Self-referral in point-of-service health plans.
Most health maintenance organizations offer products with loosened restrictions on patients' access to specialty care. One such product is the point-of-service (POS) plan, which combines "gatekeeping" arrangements with the ability to self-refer at increased out-of-pocket costs. Few data are available from formal evaluations of this new type of plan. To comprehensively describe the self-referral process in POS plans by quantifying rates of self-referral, identifying patients most likely to self-refer, characterizing patients' reasons for self-referral, and assessing satisfaction with specialty care. Retrospective cohort analysis using administrative databases composed of members aged 0 to 64 years who were enrolled in 3 POS health plans in the Midwest (n = 265 843), Northeast (n = 80 292), and mid-Atlantic (n = 39 888) regions for 6 to 12 months in 1996, and a 1997 telephone survey of specialty care users (n = 606) in the midwestern plan. Self-referred service use and charges, reasons for self-referral, and satisfaction with specialty care. Overall, 8.8% of enrollees in the midwestern POS plan, 16.7% in the northeastern plan, and 17.3% in the mid-Atlantic plan self-referred for at least 1 physician or nonphysician clinician visit. The proportions of enrollees self-referring to generalists (4.7%-8.5%) were slightly higher than the proportions self-referring to specialists (3.7%-7.2%) across all 3 plans. Nine percent to 16% of total charges were due to self-referral. The chances of self-referral to a specialist were increased for patients with chronic and orthopedic conditions, higher cost sharing for physician-approved services, and less continuity with their regular physician. Patients who self-referred to specialists preferred to access specialty care directly (38%), reported relationship problems with their regular physicians (28%), had an ongoing relationship with a specialist (23%), were confused about insurance rules (8%), and did not have a regular physician (3%). Compared with those referred to specialists by a physician, patients who self-referred were more satisfied with the specialty care they received. Having the option to self-refer is enough for most POS plan enrollees; 93% to 96% of enrollees did not exercise their POS option to obtain specialty care via self-referral during a 1-year interval. The potential downside of uncoordinated, self-referred service use in POS health plans is limited and counterbalanced by higher patient satisfaction with specialist services.


Comparison of risperidone and olanzapine in the control of negative symptoms of chronic schizophrenia and related psychotic disorders in patients aged 50 to 65 years.
This analysis compares the efficacy of risperidone and olanzapine in controlling negative and positive symptoms of chronic psychosis in older patients. Post hoc assessments were made in a subset of risperidone-treated (N = 19) and olanzapine-treated (N = 20) older patients (aged 50 to 65 years) from a large international, multicenter, parallel, double-blind, 28-week study of patients aged 18 to 65 years (N = 339) randomly assigned to receive risperidone (4-12 mg/day) or olanzapine (10-20 mg/day). Assessments were made using repeated-measures analysis. At both 8 weeks and 28 weeks, the magnitude of changes in Positive and Negative Syndrome Scale (PANSS) positive symptom subscale scores did not differ between treatment groups (8 weeks: risperidone, -6.5; olanzapine, -6.8, p = .866; 28 weeks: risperidone, -6.5; olanzapine, -7.0; p = .804). However, by the 8-week timepoint, olanzapine had reduced PANSS negative subscale scores significantly more than risperidone (-8.8 vs. -4.9, p = .032). By the 28-week endpoint, olanzapine had continued to maintain significantly greater reduction in baseline-to-endpoint PANSS negative scores (-8.1 vs. -3.5, p = .032) and led to significantly greater reduction in scores on the Scale for the Assessment of Negative Symptoms (SANS) dimensions of affective flattening (-5.2 vs. -0.6, p = .033) and alogia (-3.8 vs. -0.3, p = .007). Patients in the olanzapine treatment group also demonstrated numerically greater reduction of both SANS summary (-3.7 vs. -1.0, p = .078) and SANS composite scores (-14.1 vs. -4.1, p = .075). These data demonstrate that, in older patients with schizophrenia and related psychotic disorders, risperidone and olanzapine have approximately equal efficacy in controlling positive symptoms. However, olanzapine appears to be more efficacious in maintaining control over negative symptoms.


Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse.
The immunological synapse (IS) is a junction between the T cell and antigen-presenting cell and is composed of supramolecular activation clusters (SMACs). No studies have been published on naive T cell IS dynamics. Here, we find that IS formation during antigen recognition comprises cycles of stable IS formation and autonomous naive T cell migration. The migration phase is driven by PKCtheta, which is localized to the F-actin-dependent peripheral (p)SMAC. PKCtheta(-/-) T cells formed hyperstable IS in vitro and in vivo and, like WT cells, displayed fast oscillations in the distal SMAC, but they showed reduced slow oscillations in pSMAC integrity. IS reformation is driven by the Wiscott Aldrich Syndrome protein (WASp). WASp(-/-) T cells displayed normal IS formation but were unable to reform IS after migration unless PKCtheta was inhibited. Thus, opposing effects of PKCtheta and WASp control IS stability through pSMAC symmetry breaking and reformation.


Challenges in diabetes mellitus type 2 management in Nepal: a literature review.
Diabetes has become an increasingly prevalent and severe public health problem in Nepal. The Nepalese health system is struggling to deliver comprehensive, quality treatment and services for diabetes at all levels of health care. This study aims to review evidence on the prevalence, cost and treatment of diabetes mellitus type 2 and its complications in Nepal and to critically assess the challenges to be addressed to contain the epidemic and its negative economic impact. A comprehensive review of available evidence and data sources on prevalence, risk factors, cost, complications, treatment, and management of diabetes mellitus type 2 in Nepal was conducted through an online database search for articles published in English between January 2000 and November 2015. Additionally, we performed a manual search of articles and reference lists of published articles for additional references. Diabetes mellitus type 2 is emerging as a major health care problem in Nepal, with rising prevalence and its complications especially in urban populations. Several challenges in diabetes management were identified, including high cost of treatment, limited health care facilities, and lack of disease awareness among patients. No specific guideline was identified for the prevention and treatment of diabetes in Nepal. We conclude that a comprehensive national effort is needed to stem the tide of the growing burden of diabetes mellitus type 2 and its complications in Nepal. The government should develop a comprehensive plan to tackle diabetes and other non-communicable diseases supported by appropriate health infrastructure and funding.


Metastatic Bulk Independently Predicts Outcomes for EGFR Precision Targeting in Colorectal Cancer.
Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti-epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit.


Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence.
The phytochemical resveratrol has been shown to exert numerous health benefits in preclinical studies, but its rapid metabolism and resulting poor bioavailability may limit translation of these effects to humans. Resveratrol metabolites might contribute to in vivo activity through regeneration of the parent compound. We present quantitation of sulfate and glucuronide conjugates of resveratrol in human plasma and tissue after repeated ingestion of resveratrol by volunteers and cancer patients, respectively. Subsequent pharmacokinetic characterization of a mixture of resveratrol-3-O-sulfate and resveratrol-4'-O-sulfate in mice showed that these metabolites are absorbed orally but have low bioavailabilities of ~14 and 3%, respectively. Sulfate hydrolysis in vivo liberated free resveratrol, which accounted for ~2% of the total resveratrol species present in mouse plasma. Monosulfate metabolites were also converted to the parent in human colorectal cells. The extent of cellular uptake was dependent on specific membrane transporters and dictated antiproliferative activity. Sulfate metabolites induced autophagy and senescence in human cancer cells; these effects were abrogated by inclusion of a sulfatase inhibitor, which reduced intracellular resveratrol. Together, our findings suggest that resveratrol is delivered to target tissues in a stable sulfate-conjugated form and that the parent compound is gradually regenerated in selected cells and may give rise to the beneficial effects in vivo. At doses considered to be safe in humans, resveratrol generated via this route may be of greater importance than the unmetabolized form.


Resident Perception of Technical Skills Education and Preparation for Independent Practice.
Surgical skills are traditionally taught and practiced in the operating room. However, changes in health care policy and outcome-based evaluation have decreased trainee operative autonomy. We examined cardiothoracic residents' perceptions of operative experience and the role of simulation. The In-Training Examination (ITE) is taken each year by all residents. Completion of a 30-question preexamination survey is mandatory, ensuring a 100% response rate. Survey data related to operative experience, career preparedness, and surgical simulation were analyzed. Opinion questions were asked on a 5-point Likert scale. Respondents were grouped into three cohorts by training paradigm (2-year versus 3-year traditional programs and 6-year integrated programs). In all, 314 respondents (122 2-year, 96 3-year, and 96 6-year integrated) completed the survey. Of the three groups, residents in 3-year programs had the highest levels of satisfaction. Advanced training was most common among residents in 6-year integrated programs (66%, versus 49% for 2-year and 26% for 3-year programs; p = 0.63). Desire to specialize drove further training (97%), with 2% stating further training was needed owing to inadequacy and 1% owing to a poor job market. In all assessed categories, the majority of residents believed that simulation did not completely replicate the educational value of an operative case. Cardiothoracic residents largely feel well prepared for the transition to practice under the current educational paradigm. Although many residents seek advanced training, it seems driven by the desire for specialization. Residents view simulation as an adjunct to traditional intraoperative education, but not as a viable replacement. Further study is necessary to better understand how best to integrate simulation with operative experience.


Abuse of anabolic-androgenic steroids and bodybuilding acne: an underestimated health problem.
Abuse of anabolic-androgenic steroids (AAS) by members of fitness centers and others in Germany has reached alarming dimensions. The health care system provides the illegal AAS to 48.1 % of abusers. Physicians are involved in illegal prescription of AAS and monitoring of 32.1 % of AAS abusers. Besides health-threatening cardiovascular, hepatotoxic and psychiatric long-term side effects of AAS, acne occurs in about 50 % of AAS abusers and is an important clinical indicator of AAS abuse, especially in young men 18-26 years of age. Both acne conglobata and acne fulminans can be induced by AAS abuse. The dermatologist should recognize bodybuilding acne, address the AAS abuse, and warn the patient about other potential hazards.


Predicted Effectiveness of Daily and Nondaily Preexposure Prophylaxis for Men Who Have Sex With Men Based on Sex and Pill-taking Patterns From the Human Immuno Virus Prevention Trials Network 067/ADAPT Study.
The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.


Circulating blood cellular glucose transporters - Surrogate biomarkers for neonatal hypoxic-ischemic encephalopathy assessed by novel scoring systems.
We examined Red Blood Cell (RBC) Glucose Transporter isoform 1 (GLUT1) and White Blood Cell (WBC) Glucose Transporter isoform 3 (GLUT3) protein concentrations to assess their potential as surrogate biomarkers for the presence of hypoxic-ischemic encephalopathy (HIE) and response to therapeutic hypothermia (TH), with respect to the neurodevelopmental prognosis. A prospective feasibility study of 10 infants with HIE and 8 age-matched control subjects was undertaken. Following parental consent, blood samples were obtained at baseline before institution of TH (<6 h of life), during TH, at rewarming and post-TH in the HIE group with a baseline sample from the control group. GLUT1 and GLUT3 were measured by Enzyme-linked immunosorbent assay (ELISA) with brain biomarkers, Neuron-Specific Enolase (NSE) and Glial Fibrillary Acidic Protein (GFAP). Novel "HIE-high risk" and "Neurological" scores were developed to help identify HIE and to assess severity and prognosis, respectively. RBC GLUT1 concentrations were increased at the baseline pre-TH time point in HIE versus control subjects (p = .006), normalizing after TH (p = .05). An association between GLUT1 and NSE concentrations (which was reflective of the HIE-high risk and the Neuro-scores) in controls and HIE pre-TH was seen (R2 = 0.36, p = .008), with GLUT1 demonstrating 90% sensitivity and 88% specificity for presence of HIE identified by Sarnat Staging. WBC GLUT3 concentrations were low and no different in HIE versus control, and GFAP concentrations trended higher during re-warming (p = .11) and post-TH (p = .16). We demonstrated a significant difference between HIE and controls for both the "HIE-high risk" and the "Neurological" Scores. The latter score revealing the severity of clinical neurological illness correlated with the corresponding RBC GLUT1 (R2 value = 0.39; p = .006). Circulating RBC GLUT1 concentrations with NSE demonstrate a significant potential in reflecting the severity of HIE pre-TH and gauging effectiveness of TH. In contrast, the low neonatal WBC GLUT3 concentrations make discerning differences between degrees of HIE as well as assessing effectiveness of TH difficult. The HIE-high risk and Neurological scores may extend the "Sarnat staging" towards assessing severity and neuro-developmental prognosis of HIE.


Functional connectivity in autosomal dominant and late-onset Alzheimer disease.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.


Dysregulation of mTOR signaling in fragile X syndrome.
Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.


Cardiovascular disease and risk factors in three Alaskan Eskimo populations: the Alaska-Siberia project.
To determine the prevalence of CVD and to identify and characterize associated risk factors in three distinct Eskimo populations. Cross-sectional. A slightly modified Strong Heart Study protocol was followed to examine 454 participants, aged 25-91, from four villages. Overall, 6% of the participants under 55 years of age and 26% of those > or = 55 years of age showed evidence of CHD by ECG, or in patient records. The prevalence of "definite coronary heart disease" (CHD) in women with glucose intolerance (GI) was 21.0%, compared to 2.4% in those with normal glucose tolerance (NGT). Men had comparable values of 26.7% and 6.3%. In addition, comparable values for "possible CHD" were 29.7% vs 6.0% for women and 21.4% vs 8.0% for men. GI was associated with relatively higher prevalences of CHD in women than in men (prevalence ratio = 8.5 vs 4.3). CHD was significantly related to age, glucose intolerance and insulin. Hypertension and obesity were significantly associated with CHD only in some ethnic groups. The prevalence of current smokers was 56%. Recent changes in lifestyle and diet of Alaskan Eskimos, leading to obesity, hypertension, insulin resistance and DM, contribute to an increased risk for cardiovascular disease.


Selective digestive tract decontamination decreases time on ventilator in Guillain-Barré syndrome.
Ventilator-associated pneumonia (VAP) occurs in more than half of mechanically ventilated patients with Guillain-Barré syndrome (GBS) and is associated with prolonged mechanical ventilation (MV). We investigated the impact of selective decontamination of the digestive tract (SDD), an intervention that reduces hospital acquired infections in ICU patients, on duration of MV in GBS and neurological outcome at 6 months. We performed a retrospective study in mechanically ventilated GBS patients in the Netherlands. We compared patients treated with and without SDD. Main outcomes were duration of MV and the ability to walk independently at 6 months. Statistical comparison was done with logistic and ordinal regression analyses. We included 124 GBS patients on MV at 2 weeks after first symptoms (SDD, n = 54 and non-SDD, n = 70). The median duration of MV without SDD was 42 days (interquartile range, IQR 25-77 days) versus 29 days with SDD (IQR 17-45 days). Median duration of MV for all included patients was 35 days. The adjusted odds ratio (OR) for duration of MV > 35 days in the SDD versus the non-SDD cohort was 0.37 (95% CI 0.17-0.77). SDD did not affect neurological recovery after 6 months from first symptoms. VAP occurred in 12% (95% CI 2-22%) in the SDD cohort and in 47% (95% CI 35-59%) in the non-SDD cohort. SDD in mechanically ventilated GBS patients reduced the time on the ventilator, probably by preventing VAP, but did not affect neurological recovery after 6 months.


Risk of infection-related cancers after the loss of a child: a follow-up study in Sweden.
It is unknown whether severe emotional stress due to loss of a child influences the risk of cancers susceptible to immune modulation such as infection-related cancers. We conducted a historic cohort study in 1990 to 2004 on the basis of the Swedish Multi-Generation Register including 4,687,073 parents. Death of a child was identified through the Causes of Death Register. Poisson regression was used to derive the relative risks (RR) and 95% confidence intervals (CI) of infection-related cancers, comparing the incidence rates of parents who lost a child with those who never lost a child. A total of 101,306 parents (2%) had lost a child during follow-up, among whom 1,608 subsequently developed infection-related cancers. After adjustment for age, sex, calendar year, educational level, and civil status, the overall RR of 14 cancers studied was 1.07 (95% CI: 1.02-1.12). Parents who lost a child were particularly at a higher risk for cancers potentially associated with human papilloma virus (HPV) infection such as cervical cancer (RR: 1.46; 95% CI: 1.17-1.80). Higher RRs for most cancers were obtained within 5 years after child loss and excess risk for liver and stomach cancers was confined to that period. No association was observed for lymphoma and nonmelanoma skin cancer at any time point after child loss. Although potential confounding by unmeasured factors cannot be ruled out, our findings lend support to the hypothesis that severe life stressors, such as child loss, may raise the risk for several, chiefly HPV-related, cancers.


Anger and incident heart disease in the caerphilly study.
The idea that anger may predict ischemic heart disease (IHD) is more than 30 years old. Some, but not all, prospective studies have supported this suggestion. Attention has focused on hostility as the critical component of anger for IHD risk. This idea is explored using prospective data from the Caerphilly study. A sample of 2890 men aged 49 to 65 years living in and around Caerphilly, South Wales, was identified. Anger was assessed using the Framingham scales comprising "anger symptoms," "anger in," "anger out," and "anger discuss." A new "suppressed anger" scale was also constructed. Cardiovascular risk factors assessed included baseline blood pressure, total and high-density lipoprotein cholesterol, fibrinogen, white cell count, psychiatric caseness as assessed by the General Health Questionnaire, social support, smoking habit, alcohol consumption, leisure exercise, body mass index, and calorie intake. Prediction of IHD, measured as the occurrence of a major event over a follow-up period of 9 years, was assessed using multiple logistic regression analysis. A low anger out score predicted increased risk of a major IHD event (relative odds (RO) = 1.70; 95% confidence interval = 1.26-2.29 for all RO). This association was unchanged on controlling for physiological risk factors (RO = 1.74), psychosocial risk factors (RO = 1.72), and behavioral risk factors (RO = 1.69). Suppressed anger showed associations with incident IHD similar to those of anger out but identified the population at risk more closely. Anger out and suppressed anger were predictive of incident IHD. Neither of these constructs are overtly similar to hostility. These findings suggest there may be mechanisms other than hostility by which anger predicts IHD risk and that a conceptually varied approach to anger is currently appropriate.


Effect of age at onset of deafness on binaural sensitivity in electric hearing in humans.
Sensitivity to binaural cues was studied in 11 bilateral cochlear implant users, all of whom received both of their cochlear implants as adults, but who varied in the age at onset of deafness, from pre-lingual to childhood-onset to adult-onset. Sensitivity to interaural timing difference (ITD) and interaural level difference (ILD) cues was measured at basal, middle, and apical pitch-matched places of stimulation along the cochlear arrays, using a stimulation rate of 100 Hz. Results show that there is a trend for people whose onset of deafness occurred during adult life or late childhood to retain at least some sensitivity to ITDs, whereas people with onset of deafness earlier in life were insensitive to ITDs. In contrast, ILD cue sensitivity was present in all subjects. There were no effects of place of stimulation on binaural sensitivity, suggesting that there is no indication of a dependence of ITD sensitivity on apical vs basal electrode location.


The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation.
The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is a collection of health-related quality of life (HRQOL) questionnaires targeted to the management of chronic illness. The measurement system, under development since 1987, began with the creation of a generic CORE questionnaire called the Functional Assessment of Cancer Therapy-General (FACT-G). The FACT-G (now in Version 4) is a 27-item compilation of general questions divided into four primary QOL domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. It is appropriate for use with patients with any form of cancer, and extensions of it have been used and validated in other chronic illness condition (e.g., HIV/AIDS; multiple sclerosis; Parkinson's disease; rheumatoid arthritis), and in the general population. The FACIT Measurement System now includes over 400 questions, some of which have been translated into more than 45 languages. Assessment of any one patient is tailored so that the most-relevant questions are asked and administration time for any one assessment is usually less than 15 minutes. This is accomplished both by the use of specific subscales for relevant domains of HRQOL, or computerized adaptive testing (CAT) of selected symptoms and functional areas. FACIT questionnaires can be administered by self-report (paper or computer) or interview (face-to-face or telephone). Available scoring, normative data and information on meaningful change now allow one to interpret results in the context of a growing literature base.


The morphology of venovenous bypass graft endothelium.
Venovenous bypass grafts are commonly used in the repair of vascular trauma to large- and small-caliber veins. This study examines the morphology of the venous wall in an experimental model of the venovenous bypass graft. The morphology of the venous endothelium from unmanipulated jugular veins and from jugular veins implanted as a venovenous bypass graft in the external jugular venous system for 10 min, 6 h, and 1, 3, 5, 7 and 28 days was examined. Veins and venovenous grafts were pressure fixed in situ at 80 mmHg and were examined by scanning and transmission electron microscopy. The endothelial cell lining remained confluent and intact over the 28-day period with evidence of endothelial cell contraction (spindle-shaped cells) for the first 72 h. Pinocytotic activity in endothelial cells and underlying smooth muscle cells was observed throughout the study, strongly indicating physiologically active cells. There was some accumulation of blood cells, predominantly polymorphonuclear leukocytes on the endothelial surface. Polymorphonuclear leukocytes were observed to infiltrate into the subendothelium through endothelial cell junctions within 6 h but by day 3, none was noted in the subendothelial space. There was no major disruption of the graft wall at any time point. By day 28, there was evidence of intimal thickening in the venovenous bypass grafts but no well-demarcated intimal hyperplasia. This study shows that there is no significant endothelial injury in the venovenous bypass grafts and that the endothelial cells remain physiologically active. Short-term failure of venovenous bypass grafts, therefore, appears not be due to significant endothelial cell damage in the graft.


All-optical controlled switching in centrally coupled circular array of nonlinear optical fibers.
We show that, in a nonlinear centrally coupled circular array of evanescently coupled fibers, the coupling dynamics of a weak signal beam can be efficiently influenced by a high-power control beam that induces nonlinear defects. When the intense control beam is launched into the central core and one core in the periphery, then localized solitons are formed and cause the fibers with induced defects (defected fibers) to decouple from the other array elements. In the presence of a high-intensity control beam, the propagation of weak signal is restricted to the defected optical fibers. The weak signal periodically couples between the induced defects. This oscillatory behavior depends on the sign of the (Kerr-type) nonlinearity and the initial phase difference between the control fields injected to the central and one of the peripheral fibers. This all-optical network has the advantage of routing and switching the weak signal field in a controlled way by adjusting the parameters of intense control field.


Effects of four premolar extractions on vermilion height and lip area during a posed smile in patients with bimaxillary protrusion.
The purpose of this study was to evaluate the effects of four premolar extractions and orthodontic treatment on changes to the lips and vermilion height during a posed smile. Fifteen female patients who were diagnosed with bimaxillary protrusion and treated with four premolar extractions were selected. The control group consisted of 25 female volunteers with a normal occlusion. Frontal photographs of the patients during a posed smile were taken before and after orthodontic treatment. Thirty-five landmarks on the upper and lower lips were identified and used to generate measurements of lip area and vermilion height. Linear and angular cephalometric measurements were also obtained. The mean values for vermilion height and lip form before orthodontic treatment were significantly larger in the treatment group compared with those of the control group. Following treatment, values significantly decreased to the extent that there was no significant difference in the vermilion height and lip form between the post-treatment and control groups. Only three and four significant correlations were found between the changes in incisor position and changes in vermilion height and lip area for the upper and lower lips, respectively. The vermilion height and lip area in patients with bimaxillary protrusion approached comparative and normal values as a result of four premolar extractions and orthodontic retraction.


Atypical leiomyomas of the uterus: a clinicopathologic study of 51 cases.
Atypical leiomyoma is a well-described smooth muscle neoplasm of the uterus. Only 1 study has addressed long-term clinical follow-up in a large series, and little is known about the adequacy of treatment by myomectomy. The surgical pathology archives were searched for consecutive cases of uterine atypical leiomyoma from 1992 to 2003. Glass slides were reviewed to confirm the diagnoses, and patient age, treatment modality, and clinical follow-up data were recorded. Fifty-one atypical leiomyomas with available glass slides and clinical follow-up data were identified. Thirty tumors exhibited diffuse, moderately to severely atypical cells, whereas 21 showed atypical cells in a more focal or patchy distribution. Twelve had ischemic-type necrosis. By the highest count method, 37 cases were found to have ≤1 MF/10 HPF, 13 showed 1 to 3 MF/10 HPF, and 1 was nearly entirely necrotic precluding mitotic assessment. Among cases in which adjacent non-neoplastic tissue was well visualized, all were found to have pushing margins (46 cases). The average tumor size was 6.8 cm (median 6.5 cm; range, 0.7 to 14 cm). The average patient age was 42.5 years (median 42 y; range, 21 to 72 y). In all cases, the initial diagnostic procedure was hysterectomy (34) or myomectomy (17). Average follow-up was 42 months (range, 0.3 to 121.8 mo). Of those treated with hysterectomy, 1 had recurrent atypical leiomyoma in the retroperitoneum at 87.5 months, 1 died of other causes, and the remaining 32 (94%) were free of disease. Of the myomectomy group, 82% had no evidence of recurrent disease on follow-up: 2 had residual atypical leiomyoma in the subsequent hysterectomy specimen; and 1 underwent second myomectomy for atypical leiomyoma with 2 subsequent successful pregnancies. Atypical leiomyoma has a low rate of extrauterine, intra-abdominal recurrence (<2%) with a negligible risk for distant metastasis. Patients may be treated by myomectomy alone with successful pregnancy, but should be monitored for local intrauterine residual/recurrent disease.


Percutaneous nephrolithotomy.
A new method of removing calculi from the renal collecting system, in which the large and traumatic incision in the loin currently used is unnecessary, was attempted in 31 patients. Small dilators were introduced over a guide wire through a nephrostomy tube into the renal pelvis and a catheter inserted. The track was dilated in stages and two days later the nephrostomy tube was removed and a cystoscope introduced into the interior of the kidney. A stone basket was introduced down the operating channel of the cystoscope and maneuvered to secure the stone; the cystoscope, stone basket, and stone were then removed. The procedure failed in 11 of the 31 patients, in five because the needle could not be placed accurately initially and in six because the stone could not be removed despite the establishment of a nephrostomy track. In the remaining 20 patients the procedure was successful. This procedure is far less traumatic than the conventional operation. With the development of a flexible nephroscope and an ultrasonic stone disintegrator it will be possible also to remove larger stones and stones in the peripheral calices using this method.


Beneficial effects of dietary probiotics mixture on hemato-immunology and cell apoptosis of Labeo rohita fingerlings reared at higher water temperatures.
Probiotics play an important role in growth increment, immune enhancement and stress mitigation in fish. Increasing temperature is a major concern in present aquaculture practices as it markedly deteriorates the health condition and reduces the growth in fish. In order to explore the possibilities of using probiotics as a counter measure for temperature associated problems, a 30 days feeding trial was conducted to study the hemato-immunological and apoptosis response of Labeo rohita (8.3±0.4 g) reared at different water temperatures, fed with or without dietary supplementation of a probiotic mixture (PM) consisting of Bacillus subtilis, Lactococcus lactis and Saccharomyces cerevisiae) (1011 cfu kg(-1)). Three hundred and sixty fish were randomly distributed into eight treatment groups in triplicates, namely, T1(28°C+BF(Basal feed)+PM), T2(31°C+BF+PM), T3(34°C+BF+PM), T4(37°C+BF+PM), T5(28°C+BF), T6(31°C+BF), T7(34°C+BF) and T8(37°C+BF). A significant increase (P<0.01) in weight gain percentage was observed in the probiotic fed fish even when reared at higher water temperature (34-37°C). Respiratory burst assay, blood glucose, erythrocyte count, total serum protein, albumin, alkaline phosphatase and acid phosphatase were significantly higher (P<0.01) in the probiotic fed groups compared to the non-probiotic fed groups. A significant (P<0.01) effect of rearing temperature and dietary probiotic mixture on serum myeloperoxidase activity, HSP70 level and immunoglobulin production was observed. Degree of apoptosis in different tissues was also significantly reduced in probiotic-supplemented groups. Hence, the present results show that a dietary PM could be beneficial in enhancing the immune status of the fish and also help in combating the stress caused to the organism by higher rearing water temperature.


Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men's Health Study (2002-2009).
Most epidemiological studies evaluating the association of fruit and vegetable intakes on lung cancer risk were conducted in North American and European countries. We investigated the association of intakes of fruits, vegetables, dietary vitamins A and C, and folate with lung cancer risk among 61,491 adult Chinese men who were recruited into the Shanghai Men's Health Study, a population-based, prospective cohort study. Baseline dietary intake was assessed through a validated food frequency questionnaire during in-home visits. Multivariate Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer risk associated with dietary intakes. During a median follow-up of 5.5 yr, 359 incident lung cancer cases accrued after the first year of follow-up and 68.8% of them were current smokers. Intakes of green leafy vegetables, β-carotene-rich vegetables, watermelon, vitamin A, and carotenoids were inversely associated with lung cancer risk; the corresponding HR (95% CI) comparing the highest with the lowest quartiles were 0.72 (0.53-0.98), 0.69 (0.51-0.94), 0.65 (0.47-0.90), 0.63 (0.44-0.88), and 0.64 (0.46-0.88). Intake of all fruits and vegetables combined was marginally associated with lower risk. Our study suggests that the consumption of carotenoid-rich vegetables is inversely associated with lung cancer risk.


Fearless dominance and the U.S. presidency: implications of psychopathic personality traits for successful and unsuccessful political leadership.
Although psychopathic personality (psychopathy) is marked largely by maladaptive traits (e.g., poor impulse control, lack of guilt), some authors have conjectured that some features of this condition (e.g., fearlessness, interpersonal dominance) are adaptive in certain occupations, including leadership positions. We tested this hypothesis in the 42 U.S. presidents up to and including George W. Bush using (a) psychopathy trait estimates derived from personality data completed by historical experts on each president, (b) independent historical surveys of presidential leadership, and (c) largely or entirely objective indicators of presidential performance. Fearless Dominance, which reflects the boldness associated with psychopathy, was associated with better rated presidential performance, leadership, persuasiveness, crisis management, Congressional relations, and allied variables; it was also associated with several largely or entirely objective indicators of presidential performance, such as initiating new projects and being viewed as a world figure. Most of these associations survived statistical control for covariates, including intellectual brilliance, five factor model personality traits, and need for power. In contrast, Impulsive Antisociality and related traits of psychopathy were generally unassociated with rated presidential performance, although they were linked to some largely or entirely objective indicators of negative job performance, including Congressional impeachment resolutions, tolerating unethical behavior in subordinates, and negative character. These findings indicate that the boldness associated with psychopathy is an important but heretofore neglected predictor of presidential performance, and suggest that certain features of psychopathy are tied to successful interpersonal behavior.


Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes.
The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.


TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma.
Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.


Variation in Phenotypic Characteristics of Phytophthora capsici Isolates from a Worldwide Collection.
To determine variation within Phytophthora capsici, 124 P. capsici isolates from 12 countries were characterized for sporangial length and width, pedicle length, oospore diameter, sporangia and chlamydospore production, and growth at 32, 35, and 38°C. Sporangia were 23 to 35 μm wide and 38 to 60 μm long; differences in width and length were noted when isolates were grouped by genetic cluster and continent of origin. Length:breadth ratio (1.34 to 2.07) and pedicle length (20 to 260 μm long) varied widely among isolates; differences were apparent by continent and host family of origin. Oospore diameters varied among isolates (22 to 37 μm), but no differences were noted by isolate genetic cluster, host family of origin, continent of origin, mating type, or sensitivity to mefenoxam. Differences in sporangia production were observed among isolates grouped by continent, and isolates from nonvegetable hosts produced fewer sporangia than isolates from vegetable hosts. When cultures were incubated in a liquid medium, 35 P. capsici isolates formed chlamydospores. Most (122 of 124) of the isolates were able to grow at 35°C, but all of the isolates grew poorly at 38°C. The results of this study indicate substantial variation in morphological and physiological characteristics among P. capsici isolates.


Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity.
The aim was to determine whether lower visceral pain thresholds in irritable bowel syndrome (IBS) primarily reflect physiological or psychological factors. Firstly, 121 IBS patients and 28 controls underwent balloon distensions in the descending colon using the ascending methods of limits (AML) to assess pain and urge thresholds. Secondly, sensory decision theory analysis was used to separate physiological from psychological components of perception: neurosensory sensitivity (p(A)) was measured by the ability to discriminate between 30 mm Hg vs 34 mm Hg distensions; psychological influences were measured by the report criterion-that is, the overall tendency to report pain, indexed by the median intensity rating for all distensions, independent of intensity. Psychological symptoms were assessed using the Brief Symptom Inventory (BSI). IBS patients had lower AML pain thresholds (median: 28 mm Hg vs 40 mm Hg; p<0.001), but similar neurosensory sensitivity (median p(A): 0.5 vs 0.5; p = 0.69; 42.6% vs 42.9% were able to discriminate between the stimuli better than chance) and a greater tendency to report pain (median report criterion: 4.0 ("mild" pain) vs 5.2 ("weak" pain); p = 0.003). AML pain thresholds were not correlated with neurosensory sensitivity (r = -0.13; p = 0.14), but were strongly correlated with report criterion (r = 0.67; p<0.0001). Report criterion was inversely correlated with BSI somatisation (r = -0.26; p = 0.001) and BSI global score (r = -0.18; p = 0.035). Similar results were seen for the non-painful sensation of urgency. Increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity.


Role of neuroinflammation in the emotional and cognitive alterations displayed by animal models of obesity.
Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.


Anticancer drugs with chemotherapeutic interactions with thymoquinone in osteosarcoma cells.
Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Treatment options include surgery, chemotherapy, and radiotherapy. Following surgery, multi-agent chemotherapy drugs are effective but are associated with significant side effects and toxicity. Thymoquinone (TMQ) is a pharmacological component of black cumin that has multiple anti-tumorigenic effects. The goal of this study was to determine the effect of TMQ in combination with chemotherapy drugs on the growth inhibition of osteosarcoma and the potential clinical utility of TMQ in the treatment of OS. We evaluated the effects on the MG63 OS cell line when TMQ, 5-fluorouracil, and oxaliplatin combinations were applied that MG63 OS cell line viability was measured with the cell proliferation and apoptosis assay according to dose and time-dependent effects. Application of 10 µM TMQ combined with 5FU and OXA at a low concentration of 1 µM that was discovered an ineffective dose of the used drugs as anticancer decreased cell viability and increased apoptosis in cells at a significant rate at 48 and 72 h. TMQ has potential benefits in preventing the onset and progression of chemotherapy drug-induced toxicity and side effects, and may reduce resistance to chemotherapy drugs. We consider that TMQ may be a potential therapeutic drug for OS and/or other cancers.


The MEE principle in data classification: a perceptron-based analysis.
This letter focuses on the issue of whether risk functionals derived from information-theoretic principles, such as Shannon or Rényi's entropies, are able to cope with the data classification problem in both the sense of attaining the risk functional minimum and implying the minimum probability of error allowed by the family of functions implemented by the classifier, here denoted by min Pe. The analysis of this so-called minimization of error entropy (MEE) principle is carried out in a single perceptron with continuous activation functions, yielding continuous error distributions. In spite of the fact that the analysis is restricted to single perceptrons, it reveals a large spectrum of behaviors that MEE can be expected to exhibit in both theory and practice. In what concerns the theoretical MEE, our study clarifies the role of the parameters controlling the perceptron activation function (of the squashing type) in often reaching the minimum probability of error. Our study also clarifies the role of the kernel density estimator of the error density in achieving the minimum probability of error in practice.


Open-label adjunctive topiramate in the treatment of bipolar disorders.
To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder, we evaluated the response of 56 bipolar outpatients in the Stanley Foundation Bipolar Outcome Network (SFBN) who had been treated with adjunctive topiramate in an open-label, naturalistic fashion. In this case series, response to topiramate was assessed every 2 weeks for the first 3 months according to standard ratings in the SFBN, and monthly thereafter while patients remained on topiramate. Patients' weights, body mass indices (BMIs), and side effects were also assessed. Of the 54 patients who completed at least 2 weeks of open-label, add-on topiramate treatment, 30 had manic, mixed, or cycling symptoms, 11 had depressed symptoms, and 13 were relatively euthymic at the time topiramate was begun. Patients who had been initially treated for manic symptoms displayed significant reductions in standard ratings scores after 4 weeks, after 10 weeks, and at the last evaluation. Those patients who were initially depressed or treated while euthymic showed no significant changes. Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4, to week 10, and to the last evaluation. The most common adverse side effects were neurologic and gastrointestinal. These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician. Controlled studies of topiramate's acute and long-term efficacy and side effects in bipolar disorder appear warranted.


Musical stem completion: humming that note.
This study looked at how people store and retrieve tonal music explicitly and implicitly using a production task. Participants completed an implicit task (tune stem completion) followed by an explicit task (cued recall). The tasks were identical except for the instructions at test time. They listened to tunes and were then presented with tune stems from previously heard tunes and novel tunes. For the implicit task, they were asked to sing a note they thought would come next musically. For the explicit task, they were asked to sing the note they remembered as coming next. Experiment 1 found that people correctly completed significantly more old stems than new stems. Experiment 2 investigated the characteristics of music that fuel retrieval by varying a surface feature of the tune (same timbre or different timbre) from study to test and the encoding task (semantic or nonsemantic). Although we did not find that implicit and explicit memory for music were significantly dissociated for levels of processing, we did find that surface features of music affect semanticjudgments and subsequent explicit retrieval.


Robust moving-blocker scatter correction for cone-beam computed tomography using multiple-view information.
Scatter contamination is one of the main sources of decreasing the image quality in cone-beam computed tomography (CBCT). The moving blocker method is economic and effective for scatter correction (SC), which can simultaneously estimate scatter and reconstruct the complete volume within the field of view (FOV) from a single CBCT scan. However, at the regions with large intensity transition in the projection images along the axial blocker moving direction, the estimation of scatter signal from blocked regions in a single projection view can produce large error and cause significant artifacts in reconstructed images and null the usability of these regions. Furthermore, blocker edge detection error can significantly deteriorate both primary signal and scatter signal estimation and lead to unacceptable reconstruction results. In this study, we propose to use the adjacent multi-view projection images to jointly estimate scatter signal more accurately. In return, the more accurately estimated scatter signal can be utilized to detect blocker edges more accurately for greatly improved robustness of moving-blocker based SC. The experimental results using a Catphan phantom and an anthropomorphic pelvis phantom CBCT data show that the new method can effectively suppress the estimation errors of scatter signal in the fast signal transition regions and is able to correct the blocker detection errors. This development will expand the utility of moving-blocker based SC for the target with sharp intensity changes in the projection images and provide the needed robustness for its clinical translation.


Implications of gendered behaviour and contexts for social mobility in the USA: a nationally representative observational study.
We constructed measures of an individual's gendered behaviour and their gendered environment to investigate the salience of gender norms during adolescence for social mobility during the next decade of life. In this nationally representative observational study, we collected individual-level data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), which enrolled a cohort of nationally representative school students aged 11-19 years from across the USA and followed them up for 14 years (ie, to age 25-33 years). We characterised gendered behaviour for adolescents in a performative sense via self-reports of behaviours and beliefs. We aggregated this individual-level measure to create a proxy measure of an individual's social context by taking averages for an individual's peers of the same sex and school year. Between Jan 5, 1994, and Dec 26, 1995, Add Health collected data on a cohort of 20 745 students. 14 540 respondents were followed-up 14 years later between April 3, 2007, and Feb 1, 2009, of whom 7722 (53·1%) were female. More masculine male respondents were downwardly mobile; they were enrolled in school for fewer years and were more likely to have lower status jobs than their less masculine same-sex school peers. More masculine male respondents were also more likely to have jobs in occupational categories with larger proportions of males than their same-sex school peers. Gendered behaviour was not predictive of future educational and occupational attainment for female respondents. Male adolescents in school years with more masculine same-sex peers than male adolescents in other school years also tended to have lower educational and occupational attainment than their male peers. Educational and occupational attainment in early midlife for female respondents was not affected by their gendered environment. Gender, when measured as a set of gender-distinct behaviours in adolescence, was associated with differential patterns of social mobility from adolescence to young adulthood. Moreover, variation in an individual's local gender norms has implications for subsequent socioeconomic attainment, especially for male adolescents. These findings have potential implications for observed health disparities. Bill & Melinda Gates Foundation.


High-performance electrochromic films with fast switching times using transparent/conductive nanoparticle-modulated charge transfer.
One of the most critical issues in electrochromic (EC) films based on transition metal oxides such as tungsten oxides (WOx) is their poor charge transfer property, which is closely related to EC performance. Herein, high-performance EC films with enhanced charge transport are prepared using small-molecule linkers and transparent/conductive nanoparticles (NPs). In this work, oleylamine (OAm)-stabilized WO2.72 nanorods (NRs) and OAm-stabilized indium tin oxide (ITO) NPs are layer-by-layer (LbL)-assembled with small-molecule linkers (tris(2-aminoethyl)amine, TREN) using a ligand-exchange reaction between bulky/insulating OAm ligands and TREN molecules. In this case, there is only one TREN layer between neighboring inorganic components (WO2.72 NRs and/or ITO NPs), resulting in a dramatic decrease in the separation distance. This minimized separation distance as well as the periodic insertion of transparent/conductive ITO NPs can significantly reduce the charge transfer resistance within WO2.72 NR-based EC films, which remarkably improves their EC performance. Compared to EC films without ITO NPs, the formed EC films with ITO NPs exhibit faster switching responses (4.1 times in coloration time and 3.5 times in bleaching time) and a maximum optical modulation of approximately 55.8%. These results suggest that electrochemical performance, including EC performance, can be significantly improved through structural/interfacial designing of nanocomposites.


The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.
D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.


Host gene expression classifiers diagnose acute respiratory illness etiology.
Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.


Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.
We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.


SHP1 protein-tyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous Cis elements in the CYBB and NCF2 genes.
The CYBB and NCF2 genes encode the phagocyte respiratory burst oxidase proteins, gp91PHOX and p67PHOX. Previously, we identified homologous CYBB and NCF2 cis elements that are necessary for lineage-specific transcription during late myeloid differentiation. We determined that these homologous cis elements are activated by PU.1, IRF1, interferon consensus sequence-binding protein (ICSBP), and the CREB-binding protein (CBP). Since expression of PU.1 and ICSBP is lineage-restricted, our investigations identified a mechanism of lineage-specific CYBB and NCF2 transcription. Since PU.1, IRF1, ICSBP, and CBP are expressed in undifferentiated myeloid cells, our investigations did not determine the mechanism of differentiation stage-specific CYBB and NCF2 transcription. In the current investigations, we determine that SHP1 protein-tyrosine phosphatase (SHP1-PTP) inhibits gp91PHOX and p67PHOX expression, in undifferentiated myeloid cell lines, by decreasing interaction of PU.1, IRF1, ICSBP, and CBP with the CYBB and NCF2 genes. We also determine that IRF1 and ICSBP are tyrosine-phosphorylated during interferon gamma differentiation of myeloid cell lines, and we identify IRF1 and ICSBP tyrosine residues that are necessary for CYBB and NCF2 transcription. Therefore, these investigations identify a novel mechanism by which SHP1-PTP antagonizes myeloid differentiation and determine that tyrosine phosphorylation of IRF1 and ICSPB mediates stage-specific transcriptional activation in differentiating myeloid cells.


Alteration of microRNAs regulated by c-Myc in Burkitt lymphoma.
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma, with a characteristic clinical presentation, morphology and immunophenotype. Over the past years, the typical translocation t(8;14) and its variants have been considered the molecular hallmark of this tumor. However, BL cases with no detectable MYC rearrangement have been identified. Intriguingly, these cases express MYC at levels comparable with cases carrying the translocation. In normal cells c-Myc expression is tightly regulated through a complex feedback loop mechanism. In cancer, MYC is often dysregulated, commonly due to genomic abnormalities. It has recently emerged that this phenomenon may rely on an alteration of post-transcriptional regulation mediated by microRNAs (miRNAs), whose functional alterations are associated with neoplastic transformation. It is also emerging that c-Myc modulates miRNA expression, revealing an intriguing crosstalk between c-Myc and miRNAs. Here, we investigated the expression of miRNAs possibly regulated by c-Myc in BL cases positive or negative for the translocation. A common trend of miRNA expression, with the exception of hsa-miR-9*, was observed in all of the cases. Intriguingly, down-regulation of this miRNA seems to specifically identify a particular subset of BL cases, lacking MYC translocation. Here, we provided evidence that hsa-miR-9-1 gene is heavily methylated in those cases. Finally, we showed that hsa-miR-9* is able to modulate E2F1 and c-Myc expression. Particularly, this study identifies hsa-miR-9* as potentially relevant for malignant transformation in BL cases with no detectable MYC translocation. Deregulation of hsa-miR-9* may therefore be useful as a diagnostic tool, suggesting it as a promising novel candidate for tumor cell marker.


Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes.
Nanoelectronic devices offer substantial potential for interrogating biological systems, although nearly all work has focused on planar device designs. We have overcome this limitation through synthetic integration of a nanoscale field-effect transistor (nanoFET) device at the tip of an acute-angle kinked silicon nanowire, where nanoscale connections are made by the arms of the kinked nanostructure, and remote multilayer interconnects allow three-dimensional (3D) probe presentation. The acute-angle probe geometry was designed and synthesized by controlling cis versus trans crystal conformations between adjacent kinks, and the nanoFET was localized through modulation doping. 3D nanoFET probes exhibited conductance and sensitivity in aqueous solution, independent of large mechanical deflections, and demonstrated high pH sensitivity. Additionally, 3D nanoprobes modified with phospholipid bilayers can enter single cells to allow robust recording of intracellular potentials.


Efficacy of homeopathy in livestock according to peer-reviewed publications from 1981 to 2014.
Homeopathy is widely used in livestock, especially in order to reduce the use of antibiotics, although it is often seen as controversial. A comprehensive literature review has been conducted to assess the efficacy of homeopathy in cattle, pigs and poultry. Only peer-reviewed publications dealing with homeopathic remedies, which could possibly replace or prevent the use of antibiotics in the case of infective diseases or growth promotion in livestock were included. Search results revealed a total number of 52 trials performed within 48 publications fulfilling the predefined criteria. Twenty-eight trials were in favour of homeopathy, with 26 trials showing a significantly higher efficacy in comparison to a control group, whereas 22 showed no medicinal effect. Cure rates for the treatments with antibiotics, homeopathy or placebo varied to a high degree, while the remedy used did not seem to make a big difference. Looking at all the studies, no study was repeated under comparable conditions. Consequently, the use of homeopathy currently cannot claim to have sufficient prognostic validity where efficacy is concerned. When striving for high therapeutic success in treatment, the potential of homeopathy in replacing or reducing antibiotics can only be validated if evidence of efficacy is confirmed by randomised controlled trials under modified conditions.


Differential gene expression in motor and sensory Schwann cells in the rat femoral nerve.
Phenotypic differences in Schwann cells (SCs) may help to guide axonal regeneration down motor or sensory specific pathways following peripheral nerve injury. The goal of this study was to identify phenotypic markers for SCs harvested from the cutaneous (sensory) and quadriceps (motor) branches of the rat femoral nerve and to study the effects of expansion culture on the expression patterns of these motor or sensory phenotypic markers. RNA was extracted from SCs harvested from the motor and sensory branches of the rat femoral nerve and analyzed using Affymetrix Gene Chips (Rat Genome 230 v2.0 Array A). Genes that were upregulated in motor SCs compared with the sensory SCs or vice versa were identified, and the results were verified for a subset of genes using quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of the "phenotype-specific" genes were then evaluated in SC expansion cultures at various time points over 30 days by qRT-PCR to determine the effect of expansion on SC phenotype. Expression levels of the phenotype-specific genes were significantly altered after expansion culture for both the motor and the sensory markers compared with fresh nerve tissue. These results indicate that both motor and sensory SC gene expression patterns are disrupted during expansion in vitro and may affect the ability of SCs to express phenotype-specific genes after transplantation.


Negative effects of internet interventions: a qualitative content analysis of patients' experiences with treatments delivered online.
Internet interventions are defined as the delivery of health care-related treatments via an online or a smartphone interface, and have been shown to be a viable alternative to face-to-face treatments. However, not all patients benefit from such treatments, and it is possible that some may experience negative effects. Investigations of face-to-face treatments indicate that deterioration occurs in 5-10% of all patients. The nature and scope of other negative effects of Internet interventions is, however, largely unknown. Hence, the current study explored patients' reported negative experiences while undergoing treatments delivered via the Internet. Data from four large clinical trials (total N = 558) revealed that 9.3% of patients reported some type of negative effects. Qualitative content analysis was used to explore the patients' responses to open-ended questions regarding their negative experiences. Results yielded two broad categories and four subcategories of negative effects: patient-related negative effects (insight and symptom) and treatment-related negative effects (implementation and format). Results emphasize the importance of always considering negative effects in Internet-based interventions, and point to several ways of preventing such experiences, including regular assessment of negative events, increasing the flexibility of treatment schedules and therapist contact, as well as prolonging the treatment duration.


Links Between Communication and Relationship Satisfaction Among Patients With Cancer and Their Spouses: Results of a Fourteen-Day Smartphone-Based Ecological Momentary Assessment Study.
Cancer treatment poses significant challenges not just for those diagnosed with the disease but also for their intimate partners. Evidence suggests that couples' communication plays a major role in the adjustment of both individuals and in the quality of their relationship. Most descriptive studies linking communication to adjustment have relied on traditional questionnaire methodologies and cross-sectional designs, limiting external validity and discernment of temporal patterns. Using the systemic-transactional model of dyadic coping as a framework, we examined intra- and inter-personal associations between communication (both enacted and perceived) and relationship satisfaction (RS) among patients with stage II-IV breast or colorectal cancer and their spouses (N = 107 couples). Participants (mean age = 51, 64.5% female patients, and 37.4% female spouses) independently completed twice-daily ecological momentary assessments (EMA) via smartphone for 14 consecutive days. Items assessed RS and communication (expression of feelings, holding back from expression, support and criticism of partner, and parallel ratings of partner behavior). Linear mixed models employing an Actor Partner Interdependence Model were used to examine concurrent, time-lagged, and cross-lagged associations between communication and RS. Expressing one's feelings was unassociated with RS. Holding back from doing so, in contrast, was associated with lower RS for both patients and spouses in concurrent models. These effects were both intrapersonal and interpersonal, meaning that when individuals held back from expressing their feelings, they reported lower RS and so too did their partner. Giving and receiving support were associated with one's own higher RS for both patients and spouses in concurrent models, and for patients in lagged models. Conversely, criticizing one's partner and feeling criticized were maladaptive, associated with lower RS (own and in some cases, partner's). Cross-lagged analyses (evening RS to next-day afternoon communication) yielded virtually no effects, suggesting that communication may have a stronger influence on short-term RS than the reverse. Findings underscore the importance of responsive communication, more so than expression per se, in explaining both concurrent and later relationship adjustment. In addition, a focus on holding back from expressing feelings may enhance the understanding of RS for couples coping with cancer.


Considerations that affect optimised simulation in a running jump for height.
This study used a computer simulation model to investigate various considerations that affect optimum peak height in a running jump. A planar eight-segment computer simulation model with extensor and flexor torque generators at five joints was formulated and customised to an elite male high jumper. A simulation was matched to a recorded high jumping performance by varying the activation profiles of each of the torque generators giving a simulated peak height of 1.99m compared to the recorded performance of 2.01 m. In order to maximise the peak height reached by the mass centre in the flight phase, the activation profiles were varied, keeping the same initial conditions as in the matching simulation. Optimisations were carried out without any constraints, with constraints on the angular momentum at take-off, with further constraints on joint angles, and with additional requirements of robustness to perturbations of activation timings. A peak height of 2.37 m was achieved in the optimisation without constraints. Introducing the three constraints in turn resulted in peak heights of 2.21, 2.14 and 1.99m. With all three types of constraints included, the peak height was similar to that achieved in the recorded performance. It is concluded that such considerations have a substantial influence on optimum technique and must be included in studies using optimised simulations.


Genetic dissection of developmental behavior of grain weight in wheat under diverse temperature and water regimes.
As a quantitatively inherited trait related to high yield potential, grain weight (GW) development in wheat is constrained by abiotic stresses such as limited water supply and high temperature. Data from a doubled haploid population, derived from a cross of (Hanxuan 10 × Lumai 14), grown in four environments were used to explore the genetic basis of GW developmental behavior in unconditional and conditional quantitative trait locus (QTL) analyses using a mixed linear model. Thirty additive QTLs and 41 pairs of epistatic QTLs were detected, and were more frequently observed on chromosomes 1B, 2A, 2D, 4A, 4B and 7B. No single QTL was continually active during all stages or periods of grain growth. The QTLs with additive effects (A-QTLs) expressed in the period S1|S0 (the period from the flowering to the seventh day after) formed a foundation for GW development. GW development at these stages can be used as an index for screening superior genotypes under diverse abiotic stresses in a wheat breeding program. One QTL, i.e. Qgw.cgb-6A.2, showed high adaptability for water-limited and heat-stress environments. Many A-QTLs interacted with more than one other QTL in the two genetic models, such as Qgw.cgb-4B.2 interacted with five QTLs, showing that the genetic architecture underlying GW development involves a collective expression of genes with additive and epistatic effects.


The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear.
In mammals, six separate sensory regions in the inner ear are essential for hearing and balance function. Each sensory region is made up of hair cells, which are the sensory cells, and their associated supporting cells, both arising from a common progenitor. Little is known about the molecular mechanisms that govern the development of these sensory organs. Notch signaling plays a pivotal role in the differentiation of hair cells and supporting cells by mediating lateral inhibition via the ligands Delta-like 1 and Jagged (JAG) 2. However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear. Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear. Cristae are completely lacking in Jag1-conditional knockout (cko) mutant inner ears, whereas the cochlea and utricle show partial sensory development. The saccular macula is present but malformed. Using SOX2 and p27kip1 as molecular markers of the prosensory domain, we show that JAG1 is initially expressed in all the prosensory regions of the ear, but becomes down-regulated in the nascent organ of Corti by embryonic day 14.5, when the cells exit the cell cycle and differentiate. We also show that both SOX2 and p27kip1 are down-regulated in Jag1-cko inner ears. Taken together, these data demonstrate that JAG1 is expressed early in the prosensory domains of both the cochlear and vestibular regions, and is required to maintain the normal expression levels of both SOX2 and p27kip1. These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear.


Curcumin inhibits apoptosis by regulating intracellular calcium release, reactive oxygen species and mitochondrial depolarization levels in SH-SY5Y neuronal cells.
Neurological diseases such as Alzheimer's and Parkinson's diseases are incurable progressive neurological disorders caused by the degeneration of neuronal cells and characterized by motor and non-motor symptoms. Curcumin, a turmeric product, is an anti-inflammatory agent and an effective reactive oxygen and nitrogen species scavenging molecule. Hydrogen peroxide (H2O2) is the main source of oxidative stress, which is claimed to be the major source of neurological disorders. Hence, in this study we aimed to investigate the effect of curcumin on Ca(2+) signaling, oxidative stress parameters, mitochondrial depolarization levels and caspase-3 and -9 activities that are induced by the H2O2 model of oxidative stress in SH-SY5Y neuronal cells. SH-SY5Y neuronal cells were divided into four groups namely, the control, curcumin, H2O2, and curcumin + H2O2 groups. The dose and duration of curcumin and H2O2 were determined from published data. The cells in the curcumin, H2O2, and curcumin + H2O2 groups were incubated for 24 h with 5 µM curcumin and 100 µM H2O2. Lipid peroxidation and cytosolic free Ca(2+) concentrations were higher in the H2O2 group than in the control group; however, their levels were lower in the curcumin and curcumin + H2O2 groups than in the H2O2 group alone. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values were lower in the H2O2 group although they were higher in the curcumin and curcumin + H2O2 groups than in the H2O2 group. Caspase-3 activity was lower in the curcumin group than in the H2O2 group. In conclusion, curcumin strongly induced modulator effects on oxidative stress, intracellular Ca(2+) levels, and the caspase-3 and -9 values in an experimental oxidative stress model in SH-SY5Y cells.


Measuring and modeling behavioral decision dynamics in collective evacuation.
Identifying and quantifying factors influencing human decision making remains an outstanding challenge, impacting the performance and predictability of social and technological systems. In many cases, system failures are traced to human factors including congestion, overload, miscommunication, and delays. Here we report results of a behavioral network science experiment, targeting decision making in a natural disaster. In a controlled laboratory setting, our results quantify several key factors influencing individual evacuation decision making in a controlled laboratory setting. The experiment includes tensions between broadcast and peer-to-peer information, and contrasts the effects of temporal urgency associated with the imminence of the disaster and the effects of limited shelter capacity for evacuees. Based on empirical measurements of the cumulative rate of evacuations as a function of the instantaneous disaster likelihood, we develop a quantitative model for decision making that captures remarkably well the main features of observed collective behavior across many different scenarios. Moreover, this model captures the sensitivity of individual- and population-level decision behaviors to external pressures, and systematic deviations from the model provide meaningful estimates of variability in the collective response. Identification of robust methods for quantifying human decisions in the face of risk has implications for policy in disasters and other threat scenarios, specifically the development and testing of robust strategies for training and control of evacuations that account for human behavior and network topologies.


Comprehensive analysis of 19q12 amplicon in human gastric cancers.
Amplification at 19q12 has been observed in multiple tumor types, while cyclin E1 (CCNE1) has been considered to be the key oncogene within this amplicon. We have previously applied cDNA microarray analysis to systematically characterize gene expression patterns of gastric tumor and nontumor samples. We identified a cluster of five tightly coregulated genes all located at chromosome 19q12, including CCNE1. We found that the 19q12 gene cluster is highly expressed in gastric tumors compared to nontumor gastric samples. Array based comparative genomic hybridization and real-time PCR was used to define the boundary of the 19q12 amplicon to a region of approximately 200 kb. Interestingly, we found that in some cases amplification at 19q12 was not associated with DNA copy number gain at CCNE1, suggesting that some other genes within the 19q12 amplicon may also have important function during gastric tumorigenesis. We found high expression of the 19q12 gene cluster to be statistically correlated with the cell proliferation gene signature. Using the SAM software, we identified a set of 577 genes whose expression levels positively correlated with the 19q12 gene cluster. GO term analysis revealed that this genelist is enriched with genes involved in cell cycle regulation and cell proliferation. In conclusion, expression array analysis combined with array comparative genomic hybridization and real-time PCR provides a new and powerful tool to identify clusters of genes which may be regulated by genomic DNA aberrations. In addition, our study indicates that amplification at 19q12 is associated with cell proliferation in vivo.


Balancing "we" and "me".
The open office is the dominant form of workspace design for good reason: It fosters collaboration, promotes learning, and nurtures strong culture. But what most companies fail to realize is that collaboration has a natural rhythm that requires both interaction and private contemplation. Companies have been trying for decades to find the balance between public and private workspace that best supports collaboration. In 1980 52% of U.S. employees lacked workspaces where they could concentrate without distraction. In response, high-walled cubicles took over the corporate landscape. By the late 1990s, the tide had turned, and only 23% of employees wanted more privacy, and 50% wanted more access to other people. Ever since, firms have been beefing up spaces that support collaboration and shrinking areas for individual work. But the pendulum seems to have swung too far: Once again, people feel a pressing need for privacy, not only to do heads-down work but to cope with the intensity of work today. To address these needs, according to the authors, we have to rethink our assumptions about privacy. Traditionally defined in physical terms, privacy is now about the individual's ability to control information and stimulation. In this article, the authors examine workspace design through the new lens of privacy and offer insights on how to foster teamwork and solitude.


An Exploratory Study of Fatigue and Physical Activity in Canadian Thyroid Cancer Patients.
Fatigue is common among cancer survivors, but fatigue in thyroid cancer (TC) survivors may be under-appreciated. This study investigated the severity and prevalence of moderate and severe fatigue in TC survivors. Potential predictive factors, including physical activity, were explored. A cross-sectional, written, self-administered TC patient survey and retrospective chart review were performed in an outpatient academic Endocrinology clinic in Toronto, Canada. The primary outcome measure was the global fatigue score measured by the Brief Fatigue Inventory (BFI). Physical activity was evaluated using the International Physical Activity Questionnaire-7 day (IPAQ-7). Predictors of BFI global fatigue score were explored in univariate analyses and a multivariable linear regression model. The response rate was 63.1% (205/325). Three-quarters of the respondents were women (152/205). The mean age was 52.5 years, and the mean time since first TC surgery was 6.8 years. The mean global BFI score was 3.5 (standard deviation 2.4) out of 10 (10 is worst). The prevalence of moderate-severe fatigue (global BFI score 4.1-10 out of 10) was 41.4% (84/203). Individuals who were unemployed or unable to work due to disability reported significantly higher levels of fatigue compared to the rest of the study population, in uni-and multivariable analyses. Furthermore, increased physical activity was associated with reduced fatigue in uni- and multivariable analyses. Other socio-demographic, disease, or biochemical variables were not significantly associated with fatigue in the multivariable model. Moderate or severe fatigue was reported in about 4/10 TC survivors. Independent predictors of worse fatigue included unemployment and reduced physical activity.


The correlation of specific orthopaedic features of polyostotic fibrous dysplasia with functional outcome scores in children.
Polyostotic fibrous dysplasia has a wide clinical spectrum, with substantial variation between patients in terms of orthopaedic manifestations, including the number of fractures, the degree of deformity of the limbs, and the presence of scoliosis. Data from bone scans, skeletal surveys, and records were correlated with the Pediatric Outcomes Data Collection Instrument scales to examine whether any specific facet of orthopaedic involvement could be related to functional abilities. All patients who were sixteen years of age or younger and who were part of an ongoing natural history study of polyostotic fibrous dysplasia (including McCune-Albright syndrome) were sent an age-appropriate Pediatric Outcomes Data Collection Instrument outcomes tool. The medical records and radiographs of the patients who returned forms were reviewed. Radiographic measurements of scoliosis, the femoral neck-shaft angle, and limb deformities were then performed. The extent of skeletal involvement with polyostotic fibrous dysplasia (disease burden) was assessed on bone scans with use of a validated tool. A chart review was performed to determine the fracture rate, the use of bisphosphonates, and the endocrine status. These measurements were correlated with the Pediatric Outcomes Data Collection Instrument scores. The outcomes tool was sent to twenty-seven patients and the completed instrument was returned by twenty patients, for a response rate of 74%. The parent-child form was filled out for twelve patients and the parent-adolescent form was filled out for eight patients. The mean standardized Pediatric Outcomes Data Collection Instrument scores for all twenty patients were lowest for sports (62; range, 14 to 100) and happiness (72; range, 25 to 100). Adolescents and parents disagreed with regard to sports (with adolescent scores being higher than parental scores) and pain (with parental scores being higher than adolescent scores). However, the overall global scores correlated well between the parents and the adolescents (r = 0.78, p = 0.03). The femoral neck-shaft angle correlated strongly with the Pediatric Outcomes Data Collection Instrument score for sports (r = 0.46, p = 0.03) but not for transfers. The bone scan scores for the lower extremity disease burden correlated with both the transfer scale (r = 0.76, p = 0.03) and the sports scale (r = 0.77, p = 0.02). Deformity of the limbs, the presence of scoliosis, the prevalence of endocrine dysfunction, and the number of fractures did not correlate with the Pediatric Outcomes Data Collection Instrument scores. In patients with polyostotic fibrous dysplasia, the loss of the normal femoral neck-shaft angle and the disease burden in the lower extremities appear to have the greatest effect on functional activity as measured with the Pediatric Outcomes Data Collection Instrument tool.


[Observation on therapeutic effect of acupoint sticking at Neiguan (PC 6) and Xinshu (BL 15) for treatment of bradycardia].
To observe the therapeutic effect of acupoint sticking of Wuzhuyu (Evodia Rutaecarpa) for treatment of bradycardia. Sixty cases were randomly divided into an observation group and a control group, 30 cases in each group. The observation group was treated with acupoint sticking of Wuzhugu (Evodia Rutaecarpa) at Neiguan (PC 6) and Xinshu (BL 15) once each day. The control group was treated with oral administration of Xinbao pills, 3 pills each time, thrice each day. The therapeutic effects and changes of 24 hours' holter were observed after 4 weeks. After treatment, 24 hours' average heart rate was significantly improved in the two groups, with significant differences as compared with those before treatment (both P<0.01) and with no significant difference between the two groups (P>0.05). The total effective rate was 86.7% (26/30) in the observation group and 83.3% (25/30) in the control group, their therapeutic effect being similar. Acupoint sticking of Wuzhugu (Evodia Rutaecarpa) can significantly raise the levels of 24 hours' average heart rate in the patients of bradycardia. This therapy and Xinbao pills have similar therapeutic effect on the improvement of clinical symptom and heart rate levels.