensive models studied, high plasma levels of AVP had relatively weak hypertensive effects. Although variations in plasma AVP concentration were associated with rather pronounced acute effects on MAP, the long-term changes in MAP produced by AVP were either minimal or, in the case of the animals made hypertensive by other agents, nonexistent.


Power and perspectives not taken.
Four experiments and a correlational study explored the relationship between power and perspective taking. In Experiment 1, participants primed with high power were more likely than those primed with low power to draw an E on their forehead in a self-oriented direction, demonstrating less of an inclination to spontaneously adopt another person's visual perspective. In Experiments 2a and 2b, high-power participants were less likely than low-power participants to take into account that other people did not possess their privileged knowledge, a result suggesting that power leads individuals to anchor too heavily on their own vantage point, insufficiently adjusting to others' perspectives. In Experiment 3, high-power participants were less accurate than control participants in determining other people's emotion expressions; these results suggest a power-induced impediment to experiencing empathy. An additional study found a negative relationship between individual difference measures of power and perspective taking. Across these studies, power was associated with a reduced tendency to comprehend how other people see, think, and feel.


Prevalence and recurrence rate of perianal abscess--a population-based study, Sweden 1997-2009.
The aim of this study was to assess the impact of diabetes mellitus, Crohn's disease, HIV/aids, and obesity on the prevalence and readmission rate of perianal abscess. The study cohort was based on the Swedish National Patient Register and included all patients treated for perianal abscess in Sweden 1997-2009. The prevalence and risk for readmission were assessed in association with four comorbidity diagnoses: diabetes mellitus, Crohn's disease, HIV, and/or AIDS and obesity. A total of 18,877 patients were admitted during the study period including 11,138 men and 4557 women (2.4:1). Crohn's disease, diabetes, and obesity were associated with a significantly higher prevalence of perianal abscess than an age- and gender-matched background population (p < 0.05). In univariate analysis, neither age nor gender had any significant impact on the risk for readmission. In a multivariate Cox proportional hazard analysis, Crohns disease was the only significant risk factor for readmission of perianal abscess. Crohn's disease, diabetes, and obesity increase the risk for perianal abscess. Of these, Crohn's and HIV has an impact on readmission. The pathogenesis and the influence of diabetes and obesity need further research if we are to understand why these diseases increase the risk for perianal abscess but not its recurrence.


Hypercapnia-induced cerebral hyperperfusion: an underrecognized clinical entity.
The incidence of cerebral hyperperfusion and hypoperfusion, respectively, resulting from hypercapnia and hypocapnia in hospitalized patients is unknown but is likely underrecognized by radiologists and clinicians without routine performance of quantitative perfusion imaging. Our purpose was to report the clinical and perfusion imaging findings in a series of patients confirmed to have hypercapnic cerebral hyperperfusion and hypocapnic hypoperfusion. Conventional cerebral MR imaging examination was supplemented with arterial spin-labeled (ASL) MR perfusion imaging in 45 patients during a 16-month period at a single institution. Patients presented with an indication of altered mental status, metastasis, or suspected stroke. Images were reviewed and correlated with arterial blood gas (ABG) analysis and clinical history. Patients ranged in age from 1.5 to 85 years. No significant acute findings were identified on conventional MR imaging. Patients with hypercapnia showed global hyperperfusion on ASL cerebral blood flow (CBF) maps, respiratory acidosis on ABG, and diffuse air-space abnormalities on same-day chest radiographs. Regression analysis revealed a significant positive linear relationship between cerebral perfusion and the partial pressure of carbon dioxide (pCO(2); beta, 4.02; t, 11.03; P < .0005), such that rates of cerebral perfusion changed by 4.0 mL/100 g/min for each 1-mm Hg change in pCO(2). With the inception of ASL as a routine perfusion imaging technique, hypercapnic-associated cerebral hyperperfusion will be recognized more frequently and may provide an alternative cause of unexplained neuropsychiatric symptoms in hospitalized patients. In a similar fashion, hypocapnia may account for a subset of patients with normal MR imaging examinations with poor ASL perfusion signal.


Semi-Markov models for brownian dynamics permeation in biological ion channels.
Constructing accurate computational models that explain how ions permeate through a biological ion channel is an important problem in biophysics and drug design. Brownian dynamics simulations are large-scale interacting particle computer simulations for modeling ion channel permeation but can be computationally prohibitive. In this paper, we show the somewhat surprising result that a small-dimensional semi-Markov model can generate events (such as conduction events and dwell times at binding sites in the protein) that are statistically indistinguishable from brownian dynamics computer simulation. This approach enables the use of extrapolation techniques to predict channel conduction when performing the actual brownian dynamics simulation that is computationally intractable. Numerical studies on the simulation of gramicidin A ion channels are presented.


Generalized Topological Simplification of Scalar Fields on Surfaces.
We present a combinatorial algorithm for the general topological simplification of scalar fields on surfaces. Given a scalar field f, our algorithm generates a simplified field g that provably admits only critical points from a constrained subset of the singularities of f, while guaranteeing a small distance ||f - g||∞ for data-fitting purpose. In contrast to previous algorithms, our approach is oblivious to the strategy used for selecting features of interest and allows critical points to be removed arbitrarily. When topological persistence is used to select the features of interest, our algorithm produces a standard ϵ-simplification. Our approach is based on a new iterative algorithm for the constrained reconstruction of sub- and sur-level sets. Extensive experiments show that the number of iterations required for our algorithm to converge is rarely greater than 2 and never greater than 5, yielding O(n log(n)) practical time performances. The algorithm handles triangulated surfaces with or without boundary and is robust to the presence of multi-saddles in the input. It is simple to implement, fast in practice and more general than previous techniques. Practically, our approach allows a user to arbitrarily simplify the topology of an input function and robustly generate the corresponding simplified function. An appealing application area of our algorithm is in scalar field design since it enables, without any threshold parameter, the robust pruning of topological noise as selected by the user. This is needed for example to get rid of inaccuracies introduced by numerical solvers, thereby providing topological guarantees needed for certified geometry processing. Experiments show this ability to eliminate numerical noise as well as validate the time efficiency and accuracy of our algorithm. We provide a lightweight C++ implementation as supplemental material that can be used for topological cleaning on surface meshes.


Calciproteins regulate cyclic AMP content and melatonin secretion in trout pineal photoreceptors.
Photoreceptor cells of the fish pineal transduce photoperiodic information into the rhythmic secretion of melatonin. The nocturnal rise in melatonin secretion has been associated with an increase in cyclic AMP (cAMP) production and with an entry of Ca2+ ions through L-type voltage-dependent channels. It is shown here that two inhibitors of calciproteins, W7 and calmidazolium, inhibit melatonin secretion and, to a lesser extent, cAMP levels in cultured trout pineal photoreceptors. Kinetic studies indicated that melatonin secretion was affected earlier than cAMP in cells cultured in the presence of W7. The present results provide evidence that Ca2+ acts through one or more calciproteins to regulate melatonin production. It is suggested that Ca2+/calciprotein complexes might act at two different sites, one involving regulation of cAMP metabolism, and the other being independent from cAMP.


Complementary and alternative medicine use and cost in functional bowel disorders: a six month prospective study in a large HMO.
Functional Bowel Disorders (FBD) are chronic disorders that are difficult to treat and manage. Many patients and doctors are dissatisfied with the level of improvement in symptoms that can be achieved with standard medical care which may lead them to seek alternatives for care. There are currently no data on the types of Complementary and Alternative Medicine (CAM) used for FBDs other than Irritable Bowel Syndrome (IBS), or on the economic costs of CAM treatments. The aim of this study is to determine prevalence, types and costs of CAM in IBS, functional diarrhea, functional constipation, and functional abdominal pain. 1012 Patients with FBD were recruited through a health care maintenance organization and followed for 6 months. Questionnaires were used to ascertain: Utilization and expenditures on CAM, symptom severity (IBS-SS), quality of life (IBS-QoL), psychological distress (BSI) and perceived treatment effectiveness. Costs for conventional medical care were extracted from administrative claims. CAM was used by 35% of patients, at a median yearly cost of $200. The most common CAM types were ginger, massage therapy and yoga. CAM use was associated with female gender, higher education, and anxiety. Satisfaction with physician care and perceived effectiveness of prescription medication were not associated with CAM use. Physician referral to a CAM provider was uncommon but the majority of patients receiving this recommendation followed their physician's advice. CAM is used by one-third of FBD patients. CAM use does not seem to be driven by dissatisfaction with conventional care. Physicians should discuss CAM use and effectiveness with their patients and refer patients if appropriate.


Performance and ERP components in the equiprobable go/no-go task: Inhibition in children.
The equiprobable go/no-go task lacks the dominant go imperative found in the usual go/no-go task, and hence we previously regarded it as involving little inhibition. However, children have relative difficulty with this task, and demonstrate large frontal no-go N2s. We investigated whether this child N2 plays an inhibitory role, using performance measures to illuminate the link between N2 and inhibition. Forty children aged 8 to 13 were presented with four stimulus blocks each containing 75 go and 75 no-go tone stimuli in random order. A temporal PCA with unrestricted varimax rotation quantified the mean go and no-go ERP component amplitudes. Most identified components were differentially enhanced to go or no-go as in adults, supporting a previously proposed differential processing schema. Between subjects, larger frontocentral no-go N2bs were associated with fewer commission errors. Hence, the no-go N2b in this paradigm can be interpreted as an individual marker of inhibition in children.


Dilemmas for international mobilization around child abuse and neglect.
The goal of this commentary is to articulate some issues and dilemmas raised by various efforts to mobilize international action around child abuse and neglect (CAN). We will start by proposing a typology of international mobilization strategies, noting that initiatives to promote CAN programming in new settings have tended to emphasize one of three vectors: governments, professionals, or international NGOs. There are pros and cons to each emphasis, which we discuss. We also review the debates around some of the following dilemmas: Should low-income countries be a top priority for CAN mobilization? Are there cultural and institutional capacities that need to be present in a country in order for CAN programs to work or be ethical? Are some CAN programs more likely to be internationally transferable than others and why so? Has the field adequately considered whether non-CAN programming (e.g., family planning) might actually be more effective at preventing maltreatment than CAN programming? Does the field give adequate acknowledgment that policies and practices emanating from high-resourced and Western countries may not always be the best to disseminate? Are we relying too much on a model of program transplantation over a model of local cultivation? Should we aim for modest rather than ambitious accomplishments in international mobilization? How much emphasis should be placed on the priority dissemination of evidence-based programming? We conclude with some suggestions in the service of clarifying these dilemmas and making some of these decisions more evidence based.


Neuronal activities during palatable food consumption in the reward system of binge-like eating female rats.
Binge eating disorder (BED), characterized by bingeing episodes and compulsivity, is the most prevalent eating disorder; however, little is known about its neurobiological underpinnings. In humans, BED is associated with desensitization of the reward system, specifically, the medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA). Additionally, BED patients feel relieved during bingeing, suggesting that bingeing helps to decrease the negative emotions they were feeling prior to the binge episode. However, the mechanisms that underlie this feeling of relief in BED patients have not been well investigated. To investigate neuronal activity before and during palatable food consumption in BED, we performed in vivo electrophysiological recordings in a binge-like eating rat model (bingeing, n = 12 and non-bingeing, n = 14) and analyzed the firing rate of neurons in the mPFC, Acb, and VTA before and during access to sucrose solution. We also investigated changes in the firing rate of neurons in these regions during and between active bingeing, which may underlie the feeling of relief in BED patients. We found that neuronal firing rates of mPFC and VTA neurons in bingeing rats were lower than those in non-bingeing rats before and during sucrose consumption. Palatable food consumption increased neuronal firing rates during and between active bingeing in bingeing rats. Our results suggest a desynchronization in the activity of reward system regions, specifically in the mPFC, in bingeing rats, which may also contribute to BED. These results are consistent with those of functional magnetic resonance imaging (fMRI) studies that reported decreased activity in the reward system in BED patients. We propose that increased neuronal activity in the mPFC, Acb, or VTA produces an antidepressant effect in rats, which may underlie the sense of relief patients express during bingeing episodes.


The role of noncoding RNA in hepatocellular carcinoma.
Increasing noncoding RNAs (ncRNAs) were found to show abnormal expression patterns in various human cancers. Based on their length, ncRNAs are briefly divided into two categories. Transcripts that are shorter than 200 nucleotides are recognized as short/small noncoding RNAs and greater than 200 nucleotides as long noncoding RNAs (lncRNAs). Short/small noncoding RNAs include microRNAs, piRNAs, snoRNAs, and endogenous siRNAs. Numerous studies have revealed that these short/small ncRNA play important roles in multiple biological processes and tumorigenesis. In contrast to small ncRNAs, long noncoding RNAs are much less known concerning their functions in human cancers especially in hepatocellular carcinoma (HCC). In this review, we highlight recent progress regarding HCC development, tumorigenesis, metastasis, clinical implication, as well as the role in the risk of HBV infection.