Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection.
Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.


Matrix-Delivered Autologous Mesenchymal Stem Cell Therapy for Refractory Rectovaginal Crohn's Fistulas.
Crohn's rectovaginal fistulizing disease remains notoriously difficult to treat. A phase I clinical trial to evaluate the safety and feasibility of a novel protocol using a mesenchymal stem cell (MSC)-coated Gore Bio-A fistula plug for the treatment of medically and surgically refractory Crohn's rectovaginal fistulas was conducted. Five patients underwent an autologous subcutaneous adipose tissue harvest via a 2-cm abdominal wall incision at time of exam under anesthesia (EUA) with seton placement. MSCs were isolated, expanded, and impregnated on the plug. After 6 weeks, patients returned to the operating room for placement of the MSC-coated plug. The primary end points were safety and feasibility; the secondary end point was clinical and radiographic healing at 6 months. Five female patients (median age [range], 49 [38-53] years) with a median disease duration (range) of 23 (7-34) years who were on biologic (n = 5) or combination therapy (n = 3) had successful harvest and expansion of MSCs and delivery of the Gore Bio-A plug. There were no serious adverse events or adverse events related to the MSCs or plug during the 6-month follow-up. At 6 months, 3 patients had complete cessation of drainage, and 2 had >50% reduction in drainage; all had a persistent fistula tract identified on magnetic resonance imaging and EUA at 6 months. Surgical placement of an autologous adipose-derived MSC-coated fistula plug in diverted patients with Crohn's rectovaginal fistulas was safe and feasible. All patients had a reduction in the size of their fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing.This was a phase I clinical trial of autologous mesenchymal stem cells on a plug for rectovaginal Crohn's fistulas.


Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study.
Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)-positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.


Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer.
Small cell lung cancer (SCLC) is highly sensitive to chemotherapy. Despite a dramatic initial response, however, most patients relapse. Given the activity of gemcitabine in non-small cell lung cancer (NSCLC), and early clinical trials suggesting activity of gemcitabine in chemo-naive SCLC patients, we conducted a phase II study to determine the efficacy and toxicities of gemcitabine in SCLC patients who have failed first-line chemotherapy. Gemcitabine 1250 mg/m(2) was given intravenously on days 1 and 8, every 3 weeks. Eligibility criteria included prior treatment with only one chemotherapy regimen and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with brain metastases were eligible. Between April 1998 and October 2001, 27 patients were enrolled: 15 patients with sensitive (S) disease (recurred>3 months after first-line chemotherapy) and 12 patients with refractory (R) disease (failed<3 months after first-line chemotherapy). Median age was 61 (range 45-74). All patients had received prior platinum-based therapy involving etoposide and either cisplatin or carboplatin. There were one early death and two early withdrawals because of toxicity. No responses were observed. Of 24 patients who received at least two cycles of gemcitabine, only three achieved stable disease after six cycles while 21 progressed. The median time to progression (TTP) was 6 weeks in S group, 5.6 weeks in R group, and 6 weeks overall. After a minimum potential follow-up of almost 1 year for all patients, the median survival was 8.8 months in S group, 4.2 months in R group, and 6.4 months for the whole group. One-year survival rate was 33.3% in S group, 16.7% in R group, and 25.4% for all patients. Myelosuppression was the most commonly observed adverse effect, with grade 3/4 neutropenia in 30%, and grade 3 thrombocytopenia in 30%. One patient (3.7%) developed neutropenic fever. Respiratory failure and death, possibly related to pulmonary toxicity, was observed in one patient (3.7%). monotherapy gemcitabine as second-line agent has limited activity in previously treated SCLC.


Physicians' attitudes about the care of patients in the persistent vegetative state: a national survey.
To study the attitudes and beliefs of physicians who have experience caring for patients in the persistent vegetative state (PVS). Mailed questionnaire survey. 500 physicians, 250 from the American Academy of Neurology and 250 from the American Medical Directors Association. Physicians' beliefs about diagnosis of the PVS, patient awareness and suffering, treatment withdrawal, appropriate use of health maintenance and life-prolonging therapies, organ donation, lethal injection, and the treatment they would want if they were in the PVS. 68% of surveyed neurologists and 60% of medical directors responded. Thirteen percent of responders believe that patients in the PVS have awareness and experience hunger and thirst; 30% believe they experience pain. Fewer than 9% believe that respiratory failure, cardiogenic shock, acute renal failure, or cancer should be aggressively treated. Eighty-nine percent believe that it is ethical to withdraw artificial hydration and nutrition. Almost two thirds of responders believe that it would be ethical to use the vital organs of patients in the PVS for transplantation, and 20% believe that it would be ethical to hasten the patient's death by lethal injection. When evaluating the appropriateness of treatments for patients in the PVS, neurologists and medical directors largely concur. Most physicians in both groups believe that patients in the PVS would be better off dead; that it is not necessary to provide aggressive therapeutic interventions; and that all therapeutic interventions, including artificial nutrition and hydration, can be withheld in certain circumstances. The areas of consensus are remarkable and suggest that an ethical standard that physicians believe should be followed when caring for these patients may be emerging.


Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat.
Silymarin, a flavonoid extracted from the seeds of the milk thistle, Silybum marianum, increases the redox state and the total glutathione content of the liver, intestine, and stomach of the rat. The same treatment does not affect the levels of the tripeptides in the kidney, lung, and spleen. This selective effect of the flavonoid on the digestive organs is ascribed to its pharmacokinetics on the digestive track, where the biliary concentration of silymarin is increased and maintained via the entero-hepatic circulation.


Quantitation of transplacental haemorrhage.
On four occasions over a period of four years samples of adult blood to which known amounts of fetal blood had been added were distributed to 8-12 different laboratories taking part in clinical trials organized by an M.R.C. Working Party. Estimates were made of the proportion of fetal: adult red cells in the samples after preparing films by the acid-elution method. When the proportion of fetal: adult red cells was less than about 1:10,000, the highest and lowest estimates were separated by a factor of about 10. However, when the number of cells present was between about 1:100 and 1:1,000, most results were between half and twice the true number of cells present.It is pointed out that since fetal red cells are approximately 30% larger than adult red cells, and since only about 90% of fetal cells stain darkly in the acid-elution method, estimates of the proportion of darkly-staining cells in a film underestimate the volume of fetal red cells present by about one-third. A simple formula is proposed which corrects for this factor and which gives an estimate of the total volume of fetal red cells present, deduced from the ratio of fetal: adult red cells and assuming a maternal red cell volume at term of 1,800 ml.A method of screening blood films is suggested which, firstly, endeavours to standardize the density of adult red cells on films, and, secondly, takes into account the Poisson distribution. Thus limits are set for the number of fetal red cells which can be seen in scanning a given number of adult cells before the suspicion is aroused that a transplacental haemorrhage exceeding a certain amount is present.It is emphasized that the density of adult red cells on blood films varies very widely, and unless the cell density and the size of the low-power field are defined the practice of deducing the extent of transplacental haemorrhage from the number of fetal red cells seen per low-power field may lead to large errors.


Reproductive and menstrual factors and colorectal cancer incidence in the Women's Health Initiative Observational Study.
Reproductive and menstrual factors have been evaluated as surrogates for long-term hormonal exposures in several prospective studies of colorectal cancer, yet findings have been conflicting. The relation of reproductive and menstrual factors (self-reported via a reproductive history questionnaire) with incident colorectal cancer was investigated among women enrolled in the Women's Health Initiative Observational Study (WHI-OS), a longitudinal cohort of 93 676 postmenopausal women (aged 50-79 years at enrolment) in which 1149 incident cases of colorectal cancer occurred over a median follow-up of 11.9 years. Multivariable Cox proportional hazards models that included established colorectal cancer risk factors were constructed to examine the association of colorectal cancer incidence with reproductive and menstrual factors. Having had two children (vs nulliparous: hazard ratio (HR)=0.80, 95% confidence interval (CI): 0.64-0.99) was inversely associated with colorectal cancer risk. Compared with never users, ever use of oral contraceptives was associated with lower colorectal cancer risk (HR=0.74, 95% CI: 0.63-0.86); however, no relationship was observed for duration of oral contraceptives use (4 years vs 1 year: HR=0.94, 95% CI: 0.67-1.32). None of the remaining reproductive and menstrual factors was associated with colorectal cancer incidence. Parity and prior use of oral contraceptives were associated with lower colorectal cancer risk in this cohort of postmenopausal women.


The utilization of colonoscopy in Germany.
Colorectal cancer is one of the three most common cancers in German adults. There are several legally based examinations for the early detection of colorectal cancer. People aged 50 to 54 years can have a faecal blood test annually. From the age of 55, this test is offered every two years as part of cancer screening, or alternatively a preventive colonoscopy, which can be repeated after ten years if the findings are inconspicuous. However, colonoscopies are also carried out to clarify complaints or other diseases (curative colonoscopy). In the GEDA 2014/2015-EHIS study, the respondents provided the date of their last colonoscopy. No data was collected on the reason why this colonoscopy was performed. 57% of women and 61% of men aged 55 years or older reported that they had a colonoscopy within the last 10 years. New legal regulations envisage the expansion of colorectal cancer screening and its development into an organised, quality-assured early detection programme.


Cohort profile: seek, test, treat and retain United States criminal justice cohort.
The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement. The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved in the criminal justice system, often but not exclusively for reasons related to substance use. The studies were conducted in a variety of CJ settings and collected information across 11 pre-selected domains: demographic characteristics, CJ involvement, HIV risk behaviors, HIV and/or Hepatitis C infections, laboratory measures of CD4 T-cell count (CD4) and HIV RNA viral load (VL), mental illness, health related quality of life (QoL), socioeconomic status, health care access, substance use, and social support. The STTR CJ cohort includes data on 11,070 individuals with and without HIV infection who range in age from 18 to 77 years, with a median age at baseline of 37 years. The cohort reflects racial, ethnic and gender distributions in the U.S. CJ system, and 64% of participants are African-American, 12% are Hispanic and 83% are men. Cohort members reported a wide range of HIV risk behaviors including history of injection drug use and, among those who reported on pre-incarceration sexual behaviors, the prevalence of unprotected sexual intercourse ranged across studies from 4% to 79%. Across all studies, 53% percent of the STTR CJ cohort reported recent polysubstance use. The STTR CJ cohort is comprised of participants from a wide range of CJ settings including jail, prison, and community supervision who report considerable diversity in their characteristics and behavioral practices. We have developed harmonized measures, where feasible, to improve the integration of these studies together to answer questions that cannot otherwise be addressed.


Barriers to Shared Use of Indoor and Outdoor Facilities at US Elementary Schools.
School policies and practices, such as the sharing of school facilities with the surrounding community, support physical activity among students and community members, but are often underutilized. This study examined variations in shared use practices, and associations with perceived barriers. Surveys were completed by a nationally representative sample of 640 public elementary schools across the United States. Administrators reported on their school's practices related to the shared use of indoor and outdoor facilities, and perceived barriers to sharing. Multivariate logistic regression models were used to examine associations between barriers and practices. Liability or legal concerns, staffing expenses, and facility operation costs were most frequently reported as barriers, while lack of adequate facilities and perceived lack of community interest were less common. Cost concerns and perceived lack of community interest were most strongly associated with lack of sharing. Although liability or legal concerns are common, such concerns are not necessarily associated with less sharing when other factors are taken into account. Administrators' perceptions about lack of community interest were associated with less sharing, but these perceptions may not accurately reflect the community's perspective. Active development of partnerships could increase access to school facilities.


Why doctors use or do not use ethics consultation.
Ethics consultation is used regularly by some doctors, whereas others are reluctant to use these services. To determine factors that may influence doctors to request or not request ethics consultation. A survey questionnaire was distributed to doctors on staff at the University Community Hospital in Tampa, Florida, USA. The responses to the questions on the survey were arranged in a Likert Scale, from strongly disagree, somewhat disagree, neither agree nor disagree, somewhat agree to strongly agree. Data were analysed with the Wilcoxon test for group comparisons, the chi2 test to compare proportions and a logistic regression analysis. Of the 186 surveys distributed, 121 were returned, giving a 65% response rate. Demographic data were similar between the groups saying yes (I do/would use ethics consultation when indicated) and no (I do not/would not use ethics consultation when indicated). No statistically significant differences were observed between the user and non-user groups in terms of opinions about ethics consultants having extensive training in ethics or participating in ethics educational opportunities. On the issue "Ethics committee members or consultants cannot grasp the full picture from the outside", the non-users were neutral, whereas the users somewhat disagreed (p=0.012). Even more significant was the difference between surgeons and non-surgeons, where, by logistic regression analysis, surgeons who believed that ethics consultants could not grasp the full picture from the outside were highly likely to not use (p=0.0004). Non-users of ethics consultations thought that it was their responsibility to resolve issues with the patient or family (72.2% agree, p<0.05). Users of ethics consultation believed in shared decision making or the importance of alternate points of view (90.8% agree, p<0.05). Ethics consultations are used by doctors who believe in shared decision making. Doctors who did not use ethics consultation tended to think that it was their responsibility to resolve issues with patients and families and that they were already proficient in ethics.


Gallbladder carcinoma in a pregnant patient with Crohn's disease complicated with gallbladder involvement.
Primary gallbladder (GB) carcinoma and Crohn's disease (CD) of the GB are individually rare. We present a case of a pregnant woman with CD found to have GB involvement and primary GB carcinoma. A 34-year-old female at 6 wk gestation with a 21 year history of CD of uncertain extent presented with 3 mo of diarrhea, urgency and abdominal pain. During work-up, she was found to have elevated transaminases and an abnormal alkaline phosphatase. Imaging revealed two gallbladder polyps both greater than 1 cm in size. Resection and histological evaluation was consistent with Crohn's involvement of the GB, poorly differentiated adenocarcinoma of the GB with invasion through the muscularis propria and matted lymph nodes in the porta hepatis positive for metastatic carcinoma (stage pT2N1). Six cases of CD involving the GB, two cases of primary GB carcinoma in CD, and ten cases of cholangiocarcinoma in pregnancy have been published. This is the only case that describes all three factors. Common features in CD of the GB include acute cholecystitis, ileal involvement, and presence independent of active intestinal disease. Common features in CD patients with GB malignancy include younger age of detection, a long history of CD, extensive colonic and ileal involvement of disease, the absence of cholelithiasis, and pre-existing gallbladder disease (primary sclerosing cholangitis and gallbladder polyps). Pregnancy is specific to this case. The role of CD in the development of GB malignancy is not well understood nor is the contribution of pregnancy to the spread of disease. Chronic inflammation and immunosuppression compounded by hormonal influence is implicated.


The Desires of Their Hearts: The Multidisciplinary Perspectives of African Americans on End-of-Life Care in the African American Community.
Studies have identified racial differences in advance care planning and use of hospice for care at the end of life. Multiple reasons for underuse among African American patients and their families have been proposed and deserve further exploration. The goal of this study was to examine perceptions of advance care planning, palliative care, and hospice among a diverse sample of African Americans with varying degrees of personal and professional experience with end-of-life care and use these responses to inform a culturally sensitive intervention to promote awareness of these options. Semistructured interviews and focus groups were conducted with African Americans who had varying degrees of experience and exposure to end-of-life care both personally and professionally. We conducted in-depth qualitative analyses of these interviews and focus group transcripts and determined that thematic saturation had been achieved. Several themes emerged. Participants felt that advance care planning, palliative care, and hospice can be beneficial to African American patients and their families but identified specific barriers to completion of advance directives and hospice enrollment, including lack of knowledge, fear that these measures may hasten death or cause providers to deliver inadequate care, and perceived conflict with patients' faith and religious beliefs. Providers described approaches they use to address these barriers in their practices. Findings, which are consistent with and further elucidate those identified from previous research, will inform design of a culturally sensitive intervention to increase awareness and understanding of advance care planning, palliative care, and hospice among members of the African American community.


Leveraging crowdsourcing to facilitate the discovery of new medicines.
Gloomy predictions about the future of pharma have forced the industry to investigate alternative models of drug discovery. Public-private partnerships (PPPs) have the potential to revitalize the discovery and development of first-in-class therapeutics. The new PPP Arch2POCM hopes to foster biomedical innovation through precompetitive validation of pioneer therapeutic targets for human diseases. In this meeting report, we capture insights garnered from the April 2011 Arch2POCM conference.


Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing.
During the clonal expansion of cancer from an ancestral cell with an initiating oncogenic mutation to symptomatic neoplasm, the occurrence of somatic mutations (both driver and passenger) can be used to track the on-going evolution of the neoplasm. All subclones within a cancer are phylogenetically related, with the prevalence of each subclone determined by its evolutionary fitness and the timing of its origin relative to other subclones. Recently developed massively parallel sequencing platforms promise the ability to detect rare subclones of genetic variants without a priori knowledge of the mutations involved. We used ultra-deep pyrosequencing to investigate intraclonal diversification at the Ig heavy chain locus in 22 patients with B-cell chronic lymphocytic leukemia. Analysis of a non-polymorphic control locus revealed artifactual insertions and deletions resulting from sequencing errors and base substitutions caused by polymerase misincorporation during PCR amplification. We developed an algorithm to differentiate genuine haplotypes of somatic hypermutations from such artifacts. This proved capable of detecting multiple rare subclones with frequencies as low as 1 in 5000 copies and allowed the characterization of phylogenetic interrelationships among subclones within each patient. This study demonstrates the potential for ultra-deep resequencing to recapitulate the dynamics of clonal evolution in cancer cell populations.


Maternal mortality, stillbirth and measures of obstetric care in developing and developed countries.
Maternal mortality and stillbirths are important adverse pregnancy outcomes, especially in developing countries. Because underlying causes of both outcomes appeared similar, the relationship between maternal mortality, stillbirth and three measures of obstetrical care were studied. Using data provided by the World Health Organization from 188 developed and developing countries, correlations and linear regression analyses between maternal mortality and stillbirth rates and cesarean section rates, skilled delivery attendance, and >or=4 prenatal visits) were developed. Stillbirth and maternal mortality rates were strongly correlated, with about 5 stillbirths for each maternal death. However, the ratio increased from about 2 to 1 in least developed countries to 50 to 1 in the most developed countries. In developing countries, as the cesarean section rates increased from 0 to about 10%, both maternal mortality and stillbirth rates decreased sharply. Skilled delivery attendance was not associated with significant reductions in maternal mortality or stillbirth rates until coverage rates of about 40% were achieved. Four or more antenatal visits were not associated with significant reductions in maternal deaths until about 60% coverage was achieved. The same measure was associated with only modest decreases in stillbirth. Across countries, stillbirth was significantly associated with maternal mortality. Both stillbirth and maternal mortality were similarly related to all three measures of obstetric care. An increase in cesarean section rates from 0 to 10% was associated with sharp decreases in both maternal mortality and stillbirths.


Selective autophagy mediated by autophagic adapter proteins.
Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.


The changing scene--an unnecessary pill crisis.
A number of case-control studies published in 1995/1996 have shown an apparent increase in the risk of venous thromboembolism (VTE) associated with the use of third-generation oral contraceptives (OC). However, it was discussed very early on that these studies were subject to a number of biases or residual confounding that would have increased the risk estimates for third-generation OC while lowering those for second-generation preparations. Six new studies or analyses were performed trying to take into account many of the methodological problems that were discussed for the initial studies: Two population-based database analyses in the UK and Germany, a new analysis of the General Practice Registry database (GPRD) in the UK, an analysis of a new database of the Transnational study, a re-analysis of the original Transnational study with a new technique, and a population-based study in Denmark. These studies could not confirm a higher VTE risk in users of third-generation OC compared with those using second-generation OC. Data on the risk of arterial thromboembolism (ischaemic stroke and myocardial infarction) show no such difference between generations of OC, with a statistically significant reduction in the risk of acute myocardial infarction from first- to third-generation preparations in one major study. Some of the investigators concluded that there is very likely no increased risk of arterial thromboembolism associated with the use of low-dose oestrogen OC in young women who are properly screened for cardiovascular risk factors or for such conditions. These findings should be taken into account when interpreting the results of studies on the risk of VTE in women taking combined OC.


How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol.
Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.


Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer.
The development and sustenance of specific neuronal populations in the peripheral and central nervous systems are controlled through the binding of neurotrophic factors to high-affinity cell surface receptors. The neurotrophins (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; neurotrophin 3, NT3; and neurotrophin 4, NT4) are dimeric molecules which share approximately 50% sequence identity. The crystal structure of the murine NGF homodimer [McDonald et al. (1991) Nature 354, 411-414] indicated that the dimer interface corresponds to regions of high sequence conservation throughout the neurotrophin family. This potential compatibility was duly exploited for the production in vitro of noncovalent heterodimers between the different neurotrophins [Radziejewski, C., & Robinson, R.C. (1993) Biochemistry 32, 13350-13356; Jungbluth et al. (1994) Eur. J. Biochem. 221, 677-685]. Here, we report the X-ray structure at 2.3 A resolution of one such heterodimer, between human BDNF, and human NT3. The NGF, BDNF, and NT3 protomers share the same topology and are structurally equivalent in regions which contribute to the dimer interface in line with the propensity of the neurotrophins to form heterodimers. Analysis of the structure of regions of the BDNF/NT3 heterodimer involved in receptor specificity led us to conclude that heterodimer binding to p75 involves distant binding sites separately located on each protomer of the heterodimer. In contrast, heterodimer interactions with the trk receptors probably utilize hybrid binding sites comprised of residues contributed by both protomers in the heterodimer. The existence of such hybrid binding sites for the trk receptor provides an explanation for the lower activity of the BDNF/NT3 heterodimer in comparison to the homodimers.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantity and quality of mental activities and the risk of incident mild cognitive impairment.
To investigate whether timing, number, and frequency of mentally stimulating activities in midlife and late life are associated with the risk of incident mild cognitive impairment (MCI). We conducted a prospective cohort study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, including 2,000 individuals aged ≥70 years who were cognitively unimpaired at baseline and were followed for a median of 5.0 years. Participants completed a self-reported survey on timing, number, and frequency of engagement in 5 mentally stimulating activities (reading books, computer use, social activities, playing games, craft activities) at baseline. The risk of incident MCI was significantly reduced for participants who engaged in social activities (hazard ratio [95% confidence interval] 0.80 [0.64-0.99]) and playing games (0.80 [0.66-0.98]) in both late life and midlife combined. Using a computer was associated with a decreased risk regardless of timing (not late life but midlife: 0.52 [0.31-0.88]; late life but not midlife: 0.70 [0.56-0.88]; late life and midlife: 0.63 [0.51-0.79]). Craft activities were associated with a reduced risk of incident MCI only when carried out in late life but not midlife (0.58 [0.34-0.97]). Furthermore, engaging in a higher number of activities in late life was associated with a significantly reduced risk of incident MCI (any 2 activities: 0.72 [0.53-0.99], any 3: 0.55 [0.40-0.77], any 4: 0.44 [0.30-0.65], all 5: 0.57 [0.34-0.96]). Engaging in a higher number of mentally stimulating activities, particularly in late life, is associated with a decreased risk of MCI among community-dwelling older persons.


Biochemistry of human skin--our brain on the outside.
The skin, our body's largest organ, is located at the interface between the external and internal environments, and so is strategically placed to provide not only a barrier against a range of noxious stressors (UV radiation, mechanical, chemical and biological insults) but also to act as the periphery's 'sensing' system. Recent developments suggest that this organ is much more critical to maintaining body homeostasis than previously thought. This tutorial review introduces the reader to some of the biochemistry that underpins the skin's enormous multi-functionality.


Adverse childhood experience categories and subjective cognitive decline in adulthood: an analysis of the Behavioral Risk Factor Surveillance System.
Adverse childhood experiences (ACEs) negatively impact health outcomes later in life, in a dose-dependent relationship; however, little is known about the impact of the individual ACE categories and subjective cognitive decline (SCD) later in life. The aim of this study was to determine the associations among the eight ACEs and SCD. We analyzed data from two cycles of the Behavioral Risk Factor Surveillance System (BRFSS; 2019-2020). We assessed the accumulation of ACEs and their association with SCD, and among individuals reporting only one ACE, we utilized logistic regression to compare the likelihood of reporting SCD and symptomology among the eight categories of adversity. Among included respondents, 10.14% reported experiencing SCD. More ACEs were reported among those with SCD (mean, 2.61; SD, 2.56) compared to those without SCD (mean, 1.44; SD, 1.91). Those with higher ACE scores were significantly less likely to have spoken with a healthcare provider about their cognitive decline. Individuals reporting one ACE of either family mental illness, family substance abuse, family incarceration, emotional abuse, or physical abuse had significantly greater odds of reporting memory loss compared to individuals with no ACEs. Having multiple ACEs was significantly associated with higher odds of SCD and associated limitation of social activity and was inversely associated with getting help when it is needed. Further, many ACE categories were associated with SCD - a novel addition to the literature and the methodology utilized herein. Interventions focused on improving cognitive health and preventing cognitive decline should consider the potential role of ACEs among affected populations.


Inhibitory effect of soluble RAGE in disturbed flow-induced atherogenesis.
Soluble receptor for advanced glycation end products RAGE (sRAGE), a secretory form of RAGE, plays an important role in suppressing RAGE signals that induce pro-inflammatory gene activation in a range of inflammatory diseases, such as Alzheimer's disease, complications of diabetes mellitus and atherosclerosis. Recent studies have suggested that fluid shear stress generated by laminar blood flow protects blood vessels from atherosclerosis, whereas low and oscillatory shear stress (OSS) generated by disturbed blood flow causes atherosclerosis. Although RAGE levels are increased in atherosclerotic plaque, the regulatory mechanisms of sRAGE in the occurrence of atherosclerotic plaque induced by disturbed blood flow remain largely unknown. This study aimed to determine the effects of sRAGE as a competitive inhibitor of RAGE in atherogenesis induced by disturbed blood flow. To determine the role of sRAGE in atherosclerosis induced by disturbed blood flow, we used a mouse model of partial carotid artery ligation using ApoE(-/-) and C57BL/6 mice. Our results revealed that the expression of RAGE was significantly increased in the region of atherosclerotic plaque and that treatment with sRAGE attenuated the development of plaque formation. We found that the expression levels of RAGE and high mobility group box 1 (HMGB1), the agonistic ligand of RAGE, were significantly increased in human umbilical vein endothelial cells (HUVECs) under shear stress conditions induced by disturbed blood flow and suppressed following treatment with sRAGE. We further observed that treatment with sRAGE decreased the expression of vascular cell adhesion molecule‑1 (VCAM-1) and markedly attenuated monocyte-endothelial cell adhesion. Taken together, our results reveal that sRAGE exerts anti-atherogenic effects by blocking the activation of the RAGE signaling pathway induced by disturbed blood flow and may thus be a potential therapeutic target for the prevention of atherosclerosis.


The role of dressings in the prevention of vascular access device infections.
The risk of a catheter-related bloodstream infection (CRBSI) is an ever-present spectre for a patient with a vascular access device (VAD) in situ. The morbidity associated with these infections is high and incurs substantial costs. Worse still, thousands of patients with a VAD die of a CRBSI each year. Healthcare providers are championing the implementation of strategies that minimise or even eliminate the risk of CRBSIs, as these will improve patient outcomes and reduce healthcare costs. However, it is not only the financial implications of CRBSIs that must be considered. The impact of a CRBSI on the physical, emotional and mental wellbeing of a patient cannot be underestimated. This article will consider how the use of dressings can reduce the risk of CRBSI.


Factors influencing advanced practice nurses' ability to promote evidence-based practice among frontline nurses.
Advanced practice nurses (APNs) have an important role in promoting evidence-based practice (EBP) among frontline nurses (FLNs). Factors influencing FLNs' engagement with EBP are well documented but little is known about factors that affect APNs' ability to facilitate evidence in practice. To identify factors that influence APNs' ability to promote EBP among FLNs. A multiple case study of 23 APNs from hospital and primary care settings across seven English health authorities was undertaken. Data collection comprised interviews and observation of APNs and interviews with FLNs and other healthcare professionals. Data were analysed using the Framework approach. Four groups of influencing factors were identified: (1) Personal attributes of APNs included knowledge and skills in EBP, clinical credibility with frontline staff and leadership style. (2) Relationships with stakeholders included APNs' interactions with FLNs and the level of support from managers and medical colleagues. (3) Aspects of the APN role included their sphere of responsibility and workload. (4) Organisational context included the organisational culture, FLNs' workload, professional networks and available resources. Educational preparation for APNs should enable them to develop expertise in EBP plus interpersonal and leadership skills to manage relational dynamics in clinical settings. APN role specifications should provide the opportunity to promote EBP. The organisational culture should be conducive to enabling EBP with managers supportive of this aspect of the APNs' role. APNs need to be supported to address the individual, interpersonal and organisational factors, which influence their ability to promote EBP. Organisational commitment at the highest level is key to APNs' ability to fulfil this aspect of their role.


Large thigh circumference is associated with lower blood pressure in overweight and obese individuals: a community-based study.
A small thigh circumference is associated with an increased risk of diabetes, cardiovascular diseases, and total mortality. The purpose of this study was to evaluate the association between thigh circumference and hypertension in the middle-aged and elderly population. A total of 9520 individuals aged 40 years and older with measurement of thigh circumference were available for analysis. The measurement of thigh circumference was performed directly below the gluteal fold of the thigh. The association of thigh circumference with hypertension was tested in logistic regression analyses and reported as odds ratio (OR) with 95% CI. Thigh circumference was negatively correlated with systolic blood pressure, diastolic blood pressure, fasting glucose, and total cholesterol. Compared with the lowest thigh circumference tertile group, the risk of hypertension was significantly lower in the highest tertile group, both in overweight individuals (OR 0.68; 95% CI 0.59-0.79, P < 0.001) and obese individuals (OR 0.51; 95% CI 0.38-0.70, P < 0.001). In the present study, large thigh circumference is associated with lower risk of hypertension in overweight and obese Chinese individuals.


50 fs soliton compression of optical clock pulse recovered from NRZ data injected SOAFL.
Mode-locking of semiconductor optical amplifier fiber laser (SOAFL) with 50 fs pulses by extracting the clock of an optical non-return-to-zero (NRZ) data injection is demonstrated. The efficiency of mode-locking in the SOAFL is improved by increasing the seeding power of the large-duty-cycle NRZ data from 3 to 8 dBm into the SOA driven at biased current of 350 mA. After linear dispersion compensation, the mode-locked SOAFL pulsewidth can be further shortened from 20 to 3 ps by increasing the DCF length up to 110 m. By using a booster the EDFA to enlarge the average power of mode-locked SOAFL pulse to 1.3 W, the shortest soliton pulse is occurred after propagating through a 12-m-long SMF. The amplified SOAFL pulse can be compressed to 50 fs after nonlinear compression with its spectral linewidth broadening to 64 nm. Nearly transform-limited time-bandwidth product of 0.436 and the maximum pulse compressing ratio of 400 are reported to date.


Controlling compartmentalization by non-membrane-bound organelles.
Compartmentalization is a characterizing feature of complexity in cells, used to organize their biochemistry. Membrane-bound organelles are most widely known, but non-membrane-bound liquid organelles also exist. These have recently been shown to form by phase separation of specific types of proteins known as scaffolds. This forms two phases: a condensate that is enriched in scaffold protein separated by a phase boundary from the cytoplasm or nucleoplasm with a low concentration of the scaffold protein. Phase separation is well known for synthetic polymers, but also appears important in cells. Here, we review the properties of proteins important for forming these non-membrane-bound organelles, focusing on the energetically favourable interactions that drive condensation. On this basis we make qualitative predictions about how cells may control compartmentalization by condensates; the partition of specific molecules to a condensate; the control of condensation and dissolution of condensates; and the regulation of condensate nucleation. There are emerging data supporting many of these predictions, although future results may prove incorrect. It appears that many molecules may have the ability to modulate condensate formation, making condensates a potential target for future therapeutics. The emerging properties of condensates are fundamentally unlike the properties of membrane-bound organelles. They have the capacity to rapidly integrate cellular events and act as a new class of sensors for internal and external environments.This article is part of the theme issue 'Self-organization in cell biology'.


Specialty choices, compensation, and career satisfaction of underrepresented minority faculty in academic medicine.
Despite efforts to increase the numbers of underrepresented minorities (URMs), only 3.9% of medical school faculty are URMs. The authors compared the specialty choices, compensation, and career satisfaction of minority faculty with those of their majority counterparts to determine whether there were differences that might affect the recruitment and retention of minority faculty. In 1995, the authors mailed a self-administered survey to a stratified random sample of 3,013 eligible full-time salaried faculty in 24 randomly selected medical schools. Those schools, which had at least 200 faculty, did not include the Puerto Rican or historically black medical schools. Of the eligible faculty surveyed, 1,807 (60%) responded; 1,463 were majority faculty, 195 were URM faculty, and 149 were other-minority faculty. Similar proportions of the three groups were in the primary care specialties. Only 11% of the URM respondents were in basic science departments. There was no significant difference in adjusted mean compensation between majority, URM, and other-minority faculty. However, URM faculty were significantly less satisfied with their careers (adjusted scores: 60 versus > 65; p = .001) and more often considered leaving academic medicine within five years (58% versus < 45%). Given the demographic changes of the U.S. population, these issues should be addressed by deans and department heads in order to enhance recruitment and facilitate retention of URM faculty in academic medicine.


Production of refractory dissolved organic matter by bacteria.
Most of the oceanic reservoir of dissolved organic matter (DOM) is of marine origin and is resistant to microbial oxidation, but little is known about the mechanisms of its formation. In a laboratory study, natural assemblages of marine bacteria rapidly (in <48 hours) utilized labile compounds (glucose, glutamate) and produced refractory DOM that persisted for more than a year. Only 10 to 15% of the bacterially derived DOM was identified as hydrolyzable amino acids and sugars, a feature consistent with marine DOM. These results suggest that microbial processes alter the molecular structure of DOM, making it resistant to further degradation and thereby preserving fixed carbon in the ocean.


Hybrid imaging in planar scintigraphy: new implementations and historical precedents.
Fusion of tomographic radionuclide studies with anatomical examinations has become standard practice in positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging. Nonetheless, fusion of planar scintigraphic images with an anatomical modality remains distinctly uncommon, although methods to do so have appeared sporadically in the literature during the past 2 decades. In this article we review several techniques that have been used to combine planar scintigraphic images with radiographs and visual (photographic) images. Rigid or affine transformations have been performed to co-register the planar images with each other using custom, commercial, or public domain software. Display of the hybrid images has been achieved primarily with nonselective color-fusion methods. Promising efforts are underway to develop a technique of fusing planar lymphoscintigraphic images with CT topograms (scout images) obtained on the SPECT-CT camera in a manner that compensates for position-dependent variation in magnification that affects the CT scout. An advantage of this approach is that both of the component images are acquired on the same gantry, without need for repositioning of the patient. It is instructive to note that techniques of fusing rectilinear scans with radiographic and visual images were first developed more than 50 years ago. The revisiting of these methods after many decades reflects a fundamental need for spatial orientation in nuclear medicine that fusion imaging can also bring to planar scintigraphic studies.


Morphologic and molecular characterization of traditional serrated adenomas of the distal colon and rectum.
Of the serrated polyps, the origin, morphologic features, molecular alterations, and natural history of traditional serrated adenomas (TSAs) are the least understood. Recent studies suggest that these polyps may arise from precursor lesions. The frequencies of KRAS and BRAF mutations vary between these studies, and only 1 small study has measured CpG island methylation using current markers of methylation. Mutations in GNAS, a gene commonly mutated in colorectal villous adenomas, have not been fully evaluated in TSAs. Finally, the expression of annexin A10 (ANXA10), a recently discovered marker of sessile serrated adenomas/polyps, has not been studied in these polyps. To further characterize these polyps, 5 gastrointestinal pathologists reviewed 55 left-sided polyps diagnosed as TSA at a single institution. Pathologists assessed various histologic features including cytoplasmic eosinophilia, ectopic crypt foci, presence of conventional dysplasia, and presence of precursor serrated lesions. KRAS, BRAF, and GNAS mutational analysis was performed, as well as CpG island methylation and ANXA10 immunohistochemistry. Ectopic crypt foci were seen in 62% of TSAs. Precursor lesions were seen in 24% of the study polyps, most of which were hyperplastic polyps. KRAS and BRAF mutations were common and were present in 42% and 48% of polyps, respectively. GNAS mutations occurred in 8% of polyps, often in conjunction with a BRAF mutation. Unlike sessile serrated adenomas/polyps, TSAs rarely had diffuse expression of ANXA10. Importantly, BRAF-mutated TSAs had more widespread methylation of a 5-marker CpG island panel compared with KRAS-mutated polyps. However, ectopic crypt foci, a proposed defining feature of TSA, were not associated with any specific molecular alteration.


Design, synthesis and bioactivities of phenithionate analogues or derivatives for anti-schistosomiasis.
A novel series of phenithionate analogues or derivatives were designed and synthesized using phenithionate as the lead compound, and their bioactivities were studied. Their structures were confirmed by 1H NMR, 13C NMR, HR-ESI-MS, and elemental analysis, respectively. The results of in vitro inhibitory activity measurement proved that compounds 5a, 5c, 5g, 5i, 5m and 5o had a better inhibitory effect on larva and imago schistosoma. Among them, the inhibitory activity of compound 5i for larva schistosoma was IC50 = 5.21 ± 0.04 μg mL-1, and for imago schistosoma it was IC50 = 6.35 ± 0.08 μg mL-1. Moreover, the experimental results of in vivo anti-schistosomiasis activity measurement showed that they had good anti-schistosomiasis activity. Therefore, these compounds had better drugability.


Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.


Utility of intraoperative frozen section histopathology in the diagnosis of periprosthetic joint infection: a systematic review and meta-analysis.
The accuracy of intraoperative periprosthetic frozen section histologic evaluation in predicting a diagnosis of periprosthetic joint infection prior to microbiologic culture results is unknown. We performed a systematic review and meta-analysis of all longitudinal studies that compared frozen section histologic results with simultaneously obtained microbiologic culture at the time of revision total hip or total knee arthroplasty. The data sources were Ovid MEDLINE, Ovid EMBASE, the Cochrane Library, ISI Web of Science, and SCOPUS, from the inception of each database to January 2010. Twenty-six studies involving 3269 patients undergoing revision hip or knee arthroplasty met the inclusion criteria. A culture-positive periprosthetic joint infection was confirmed in 796 (24.3%) of the patients. Frozen section results, using any of the diagnostic criteria chosen by the investigating pathologist, had a pooled diagnostic odds ratio of 54.7 (95% confidence interval [CI], 31.2 to 95.7), a likelihood ratio of a positive test of 12.0 (95% CI, 8.4 to 17.2), and a likelihood ratio of a negative test of 0.23 (95% CI, 0.15 to 0.35) for the diagnosis of periprosthetic joint infection. Fifteen studies utilizing a threshold of five polymorphonuclear leukocytes (PMNs) per high-power field to define a positive frozen section had a diagnostic odds ratio of 52.6 (95% CI, 23.7 to 116.2), and six studies utilizing a diagnostic threshold of ten PMNs per high-power field had a diagnostic odds ratio of 69.8 (95% CI, 33.6 to 145.0). There was no significant difference between the diagnostic odds ratio or likelihood ratios associated with these thresholds. The moderate to high heterogeneity among the included studies was unexplained by variability in the study design, diagnostic criteria for acute inflammation, reference standard for periprosthetic joint infection, or prevalence of infection. This heterogeneity could be due to differences in the inclusion and exclusion criteria, tissue sampling error, experience or technique of the pathologists, number of microscopic fields visualized, and field diameter examined. Intraoperative frozen sections of periprosthetic tissues performed well in predicting a diagnosis of culture-positive periprosthetic joint infection but had moderate accuracy in ruling out this diagnosis. Frozen section histopathology should therefore be considered a valuable part of the diagnostic work-up for patients undergoing revision arthroplasty, especially when the potential for infection remains after a thorough preoperative evaluation. The optimum diagnostic threshold (number of PMNs per high-power field) required to distinguish periprosthetic joint infection from aseptic failure could not be discerned from the included studies. There was no significant difference between the diagnostic accuracy of frozen section histopathology utilizing the most common thresholds of five or ten PMNs per high-power field.


Prolonged grievers: a qualitative evaluation of a support group intervention.
The aim of this project was to study prolonged grievers psychosocial processes and experience during participation in a group intervention and 6-8 weeks after discontinuation. The intervention in this study was a group therapy with the aim of getting in contact with their pain and loss and confronting and working with this loss. Data was collected by using diaries and tape-recorded interviews, analyzed with grounded theory. The participants were 11 females between the ages of 33 and 71. The main process that was found in the qualitative data was: Ambivalence when struggling and learning through work and rest towards a balance. Sub-processes were: To share and be confirmed in the group through sense of cohesion; To dare/venture to discover problems and solutions; To react when you get emotionally involved, and to compare and discover. This study gives insight into prolonged grievers' thinking, which is valuable knowledge. Rather than assuming that all individuals suffering from prolonged grief need the same treatment, we suggest that there should be a range of different therapies.


The value of fundoscopy in general practice.
Many of the common systemic diseases present characteristic changes in the fundus of the eye, but fundoscopy is often performed by an ophthalmologist. Our purpose was to assess the value of fundoscopy for the general practitioners (GPs) regarding the diagnosis and management of the cases which they face in daily practice. 689 patients were referred by GPs to the outpatient ophthalmology department for fundoscopy during the year 2010. The causes of this referral, the results of ophthalmoscopy and its significance in the final diagnosis were recorded and analyzed. In 22 patients (3.1%), fundoscopy revealed optic disc edema. In 7 patients with head trauma (9.7%), fundoscopy revealed intravitreous haemorrhage and Berlin edema. From the patients with photopsias or floaters, 5 (10.2%) had retinal detachment. Finally, in cases with diabetes mellitus or hypertension, ophthalmoscopy was very important to detect the existence and grade the degree of diabetic or hypertensive retinopathy, if they appeared, and as a result to evaluate the prognosis of the disease. Fundoscopy is fundamental for the GP, as it may help to confirm or exclude the diagnosis of many common diseases. Nevertheless, there are clinical entities where ophthalmoscopy should be performed by an ophthalmologist, in order to be more specific and accurate, and GP should be able to recognise these cases.


Kennedy Axis V: Clinimetric properties assessed by mental health nurses.
The Kennedy Axis V is a routine outcome measurement instrument which can assist the assessment of the short-term risk for violence and other adverse patient outcomes. The purpose of this study was to evaluate the interrater reliability and clinical utility of the instrument when used by mental health nurses in daily care of patients with mental illness. This cross-sectional study was conducted in inpatient and outpatient adult psychiatric care units and in one adolescent inpatient unit at a university hospital in the Netherlands. Interrater reliability was measured based on the independent scores of two different nurses for the same patients. The clinical utility of the instrument was evaluated by means of a clinical utility questionnaire. To gain a deeper understanding of rating difficulties at the adolescent unit, additional data were collected in two focus group interviews. The overall results revealed a substantial level of agreement between nurses (intraclass correlation coefficient and Pearson 0.79). Some rating challenges were identified, including difficulties with scoring the instrument and using tailor-made interventions related to the scores. These challenges can be resolved using refined training and implementation strategies. When the Kennedy Axis V is accompanied by a solid implementation strategy in adult mental health care, the instrument can be used for short-term risk assessment and thereby contribute in efforts to reduce violence, suicide, self-harm, severe self-neglect, and enhanced objectivity in clinical decision-making.


Factors of importance for self-reported mental health and depressive symptoms among ages 60-75 in urban Iran and Sweden.
Depression is a common experience affecting 121 million people around the world. In high income countries, depression is one of the most common psychiatric conditions among the elderly. Studies show that immigrants are particularly at risk for mental ill health. This study investigates the self-reported mental health among two Iranian groups; one born and residing in Iran and one consisting of Iranian immigrants in Sweden, as well as native Swedes living in Sweden. The study also aims to explore and compare self-reported depressive symptoms among three groups. This study is based on a cross-sectional design measuring self-reported health with a study specific questionnaire. The programme SPSS V.17.0 was used for all statistical analyses. 1088 participants were approached (668 Iranians in Iran; 105 immigrated Iranians in Sweden; and 305 Swedes in Sweden). Factors effecting self-reported mental health was self-reported health, smoking, satisfaction with social life and also a sense of connection to ones cultural roots and traditions. Also demographic variables such as group belonging (Swedes vs. Iranians), sex and satisfaction with Income were shown to be important when performing the regression analysis. In the chi-square analysis the Iranian samples reported depressive symptoms to a larger extent than the Swedish group in all aspects of self-reported depressive symptoms. Self-reported depressive symptoms were reported to a greater extend in women compared to men. Our findings indicate that the Iranian populations living in both Tehran and Stockholm report depressive symptoms to an extent that merits concern. The findings indicate that Iranians living in Tehran and Iranians who have immigrated to Sweden require more attention regarding mental health care. Health care providers in both countries should be aware of the current state of mental health among Iranians in both Sweden and Iran.


Chiropractic biophysics technique: a linear algebra approach to posture in chiropractic.
This paper discusses linear algebra as applied to human posture in chiropractic, specifically chiropractic biophysics technique (CBP). Rotations, reflections and translations are geometric functions studied in vector spaces in linear algebra. These mathematical functions are termed rigid body transformations and are applied to segmental spinal movement in the literature. Review of the literature indicates that these linear algebra concepts have been used to describe vertebral motion. However, these rigid body movers are presented here as applying to the global postural movements of the head, thoracic cage and pelvis. The unique inverse functions of rotations, reflections and translations provide a theoretical basis for making postural corrections in neutral static resting posture. Chiropractic biophysics technique (CBP) uses these concepts in examination procedures, manual spinal manipulation, instrument assisted spinal manipulation, postural exercises, extension traction and clinical outcome measures.


Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: a European mother-child study (NewGeneris).
Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates. Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006-2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population. Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England. These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates.


Expression of the tachykinin receptor mRNAs in healthy human colon.
Tachykinins are a family of neuropeptides, involved in a variety of physiological and pathological processes occurring in the gastrointestinal tract. They act via three distinct types of receptors, tachykinin NK(1), NK(2), and NK(3) receptors, which belong to the family of G protein-coupled receptors. The aim of the present study was to characterize, for the first time in the healthy human colon, the TACR(1), TACR(2) and TACR(3) mRNAs encoding the three different tachykinin receptors and to measure their relative expression by quantitative reverse transcription-PCR assay. Our results confirm the broad distribution of the tachykinin receptors but evidenced significant differences in the expression level of their respective mRNAs. A higher expression level of the TACR2 mRNA alpha isoform, the gene encoding the functional tachykinin NK(2) receptor, was observed in comparison to TACR1 and TACR3 mRNAs genes encoding for NK(1) and NK(3) receptors respectively. The prevalence of the TACR2 mRNA alpha isoform strongly suggests a major involvement of tachykinin NK(2) receptor in the regulation of human colonic functions.


A novel adaptive servoventilation (ASVAuto) for the treatment of central sleep apnea associated with chronic use of opioids.
To compare the efficacy and patient comfort of a new mode of minute ventilation-targeted adaptive servoventilation (ASVAuto) with auto-titrating expiratory positive airway pressure (EPAP) versus bilevel with back-up respiratory rate (bilevel-ST) in patients with central sleep apnea (CSA) associated with chronic use of opioid medications. Prospective, randomized, crossover polysomnography (PSG) study. Eighteen consecutive patients (age ≥ 18 years) who had been receiving opioid therapy (≥ 6 months), and had sleep disordered breathing with CSA (central apnea index [CAI] ≥ 5) diagnosed during an overnight sleep study or positive airway pressure (PAP) titration were enrolled to undergo 2 PSG studies-one with ASVAuto and one with bilevel-ST. Patients completed 2 questionnaires after each PSG; Morning After Patient Satisfaction Questionnaire and PAP Comfort Questionnaire. Patients had a mean age of 52.9 ± 15.3 years. PSG prior to randomization showed an apnea hypopnea index (AHI) of 50.3 ± 22.2 and CAI of 13.0 ± 18.7. Titration with ASVAuto versus bilevel-ST showed that there were significant differences with respect to AHI and CAI. The AHI and CAI were significantly lower on ASVAuto than bilevel-ST (2.5 ± 3.5 versus 16.3 ± 20.9 [p = 0.0005], and 0.4 ± 0.8 versus 9.4 ± 18.8 [p = 0.0002], respectively). Respiratory parameters were normalized in 83.3% of patients on ASVAuto versus 33.3% on bilevel-ST. Patients felt more awake and alert on ASVAuto than bilevel-ST based on scores from Morning After Patient Satisfaction Questionnaire (p = 0.0337). The ASVAuto was significantly more effective than bilevel-ST for the treatment of CSA associated with chronic opioid use.


Design of pitch conversion component for formation of multibeam optical recording head.
We describe a design of a planar lightwave circuit for parallel information processing using visible light. The circuit serves as a pitch conversion component (PCC) that can align multiple beams close together and easily composes a compact optical system that can project optical spots at a narrow pitch on a certain small plane. From the viewpoint of its application to optical recording, a PCC is designed to have over 50 waveguides according to the fabrication of waveguides for a blue-violet beam. It is analytically confirmed that a PCC contributes to the formation of a multibeam optical recording head with numerous beams.


Another new Cyrtodactylus (Squamata: Gekkonidae) from Guwahati, Assam, India.
We describe a new species of Cyrtodactylus from Guwahati city in the state of Assam, India and provide additional data on the recently described Cyrtodactylus guwahatiensis. Cyrtodactylus urbanus sp. nov. falls in the newly defined khasiensis group within the Indo-Burma clade of Cyrtodactylus and is the poorly supported sister taxon to Cyrtodactylus khasiensis. The new species differs from other members of the khasiensis group in mitochondrial sequence data (12.5-17.1 % uncorrected pairwise ND2 sequence divergence) as well as aspects of morphology including the number and arrangement of precloacal pores in males, the number of mid-ventral scales and paravertebral tubercles, and colour pattern. This is the second Cyrtodactylus endemic to the Guwahati region, the fourth from Assam and the twelfth from Northeast India.


BabA-mediated adherence is a potentiator of the Helicobacter pylori type IV secretion system activity.
Chronic infection of Helicobacter pylori in the stomach mucosa with translocation of the bacterial cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV secretion system (TFSS) into host epithelial cells are major risk factors for gastritis, gastric ulcers, and cancer. The blood group antigen-binding adhesin BabA mediates the adherence of H. pylori to ABO/Lewis b (Le(b)) blood group antigens in the gastric pit region of the human stomach mucosa. Here, we show both in vitro and in vivo that BabA-mediated binding of H. pylori to Le(b) on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. We successfully generated Le(b)-positive cell lineages by transfecting Le(b)-negative cells with several glycosyltransferase genes. Using these established cell lines, we found increased mRNA levels of proinflammatory cytokines (CCL5 and IL-8) as well as precancer-related factors (CDX2 and MUC2) after the infection of Le(b)-positive cells with WT H. pylori but not with babA or TFSS deletion mutants. This increased mRNA expression was abrogated when Le(b)-negative cells were infected with WT H. pylori. Thus, H. pylori can exploit BabA-Le(b) binding to trigger TFSS-dependent host cell signaling to induce the transcription of genes that enhance inflammation, development of intestinal metaplasia, and associated precancerous transformations.


A material-based platform to modulate fibronectin activity and focal adhesion assembly.
We present a detailed characterization of fibronectin (FN) adsorption and cell adhesion on poly(ethyl acrylate) (PEA) and poly(methyl acrylate) (PMA), two polymers with very similar physicochemical properties and chemical structure, which differ in one single methyl group in the lateral chain of the polymer. The globular solution conformation of FN was retained following adsorption onto PMA, whereas spontaneous organization of FN into protein (nano) networks occurred on PEA. This distinct distribution of FN at the material interface promoted a different availability, measured via monoclonal antibody binding, of two domains that facilitated integrin binding to FN: FNIII10 (RGD sequence) and FNIII9 (PHSRN synergy sequence). The enhanced exposure of the synergy domain on PEA compared to PMA triggered different focal adhesion assemblies: L929 fibroblasts showed a higher fraction of smaller focal plaques on PMA (40%) than on PEA (20%). Blocking experiments with monoclonal antibodies against FNIII10 (HFN7.1) and FNIII9 (mAb1937) confirmed the ability of these polymeric substrates to modulate FN conformation. Overall, we propose a simple and versatile material platform that can be used to tune the presentation of a main extracellular matrix protein (FN) to cells, for applications than span from tissue engineering to disease biology.


Modeling the adhesion of human embryonic stem cells to poly(lactic-co-glycolic acid) surfaces in a 3D environment.
Human embryonic stem cells (hESCs) have previously been cultured on three dimensional (3D) biodegradable polymer scaffolds. Although complex structures were formed from the hESCs, very little is known about the mechanism of adhesion of these cells to the surfaces of the scaffolds. In this study, we achieved the efficient adhesion of pluripotent hESCs to 3D poly(lactic-co-glycolic acid) (PLGA) scaffolds based on our data from a novel two dimensional (2D) model that imitates the surface properties of the scaffolds. In the 2D model, single cell preparations of pluripotent hESCs adhered efficiently and predominantly to PLGA surfaces coated with laminin in comparison to collagen I, collagen IV, or fibronectin-coated surfaces. Flow cytometry analysis revealed that almost all of the pluripotent single cells expressed the integrin alpha 6, with a small percentage also expressing alpha 3ss1, which facilitates adhesion to laminin. This data was then translated into the 3D environment, with the efficient binding of single pluripotent hESCs to PLGA scaffolds coated with laminin. The utility of this system was shown by the directed differentiation of single hESCs seeded within laminin-coated scaffolds toward the endoderm lineage.


LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization.
Long non-coding RNAs (lncRNAs) play key roles in various biological processes. However, the roles of lncRNAs in macrophage polarization remain largely unexplored. In this study, thousands of lncRNAs were identified that are differentially expressed in distinct polarized bone marrow-derived macrophages. Among them, Dnmt3aos (DNA methyltransferase 3A, opposite strand), as a known lncRNA, locates on the antisense strand of Dnmt3a. Functional experiments further confirmed that Dnmt3aos were highly expressed in M(IL-4) macrophages and participated in the regulation of Dnmt3a expression, and played a key role in macrophage polarization. The DNA methylation profiles between the Dnmt3aos knockdown group and the control group in M(IL-4) macrophages were determined by MeDIP-seq technique for the first time, and the Dnmt3aos-Dnmt3a axis-mediated DNA methylation modification-regulated macrophage polarization- related gene IFN-γ was identified. Our study will help to enrich our knowledge of the mechanism of macrophage polarization.


Gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions.
Monkeypox virus (MPV) is a zoonotic Orthopoxvirus and a potential biothreat agent that causes human disease with varying morbidity and mortality. Members of the Orthopoxvirus genus have been shown to suppress antiviral cell defenses, exploit host cell machinery, and delay infection-induced cell death. However, a comprehensive study of all host genes and virus-targeted host networks during infection is lacking. To better understand viral strategies adopted in manipulating routine host biology on global scale, we investigated the effect of MPV infection on Macaca mulatta kidney epithelial cells (MK2) using GeneChip rhesus macaque genome microarrays. Functional analysis of genes differentially expressed at 3 and 7 hours post infection showed distinctive regulation of canonical pathways and networks. While the majority of modulated histone-encoding genes exhibited sharp copy number increases, many of its transcription regulators were substantially suppressed; suggesting involvement of unknown viral factors in host histone expression. In agreement with known viral dependence on actin in motility, egress, and infection of adjacent cells, our results showed extensive regulation of genes usually involved in controlling actin expression dynamics. Similarly, a substantial ratio of genes contributing to cell cycle checkpoints exhibited concerted regulation that favors cell cycle progression in G1, S, G2 phases, but arrest cells in G2 phase and inhibits entry into mitosis. Moreover, the data showed that large number of infection-regulated genes is involved in molecular mechanisms characteristic of cancer canonical pathways. Interestingly, ten ion channels and transporters showed progressive suppression during the course of infection. Although the outcome of this unusual channel expression on cell osmotic homeostasis remains unknown, instability of cell osmotic balance and membrane potential has been implicated in intracellular pathogens egress. Our results highlight the role of histones, actin, cell cycle regulators, and ion channels in MPV infection, and propose these host functions as attractive research focal points in identifying novel drug intervention sites.


Adenosine as an Adjunct Therapy in ST Elevation Myocardial Infarction Patients: Myth or Truth?
Early reperfusion represents the key strategy in ST elevation myocardial infarction. However, reperfusion may induce myocardial damage due to the reperfusion myocardial injury, compromising the full potential of reperfusion therapy and accounting for unfavourable results in high risk patients. Adenosine seems to attenuate ischemia reperfusion injury, and thus represents a promising therapeutic option for treating such patients. However, previous randomized clinical trials have collectively failed to demonstrate whether adenosine can effectively reduce measures of myocardial injury and improve clinical outcome, despite its good basic evidence. The failure of such trials to show a real beneficial action may be in part related to specific factors other than adenosine's clinical efficacy. The purpose of this review is to explain the rationale for the use of adenosine as an adjunctive pharmacological cardio-protective agent following reperfusion of the ischemic myocardium, to address the weakness of previous trials and to summarize the current state of knowledge regarding the effect of adenosine administration on reperfusion myocardial injury in patients with myocardial infarction. Although some preclinical and clinical studies point towards the beneficial role of adenosine in the prevention and treatment of no-reflow phenomenon in myocardial infarction, many unanswered questions still remain, including the optimal clinical indication, mode, dosage, duration and timing of application, and the exact mechanisms leading to potential benefits. Clarifying these issues will depend on further properly designed, adequately powered and well conducted clinical trials, which will probably provide us with the definite answers.


Fine-mapping of restless legs locus 4 (RLS4) identifies a haplotype over the SPATS2L and KCTD18 genes.
Restless legs syndrome (RLS) is a sleep-related movement disorder that affects up to 15 % of the population. Linkage studies have identified several genomic loci in single families (12q, 14q, 9p, 2q, 20p and 16p, respectively). However, confirmation of these loci has not always been achieved, and causative mutations have not yet been identified. The locus on chromosome 2q33 (RLS4) was identified in two South Tyrolean families who shared a haplotype of microsatellite marker alleles across an 8.2-cM region. To pinpoint the gene localisation within RLS4, additional families from the same geographic region were evaluated, and linkage was replicated in one family. Within the candidate region, we initially found a haplotype of 23 single nucleotide polymorphism markers spanning 131.6 Kb shared by all affected members of the three linked families. Using a next generation sequencing approach, we further restricted the shared candidate region to 46.9 Kb over the potassium channel-related gene KCTD18 and exons 10-13 of SPATS2L.


'Information on the fly': Challenges in professional communication in high technological nursing. A focus group study from a radiotherapy department in Sweden.
Radiotherapy (RT) units are high-tech nursing environments. In Sweden, RT registered nurses (RNs) provide and manage RT in close collaboration with other professional groups, as well as providing nursing care for patients with cancer. Communication demands on these RNs are thus particularly complex. In this study, we aimed to better understand problems, strengths and change needs related to professional communication with and within the RT department, as a basis for developing a situation-specific intervention. Focus groups discussions (FGDs) were conducted with different professional (RNs, assistant nurses, physicians, engineers and physicists) and user stakeholders. Transcripts of the FGDs were inductively analyzed by a team of researchers, to generate clinically relevant and useful data. These findings give insight into RT safety climate and are presented under three major headings: Conceptualization of professional domains; Organization and leadership issues; and Communication forms, strategies and processes. The impact of existing hierarchies, including how they are conceptualized and acted out in practice, was noted throughout these data. Despite other differences, participating professionals agreed about communication problems related to RT, i.e. a lack of systems and processes for information transfer, unclear role differentiation, a sense of mutual disrespect, and ad hoc communication taking place 'on the fly'. While all professional groups recognized extensive communication problems, none acknowledged the potential negative effects on patient safety or care described in the FGD with patient representatives. While RNs often initially denied the existence of a hierarchy, they placed themselves on a hierarchy in their descriptions, describing their own role as passive, with a sense of powerlessness. Potential safety hazards described in the FGDs include not reporting medical errors and silently ignoring or actively opposing new guidelines and regulations. There is a risk that RNs who view themselves as disenfranchised within an organization will act with passive resistance to change, rather than as change promoters. As interventions to strengthen teams cannot be stronger than the weakest link, RNs may need support in the transition "from silence to voice" in order to take a position of full professional responsibility in a multi-professional health care team.


Histone Deacetylases in Bone Development and Skeletal Disorders.
Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn(2+) for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2(+). Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering.


[EpiInfo as a research and teaching tool in epidemiology and statistics: strengths and weaknesses].
EpiInfo is a free software developed in 1988 by the Centers for Disease Control and Prevention (CDC) in Atlanta to facilitate field epidemiological investigations and statistical analysis. The aim of this study was to assess whether the software represents, in the Italian biomedical field, an effective analytical research tool and a practical and simple epidemiology and biostatistics teaching tool. A questionnaire consisting of 20 multiple-choice and open questions was administered to 300 healthcare workers, including doctors, biologists, nurses, medical students and interns, at the end of a CME course in epidemiology and biostatistics. Sixty-four percent of participants were aged between 26 and 45 years, 52% were women and 73% were unmarried. Results show that women are more likely to utilize EpiInfo in their research activities with respect to men (p = 0.023), as are individuals aged 26-45 years with respect to the older and younger age groups (p = 0.023) and unmarried participants with respect to those married (p = 0.010). Thirty-one percent of respondents consider EpiInfo to be more than adequate for analysis of their research data and 52% consider it to be sufficiently so. The inclusion of an EpiInfo course in statistics and epidemiology modules facilitates the understanding of theoretical concepts and allows researchers to more easily perform some of the clinical/epidemiological research activities.


Impact of food supplementation on weight loss in randomised-controlled dietary intervention trials: a systematic review and meta-analysis.
Dietary trials provide evidence for practice and policy guidelines, but poor adherence may confound results. Food supplementation may improve adherence to dietary interventions, but the impact of supplementation on study outcomes is not known. The aim of this review was to examine the impact of food supplementation on weight loss in dietary intervention trials. The databases Scopus, PubMed and the Cochrane Library were searched for dietary intervention trials published between January 2004 and March 2015 using the following keyword combinations: 'trial' OR 'intervention', 'food' OR 'diet', 'weight loss' and 'adherence' OR 'adherence'. Studies were included if food was provided to at least one study group and both 'weight change' and 'adherence' were reported. Random effects meta-analyses were conducted to assess weighted mean differences (WMD) in body weight (change or final mean values). The included studies formed two groups: trials involving an intervention group supplemented with a food and a control without food supplementation (food v. no food), and trials in which food was provided to all subjects (food v. food) (PROSPERO registration: CRD42015017563). In total, sixteen studies were included. Significant weight reduction was reported in the food v. no food studies (WMD -0·74 kg; 95 % CI -1·40, -0·08; P=0·03, I 2=63 %). A non-significant increase in weight was found among the food v. food studies (WMD 0·84 kg; 95 % CI -0·60, 2·27; P=0·25, I 2=0 %). Food supplementation appeared to result in greater weight loss in dietary trials. Energy restrictions and intensity of interventions were other significant factors influencing weight loss.


Gender, reproductive output covariation and their role on gene diversity of Pinus koraiensis seed orchard crops.
Gender and fertility variation have an impact on mating dynamics in a population because they affect the gene exchange among parental members and the genetic composition of the resultant seed crops. Fertility is the proportional gametic contribution of parents to their progeny. An effective number of parents, derivative of effective population size, is the probability that two alleles randomly chosen from the gamete gene pool originated from the same parent. The effective number of parents is directly related to the fertility variation among parents, which should be monitored for manipulating gene diversity of seed crops. We formulated a fundamental equation of estimating the effective number of parents and applied it to a seed production population. Effective number of parents (Np) was derived from fertility variation (Ψ) considering covariance (correlation coefficient, r) between maternal and paternal fertility. The Ψ was calculated from the coefficient of variation in reproductive outputs and divided into female (ψf) and male (ψm) fertility variation in the population under study. The Np was estimated from the parental Ψ estimated by the fertility variation of maternal (ψf) and paternal (ψm) parents. The gene diversity of seed crops was monitored by Ψ and Np. in a 1.5 generation Pinus koraiensis seed orchard as a case of monoecious species. A large variation of female and male strobili production was observed among the studied 52 parents over four consecutive years, showing statistically significant differences across all studied years. Parental balance curve showed greater distortion in paternal than maternal parents. The Ψ ranged from 1.879 to 4.035 with greater ψm than ψf, and the Np varied from 14.8 to 36.8. When pooled, the relative effective number of parents was improved as 80.0% of the census number. We recommend the use of fertility variation (i.e., CV, Ψ), Person's product-moment correlation (r), and effective number of parents (Np) as tools for gauging gene diversity of seed crops in production populations. For increasing Np and gene diversity, additional management options such as mixing seed-lots, equal cone harvest and application of supplemental-mass-pollination are recommended.


Luteoprotective mechanisms of prostaglandin F2α stimulated by luteinizing hormone in the bovine corpus luteum.
Luteinizing hormone (LH) regulates several ovarian functions. However, the luteoprotective mechanisms of LH involved in the maintenance of bovine corpus luteum (CL) function are not well understood. Since prostaglandin F2α (PGF), PGE2 and progesterone (P4) are well documented as antiapoptotic factors in the bovine CL, we hypothesized that LH protects the CL by stimulating the local production and action of PGF, PGE2 and P4. Cultured bovine luteal cells obtained at the mid-luteal stage (days 8-12 of the estrous cycle) were treated with LH (10 ng/ml), onapristone (OP: a specific P4 receptor antagonist, 100 μM) and indomethacin [INDO; a cyclooxygenase (COX) inhibitor, 100 μM] for 24 h. LH with and without OP significantly increased the mRNA and protein expressions of COX-2, PGF synthase and carbonyl reductase (P<0.05) but not the mRNA and protein expressions of COX-1 and PGE synthase in bovine luteal cells. In addition, these treatments significantly increased PGF and P4 production (P<0.05) but not PGE2 production. Luteal cell viability was significantly increased by LH alone (P<0.05), but LH-increased cell viability was reduced by LH in combination with INDO as well as OP (P<0.05). The overall results suggest that LH prevents luteal cell death by stimulating luteal PGF and P4 production and supports CL function during the luteal phase in cattle.


Internet Use for School-Mandated and Self-Initiated Learning: Good, Bad, or Both?
Because delivery of school assignments and other learning materials has been migrating to online learning environments, use of the Internet for learning has become obligatory for high school students. However, research on the consequences of Internet learning remains equivocal, with some advocating benefits of such learning and others warning about its potential negative effects. In this study, we approach Internet use for learning from a motivational perspective and argue that such learning can be both positive and negative depending on whether it contributes to harmonious or obsessive Internet passion. We test how two types of Internet use for learning, school mandated and self-initiated, may relate to harmonious and obsessive Internet passion among high schoolers in the United States and Russia. The results indicate that Internet use for school-mandated learning is positively related to both harmonious and obsessive Internet passion, and these results hold in both countries. Internet use for self-initiated learning was also positively related to harmonious Internet passion in both Russia and the United States, but was unrelated to obsessive Internet passion in either country. This research not only augments the nomological network of the Internet passion construct but also informs educators on how to incorporate Internet use into the learning environment in ways that are likely to promote harmonious Internet passion and decrease obsessive Internet passion.


Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein.
Interleukin 1 receptor antagonist (IL-1Ra) levels are elevated in the blood of patients with a variety of infectious, immune, or traumatic conditions. To examine whether IL1Ra is produced by liver cells with characteristics resembling an acute-phase protein, human primary hepatocytes isolated from liver biopsies and HepG2 hepatoma cells were stimulated with IL-1beta, IL-6, and TNFalpha. IL-1Ra was present in the supernatants of both cells, with production significantly enhanced by IL-1beta, and by the combination of IL-1beta and IL-6. The term IL-1Ra refers to two different proteins encoded by the same gene, but generated by alternative splicing of two different first exons. One isoform is secreted (17-kD sIL-1Ra), and the other isoform remains in the cytoplasm (18-kD icIL-1Ra). By Western blot analysis, the supernatants of human hepatoma (HepG2) cells contained only sIL-1Ra, whereas the lysates contained a novel smaller molecular mass isoform of 16 kD. RT-PCR and ribonuclease protection assay with RNA from HepG2 cells showed that only sIL-1Ra mRNA was expressed, and confirmed the inducing effect of IL-1beta and IL-6. Transfection studies were performed using constructs containing the promoters of either sIL-1Ra or icIL-1Ra coupled to the luciferase reporter gene. The sIL-1Ra promoter was active in HepG2 cells stimulated by IL-1beta and/or IL-6, whereas the icIL-1Ra promoter was inactive. Mutation of binding sites for transcription factors NF-kappaB and/or C/EBP within the proximal sIL-1Ra promoter led to significant decreases in response to IL-1beta and IL-6 in comparison to the wild-type promoter. Electromobility gel shift assays confirmed the presence of NF-kappaB and C/EBP binding sites within the sIL-1Ra promoter, and indicated a significant increase in the binding activities of nuclear proteins from HepG2 cells treated with IL-1beta and IL-6. In summary, sIL-1Ra, but not icIL-1Ra, is produced by hepatocytes, and is regulated by proinflammatory cytokines as an acute-phase protein. In addition, NF-kappaB and C/EBP family members are likely to play important roles in the full expression of IL-1Ra by hepatocytes during inflammatory conditions.