Essential metal and metalloid elements in the Philippi Horticultural area, and their uptake into selected vegetable crops.
This study evaluated Co, Cr, Mn, Ni, Se, Sn and V status in the soils of the PHA, as well as the vegetables produced on these soils. We also determined the agronomic sources of these elements to the soils in the PHA. Farmyard manures applied as fertilizer amendments to the soils in the PHA were found to be the major agronomic sources of the metal and metalloid elements. These elements were however, retained in significantly higher concentrations in the soils compared to the concentrations found in the edible portions of the vegetable crops collected. This, in turn, resulted in these vegetables being poor sources of several of the essential mineral nutrients. It is therefore suggested that: (1) a wider variety of crops are assessed for their mineral nutrient status, (2) to find ways to increase the availability of these mineral nutrients and (3), that the possibilities of micronutrient and trace element deficiencies be assessed in the communities surrounding the PHA.


Psychological distress among recent Russian immigrants in the United States.
The purpose of this study was to examine the psychological status of Russian immigrants who have recently come to the United States. The project included creation of a Russian version of the Hopkins Symptom Checklist-25 (HSCL-25) in order to identify anxiety and depression in members of the Russian-speaking immigrant population. Translation and adaptation included (a) cross-cultural adaptation; (b) translation; (c) pre-testing; and (d) analysis of validity, reliability and internal consistency. Seventeen Russian-speaking patients at a Russian psychiatric clinic were recruited for the study and were compared with a sample of 42 Russian-speaking members of the community. The instrument showed internal consistency when evaluated with coefficient alpha. Clinic patients had significantly higher anxiety and depression symptom scores than community subjects. Russian immigrants' scores on the anxiety and depression scales were less than comparative data for the United States and notably less than similar measures for Russian immigrants to Israel. Recent Russian immigrants to the United States appear to have low prevalences of anxiety and depression.


Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Origin, distribution and 3D-modeling of Gr-EXPB1, an expansin from the potato cyst nematode Globodera rostochiensis.
Southern analysis showed that Gr-EXPB1, a functional expansin from the potato cyst nematode Globodera rostochiensis, is member of a multigene family, and EST data suggest expansins to be present in other plant parasitic nematodes as well. Homology modeling predicted that Gr-EXPB1 domain 1 (D1) has a flat beta-barrel structure with surface-exposed aromatic rings, whereas the 3D structure of Gr-EXPB1-D2 was remarkably similar to plant expansins. Gr-EXPB1 shows highest sequence similarity to two extracellular proteins from saprophytic soil-inhabiting Actinobacteria, and includes a bacterial type II carbohydrate-binding module. These results support the hypothesis that a number of pathogenicity factors of cyst nematodes is of procaryotic origin and were acquired by horizontal gene transfer.


Paediatric referrals in rural Tanzania: the Kilombero District Study - a case series.
BACKGROUND: Referral is a critical part of appropriate primary care and of the Integrated Management of Childhood Illness (IMCI) strategy. We set out to study referrals from the aspect both of primary level facilities and the referral hospital in Kilombero District, southern Tanzania. Through record review and a separate prospective study we estimate referral rates, report on delays in reaching referral care and summarise the appropriateness of pediatric referral cases in terms of admission to the pediatric ward at a district hospital METHODS: A sample of patient records from primary level government health facilities throughout 1993 were summarised by age, diagnosis, whether a new case or a reattendance, and whether or not they were referred. From August 1994 to July 1995, mothers or carers of all sick children less than five years old attending the Maternal and Child Health (MCH) clinic or outpatient department (OPD) of SFDDH were interviewed using a standard questionnaire recording age, sex, diagnosis, place of residence, whether the child was admitted to the paediatric ward, and whether the child was referred. RESULTS: From record review, only 0.6% of children from primary level government facilities were referred to a higher level of care. At the referral hospital, 7.8 cases per thousand under five catchment population had been referred annually. The hospital MCH clinic and OPD were generally used by children who lived nearby: 91% (n = 7,166) of sick children and 75% (n = 607) of admissions came from within 10 km. Of 235 referred children, the majority (62%) had come from dispensaries. Almost half of the referrals (48%) took 2 or more days to arrive at the hospital. Severe malaria and anaemia were the leading diagnoses in referred children, together accounting for a total of 70% of all the referrals. Most referred children (167/235, 71%) were admitted to the hospital paediatric ward. CONCLUSIONS: The high admission rate among referrals suggests that the decision to refer is generally appropriate, but the low referral rate suggests that too few children are referred. Our findings suggest that the IMCI strategy may need to be adapted in sparsely-populated areas with limited transport, so that more children may be managed at peripheral level and fewer children need referral.


Taming the beast: fluoromesityl groups induce a dramatic stability enhancement in boroles.
The electron-deficient pentaarylborole 1-(2',4',6'-tris(trifluoromethyl)phenyl)-2,3,4,5-tetraphenylborole (1) has been synthesised with the long-term aim of developing borole-based optoelectronic materials. The bulky 2,4,6-tris(trifluoromethyl)phenyl (FMes) group on the boron atom of 1 significantly improves (>600 times) its air stability relative to its mesityl analogue. Moreover, 1 shows good thermal stability without undergoing the dimerisation or isomerisation reactions reported for some other boroles. A triarylborole analogue (2), belonging to a new class of borole with the 3- and 4-positions of the BC4 ring linked by a -(CH2)3- group, has also been synthesised to elucidate the influence of carbon-bonded substituents on the stability of boroles. Both boroles were prepared through the reaction of Li[FMesBF3] and divinyldilithium reagents, a new and general method for borole syntheses. Compound 2 was found to isomerise through a [1,3]-H shift and double-bond rearrangement to an s-trans-butadienylborane species under highly basic (NaOH) conditions. The increased steric crowding at the boron centre through incorporation of the FMes group does not preclude binding of Lewis bases to either 1 or 2, as demonstrated by their fully reversible binding of pyridine. Interestingly, 1 exhibits a blue-shifted absorption spectrum, as compared with its mesityl analogue, a result contrary to previous understanding of the influence of substituent electronics on the absorption spectra of boroles. Most importantly, these boroles exhibit much greater air-stability than previously reported analogues without sacrificing the strong electron-accepting ability that makes boroles so attractive; indeed, 1 and 2 have very low reduction potentials of -1.52 and -1.69 eV vs. Fc/Fc+, respectively.


A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency.
Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). Patients have wide-spectrum clinical abnormalities associated with impaired protein N-glycosylation. Although it has been widely proposed that Pmm2 deficiency depletes M1P, a precursor of GDP-mannose, and consequently suppresses lipid-linked oligosaccharide (LLO) levels needed for N-glycosylation, these deficiencies have not been demonstrated in patients or any animal model. Here we report a morpholino-based PMM2-CDG model in zebrafish. Morphant embryos had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants. Although M1P and GDP-mannose were below reliable detection/quantification limits, Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro. In pmm2 morphants, the free glycan by-products of LLO cleavage increased nearly twofold. Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the pmm2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated pmm2-dependent LLO cleavage. In summary, we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible with other systems, including an M6P accumulation mechanism for underglycosylation.


Pulsed CO(2) TEA laser rangefinder.
A compact laser rangefinder has been developed, which incorporates a sealed-off pulsed CO(2) TEA laser and uses direct (i.e., nonheterodyne) detection. This device is essentially eye safe and benefits from the superior atmospheric transmission at 10.6-microm wavelength. Design parameters are presented and illustrated, and system performance is discussed.


Cost-effectiveness evaluation of three approaches to case management for homeless mentally ill clients.
In this study the authors compared the cost-effectiveness of three approaches to case management for individuals with severe mental illness who were at risk for homelessness: assertive community treatment alone, assertive community treatment with community workers, and brokered case management (purchase of services). Individuals were randomly assigned to the three treatment conditions and followed for 18 months. Eligibility requirements included a severe DSM-III axis I diagnosis, such as schizophrenia, and either current homelessness or risk for homelessness based on prior history of homelessness. Participants were recruited from the emergency rooms and inpatient units of local psychiatric hospitals. Data on 85 people were available for analyses: 28 in assertive community treatment alone, 35 in assertive community treatment with community workers, and 22 receiving brokered case management (purchase of services). Clients assigned to the two assertive community treatment conditions had more contact with their treatment programs, experienced greater reductions in psychiatric symptoms, and were more satisfied with their treatment than clients in the brokered condition. There was no statistically significant difference between treatment conditions in terms of the total costs of treating the participants. However, the assertive community treatment conditions spent less money on inpatient services than brokered case management, but more on case management services and maintenance (i.e., food stamps, housing subsidies, and Supplemental Security Income payments). Assertive community treatment has better client outcomes at no greater cost and is, therefore, more cost-effective than brokered case management.


A novel flexible microfluidic meshwork to reduce fibrosis in glaucoma surgery.
Fibrosis and hence capsule formation around the glaucoma implants are the main reasons for glaucoma implant failure. To address these issues, we designed a microfluidic meshwork and tested its biocompatibility in a rabbit eye model. The amount of fibrosis elicited by the microfluidic meshwork was compared to the amount elicited by the plate of conventional glaucoma drainage device. Six eyes from 3 New Zealand albino rabbits were randomized to receive either the novel microfluidic meshwork or a plate of Ahmed glaucoma valve model PF7 (AGV PF7). The flexible microfluidic implant was made from negative photoresist SU-8 by using micro-fabrication techniques. The overall size of the meshwork was 7 mm × 7 mm with a grid period of 100 μm. Both implants were placed in the subtenon space at the supratemporal quadrant in a standard fashion. There was no communication between the implants and the anterior chamber via a tube. All animal eyes were examined for signs of infection and implant erosion on days 1, 3, 7, and 14 and then monthly. Exenterations were performed in which the entire orbital contents were removed at 3 months. Histology slides of the implant and the surrounding tissues were prepared and stained with hematoxylin-eosin. Thickness of the fibrous capsules beneath the implants were measured and compared with paired student's t-test between the two groups. The gross histological sections showed that nearly no capsule formed around the microfluidic meshwork in contrast to the thick capsule formed around the plate of AGV PF7. Thickness of the fibrotic capsules beneath the AGV PF7 plate from the 3 rabbit eyes was 90μm, 82μm, and 95 μm, respectively. The thickness at the bottom of fibrotic capsules around the new microfluidic implant were 1μm, 2μm, and 1μm, respectively. The difference in thickness of capsule between the two groups was significant (P = 0.002). No complications were noticed in the 6 eyes, and both implants were tolerated well by all rabbits. The microfluidic meshwork elicited minimal fibrosis and capsule formation after 3-months implantation in a rabbit model. This provides promising evidence to aid in future development of a new glaucoma drainage implant that will elicit minimal scar formation and provide better long-term surgical outcomes.


Sacred space and the healing journey.
Sacred space and spirituality have long been used to heal the mind, body, and spirit. This article illuminates the origins of sacred space and its role as a healing environment from the first human construct, the burial mound, to the 5th Century BCE Greek healing city of Epidaurus. It then examines the role of spirituality as one of the necessary human institutions for a healthy society, according to the Italian philosopher Giambattista Vico. The conclusion then surveys three contemporary healing environments' architecture, the Department of Veteran Affairs Healing Environment Design Guideline (VAHEDG), and how these sacred spaces mend individual and community ailments.


Catalytically Active Cas9 Mediates Transcriptional Interference to Facilitate Bacterial Virulence.
In addition to defense against foreign DNA, the CRISPR-Cas9 system of Francisella novicida represses expression of an endogenous immunostimulatory lipoprotein. We investigated the specificity and molecular mechanism of this regulation, demonstrating that Cas9 controls a highly specific regulon of four genes that must be repressed for bacterial virulence. Regulation occurs through a protospacer adjacent motif (PAM)-dependent interaction of Cas9 with its endogenous DNA targets, dependent on a non-canonical small RNA (scaRNA) and tracrRNA. The limited complementarity between scaRNA and the endogenous DNA targets precludes cleavage, highlighting the evolution of scaRNA to repress transcription without lethally targeting the chromosome. We show that scaRNA can be reprogrammed to repress other genes, and with engineered, extended complementarity to an exogenous target, the repurposed scaRNA:tracrRNA-FnoCas9 machinery can also direct DNA cleavage. Natural Cas9 transcriptional interference likely represents a broad paradigm of regulatory functionality, which is potentially critical to the physiology of numerous Cas9-encoding pathogenic and commensal organisms.


Disease management interventions for heart failure.
Despite advances in treatment, the increasing and ageing population makes heart failure an important cause of morbidity and death worldwide. It is associated with high healthcare costs, partly driven by frequent hospital readmissions. Disease management interventions may help to manage people with heart failure in a more proactive, preventative way than drug therapy alone. This is the second update of a review published in 2005 and updated in 2012. To compare the effects of different disease management interventions for heart failure (which are not purely educational in focus), with usual care, in terms of death, hospital readmissions, quality of life and cost-related outcomes. We searched CENTRAL, MEDLINE, Embase and CINAHL for this review update on 9 January 2018 and two clinical trials registries on 4 July 2018. We applied no language restrictions. We included randomised controlled trials (RCTs) with at least six months' follow-up, comparing disease management interventions to usual care for adults who had been admitted to hospital at least once with a diagnosis of heart failure. There were three main types of intervention: case management; clinic-based interventions; multidisciplinary interventions. We used standard methodological procedures expected by Cochrane. Outcomes of interest were mortality due to heart failure, mortality due to any cause, hospital readmission for heart failure, hospital readmission for any cause, adverse effects, quality of life, costs and cost-effectiveness. We found 22 new RCTs, so now include 47 RCTs (10,869 participants). Twenty-eight were case management interventions, seven were clinic-based models, nine were multidisciplinary interventions, and three could not be categorised as any of these. The included studies were predominantly in an older population, with most studies reporting a mean age of between 67 and 80 years. Seven RCTs were in upper-middle-income countries, the rest were in high-income countries.Only two multidisciplinary-intervention RCTs reported mortality due to heart failure. Pooled analysis gave a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.23 to 0.95), but the very low-quality evidence means we are uncertain of the effect on mortality due to heart failure. Based on this limited evidence, the number needed to treat for an additional beneficial outcome (NNTB) is 12 (95% CI 9 to 126).Twenty-six case management RCTs reported all-cause mortality, with low-quality evidence indicating that these may reduce all-cause mortality (RR 0.78, 95% CI 0.68 to 0.90; NNTB 25, 95% CI 17 to 54). We pooled all seven clinic-based studies, with low-quality evidence suggesting they may make little to no difference to all-cause mortality. Pooled analysis of eight multidisciplinary studies gave moderate-quality evidence that these probably reduce all-cause mortality (RR 0.67, 95% CI 0.54 to 0.83; NNTB 17, 95% CI 12 to 32).We pooled data on heart failure readmissions from 12 case management studies. Moderate-quality evidence suggests that they probably reduce heart failure readmissions (RR 0.64, 95% CI 0.53 to 0.78; NNTB 8, 95% CI 6 to 13). We were able to pool only two clinic-based studies, and the moderate-quality evidence suggested that there is probably little or no difference in heart failure readmissions between clinic-based interventions and usual care (RR 1.01, 95% CI 0.87 to 1.18). Pooled analysis of five multidisciplinary interventions gave low-quality evidence that these may reduce the risk of heart failure readmissions (RR 0.68, 95% CI 0.50 to 0.92; NNTB 11, 95% CI 7 to 44).Meta-analysis of 14 RCTs gave moderate-quality evidence that case management probably slightly reduces all-cause readmissions (RR 0.92, 95% CI 0.83 to 1.01); a decrease from 491 to 451 in 1000 people (95% CI 407 to 495). Pooling four clinic-based RCTs gave low-quality and somewhat heterogeneous evidence that these may result in little or no difference in all-cause readmissions (RR 0.90, 95% CI 0.72 to 1.12). Low-quality evidence from five RCTs indicated that multidisciplinary interventions may slightly reduce all-cause readmissions (RR 0.85, 95% CI 0.71 to 1.01); a decrease from 450 to 383 in 1000 people (95% CI 320 to 455).Neither case management nor clinic-based intervention RCTs reported adverse effects. Two multidisciplinary interventions reported that no adverse events occurred. GRADE assessment of moderate quality suggested that there may be little or no difference in adverse effects between multidisciplinary interventions and usual care.Quality of life was generally poorly reported, with high attrition. Low-quality evidence means we are uncertain about the effect of case management and multidisciplinary interventions on quality of life. Four clinic-based studies reported quality of life but we could not pool them due to differences in reporting. Low-quality evidence indicates that clinic-based interventions may result in little or no difference in quality of life.Four case management programmes had cost-effectiveness analyses, and seven reported cost data. Low-quality evidence indicates that these may reduce costs and may be cost-effective. Two clinic-based studies reported cost savings. Low-quality evidence indicates that clinic-based interventions may reduce costs slightly. Low-quality data from one multidisciplinary intervention suggested this may be cost-effective from a societal perspective but less so from a health-services perspective. We found limited evidence for the effect of disease management programmes on mortality due to heart failure, with few studies reporting this outcome. Case management may reduce all-cause mortality, and multidisciplinary interventions probably also reduce all-cause mortality, but clinic-based interventions had little or no effect on all-cause mortality. Readmissions due to heart failure or any cause were probably reduced by case-management interventions. Clinic-based interventions probably make little or no difference to heart failure readmissions and may result in little or no difference in readmissions for any cause. Multidisciplinary interventions may reduce the risk of readmission for heart failure or for any cause. There was a lack of evidence for adverse effects, and conclusions on quality of life remain uncertain due to poor-quality data. Variations in study location and time of occurrence hamper attempts to review costs and cost-effectiveness.The potential to improve quality of life is an important consideration but remains poorly reported. Improved reporting in future trials would strengthen the evidence for this patient-relevant outcome.


The laboratory opossum (Monodelphis domestica) as a natural mammalian model for human cancer research.
This study established that human cancer cells (A375 melanoma, HT-29 colon cancer, PC-3p prostate cancer) that were xenografted into suckling opossums could proliferate and globally metastasize as early as 11 days after injection. Light and electron microscopic examinations (HT-29 colon cancer) determined that the cellular features exhibited by the xenogeneic human tumors grown in laboratory opossums were consistent with those observed in tumors removed from humans. The tumor induction rate, patterns of tumor growth and regression, and types of host immune responses against the xenografted tumors were influenced by injection dosages, injection sites and injection ages of suckling opossums. The results highlight the value of the opossum model as a natural in vivo system for investigating human cancer growth, metastasis and apoptosis at the cellular and molecular levels; enhancing identification of tumor associated antigens or T cell epitopes through use of humoral and cellular expression cloning techniques; elucidating mechanisms utilized by tumor cells to evade host immunosurveillance; and devising diagnostic and therapeutic methods for cancer treatment.


Definitions of the phenotypic manifestations of sickle cell disease.
Sickle cell disease (SCD) is a pleiotropic genetic disorder of hemoglobin that has profound multiorgan effects. The low prevalence of SCD ( approximately 100,000/US) has limited progress in clinical, basic, and translational research. Lack of a large, readily accessible population for clinical studies has contributed to the absence of standard definitions and diagnostic criteria for the numerous complications of SCD and inadequate understanding of SCD pathophysiology. In 2005, the Comprehensive Sickle Cell Centers initiated a project to establish consensus definitions of the most frequently occurring complications. A group of clinicians and scientists with extensive expertise in research and treatment of SCD gathered to identify and categorize the most common complications. From this group, a formal writing team was formed that further reviewed the literature, sought specialist input, and produced definitions in a standard format. This article provides an overview of the process and describes 12 body system categories and the most prevalent or severe complications within these categories. A detailed Appendix provides standardized definitions for all complications identified within each system. This report proposes use of these definitions for studies of SCD complications, so future studies can be comparably robust and treatment efficacy measured. Use of these definitions will support greater accuracy in genotype-phenotype studies, thereby achieving a better understanding of SCD pathophysiology. This should nevertheless be viewed as a dynamic rather than final document; phenotype descriptions should be reevaluated and revised periodically to provide the most current standard definitions as etiologic factors are better understood, and new diagnostic options are developed.


The surprising heart revisited: an early history of the funny current with modern lessons.
40 years ago a single experiment upset a decade of painstaking research on the mechanisms of rhythm generation in the heart. It did so by turning a theory of pacemaker activity upside down. Instead of attributing rhythm to decaying potassium current carrying outward current, it attributed the pacemaker depolarization to the slow activation of a channel conducting sodium ions into cardiac cells. But this was no standard upset of a theory. Like the replacement of Newtonian mechanics by relativity theory, the new theory explained every minute detail of the experimental observations that had established the theory it was replacing. Computational modelling of the heart achieved one of the major successes, the complete mapping of one theory onto another without challenging the correctness of any of the experimental findings. This review details the way in which this transition occurred and draws some important lessons for modelling of biological processes today.


Timing, Distribution, and Relationship Between Nonpsychotic and Subthreshold Psychotic Symptoms Prior to Emergence of a First Episode of Psychosis.
Prospective population studies suggest that psychotic syndromes may be an emergent phenomenon-a function of severity and complexity of more common mental health presentations and their nonpsychotic symptoms. Examining the relationship between nonpsychotic and subthreshold psychotic symptoms in individuals who later developed the ultimate outcome of interest, a first episode of psychosis (FEP), could provide valuable data to support or refute this conceptualization of how psychosis develops. We therefore conducted a detailed follow-back study consisting of semistructured interviews with 430 patients and families supplemented by chart reviews in a catchment-based sample of affective and nonaffective FEP. The onset and sequence of 27 pre-onset nonpsychotic (NPS) or subthreshold psychotic (STPS) symptoms was systematically characterized. Differences in proportions were analyzed with z-tests, and correlations were assessed with negative binomial regressions. Both the first psychiatric symptom (86.24% NPS) and the first prodromal symptom (66.51% NPS) were more likely to be NPS than STPS. Patients reporting pre-onset STPS had proportionally more of each NPS than did those without pre-onset STPS. Finally, there was a strong positive correlation between NPS counts (reflecting complexity) and STPS counts (β = 0.34, 95% CI [0.31, 0.38], P < 2 e-16). Prior to a FEP, NPS precede STPS, and greater complexity of NPS is associated with the presence and frequency of STPS. These findings complement recent arguments that the emergence of psychotic illness is better conceptualized as part of a continuum-with implications for understanding pluripotential developmental trajectories and strengthening early intervention paradigms.


Associations between infant amygdala functional connectivity and social engagement following a stressor: A preliminary investigation.
Functional architecture of the infant brain, especially functional connectivity (FC) within the amygdala network and between the amygdala and other networks (i.e., default-mode [DMN] and salience [SAL] networks), provides a neural basis for infant socioemotional functioning. Yet, little is known about the extent to which early within- and between-network amygdala FC are related to infant stress recovery across the first year of life. In this study, we examined associations between amygdala FC (i.e., within-network amygdala connectivity, and between-network amygdala connectivity with the DMN and SAL) at 3 months and infant recovery from a mild social stressor at 3, 6 and 9 months. At 3 months, thirty-five infants (13 girls) underwent resting-state functional magnetic resonance imaging during natural sleep. Infants and their mothers completed the still-face paradigm at 3, 6, and 9 months, and infant stress recovery was assessed at each time point as the proportion of infant social engagement during the reunion episode. Bivariate correlations indicated that greater positive within-network amygdala FC and greater positive amygdala-SAL FC, but not amygdala-DMN FC, at 3 months predicted lower levels of stress recovery at 3 and 6 months, but were nonsignificant at 9 months. These findings provide preliminary evidence that early functional synchronization within the amygdala network, as well as segregation between the amygdala and the SAL, may contribute to infant stress recovery in the context of infant-mother interaction.


Ischemia Modified Albumin (IMA) - A Marker of Glycaemic Control and Vascular Complications in Type 2 Diabetes Mellitus.
Ischemia modified albumin (IMA) has emerged as a marker for ischemic injury and oxidative damage, particularly in myocardial infarction. There are very few studies on the significance of IMA in other conditions associated with ischemia. The complications of diabetes mellitus (DM) arising out of poor glycaemic control have an underlying ischemic aetiology. To evaluate correlation of IMA with glycaemic control in type 2 DM (T2DM). Secondary aim was to assess the utility of IMA as a marker for vascular complications in T2DM. During this cross-sectional study, a total of 100 diagnosed cases of T2DM were recruited between May 2013 and September 2013. The IMA, HbA1c, lipid profile, creatinine and urine micro-albumin levels were measured and analysed with respect to clinical condition of the patients. The epidemiological software, Epi-Info 7.1.5, was used for the statistical analysis, p-value<0.05 was defined as level of significance. The study subjects were in the age group from 30 to 75 years and 52.4% were males. There was a great degree of variance in the level of glycaemic control and majority (64.6%) had poor or very poor glycaemic control as reflected by their HbA1c levels. The IMA (Mean ± SEM) levels were found to be higher (62.9 ± 1.7ABSU) in the patients with poor glycaemic control compared to those with good glycaemic control (54.2 ± 3.5 ABSU, p-value < 0.05) and correlated with HbA1c levels (r(2)=0.14). IMA levels also appeared to be related with the changes in lipid profile and increased with increasing total cholesterol levels. The subjects with macro-vascular complications (retinopathy and neuropathy) showed non-significantly higher levels of IMA. The elevation in IMA correlated with the HbA1c and changes in the lipid profile. IMA correlates with poor glycaemic control and dyslipidaemia associated with T2 DM and could serve as an indicator of oxidant stress in these patients.


Oleuropein protects L-02 cells against H2O2-induced oxidative stress by increasing SOD1, GPx1 and CAT expression.
Oleuropein (OL), a natural phenolic compound, comprises the major constituent of Olea europea leaves and unprocessed olives, and OL is considered to be the principal components that confer the characteristic taste and stability of olive oil. Oxidative damage induced by H2O2 treatment can irreversibly damage the L-02 cells, resulting in cell death and apoptosis. Whether the effects of oxidative stress could be attenuated in cultured human L-02 cells by incubation with OL is still unknown. In this research, the function of OL in protecting human L-02 cells against H2O2 induced cell death and cell apoptosis was investigated, and the mechanism by which OL underlies the effect was also examed. L-02 cells were exposed to 100μM H2O2 with or without OL pretreatment at different concentrations. Cell viabilities were monitored by WST-1 assay. ALT, AST and LDH production in culture medium were also determined. ROS levels were detected by L-012 chemiluminescence, and OL increased SOD1, CAT and GPx1 expression in a concentration-dependent manner. Further studies showed that OL also inhibited H2O2-induced P38 and JNK phosphorylation but enhanced ERK1/2 phosphorylation in a dose-dependent manner. These findings suggested that OL as a potent antioxidant agent and a natural compound found in several plants, may be exploited as a potentially useful method for hepatopathy prevention.


Cost-effectiveness of intensive exercise therapy directly following hospital discharge in patients with arthritis: results of a randomized controlled clinical trial.
To estimate the cost-utility and cost-effectiveness of a 3-week intensive exercise training (IET) program directly following hospital discharge in patients with rheumatic diseases. Patients with arthritis who were admitted to the hospital because of a disease activity flare or for elective hip or knee arthroplasty were randomly assigned to either the IET group or usual care (UC) group. Followup lasted 1 year. Quality-adjusted life years (QALYs) were derived from Short Form 6D scores and a visual analog scale (VAS) rating personal health. Function-related outcome was measured using the Health Assessment Questionnaire, the McMaster Toronto Arthritis (MACTAR) Patient Preference Disability Questionnaire, and the Escola Paulista de Medicina Range of Motion scale (EPMROM). Costs were reported from a societal perspective. Differences in costs and incremental cost-effectiveness ratios (ICERs) were estimated. Data from 85 patients (50 IET and 35 UC) could be used for health-economic analysis. VAS personal health-based QALYs were in favor of IET. Function-related outcome showed statistically significant improvements in favor of IET over the first 6 months, according to the MACTAR (P < 0.05) and the EPMROM (P < 0.01). At 1-year followup, IET was euro718 less per patient. The ICER showed a reduction in mean total costs per QALY. In 70% of cases the intervention was cost-saving. IET results in better quality of life at lower costs after 1 year. Thus, IET is the dominant strategy compared with UC. This highlights the need for implementation of IET after hospital discharge in patients with arthritis.


A constrained factor mixture analysis model for consistent and inconsistent respondents to mixed-worded scales.
Mixed-worded scales require a more careful reading and answering process than scales with only one type of wording. The present study is about the unintended consequences of using such scales, because typically, not all respondents answer positively and negatively worded items consistently. This population heterogeneity-meaning that there are distinct groups of consistently and inconsistently answering respondents-may arguably underlie wording-related effects in mixed-worded scales. We formulated a constrained factor mixture analysis model that operationalized these two assumed classes of respondents. We investigated five data sets that contained four mixed-worded attitude scales, large-scale samples from three countries (Germany, Australia, and the U.S.), and two age groups (children and adolescents). The constrained factor mixture analysis model showed estimated parameter patterns in line with theoretical expectations and consistently outperformed its more traditional competitor, confirmatory factor analysis with one global and one orthogonal method factor across all used data sets. We found proportions of between 7% and 20% of respondents belonging to the inconsistent classes. To further substantiate and validate the interpretation of the proposed model, we related class membership to theoretically relevant respondent characteristics such as reading achievement, cognitive skills, or conscientiousness. Further, we undertook an initial exploration of the overlap in inconsistent respondents' class membership across time and across scales within a survey. The article discusses implications for future research as well as for the use of mixed-worded scales. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Deals without delusions.
Pursuing a merger or acquisition is inherently difficult. Things get even harder when executives are blind to their own faulty assumptions, say Lovallo--a professor at the University of Western Australia Business School and a senior adviser to McKinsey--and three of his McKinsey colleagues. The authors identify biases that can surface at each step of the M&A process and provide practical tips for rising above them--an approach they call targeted debiasing. During the preliminary due-diligence stage, biases abound. To overcome the confirmation bias, aggressively seek evidence that challenges your initial hypothesis about a deal. The best medicine for overconfidence in identifying revenue and cost synergies is to learn from precedents at your firm and others. Avoiding underestimation of cultural differences between your company and the target requires understanding the differences in the ways people interact at each organization. Misjudging the time and resources you need is at the core of the planning fallacy, which you can elude by formally identifying best practices and continually revisiting them. Finally, dilute conflict of interest by soliciting dispassionate external expertise. The bidding phase is vulnerable to the winner's curse, a phenomenon common in auctions. To avoid paying too much for a target, actively generate alternatives to the deal under consideration and develop a set of bidding cutoff rules. After offering an initial bid, deal makers are susceptible to anchoring, whereby they remain attached to their original price estimate, and to the sunk cost fallacy that they've invested too much to stop now. The secret to overcoming both: Use your newly available access to the target's books to better assess the investment case--and change your tune accordingly.


Opioid receptor subtypes that mediate a microwave-induced decrease in central cholinergic activity in the rat.
We performed experiments to investigate subtypes of opioid receptors in the brain involved in the effect of acute (45 min) pulsed microwave exposure (2,450-MHz, 2-microseconds pulses, 500 pps, average power density 1 mW/cm2, peak-power density, 1 W/cm2, average whole body SAR 0.6 W/kg) on cholinergic activity in the rat brain. Rats were pretreated by microinjection of specific antagonists of mu, delta, and kappa opioid-receptors into the lateral cerebroventricle before exposure to microwaves. The data showed that all three subtypes of opioid receptors are involved in the microwave-induced decrease in cholinergic activity in the hippocampus. However, the microwave-induced decrease in cholinergic activity in the frontal cortex was not significantly affected by any of the drug treatments, confirming our previous conclusion that the effect of microwaves on the frontal cortex is not mediated by endogenous opioids.


Monocyte expression of Toll-like receptor-4 in patients with stable angina undergoing percutanoeus coronary intervention.
Toll like receptors (TLRs) are well recognized players in inflammatory conditions. Among them TLR-4 is involved in chronic inflammatory processes such as formation of atherosclerotic plaques. The present study was aimed to examine the effects of percutanoeus coronary intervention (PCI) as a revascularization method on monocyte expression of hTLR-4 and on the serum levels of two proinflammatory cytokines (TNF-α and IL-1β). Blood samples were obtained from 41 patients with stable angina who were candidates for PCI. The samples were collected immediately before and 2h and 4h after PCI. The expression of hTLR-4 on CD14+ monocytes and the serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques, respectively. By comparing the frequency of circulating hTLR-4+/CD14+ monocytes at different time points, it was observed that PCI procedure up regulates the monocyte expression of hTLR-4 (p<0.05). The increase in expression was associated with the elevation of the serum levels of proinflammatory cytokines (p<005). There was a significant correlation between monocyte expression of hTLR-4 and serum levels of TNF-α and IL-1β only before PCI. In spite of parallel increase in the serum levels of proinflammatory cytokines and the monocyte expression of hTLR-4, the correlation did not attain a significant level after PCI intervals. PCI is positively associated with an increase in the monocyte expression of hTLR-4. It is also associated with the elevation in the serum levels of proinflmmatory cytokines. These findings suggest that hTLR-4 monocyte expression may be used as a potential prognostic tool in patients with stable angina undergoing PCI.


Evaluation of a real-time quantitative polymerase chain reaction assay for detection and quantitation of virulent Rhodococcus equi.
To evaluate a real-time quantitative polymerase chain reaction (QPCR) assay in the detection and quantitation of virulent Rhodococcus equi. 1 virulent, 2 intermediately virulent, and 2 avirulent strains of R. equi and 16 isolates of bacteria genetically related to R. equi. The QPCR assay was evaluated for detection and quantitation of the virulence-associated gene (vapA) of R. equi in pure culture and in samples of tracheobronchial fluid, which were inoculated with known numbers of virulent R. equi. Results were compared with those derived via quantitative microbial culture and standard polymerase chain reaction methods. The QPCR assay detected the vapA gene in pure culture of R. equi and in tracheobronchial fluid samples that contained as few as 20 CFUs of virulent R. equi/mL and accurately quantitated virulent R. equi to 10(3) CFUs/mL of fluid. The assay was highly specific for detection of the vapA gene of virulent R. equi and was more sensitive than standard polymerase chain reaction for detection of R. equi in tracheobronchial fluid. The QPCR assay appears to be a rapid and reliable method for detecting and quantitating virulent R. equi. The accuracy of the QPCR assay is comparable to that of quantitative microbial culture. The increased sensitivity of the QPCR method in detection of virulent R. equi should facilitate rapid and accurate diagnosis of R. equi pneumonia in foals.


Factors associated with psychotropic prescriptions, psychiatric hospitalization, and spending among Medicare beneficiaries under 65.
Medicare beneficiaries under 65 are a medically heterogenous population with significant psychiatric health service utilization. Patterns of psychiatric health services utilization and spending have not been well studied in this population. To estimate and compare annual trends in psychotropic prescriptions, psychiatric hospitalization, and total Medicare spending between Medicare beneficiaries <65 and those ≥ 65. We also identified factors associated with these outcomes among Medicare beneficiaries under 65. This serial cross-sectional study used 2006-2009 Medicare Current Beneficiary Survey (MCBS) data linked with Medicare claims. Psychotropic prescription and psychiatric hospitalization were measured using claims data. Total annual Medicare spending included reimbursements from Medicare Parts A, B, and D. Repeated person-year data were analyzed using generalized estimating equation (GEE) models to examine associations between factors and outcomes among beneficiaries <65, controlling for covariates. Over one-third of beneficiaries <65 used at least one psychotropic prescription annually. Annual prevalence of psychotropic prescription and psychiatric hospitalization was higher among beneficiaries <65 than those ≥ 65 (threefold and ten-fold, respectively), as well as Medicare spending. The annual prevalence of psychiatric hospitalization decreased over time among beneficiaries <65. Antidepressants were the most prevalently prescribed psychotropic drug class among beneficiaries <65. Factors associated with psychiatric services utilization and spending among beneficiaries <65 included demographics and health insurance access, self-reported health, smoking status, and comorbidities (all P < 0.05). Our findings highlight the special psychiatric health care needs of Medicare beneficiaries under 65 and call for the attention of policy makers and clinicians to this understudied population.


Spectroscopic ellipsometry of anisotropic materials: application to the optical constants of HgI2.
A variable angle-of-incidence spectroscopic fixed-polarizer, rotating-polarizer, fixed-analyzer ellipsometer (PRPSE) across a spectral range from 300 to 800 nm is used to determine the optical properties of anisotropic uniaxial tetragonal red mercuric iodide (HgI(2)). For the first time, to our knowledge, the bulk crystal HgI(2) surface measured by ellipsometry was not subjected to potassium iodide cutting or etching. Measurements were made at an air-HgI(2) interface with the optic axis parallel to the sample surface. To determine the optical constants, we varied both the angle of incidence and the azimuth of the optic axis with the plane of incidence. The detailed formulas needed for reliable procedures for analyzing the data are presented. The ordinary and extraordinary complex indices of refraction, (n(o)--ik(o)) and (n(e)--ik(e)), respectively, are determined. Good agreement between PRPSE and the prism technique for the refractive index is observed. The surface aging effects of the ellipsometric parameters of HgI(2), during 30 h of exposure to air, were detected by PRPSE.


Ultrasonography in the assessment of peripheral joint involvement in psoriatic arthritis : a comparison with radiography, MRI and scintigraphy.
The objective of our study was to investigate the role of musculoskeletal ultrasound (US) in the assessment of hand and foot small joints in psoriatic arthritis (PsA). Thirteen consecutive patients with PsA of hands or feet underwent B-mode US using a 9- to 13-MHz transducer and simultaneous magnetic resonance imaging (MRI), bone scintigraphy and radiography. US findings were compared with radiography, MRI and scintigraphy in 190, 182 and 109 joints, respectively. To assess the sensitivity and specificity of US, radiography was considered as gold standard for the detection of erosions and osteoproliferations and MRI as gold standard for the detection of joint effusion and synovitis. US, MRI and scintigraphy had a higher sensitivity in the detection of overall joint pathology than radiography in painful and/or swollen joints (71%, 72%, 82% vs 32%) and clinically unaffected joints (17%, 21%, 9% vs 2%). US and radiography detected more erosions and osteoproliferations than MRI, with low agreement between the methods in the detection of erosions. Radiography was superior to US in the visualisation of osteoproliferations. Joint effusions and/or synovitis were more frequently detected by MRI than US. Agreement between both imaging methods was better in carpal joints, carpometacarpal joint I, metacarpophalangeal (MCP)/metatarsophalangeal (MTP) joint I, II and V than in MCP/MTP III, IV, PIP and DIP joints. Compared with MRI, radiography and scintigraphy, the specificity of US ranges between 0.84 and 0.94, depending on the joint pathology. In conclusion, the diagnostic sensitivity of US in the detection of PsA-related synovitis of hands and feet is lower than MRI and depends on the joint region. However, the low cost and the acceptable specificity suggest that US is a useful imaging method in addition to radiography in PsA of hands and feet.


Exercise and physical activity in children with cystic fibrosis.
Regular exercise and habitual physical activity are important for patients with cystic fibrosis (CF). Research has demonstrated the benefits of aerobic, anaerobic, and strength exercise training programs for health and quality of life, however, the CF patient is faced with unique barriers and challenges to participation. Recently, increased levels of habitual physical activity have been shown to slow the decline in lung function in patients with CF, and regular participation in a variety of activities may result in greater adherence in the long term. Research is now available to justify the incorporation of exercise into the routine care of patients with CF. This paper provides the background and rationale for the implementation of exercise and habitual physical activity recommendations by the health care team. Education of health care providers regarding the importance of exercise and habitual physical activity for patients with CF is needed in order for exercise and physical activity to be incorporated as key components of clinical practice and into the lives of patients with CF.


Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function.
Vertebrate Hedgehog (HH) signaling is controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity. However, the molecular mechanisms used by these inhibitors remain poorly understood. In this paper, we investigated the mechanisms underlying HHIP1 antagonism of HH signaling. Strikingly, we found evidence that HHIP1 non-cell-autonomously inhibits HH-dependent neural progenitor patterning and proliferation. Furthermore, this non-cell-autonomous antagonism of HH signaling results from the secretion of HHIP1 that is modulated by cell type-specific interactions with heparan sulfate (HS). These interactions are mediated by an HS-binding motif in the cysteine-rich domain of HHIP1 that is required for its localization to the neuroepithelial basement membrane (BM) to effectively antagonize HH pathway function. Our data also suggest that endogenous, secreted HHIP1 localization to HS-containing BMs regulates HH ligand distribution. Overall, the secreted activity of HHIP1 represents a novel mechanism to regulate HH ligand localization and function during embryogenesis.


Compartmentation of cAMP signaling in cardiac myocytes: a computational study.
Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M(2) muscarinic receptor (M(2)R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by G(i), and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high ( approximately 1 microM) and only modestly stimulated by beta(1)AR activation ( approximately 2 microM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A ( approximately 100 nM to approximately 2 microM); 2), M(2)R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M(2)R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M(2)R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.


Effects of home-based long-term care services on caregiver health according to age.
Caregiver health is a crucial public health concern due to the increasing number of elderly people with disabilities. Elderly caregivers are more likely to have poorer health and be a care recipient than younger caregivers. The Taiwan government offers home-based long-term care (LTC) services to provide formal care and decrease the burden of caregivers. This study examined the effects of home-based LTC services on caregiver health according to caregiver age. This cross-sectional study included a simple random sample of care recipients and their caregivers. The care recipients had used LTC services under the Ten-Year Long-Term Care Project (TLTCP) in Taiwan. Data were collected through self-administered questionnaires from September 2012 to January 2013. The following variables were assessed for caregivers: health, sex, marital status, education level, relationship with care recipient, quality of relationship with care recipient, job, household monthly income, family income spent on caring for the care recipient (%) and caregiving period. Furthermore, the following factors were assessed for care recipients: age, sex, marital status, education level, living alone, number of family members living with the care recipient, quality of relationship with family and dependency level. The health of the caregivers and care recipients was measured using a self-rated question (self-rated health [SRH] was rated as very poor, poor, fair, good and very good). The study revealed that home nursing care was significantly associated with the health of caregivers aged 65 years or older; however, caregivers aged less than 65 who had used home nursing care, rehabilitation or respite care had poorer health than those who had not used these services. In addition, the following variables significantly improved the health of caregivers aged 65 years or older: caregiver employment, 20% or less of family income spent on caregiving than 81%-100% and higher care recipient health. The involvement of daughters-in-law, rather than spouses, and care recipient health were positively related to the health of caregivers aged less than 65 years. The findings suggest that home-based LTC service use benefits the health of elderly caregivers. By contrast, home-based LTC service use may be negatively correlated with the health of the caregivers aged less than 65 years.


Auricular acupuncture for postoperative pain control: a systematic review of randomised clinical trials.
The number of publications on the peri-operative use of auricular acupuncture has rapidly increased within the last decade. The aim was to evaluate clinical evidence on the efficacy of auricular acupuncture for postoperative pain control. Electronic databases: Medline, MedPilot, DARE, Clinical Resource, Scopus and Biological Abstracts were searched from their inception to September 2007. All randomised clinical trials on the treatment of postoperative pain with auricular acupuncture were considered and their quality was evaluated using the Jadad scale. Pain intensity and analgesic requirements were defined as the primary outcome measures. Of 23 articles, nine fulfilled the inclusion criteria. Meta-analytic approach was not possible because of the heterogeneity of the primary studies. In eight of the trials, auricular acupuncture was superior to control conditions. Seven randomised clinical trials scored three or more points on the Jadad scale but none of them reached the maximum of 5 points. The evidence that auricular acupuncture reduces postoperative pain is promising but not compelling.


How asset tests block low-income Medicare beneficiaries from needed benefits.
The Medicare Savings Programs and Medicaid help elderly Medicare beneficiaries with their cost-sharing responsibilities and provide much-needed additional benefits. But 40 to 50 percent of eligible low-income Medicare beneficiaries are not enrolled in the Medicare Savings Programs. One persistent barrier is the use of asset tests, which greatly complicate the application process for applicants and program staff. Older people with low incomes generally have few assets and the income and assets of older people who qualify for public programs do not change substantially over time. Findings suggest that use of asset tests should be eliminated or asset limits should be increased; at a minimum, cost-of-living adjustments should be made. Findings also indicate that the renewal process should be simplified, and use of verification documents should be reduced or eliminated.


Molecular pathogenesis of mantle cell lymphoma.
Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients.


Improving curcumin solubility and bioavailability by encapsulation in saponin-coated curcumin nanoparticles prepared using a simple pH-driven loading method.
Curcumin is a bioactive phytochemical that can be utilized as a nutraceutical or pharmaceutical in functional foods, supplements, and medicines. However, the application of curcumin as a nutraceutical in commercial food and beverage products is currently limited by its low water-solubility, chemical instability, and poor oral bioavailability. In this study, all-natural colloidal delivery systems were developed to overcome these challenges, which consisted of saponin-coated curcumin nanoparticles formed using a pH-driven loading method. The physicochemical and structural properties of the curcumin nanoparticles formed using this process were characterized, including particle size distribution, surface potential, morphology, encapsulation efficiency, and loading capacity. Fourier transform infrared spectroscopy and X-ray diffraction indicated that curcumin was present in the nanoparticles in an amorphous form. The curcumin nanoparticles were unstable to aggregation at low pH values (<3) and high NaCl concentrations (>200 mM), which was attributed to a reduction in electrostatic repulsion between them. However, they were stable at higher pH values (3 to 8) and lower NaCl levels (0 to 200 mM), due to a stronger electrostatic repulsion between them. They also exhibited good stability during refrigerated storage (4 °C) or after conversion into a powdered form (lyophilized). A simulated gastrointestinal tract study demonstrated that the in vitro bioaccessibility was around 3.3-fold higher for curcumin nanoparticles than for free curcumin. Furthermore, oral administration to Sprague Dawley rats indicated that the in vivo bioavailability was around 8.9-fold higher for curcumin nanoparticles than for free curcumin. These results have important implications for the development of curcumin-enriched functional foods, supplements, and drugs.


Climate, Birth Weight, and Agricultural Livelihoods in Kenya and Mali.
To examine an association between climate variability and birth weight in Mali and Kenya in relation to the local agricultural specialization. We combined health and sociodemographic data from the Demographic Health Surveys for Kenya (2008 and 2014) and Mali (2006 and 2012) with detailed data on precipitation, temperature, and vegetation. We analyzed the association between climate variability and birth weight by using multilevel regression models for the most common agricultural specializations: food cropping, cash cropping, and pastoralism. There are differences in sensitivity to climate among different agricultural communities. An additional 100 millimeters of rainfall during the 12-month period before birth was associated with a 47-gram (P = .001) and 89-gram (P = .10) increase in birth weight for food croppers in Kenya and Mali, respectively. Every additional hot month in food-cropping communities in Kenya was associated with a 71-gram decrease in birth weight (P = .030), likely because of food croppers' limited use of modern agricultural techniques. Overall, cash croppers are least sensitive to climate variability in both countries. Effective climate change adaptation strategies are essential for protecting and improving health outcomes and should be tailored to local households' livelihood strategies.


Extensive junctional diversity of Ig heavy chain rearrangements generated in the progeny of single fetal multipotent hematopoietic cells in the absence of selection.
We analyzed the progeny of individual multipotent hemopoietic cells, derived from the para-aortic splanchopleura, the earliest identified source of lymphocyte precursors in pre-liver mouse embryos. Single precursors were expanded in an in vitro culture system that permits both commitment and differentiation of B cell precursors. We show that from one single multipotent progenitor we could obtain large numbers of B cell precursors that rearrange the Ig heavy chain genes and generate a repertoire as diverse as that observed in adult populations. N region additions are present at V(D)J junctions, showing that terminal deoxynucleotidyl transferase expression has been switched on and is not, consequently, an intrinsic property of adult stem cells. Throughout the culture period, cells show a majority of DJ vs V(D)J rearrangements and a ratio of 2:1 of nonproductive to productive V(D)J rearrangements, which is close to the expected frequency in the absence of selection. In addition, counterselection for D-J rearrangements in reading frame 2 is observed in V(D)J joints, and allelic exclusion was consistently observed. We conclude that of the three events associated with heavy chain rearrangement, two of them, namely allelic exclusion and counterselection of cells in which the D segment is in reading frame 2, are intrinsic to the cell, while selection of productive heavy chain rearrangements is induced in the bone marrow environment.


HIV-2 infects resting CD4+ T cells but not monocyte-derived dendritic cells.
Human Immunodeficiency Virus-type 2 (HIV-2) encodes Vpx that degrades SAMHD1, a cellular restriction factor active in non-dividing cells. HIV-2 replicates in lymphocytes but the susceptibility of monocyte-derived dendritic cells (MDDCs) to in vitro infection remains partly characterized. Here, we investigated HIV-2 replication in primary CD4+ T lymphocytes, both activated and non-activated, as well as in MDDCs. We focused on the requirement of Vpx for productive HIV-2 infection, using the reference HIV-2 ROD strain, the proviral clone GL-AN, as well as two primary HIV-2 isolates. All HIV-2 strains tested replicated in activated CD4+ T cells. Unstimulated CD4+ T cells were not productively infected by HIV-2, but viral replication was triggered upon lymphocyte activation in a Vpx-dependent manner. In contrast, MDDCs were poorly infected when exposed to HIV-2. HIV-2 particles did not potently fuse with MDDCs and did not lead to efficient viral DNA synthesis, even in the presence of Vpx. Moreover, the HIV-2 strains tested were not efficiently sensed by MDDCs, as evidenced by a lack of MxA induction upon viral exposure. Virion pseudotyping with VSV-G rescued fusion, productive infection and HIV-2 sensing by MDDCs. Vpx allows the non-productive infection of resting CD4+ T cells, but does not confer HIV-2 with the ability to efficiently infect MDDCs. In these cells, an entry defect prevents viral fusion and reverse transcription independently of SAMHD1. We propose that HIV-2, like HIV-1, does not productively infect MDDCs, possibly to avoid triggering an immune response mediated by these cells.


Distinct roles for basal and induced COX-2 in podocyte injury.
Transgenic mice that overexpress cyclooxygenase-2 (COX-2) selectively in podocytes are more susceptible to glomerular injury by adriamycin and puromycin (PAN). To investigate the potential roles of COX-2 metabolites, we studied mice with selective deletion of prostanoid receptors and generated conditionally immortalized podocyte lines from mice with either COX-2 deletion or overexpression. Podocytes that overexpressed COX-2 were virtually indistinguishable from wild-type podocytes but were significantly more sensitive to PAN-induced injury, produced more prostaglandin E(2) and thromboxane B(2), and had greater expression of prostaglandin E(2) receptor subtype 4 (EP(4)) and thromboxane receptor (TP). Treatment of COX-2-overexpressing podocytes with a TP antagonist reduced apoptosis, but treatment with an EP(4) antagonist did not. In contrast, podocytes from COX-2-knockout mice exhibited increased apoptosis, markedly decreased cell adhesion, and prominent stress fibers. In vivo, selective deletion of podocyte EP(4) did not alter the increased sensitivity to adriamycin-induced injury observed in mice overexpressing podocyte COX-2. In contrast, genetic deletion of TP in these mice prevented adriamycin-induced injury, with attenuated albuminuria and foot process effacement. These results suggest that basal COX-2 may be important for podocyte survival, but overexpression of podocyte COX-2 increases susceptibility to podocyte injury, which is mediated, in part, by activation of the thromboxane receptor.


A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure.
Small conductance Ca2+ -activated K+ (SK) channels play an important role in regulating the excitability of magnocellular neurosecretory cells (MNCs). Although an increased SK channel function contributes to adaptive physiological responses, it remains unknown whether changes in SK channel function/expression contribute to exacerbated MNC activity under disease conditions. We show that the input-output function of MNCs in heart failure (HF) rats is enhanced. Moreover, the SK channel blocker apamin enhanced the input-output function in sham, although not in HF rats. We found that both the after-hyperpolarizing potential magnitude and the underlying apamin-sensitive IAHP are blunted in MNCs from HF rats. The magnitude of spike-induced increases in intracellular Ca2+ levels was not affected in MNCs of HF rats. We found a diminished expression of SK2/SK3 channel subunit mRNA expression in the supraoptic nucleus of HF rats. Our studies suggest that a reduction in SK channel expression, but not changes in Ca2+ -mediated activation of SK channels, contributes to exacerbated MNC activity in HF rats. Small conductance Ca2+ -activated K+ channels (SK) play an important role in regulating the activity of magnocellular neurosecretory cells (MNCs) and hormone release from the posterior pituitary. Moreover, enhanced SK activity contributes to the adaptive responses of MNCs to physiological challenge, such as lactation. Nevertheless, whether changes in SK function/expression contribute to exacerbated MNC activity during diseases such as heart failure (HF) remains unknown. In the present study, we used a combination of patch clamp electrophysiology, confocal Ca2+ imaging and molecular biology in a rat model of ischaemic HF. We found that the input-output function of MNCs was enhanced in HF compared to sham rats. Moreover, although the SK blocker apamin (200 nm) strengthened the input-output function in sham rats, it failed to have an effect in HF rats. The magnitude of the after-hyperpolarizing potential (AHP) following a train of spikes and the underlying apamin-sensitive IAHP were blunted in MNCs from HF rats. However, spike-induced increases in intracellular Ca2+ were not affected in the MNCs of HF rats. Real-time PCR measurements of SK channel subunits mRNA in supraoptic nucleus punches revealed a diminished expression of SK2/SK3 subunits in HF compared to sham rats. Together, our studies demonstrate that MNCs from HF rats exhibit increased membrane excitability and an enhanced input-output function, and also that a reduction in SK channel-mediated, apamin-sensitive AHP is a critical contributing mechanism. Moreover, our results suggest that the reduced AHP is related to a down-regulation of SK2/SK3 channel subunit expression but not the result of a blunted activity-dependent intracellular Ca2+ increase following a burst of action potentials.


The occurrences of chest pains and frequent coughing among residents living within the Selebi Phikwe Ni-Cu mine area, Botswana.
This study aimed at establishing occurrences of chest pains and frequent coughing among different classes of residents within Selebi Phikwe, Botswana where there are on going nickel-copper (Ni-Cu) mining and smelting activities. Through the administration of questionnaires and structured questions to 600 individuals, 7 health service providers, 200 business enterprises, and 30 educational institutions, attempts were made to establish and verify the existing human health status at Selebi Phikwe by focusing on chest pains and frequent coughing which are considered to be some of the respiratory tract related symptoms of sicknesses and diseases. With the aid of statistical package for social sciences (SPSS), interpreted results from respondents indicated that 33 % of the individuals complained of persistent chest pains; and 27 % of educational institutions, 45 % business enterprises, and all health service providers had learners, workers, and patients who complained of chest pains. Furthermore, 49 % of the individuals complained of persistent frequent coughing; and 70 % of educational institutions, 45 % business enterprises, and all health service providers had learners, workers, and patients who complained of frequent coughing. According to study sites, respondents living in sites closest to the mine and smelter / concentrator plant reported a higher incidence of chest pains and frequent coughing, compared to those living in other parts of the study area. Residents associate fumes and dust from mining activities to the frequent coughing and persistent chest pains, which could be symptoms of respiratory tract diseases. This baseline investigation calls for further studies to establish relations of mining activities to human health at Selebi Phikwe.


Variability and directionality of inferior olive neuron dendrites revealed by detailed 3D characterization of an extensive morphological library.
The inferior olive (IO) is an evolutionarily conserved brain stem structure and its output activity plays a major role in the cerebellar computation necessary for controlling the temporal accuracy of motor behavior. The precise timing and synchronization of IO network activity has been attributed to the dendro-dendritic gap junctions mediating electrical coupling within the IO nucleus. Thus, the dendritic morphology and spatial arrangement of IO neurons governs how synchronized activity emerges in this nucleus. To date, IO neuron structural properties have been characterized in few studies and with small numbers of neurons; these investigations have described IO neurons as belonging to two morphologically distinct types, "curly" and "straight". In this work we collect a large number of individual IO neuron morphologies visualized using different labeling techniques and present a thorough examination of their morphological properties and spatial arrangement within the olivary neuropil. Our results show that the extensive heterogeneity in IO neuron dendritic morphologies occupies a continuous range between the classically described "curly" and "straight" types, and that this continuum is well represented by a relatively simple measure of "straightness". Furthermore, we find that IO neuron dendritic trees are often directionally oriented. Combined with an examination of cell body density distributions and dendritic orientation of adjacent IO neurons, our results suggest that the IO network may be organized into groups of densely coupled neurons interspersed with areas of weaker coupling.


Bottom-up approaches to strengthening child protection systems: Placing children, families, and communities at the center.
Efforts to strengthen national child protection systems have frequently taken a top-down approach of imposing formal, government-managed services. Such expert-driven approaches are often characterized by low use of formal services and the misalignment of the nonformal and formal aspects of the child protection system. This article examines an alternative approach of community-driven, bottom-up work that enables nonformal-formal collaboration and alignment, greater use of formal services, internally driven social change, and high levels of community ownership. The dominant approach of reliance on expert-driven Child Welfare Committees produces low levels of community ownership. Using an approach developed and tested in rural Sierra Leone, community-driven action, including collaboration and linkages with the formal system, promoted the use of formal services and achieved increased ownership, effectiveness, and sustainability of the system. The field needs less reliance on expert-driven approaches and much wider use of slower, community-driven, bottom-up approaches to child protection.


Yeast XRS2 and human NBN gene: Experimental evidence for homology using codon optimized cDNA.
The genes, XRS2 in Saccharomyces cerevisiae and NBN in mammals, have little sequence identity at the amino acid level. Nevertheless, they are both found together with MRE11 and RAD50 in a highly conserved protein complex which functions in the repair of DNA double-strand breaks. Here, we have examined the evolutionary and functional relationship of these two genes by cross-complementation experiments. These experiments necessitated sequence correction for specific codon usage before they could be successfully conducted. We present evidence that despite extreme sequence divergence nibrin can, at least partially, replace Xrs2 in the cellular DNA damage response, and Xrs2 is able to promote nuclear localization of MRE11 in NBS cells. We discuss that the extreme sequence divergence reflects a unique adaptive pressure during evolution related to the specific eukaryotic role for both Xrs2 and nibrin in the subcellular localisation of the DNA repair complex. This, we suggest, is of particular relevance when cells are infected by viruses. The conflict hypothesis of co-evolution of DNA repair genes and DNA viruses may thus explain the very low sequence identity of these two homologous genes.


Screening for genital and anorectal sexually transmitted infections in HIV prevention trials in Africa.
To demonstrate the value of routine, basic sexually transmitted infection (STI) screening at enrolment into an HIV-1 vaccine feasibility cohort study and to highlight the importance of soliciting a history of receptive anal intercourse (RAI) in adults identified as "high risk". Routine STI screening was offered to adults at high risk of HIV-1 upon enrolment into a cohort study in preparation for HIV-1 vaccine trials. Risk behaviours and STI prevalence were summarised and the value of microscopy assessed. Associations between prevalent HIV-1 infection and RAI or prevalent STI were evaluated with multiple logistic regression. Participants had a high burden of untreated STI. Symptom-directed management would have missed 67% of urethritis cases in men and 59% of cervicitis cases in women. RAI was reported by 36% of male and 18% of female participants. RAI was strongly associated with HIV-1 in men (adjusted odds ratio (aOR) 3.8; 95% CI 2.0 to 6.9) and independently associated with syphilis in women (aOR 12.9; 95% CI 3.4 to 48.7). High-risk adults recruited for HIV-1 prevention trials carry a high STI burden. Symptom-directed treatment may miss many cases and simple laboratory-based screening can be done with little cost. Risk assessment should include questions about anal intercourse and whether condoms were used. STI screening, including specific assessment for anorectal disease, should be offered in African research settings recruiting participants at high risk of HIV-1 acquisition.


Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models.
The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850-60. ©2017 AACR.


Comparative dopamine-cholinergic mechanisms in the olfactory tubercle and the striatum: effects of metoclopramide.
The olfactory tubercle (OT) is a limbic structure containing high dopamine (DA) and acetylcholine (ACh) concentrations. We performed a comparative study of the DA-ACh interactions, the efficacy of autoreceptor control and the effects of metoclopramide in the OT and the nucleus caudate (striatum). Rabbit brain slices from both regions of the same animal were prelabeled with radioactive DA and/or choline and then superfused. Comparable magnitude of DA and ACh release was evoked by electrical stimulation from both regions. DA release was unaltered, whereas ACh release was inversely related to the stimulation frequency, both in OT and striatum. Apomorphine (APO), a D1-D2 agonist, an LY-171555 (LY), a D2 agonist, inhibited DA and ACh release from OT and striatum with similar EC50 and Emax (maximal percentage of inhibition). However, the maximal degree of inhibition of ACh release achieved with APO, LY or DA in the OT was only one-half that observed in the striatum. In both regions, the inhibitory effects of DA agonists on DA and ACh release were reduced markedly when the number of electrical pulses and/or the frequency of stimulation were increased. l-Sulpiride, a DA D2 antagonist, increased the evoked release of DA and ACh from OT in direct relationship with the frequency of stimulation. In the OT, increases in synaptic DA achieved by administration of amphetamine or by blockade of the neuronal uptake pump with nomifensine inhibited the evoked release of ACh. Again these drug treatments produced only a 40 to 50% inhibition of ACh release. SKF 38393, a D1 agonist, had no effect per se on DA or ACh release in OT slices from control or from reserpine-treated animals (2 mg/kg s.c. for 3 or 7 days). With the exception of one specific dose combination, coadministration of SKF 38393 and LY produced no additive or synergistic effects on DA or ACh release from OT. APO- and LY-induced inhibition of DA and ACh release were antagonized by l-sulpiride. However, 300 nM SCH 23390, a D1 antagonist, reduced APO inhibition of DA and ACh release without affecting the inhibitory action of LY on DA and ACh release. Metoclopramide, "a DA antagonist with poor limbic activity", had a similar affinity for OT (pA2: 7.59) and striatal (pA2: 7.59) DA autoreceptors. Its antidopaminergic efficacy on DA receptors modulating ACh release from OT and striatum was also compared.(ABSTRACT TRUNCATED AT 400 WORDS)


First Report of Fusarium Wilt of Strawberry Caused by Fusarium oxysporum in Serbia.
Strawberry (Fragaria × ananassa Duch.) is the third most important berry crop in Serbia with average production ranging from 30,000 to 35,000 t on approximately 5,000 ha (2). In June 2013, symptoms of wilt and whole plant collapse were observed on approximately 25% plants growing in commercial strawberry crop of cv. Alba in the locality of Zablaće (Moravica district). Initial symptoms included leaf chlorosis and wilt, followed by withering and necrosis of older leaves and reduced fruit production, eventually leading to plant collapse and desiccations. Internal vascular tissues of the crown showed distinct brown reddish discoloration. Three small pieces of infected roots, petioles, or crown vascular tissues were surface disinfested with 2% NaOCl and placed on five potato dextrose agars (PDA) per sample. After 7 days incubation at 23°C under 12 h of fluorescent light, nine monoconidial isolates were obtained (1) forming colonies with light purple mycelia. Colonies produced numerous hyaline, oval to ellipsoid microconidia (5 to 15 × 2.5 to 4.5 μm, average 8.45 × 2.25 μm), 3 to 5 septate fusoid macroconidia with pedicellate bases (20 to 50 × 2.70 to 6 μm, average 32.35 × 3.25 μm from 100 measured) and chlamydospores. Morphological and growth features were similar to the descriptions of Fusarium oxysporum Schlechtend emend. Snyder & Hansen (1). Pathogenicity of one selected isolate (97-13) was tested by dipping for 15 min the roots of five plants of each cultivar: Alba, Arosa, Clery, and Roxana into a conidial suspension (1 × 106 conidia/ml) harvested from a 7-day-old culture on PDA. Control plants were dipped in sterile distilled water. The inoculated plants were transplanted into pots containing sterilized peat and maintained in the greenhouse at 25°C. Thirty to thirty-five days post-inoculation, all plants developed wilt symptoms and vascular discoloration of crown tissues from which F. oxysporum was successfully re-isolated using the same method as for isolation. No symptoms were observed on any of the control plants. Morphological identification was confirmed by amplification and sequencing of a portion of the translation elongation factor-1 alpha (EF-1α) gene. Total DNA was extracted directly from fungal mycelium with a DNeasy Plant Mini Kit (Qiagen, Hilden, Germany) and PCR amplification performed with primers EF-1/EF-2 (4). Sequence analysis of EF-1α region revealed that Serbian isolate 97-13 (GenBank Accession No. KJ647280) shared 99 to 100% identity with the F. oxysporum sequences in GenBank. To our knowledge, this is the first report of Fusarium wilt on strawberry in Serbia. The presence of a new and potentially harmful disease may represent a serious constraint for strawberry production in Serbia. References: (1) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual, Blackwell Publishing, London, UK, 2006. (2) M. Nikolić et al. Acta Hort. 842:615, 2009. (3) K. O'Donnell et al. Proc. Natl. Acad. Sci. USA 95:2044, 1998.


Standards and core components for cardiovascular disease prevention and rehabilitation.
In 2017, the British Association for Cardiovascular Prevention and Rehabilitation published its official document detailing standards and core components for cardiovascular prevention and rehabilitation. Building on the success of previous editions of this document (published in 2007 and 2012), the 2017 update aims to further emphasise to commissioners, clinicians, politicians and the public the importance of robust, quality indicators of cardiac rehabilitation (CR) service delivery. Otherwise, its overall aim remains consistent with the previous publications-to provide a precedent on which all effective cardiovascular prevention and rehabilitation programmes are based and a framework for use in assessment of variation in service delivery quality. In this 2017 edition, the previously described seven standards and core components have both been revised to six, with a greater focus on measurable clinical outcomes, audit and certification. The principles within the updated document underpin the six-stage pathway of care for CR, and reflect the extensive evidence base now available within the field. To help improve current services, close collaboration between commissioners and CR providers is advocated, with use of the CR costing tool in financial planning of programmes. The document specifies how quality assurance can be facilitated through local audit, and advocates routine upload of individual-level data to the annual British Heart Foundation National Audit of Cardiac Rehabilitation, and application for national certification ensuring attainment of a minimum quality standard. Although developed for the UK, these standards and core components may be applicable to other countries.


Lactation yields and accuracies computed from test day yields and (co)variances by best production.
Lactation records are calculated from data on milk, fat, and protein obtained from one or more milkings on several days during the lactation. The test interval method, which estimated missing daily milk yields by simple interpolation, was used for many years for standard monthly data but may not be as useful for the wider variety of test plans now being proposed. More accurate 305-d yields can be computed using best prediction, which has optimum properties if means and (co)variances are known and distribution is multivariate normal. The covariance of test day and 305-d yields is multiplied by the inverse of the test day (co)variance matrix, which is then multiplied by the test day deviation vector. This predicted 305-d deviation plus the mean 305-d yield equals the predicted 305-d yield. Similar algebraic methods are used to compute the correlation of true and estimated 305-d yields, which is needed to calculate lactation weights. Computation times were affordable but not trivial; they ranged from 0.001 to 1 s per lactation. Equations were modified to account for differing accuracies of data for partial days, means for multiple days, and data for unsupervised tests. Complete or incomplete lactations recorded with very different testing plans can be graphed and compared by best prediction.


Trisenox: a paradigm shift in APL therapy, an interview with Francesco Lo-Coco.
Francesco Lo-Coco speaks to Sebastian Dennis-Beron, Commissioning Editor: Francesco Lo-Coco is currently a full professor of hematology and head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biomedicine and Prevention of the University Tor Vergata of Roma. He obtained his MD degree from the University of Pisa in 1981, and his specialization in clinical and laboratory hematology is from the University La Sapienza of Rome in 1985. From 1992 to 1994, he has trained on molecular genetics of lymphomas at Columbia University, New York. His main scientific interest and research activities include genetic characterization, monitoring and treatment of hematologic tumors, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has published over 390 internationally peer-reviewed articles, mainly focused on molecular diagnosis and follow-up of leukemia as well as on treatment of APL. He chairs at present the APL subcommittee of the Italian National Cooperative Group, GIMEMA. He served as president of the Italian Society of Experimental Hematology, chairman of the Education Committee of the European Hematology Association, board member of the Italian Foundation for Cancer Research, member of the Committe on Health Research of the Italian Ministry of Health and member of the Editorial Board of the journals Leukemia, Journal of Clinical Oncology and Haematologica.


Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres.
Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative V̇O(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.


Heterosexual romantic couples mate assortatively for facial symmetry, but not masculinity.
Preferences for partners with symmetric and sex-typical faces are well documented and considered evidence for the good-genes theory of mate choice. However, it is unclear whether preferences for these traits drive the real-world selection of mates. In two samples of young heterosexual couples from the United Kingdom (Study 1) and the United States (Study 2), the authors found assortment for facial symmetry but not for sex typicality or independently rated attractiveness. Within-couple similarity in these traits did not predict relationship duration or quality, although female attractiveness and relationship duration were negatively correlated among couples in which the woman was the more attractive partner. The authors conclude that humans may mate assortatively on facial symmetry, but this remains just one of the many physical and nonphysical traits to which people likely attend when forming romantic partnerships. This is also the first evidence that preferences for symmetry transfer from the laboratory to a real-world setting.


C-reactive protein (CRP) promotes malignant properties in pancreatic neuroendocrine neoplasms.
Elevated pre-operative C-reactive protein (CRP) serum values have been reported to be associated with poor overall survival for patients with pancreatic neuroendocrine neoplasms (pNEN). The aim of this study was to identify mechanisms linking CRP to poor prognosis in pNEN. The malignant properties of pNENs were investigated using the human pNEN cell-lines BON1 and QGP1 exposed to CRP or IL-6. Analyses were performed by ELISA, Western blot, flow cytometry and immunocytochemistry as well as invasion and proliferation assays. To compare cytokine profiles and CRP levels, 76 serum samples of pNEN patients were analyzed using Luminex technology. In parallel, the expression of CRP and growth signaling pathway proteins was assessed on cell lines and paraffin-embedded primary pNEN. In BON1 and QGP1 cells, inflammation (exposure to IL-6) significantly upregulated CRP expression and secretion as well as migratory properties. CRP stimulation of BON1 cells increased IL-6 secretion and invasion. This was accompanied by activation/phosphorylation of the ERK, AKT and/or STAT3 pathways. Although known CRP receptors - CD16, CD32 and CD64 - were not detected on BON1 cells, CRP uptake of pNEN cells was shown after CRP exposure. In patients, increased pre-operative CRP levels (≥5 mg/L) were associated with significantly higher serum levels of IL-6 and G-CSF, as well as with an increased CRP expression and ERK/AKT/STAT3 phosphorylation in pNEN tissue. The malignant properties of pNEN cells can be stimulated by CRP and IL-6 promoting ERK/AKT/STAT pathways activation as well as invasion, thus linking systemic inflammation and poor prognosis.


Social-cognitive predictors of physical exercise adherence: three longitudinal studies in rehabilitation.
Levels of physical exercise adherence are not predicted well by behavioral intentions. Therefore, action planning and recovery self-efficacy were specified as proximal predictors to bridge the gap between intentions and adherence. The prediction model was examined in 3 studies with participants who were enrolled in cardiac rehabilitation (Study 1, N = 353; Study 2, N = 114) or orthopedic rehabilitation (Study 3, N = 368). Each study included 3 measurement points in time, covering a period between 4 and 12 months. Intentions, planning, self-efficacy, and exercise levels were assessed. Structural equation modeling revealed that 1 common model fit all 3 data sets well. Results differed in terms of variance accounted for, but the overall patterns of estimated parameters were similar. Although health risk perception appeared to be a negligible factor, action planning and recovery self-efficacy were effective predictors of physical exercise adherence.


Quality of RCTs in periodontology--a systematic review.
Randomization, concealment of treatment allocation, blinding, and patient follow-up are key quality components of randomized controlled trials (RCTs). The objective of this study was to assess the quality of RCTs in periodontology using these evidence-based components. Following a detailed search, screening and quality assessments of RCTs were conducted in duplicate and independently. The results showed that although 91% of trials were described as randomised, adequate methods for randomization and allocation concealment were found in 17% and 7% of studies, respectively. Blinding was adequate for the caregiver in 17% and for the examiner in 55% of studies. A clear accounting of all participants was present in 56% of reports. This rigorous systematic review revealed that the quality of RCTs in periodontology, judged by their publications, frequently does not meet recommended standards. If this quality is reflected in actual study conduct, fundamental errors could have a significant impact on the outcomes of these trials.


Distinct localization of GLUT-1, -3, and -5 in human monocyte-derived macrophages: effects of cell activation.
We determined subcellular localization of GLUT-1, GLUT-3, and GLUT-5 as human monocytes differentiate into macrophages in culture, and effects of the activating agents N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA). Western blot analysis demonstrated progressively increased GLUT-1, rapidly decreased GLUT-3, and a delayed increase of GLUT-5 expression during differentiation. Confocal microscopy revealed that each isoform displayed a unique subcellular distribution and cell-activation response. GLUT-1 was localized primarily to the cell surface but was also detected in the perinuclear region in a pattern characteristic of recycling endosomes. GLUT-3 exhibited predominantly a distinct vesicle-like staining but was present only in monocytes. GLUT-5 was found primarily at the cell surface but was detectable intracellularly. Activation with fMLP induced similar GLUT-1 and GLUT-5 redistributions from intracellular compartments toward the cell surface. PMA elicited a similar translocation of GLUT-1, but GLUT-5 was redistributed from the plasma membrane to a distinct intracellular compartment that appeared connected to the cell surface. These results suggest specific subcellular targeting of each transporter isoform and differential regulation of their trafficking pathways in cultured macrophages.