A pepducin derived from the third intracellular loop of FPR2 is a partial agonist for direct activation of this receptor in neutrophils but a full agonist for cross-talk triggered reactivation of FPR2.
We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR) and the ATP receptor (P2Y2R) transfer formyl peptide receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Önnheim K, et al., Exp Cell Res, 323∶209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a receptor cross-talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naïve cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by receptor cross-talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct receptor activation and cross-talk reactivation of FPR2 puts the concept of functional selectivity in focus.


Skin and nail responses after 1 year of infliximab therapy in patients with moderate-to-severe psoriasis: a retrospective analysis of the EXPRESS Trial.
The EXPRESS study demonstrated the initial efficacy of infliximab in psoriasis affecting the skin and nails. To further assess how patients with a positive initial response to infliximab respond to 1 year of continuous infliximab treatment. A retrospective analysis of patients with moderate-to-severe plaque and nail psoriasis who initiated and continued infliximab treatment up to week 46 was conducted. Among all nail psoriasis patients receiving 1 year of infliximab (n = 186), 74.6 and 54.1% achieved at least 75 or 90% improvement in the Psoriasis Area and Severity Index (PASI) at week 50. These PASI-75 (n = 138) and PASI-90 (n = 100) responders had respective mean improvements from baseline to week 50 of 93.6 and 97.3% for the PASI, 90.6 and 94.1% for the Dermatology Life Quality Index (DLQI) and 78.2 and 80.3% for the Nail Psoriasis Severity Index (NAPSI). Infliximab treatment for 1 year produced sustained improvement in PASI, DLQI and NAPSI scores.


Trends in the Utilization of Sodium Hyaluronate Eye Drops, Including Disposable and Multiuse Forms, in South Korea: A 14-Year Longitudinal Retrospective Cohort Study.
Sodium hyaluronate eye drops are frequently prescribed for dry eye disease in South Korea. This study analyzed the trends in the utilization of sodium hyaluronate eye drops and evaluate the impact of the introduction of high-priced disposable forms in the South Korean market. The yearly claims data for sodium hyaluronate eye drops from 2002 to 2015 were retrieved from the National Health Insurance Service-National Sample Cohort. Prescriptions of sodium hyaluronate eye drops were sorted by the characteristics of patients and health care institutions. The number of prescriptions has continuously increased and the share of disposable forms in total prescriptions reached 37% in 2015. Particularly, the prevalence of prescriptions (general users) has increased during the study period from 2,562/100,000 persons in 2002 to 14,732/100,000 persons in 2015, while the incidence of prescriptions (new users) has remained steady during the study period, approximately 3,500/100,000 persons. More female patients were noted in terms of general users and new users, and the proportion of male patients was higher in new users than in general users. The average age of general users increased during the study period, while that of new users slightly decreased. Finally, the distribution of prescription category was significantly different between sex and age groups in frequently prescribed users. Eye drops in disposable forms, which are safe and more convenient to use, have expanded the market in South Korea and caused equity issues in utilization. Thus, the utilization of eye drops should be closely monitored from the perspectives health equity.


Relationship between dietary carotenoid intake and sleep duration in American adults: a population-based study.
To investigate the relationship between dietary carotenoid intake and sleep duration. Adults enrolled in the National Health and Nutrition Examination Survey (NHANES) 2007-2018 without missing information on dietary carotenoid intake (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin), sleep duration, and covariates were included. Participants' carotenoid consumption was divided into three groups by quartiles and sleep duration was grouped as short (< 7 h/night), optimal (7-8 h/night), and long (> 8 h/night). Multinominal logistic regression was constructed to examine the association between dietary carotenoid intake and sleep duration. Restricted cubic spline (RCS) regression was further utilized to explore their dose-response relationship. The weighted quantile sum (WQS) model was adopted to calculate the mixed and individual effect of 5 carotenoid sub-types on sleep duration. Multinominal logistic regression presented that people with higher intakes of α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin were less likely to sleep too short or too long. Consistent with the findings from multinominal logistic regression, the RCS models suggested a reverse U-shaped relationship between sleep duration and carotenoid intakes. The mixed effects were also significant, where β-cryptoxanthin and lutein + zeaxanthin were the top 2 contributors associated with the decreased risks of short sleep duration, while β-carotene, α-carotene, and β-cryptoxanthin were the main factors related to the lower risk of long sleep duration. Our study revealed that the American adults with optimal sleep duration were associated with more dietary carotenoid intake, in comparison to short or long sleepers.


Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient.
Antisense oligonucleotide-induced exon skipping is a promising approach for treatment of Duchenne muscular dystrophy (DMD). We have systemically administered an antisense phosphorodiamidate morpholino oligomer (PMO) targeting dystrophin exons 6 and 8 to a dog with canine X-linked muscular dystrophy in Japan (CXMD(J)) lacking exon 7 and achieved recovery of dystrophin in skeletal muscle. To date, however, antisense chemical compounds used in DMD animal models have not been directly applied to a DMD patient having the same type of exon deletion. We recently identified a DMD patient with an exon 7 deletion and tried direct translation of the antisense PMO used in dog models to the DMD patient's cells. We converted fibroblasts of CXMD(J) and the DMD patient to myotubes by FACS-aided MyoD transduction. Antisense PMOs targeting identical regions of dog and human dystrophin exons 6 and 8 were designed. These antisense PMOs were mixed and administered as a cocktail to either dog or human cells in vitro. In the CXMD(J) and human DMD cells, we observed a similar efficacy of skipping of exons 6 and 8 and a similar extent of dystrophin protein recovery. The accompanying skipping of exon 9, which did not alter the reading frame, was different between cells of these two species. Antisense PMOs, the effectiveness of which has been demonstrated in a dog model, achieved multi-exon skipping of dystrophin gene on the FACS-aided MyoD-transduced fibroblasts from an exon 7-deleted DMD patient, suggesting the feasibility of systemic multi-exon skipping in humans.


Restoration of function in the knee and elbow with a hinge-distractor apparatus.
External hinged distraction devices using transosseous pins and adjustable attachments were applied to mobilize joint contractures; to reduce old dislocations; and to reduce, immobilize, and compress ununited para-articular fractures. Once these procedures were accomplished the devices were then used to maintain the joint surfaces separated at predetermined distances while kinematically normal joint motion was gradually restored, first passively and then actively. The results in thirty-one knees and twenty-eight elbows treated with these devices were encouraging after follow-ups of one to six years.


Who should receive an implantable cardioverter-defibrillator after myocardial infarction?
Despite a decline in overall cardiovascular mortality, the incidence of sudden cardiac death (SCD) continues to rise. Patients who survive a myocardial infarction (MI) with depressed ejection fraction are at particularly high risk for SCD. The development of implantable cardioverter-defibrillators (ICDs) has revolutionized SCD prevention; however, despite the current fervor for device implantation, many unresolved questions remain about risk stratification in post-MI patients. This review presents the current indications and timing of ICD implantation for primary and secondary prevention of SCD after MI. Several conventional and investigational methods of risk stratification after MI, as well as current controversies regarding device implantation in specific patient populations, are also reviewed.


The hierarchical structure of DSM-5 pathological personality traits.
A multidimensional trait system has been proposed for representing personality disorder (PD) features in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to address problematic classification issues such as comorbidity. In this model, which may also assist in providing scaffolding for the underlying structure of major forms of psychopathology more generally, 25 primary traits are organized by 5 higher order dimensions: Negative Affect, Detachment, Antagonism, Disinhibition, and Psychoticism. We examined (a) the generalizability of the structure proposed for DSM-5 PD traits, and (b) the potential for an integrative hierarchy based upon DSM-5 PD traits to represent the dimensions scaffolding psychopathology more generally. A large sample of student participants (N = 2,461) completed the Personality Inventory for DSM-5, which operationalizes the DSM-5 traits. Exploratory factor analysis replicated the initially reported 5-factor structure, as indicated by high factor congruencies. The 2-, 3-, and 4-factor solutions estimated in the hierarchy of the DSM-5 traits bear close resemblance to existing models of common mental disorders, temperament, and personality pathology. Thus, beyond the description of individual differences in personality disorder, the trait dimensions might provide a framework for the metastructure of psychopathology in the DSM-5 and the integration of a number of ostensibly competing models of personality trait covariation.


ALK-negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects--a review.
Anaplastic large cell lymphoma (ALCL) can be divided into two major groups. The first is a spectrum of CD30+ T-cell lymphoproliferative disorders including primary cutaneous ALCL and lymphomatoid papulosis, usually affecting older patients but characterized by an excellent prognosis. The second is systemic nodal ALCL, which on the basis of genetic and immunophenotypic features combined with clinical parameters can be divided into two subgroups: anaplastic lymphoma kinase (ALK)-positive and ALK-negative systemic ALCL. ALK expression, usually the result of a t(2;5) translocation, correlates with the expression of other markers such as EMA and a cytotoxic phenotype, and is strongly related to younger age groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK-negative ALCL, however, shows a more heterogeneous immunophenotype and clinical behaviour, and prognostic parameters are needed to determine treatment strategies in individual patients. Besides clinical parameters included in the IPI, recent studies have pointed out several biological prognosticators of potential value, such as the percentage of tumour-infiltrating activated cytotoxic T-lymphocytes. The expression of proteins involved in the execution or regulation of apoptosis, such as activated caspase 3, Bcl-2, and PI9, was also found to be strongly related to clinical outcome. These studies indicate that inhibition of the apoptosis cascade in particular is an important mechanism that can explain the poor clinical outcome in therapy refractory ALCL. Functional studies are required to investigate whether disruption of one or more of the apoptosis pathways is the major factor in the fatal outcome of the disease and whether apoptosis resistance based on inhibition of one pathway can be overcome by activating another pathway that is still intact.


Maternal stress and family quality of life in response to raising a child with autism: from preschool to adolescence.
While the impact of raising a child with an Autism Spectrum Disorder (ASD) is well documented, with mothers reporting higher levels of stress than mothers of children with other disabilities, positive maternal outcomes have also been identified. What remains unclear, however, is the role of child age on maternal outcomes. We sought to clarify the role of child age in maternal stress and family quality of life (FQoL) in mothers raising a child with ASD. Participants included 140 mothers of children aged 3-16 years grouped to represent four key stages of childhood (preschool, early school years, middle school, early high school). Using a cross-sectional design, mothers completed questionnaires assessing potential risk (e.g., child problem behaviour, symptom severity) and protective (e.g., family characteristics) factors attributed to maternal outcomes. The results revealed significant age related group differences in child internalising behaviour and ASD symptomatology between the early and middle school years. Lower levels of adaptive social behaviour in older age groups were also found. Although mothers of older children reported significantly less support from professionals than mothers of younger children, no significant age effects were found to contribute to maternal reports of stress or FQoL. The current findings support the view that mothers appear to demonstrate stable levels of stress and FQoL despite fluctuations in key child variables and a reduction in supports, across age, highlighting the ongoing nature of maternal needs and heightened levels of child symptomatology during adolescence.


[Determination of gene Est-6 expression in the genitalia of Drosophila melanogaster males].
To determine the time of the appearance of cells capable of subsequent synthesis of esterase-6, genital imaginal discs extracted from male larvae of different instars were transplanted in female larvae just before pupation. An analysis of the esterase activity in transplants has shown that cells in which esterase-6 is to be synthesized appear 8-10 hrs after the beginning of the 3rd larval instar, i.e. long before the differentiation starts. The relations between the determination of the gene Est-6 expression and its transcription and translation were assessed by studying the effect of the inhibitors of RNA (actinomycin D) and protein synthesis (cycloheximide). It has been demonstrated that the transcription and translation of the gene Est-6 take place after metamorphosis during the first hours after emergence of imago. There exists, thus, a large interval between the appearance of cells capable of esterase synthesis and the time of expression of the structural gene controlling this enzyme. The data obtained suggest that cell determination may not be due to the accumulation of "long-living" templates (mRNA).


Immune tolerance induction in patients with IgA anaphylactoid reactions following long-term intravenous IgG treatment.
To date, there is very little information regarding the pathomechanism of IgA anaphylactoid reactions and the management of affected patients. Five adult patients with common variable immunodeficiency (CVID) and a history of anaphylactic reactions due to the administration of immunoglobulin preparations were studied. The activity of anti-IgA was determined by the gel agglutination technique using IgA-coated beads. Antibodies to IgA were detected in the serum of all five patients. Initially, IgA 'depleted' intravenous (i.v.) IgG preparations were infused carefully into the patients until the activity of anti-IgA was decreased significantly or became undetectable. Subsequently, unselected i.v. IgG preparations were infused, and the activity of anti-IgA was abolished in all cases. Intravenous IgG long-term administration results in tolerance induction in patients with IgA anaphylactoid reactions. This tolerance appears to be related to antibody blockage in the circulation and an inhibition of antibody production. Most importantly, IgA appears to play an important role in the treatment of CVID. Patients with IgA anaphylactoid reactions can be treated safely with IgA containing i.v. IgG preparations following tolerance induction.


Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation.
The NLRP3 inflammasome is activated by a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K+ concentration is a minimal upstream signal to most of the NLRP3 activation models. Here, we found that cellular K+ efflux induces a stable structural change in the inactive NLRP3, promoting an open conformation as a step preceding activation. This conformational change is facilitated by the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker also facilitates the ensemble of NLRP3PYD into a seed structure for ASC oligomerization. The introduction of the NLRP3 PYD-linker-FISNA sequence into NLRP6 resulted in a chimeric receptor able to be activated by K+ efflux–specific NLRP3 activators and promoted an in vivo inflammatory response to uric acid crystals. Our results establish that the amino-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.


Determinants of Excessive Reassurance-Seeking: Adolescents' Internalized Distress, Friendship Conflict, and Inhibitory Control as Prospective Predictors.
Substantial research suggests that excessive reassurance-seeking behavior is associated with exacerbations in depressive symptoms and later interpersonal rejection, yet remarkably few studies have examined predictors of this maladaptive social behavior. This study proposed and examined a diathesis stress model suggesting that beyond the effects of prior internalized distress, a combination of poor inhibitory control and dyadic friendship conflict may be especially relevant predictors of adolescents' excessive reassurance-seeking behavior. Longitudinal associations were examined in a sample of 865 adolescents (54.5% female, 22.2% African American, 23.1% Latinx) who completed self-reported measures of depressive rumination/intrusive thoughts, depressive symptoms, loneliness, friendship conflict, and a performance-based measure of inhibitory control at baseline, as well as a measure of excessive reassurance-seeking at baseline and 2 years later. Results initially revealed a prospective effect of depressive rumination/intrusive thoughts on later excessive reassurance-seeking, consistent with prior work. Final results yielded only a significant interaction effect, revealing that higher levels of friendship conflict coupled with low levels of inhibitory control were associated longitudinally with higher levels of excessive reassurance-seeking. Findings suggest that inhibitory control may moderate the association between adolescents' interpersonal conflict and their excessive reassurance-seeking.


Pediatricians' perspectives regarding community child health: training, involvement, and expectations according to age.
There are increasing opportunities for pediatricians to promote children's health through community involvement during and after residency training. Little is known about whether younger relative to established pediatricians have different experiences regarding community activities. In this study we examined whether pediatricians' training, perspectives, and involvement in community activities vary by age. Eight hundred seventy-six pediatricians participated in a national, random-sample, mailed periodic survey of US members of the American Academy of Pediatrics in 2004 (response rate: 58%). Chi2 statistics and median tests were used to measure associations of age (< or = 34, 35-39, 40-50, and > or = 51 years) with training, perspectives, and involvement. Younger pediatricians reported more training in community child health during and before residency but were less likely to be involved currently (37.9% for < or = 34 years, 44.4% for 35-39 years, 46.2% for 40-50 years, 48.3% for > or = 51 years). They were more likely to report that their current involvement was too little versus just right or too much (81.3%, 73.5%, 60.7%, and 47.1%, respectively). Younger pediatricians were more willing to spend > or = 1 hour/month on community child health activities (95.0%, 91.2%, 89.7%, and 85.4%, respectively). Younger versus older pediatricians were more likely to sense moderate or greater responsibility for improving children's health in their community (83.6%, 77.2%, 76.7%, and 70.2%, respectively) and expected their community work to increase during the next 5 years (80.0%, 67.5%, 59.7%, and 40.1%, respectively). Age findings persisted when adjusted for gender. Although practice constraints may limit community involvement, younger pediatricians anticipated growing participation in community activities. Longitudinal studies are needed to determine whether such expectations are realized.


Speech and language development in a parent-infant total communication program.
In the program described, the use of total communication (TC) did not impede speech development in preschool deaf children. Evidence indicates that sign language facilitated the young hearing-impaired child's acquisition of communicative oral speech. Exposure to sign language combined with speech enhanced the meaningfulness of residual hearing and lipreading. Milestones in sign language acquisition paralleled the milestones of spoken language. Young hearing-impaired TC children appeared to learn and express more language at an earlier age than is typical of orally trained hearing-impaired children. This implies that their cognition may not be as severely inhibited because their language acquisition is less severely delayed. This should have favorable consequences for later educational and social development. The families In the TC program were able to normalize their child-rearing activities and relationships.


Isolation and characterization of Heat Shock Protein 100-Batu1 from Toxoplasma gondii RH strain.
Toxoplasma gondii is an intracellular parasitic protozoon which infects human and most warm-blooded animals. Almost one-third of the world's population is affected by life-threatening infection of T. gondii tachyzoites form. Slow growing, transmissible and encysted bradyzoites forms are composed after tachyzoites stage. Cellular and environmental stresses induce conversion of tachyzoites from bradyzoites and this condition is associated with Heat Shock Protein (Hsps) family. Hsp100 is a member of this protein family, and coordinates to disassemble protein aggregates with Hsp70 and Hsp40 in an ATP dependent manner. Several proteins are involved during this stage differentiation and Hsp100 may help them to be in their native soluble form to perform their function as observed in other organisms. For this purpose, Hsp100-Batu1 was isolated from T. gondii RH strain to characterize its biochemical properties in this current study. Hsp100 proteins play a role in survival and virulence of pathogens as shown in the literature. Therefore, manipulation of protein-protein interaction may perturb T. gondii infection and impair conversion to tachyzoites by inhibiting Hsp100 function. Therefore, results of this work present a potential route for vaccination or immunotherapy.


Use of complementary and alternative medicine therapies in the province of Coronel Portillo, Ucayali, Peru.
A cross-sectional study was carried out to evaluate the use of complementary and alternative medicine (CAM) therapies and the factors associated with it, in the province of Coronel Portillo (Ucayali) during 2013. A total of 917 surveys were carried out among household heads in three districts of the province (Callería, Manantay and Yarinacocha), in which the proportion of CAM use was calculated and the relationship with sociodemographic variables (age, sex, educational level, marital status, occupation and income) was analyzed. From the total, 179 respondents (19.5%) mentioned that they used CAM in the last 12 months. A statistically significant relationship was found between the use of CAM therapies and educational level (p < 0.001), respondent's occupation (p < 0.001) and monthly income (p < 0.001). Future research will define the found associations and the variables involved.


Evidence that high activity of vacuolar invertase is required for cotton fiber and Arabidopsis root elongation through osmotic dependent and independent pathways, respectively.
Vacuolar invertase (VIN) has long been considered as a major player in cell expansion. However, direct evidence for this view is lacking due, in part, to the complexity of multicellular plant tissues. Here, we used cotton (Gossypium spp.) fibers, fast-growing single-celled seed trichomes, to address this issue. VIN activity in elongating fibers was approximately 4-6-fold higher than that in leaves, stems, and roots. It was undetectable in fiberless cotton seed epidermis but became evident in initiating fibers and remained high during their fast elongation and dropped when elongation slowed. Furthermore, a genotype with faster fiber elongation had significantly higher fiber VIN activity and hexose levels than a slow-elongating genotype. By contrast, cell wall or cytoplasmic invertase activities did not show correlation with fiber elongation. To unravel the molecular basis of VIN-mediated fiber elongation, we cloned GhVIN1, which displayed VIN sequence features and localized to the vacuole. Once introduced to Arabidopsis (Arabidopsis thaliana), GhVIN1 complemented the short-root phenotype of a VIN T-DNA mutant and enhanced the elongation of root cells in the wild type. This demonstrates that GhVIN1 functions as VIN in vivo. In cotton fiber, GhVIN1 expression level matched closely with VIN activity and fiber elongation rate. Indeed, transformation of cotton fiber with GhVIN1 RNA interference or overexpression constructs reduced or enhanced fiber elongation, respectively. Together, these analyses provide evidence on the role of VIN in cotton fiber elongation mediated by GhVIN1. Based on the relative contributions of sugars to sap osmolality in cotton fiber and Arabidopsis root, we conclude that VIN regulates their elongation in an osmotic dependent and independent manner, respectively.


Rationale, design and methods for a community-based study of clustering and cumulative effects of chronic disease processes and their effects on ageing: the Busselton healthy ageing study.
The global trend of increased life expectancy and increased prevalence of chronic and degenerative diseases will impact on health systems. To identify effective intervention and prevention strategies, greater understanding of the risk factors for and cumulative effects of chronic disease processes and their effects on function and quality of life is needed.The Busselton Healthy Ageing Study aims to enhance understanding of ageing by relating the clustering and interactions of common chronic conditions in adults to function. Longitudinal (3-5 yearly) follow-up is planned. Phase I (recruitment) is a cross-sectional community-based prospective cohort study involving up to 4,000 'Baby Boomers' (born from 1946 to 1964) living in the Busselton Shire, Western Australia. The study protocol involves a detailed, self-administered health and risk factor questionnaire and a range of physical assessments including body composition and bone density measurements, cardiovascular profiling (blood pressure, ECG and brachial pulse wave velocity), retinal photography, tonometry, auto-refraction, spirometry and bronchodilator responsiveness, skin allergy prick tests, sleep apnoea screening, tympanometry and audiometry, grip strength, mobility, balance and leg extensor strength. Cognitive function and reserve, semantic memory, and pre-morbid intelligence are assessed. Participants provide a fasting blood sample for assessment of lipids, blood glucose, C-reactive protein and renal and liver function, and RNA, DNA and serum are stored. Clinically relevant results are provided to all participants. The prevalence of risk factors, symptoms and diagnosed illness will be calculated and the burden of illness will be estimated based on the observed relationships and clustering of symptoms and illness within individuals. Risk factors for combinations of illness will be compared with those for single illnesses and the relation of combinations of illness and symptoms to cognitive and physical function will be estimated. This study will enable a thorough characterization of multiple disease processes and their risk factors within a community-based sample of individuals to determine their singular, interactive and cumulative effects on ageing. The project will provide novel cross-sectional data and establish a cohort that will be used for longitudinal analyses of the genetic, lifestyle and environmental factors that determine whether an individual ages well or with impairment.


Acute and moderate-term creatine monohydrate supplementation does not affect creatine transporter mRNA or protein content in either young or elderly humans.
Animal studies have shown that supra-physiological creatine monohydrate (Cr-mH) supplementation for 3 months reduced skeletal muscle creatine transporter (CRT) content. The doses of Cr-mH (1-2 g/kg/day) used in these studies were between 5 and 10 times those usually used in human studies, and it is unclear whether a down-regulation of CRT would occur in humans at the recommended doses of 0.1-0.2 g/kg/day. We measured CRT, and citrate synthase (CS) protein content using Western blotting before and after 2 months of Cr-mH supplementation and weight training in young men (N = 11 Cr-mH (0.125 g/kg/ day); N = 8 placebo). CRT and CS were also measured before and after 4 months of Cr-mH supplementation and weight training in elderly (> 65 years) men and women (N = 14 Cr-mH (0.075 g/kg/day); N = 14 placebo). Finally, CRT mRNA was measured using competitive RT-PCR before and after 8-9 days of Cr-mH loading in young men and women (N = 14, CR-mH (mean = 0.18 g/kg/day); N = 13, PL). Total creatine content was significantly elevated after the Cr-mH supplementation period as compared to placebo in each of the studies. Neither Cr-mH supplementation, nor exercise training resulted in measurable alterations in CRT protein content and acute Cr-mH loading did not alter CRT mRNA. There were no gender differences in CRT mRNA or total creatine content in the young subjects and no gender differences in total creatine content or CRT protein content in the elderly subjects. Weight training in young men did not increase CS protein content, however, in the elderly there was a significant increase in CS protein content after exercise training (p < 0.05). These results demonstrated that Cr-mH supplementation during weight training resulted in increases in skeletal muscle total creatine without reductions in CRT protein and acute Cr-mH loading did not decrease CRT mRNA content.


[Factors in rat liver cytosol, inhibiting chemiluminescence during nonenzymatic lipid peroxidation].
The effect of normal rat liver cytosol on the level of Fe/ADP-ascorbate-induced lipid peroxidation in the total particulate fraction (mitochondria plus microsomes) has been studied. The intensity of lipid peroxidation was measured using the chemiluminescence technique and by malonic dialdehyde (MDA) production. Dialyzed cytosol significantly decreased the level of chemiluminescence and, to a much lesser extent, the rate of MDA production. Gel filtration on a Sephadex G-200 column led to the appearance of at least three cytosolic fractions which suppressed the low-level chemiluminescence. These fractions differed from one another by their molecular masses, kinetics of chemiluminescence inhibition and effects on the intensity of MDA production. The putative functional role of antioxidative defence factors from rat liver cytosol is discussed.


Control of synaptic function by endocannabinoid-mediated retrograde signaling.
Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.


Project Medishare: a volunteer program in international health at the University of Miami.
Most U.S. medical schools have programs in international health, but there is a need to find ways to make students (particularly those with little clinical experience) more effective volunteers in international settings. The Department of Family Medicine at the University of Miami School of Medicine developed a program to help prepare students for international work and to ensure that the work they do makes a difference. Over the past four years, this program, Project Medishare, has sent groups of students to Haiti to conduct health fairs. Students prepare all year for their voluntary trips, which take place during the spring and summer breaks; they learn about Haiti's history, culture, language, and health problems. They also raise funds and donations of medicine and supplies. The health fairs, which are one-day events in orphanages and villages, emphasize patient education and preventive medicine. The success of the fairs is evaluated using testimonials from Haitian officials and patients, students' journals, and data collected by the students. Factors critical to Project Medishare's success include (1) having a "critical mass" of culturally and linguistically competent students and faculty; (2) collaboration with local authorities and providers; (3) advance preparation; and (4) using lessons learned from each event to improve the next.


Protease activity, self interaction, and small interfering RNA binding of the silencing suppressor p1b from cucumber vein yellowing ipomovirus.
The RNA silencing pathway mediated by small interfering RNAs (siRNAs) plays an important antiviral role in eukaryotes. To counteract this defense barrier, a large number of plant viruses express proteins with RNA silencing suppression activity. Recently, it was reported that the ipomovirus Cucumber vein yellowing virus (CVYV), which lacks the typical silencing suppressor of members of the family Potyviridae, i.e., HCPro, has a duplicated P1 coding sequence and that the downstream P1 copy, named P1b, has silencing suppression activity. In this study, we provide experimental evidence that P1b is a serine protease that self-cleaves at its C terminus but that its proteolytic activity is not essential for silencing suppression. In contrast, a putative zinc finger and a conserved basic motif in the N-terminal region of the protein are required for efficient silencing suppression. In vitro gel filtration-fast protein liquid chromatography and in vivo bimolecular fluorescence complementation assays showed that P1b binds itself to form oligomeric structures and that the zinc finger-like motif is essential for the self interaction. Moreover, we observed that CVYV P1b forms complexes with synthetic siRNAs, and this ability correlated with both silencing suppression activity and enhancement of Potato virus X pathogenicity in a mutational analysis. Together, these results suggest that CVYV P1b resembles potyviral HCPro and other viral proteins in interfering RNA silencing by preventing siRNA loading into the RNA-induced silencing complex.


High calcium bioglass enhances differentiation and survival of endothelial progenitor cells, inducing early vascularization in critical size bone defects.
Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with β-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n = 12). Controls (n = 6) received BG40 and the treatment group (n = 6) received BG40 seeded with 5×10(5) rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca(2+) release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects.


Spatial distribution of phlebotomine sand flies in the Aydin Mountains and surroundings: the main focus of cutaneous leishmaniasis in western Turkey.
An entomological survey was conducted to determine the spatial distribution of phlebotomine fauna and understand the effect of environmental factors. The entomological survey was carried out during 2006-2007 in a study area in the rural area of Aydin province, near the Kusadasi town where VL, CL, and canine leishmaniasis (CanL) are endemic. In 2006 and 2007, 132 locations were sampled using sticky traps mainly on embankments. Detailed environmental and meteorological information was also collected for each location. The results of entomological studies indicated that the probable vectors are Phlebotomus tobbi and P. neglectus for VL and CanL, and P. similis for CL in this western leishmaniasis focus. The data revealed a correlation between their presence and spatial variables such as altitude, sampling site location, and humidity. The distribution areas of probable vector species in this study area allowed the identification of risk levels, which may provide useful information to guide the leishmaniasis research in endemic regions.


Defining an appropriate leucoreduction strategy by serial assessment of cytokine levels in platelet concentrates prepared by different methods.
Different methods of platelet concentrate preparations leave behind certain number of residual leukocytes, accounting for most of the febrile nonhemolytic transfusion reactions, especially in multitransfused patients. Various inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 are generated during storage and have been implicated for these adverse effects. We have studied the levels of these cytokines and their correlation with leucocyte contents in platelet concentrates prepared by three different methods. Five pools of platelet rich plasma platelet concentrates (PRP-PC) and buffy-coat platelet concentrates (BC-PC) each were prepared and divided into two halves. One half of the pool was leucofiltered (LF), whereas the other half was stored as such. Ten apheresis units were also included in the study. All the platelet concentrates were assessed for leucocyte load and cytokine content (IL-1β, IL-6, and TNF-α) on different days of storage (0, 3, and 5) using Nageotte chamber and commercially available immunoassays respectively. There was a statistically significant rise in cytokine levels (IL-1β, IL-6, and TNF-α) in nonleucofiltered (NLF) random donor platelet concentrates (RDPs) (PRP-PC and BC-PC) during storage (day 3 and 5) whereas LF RDP concentrates (PRP-PC and BC-PC) and apheresis platelet concentrates (AP-PC) did not show any significant rise in cytokine levels (on day 3 and 5) over the baseline values at day 0. This data suggests that although AP-PCs are superior to PRP-PC (NLF) and BC-PC (NLF) in terms of in vitro quality control parameters and cytokine generation during storage, BC-PC mode of platelet preparation followed by leucofiltration is the best method to store platelets and minimise the cytokine accumulation. This strategy is best suited for transfusion in multitransfused hematooncologic patients, who cannot afford single donor apheresis platelets.


Neural activations associated with feedback and retrieval success.
There is substantial behavioral evidence for a phenomenon commonly called "the testing effect", i.e. superior memory performance after repeated testing compared to re-study of to-be-learned materials. However, considerably less is known about the underlying neuro-cognitive processes that are involved in the initial testing phase, and thus underlies the actual testing effect. Here, we investigated functional brain activity related to test-enhanced learning with feedback. Subjects learned foreign vocabulary across three consecutive tests with correct-answer feedback. Functional brain-activity responses were analyzed in relation to retrieval and feedback events, respectively. Results revealed up-regulated activity in fronto-striatal regions during the first successful retrieval, followed by a marked reduction in activity as a function of improved learning. Whereas feedback improved behavioral performance across consecutive tests, feedback had a negligable role after the first successful retrieval for functional brain-activity modulations. It is suggested that the beneficial effects of test-enhanced learning is regulated by feedback-induced updating of memory representations, mediated via the striatum, that might underlie the stabilization of memory commonly seen in behavioral studies of the testing effect.


The Fluoride Anion-Catalyzed Sulfurization of Thioketones with Elemental Sulfur Leading to Sulfur-Rich Heterocycles: First Sulfurization of Thiochalcones.
Fluoride anion was demonstrated as a superior activator of elemental sulfur (S8) to perform sulfurization of thioketones leading to diverse sulfur-rich heterocycles. Due to solubility problems, reactions must be carried out either in THF using tetrabutylammonium fluoride (TBAF) or in DMF using cesium fluoride (CsF), respectively. The reactive sulfurizing reagents are in situ generated, nucleophilic fluoropolysulfide anions FS(8-x)-, which react with the C=S bond according to the carbophilic addition mode. Dithiiranes formed thereby, existing in an equilibrium with the ring-opened form (diradicals/zwitterions) are key-intermediates, which undergo either a step-wise dimerization to afford 1,2,4,5-tetrathianes or an intramolecular insertion, leading in the case of thioxo derivatives of 2,2,4,4-tetramethylcyclobutane-1,3-dione to ring enlarged products. In reactions catalyzed by TBAF, water bounded to fluoride anion via H-bridges and forming thereby its stable hydrates is involved in secondary reactions leading, e.g., in the case of 2,2,4,4-tetramethyl-3-thioxocyclobutanone to the formation of some unexpected products such as the ring enlarged dithiolactone and ring-opened dithiocarboxylate. In contrast to thioketones, the fluoride anion catalyzed sulfurization of their α,β-unsaturated analogues, i.e., thiochalcones is slow and inefficient. However, an alternative protocol with triphenylphosphine (PPh3) applied as a catalyst, offers an attractive approach to the synthesis of 3H-1,2-dithioles via 1,5-dipolar electrocyclization of the in situ-generated α,β-unsaturated thiocabonyl S-sulfides. All reactions occur under mild conditions and can be considered as attractive methods for the preparation of sulfur rich heterocycles with diverse ring-size.


Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials.
Several studies suggest that neuraminidase inhibitors (NIs) can reduce the duration of influenza symptoms. However, data regarding their effectiveness in reducing influenza complications are scarce. We evaluated the effectiveness of NIs in reducing influenza complications and mortality of patients with seasonal influenza, by performing a meta-analysis of randomized controlled trials (RCTs), retrieved from PubMed, Cochrane Central Register of Controlled Trials and Scopus databases, comparing NIs with placebo. Eleven RCTs (10 double-blind) were included; 8 involved adults/adolescents. In total, 5315 patients were included; 3491 (65.7%) with confirmed infection. Total influenza-related complications were significantly less likely in otherwise healthy patients with confirmed influenza infection that were treated with NIs versus placebo [7 RCTs, 2621 patients, risk ratio (RR) = 0.74, 95% confidence interval (CI) = 0.58-0.95] This finding was more pronounced in high-risk patients [4 RCTs, 475 patients, RR = 0.37, 95% CI = 0.24-0.59]; P < 0.01 for the chi(2) test for subgroup differences. In the comparisons regarding individual complications, a trend in favour of NIs was observed. Acute otitis media was significantly less likely in patients with confirmed influenza infection treated with NIs versus placebo (3 RCTs, 1124 patients, RR = 0.50, 95% CI = 0.30-0.85). No differences were found in the comparisons regarding the safety outcomes. No deaths were observed in trials that reported on mortality. NIs seem to be effective in reducing total influenza-related complications in otherwise healthy and high-risk patients, and have an acceptable safety profile. However, RCTs providing separate data for mild to serious complications and detailed reporting of adverse events and mortality are needed.


Physical health concerns of the patient, the family and the carer.
Physical health monitoring is crucial in the light of current knowledge about the risks associated with schizophrenia and its treatment. Cooperation between psychiatrists, patients and informal carers can significantly enhance patient wellbeing in this regard. Moreover, an advocacy approach elevates patients from being passive recipients of care to active participants in an integrated system that has outcome benefits for all stakeholders. Considerable progress is being made in this regard, although there is still a long way to go to maximise the benefits of carer involvement in the global management of schizophrenia.


Crossing CTOs-the tips, tricks, and specialist kit that can mean the difference between success and failure.
Percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) remains one of the major challenges in interventional cardiology. The appropriate use of the rapidly increasing range of tools available to interventional cardiologists is bringing more and more CTOs into the 'treatable' category. The bar has now been raised to 80% success rates by some expert operators around the world, which, in our view, cannot be achieved without a thorough understanding of technique and technical know-how. CTO procedures are increasingly becoming a sub-specialist field within interventional cardiology and we would encourage centers to consider appointing 'super-specialists' who are able to concentrate experience and expertise in this area. In this paper we detail the principal characteristics of the over the wire balloons, microcatheters and guidewires at present available, the most popular and recent of which are listed in Table 1 and 2. The knowledge and the specific choice of these materials and the criteria for selection of your guidewire or microcatheter can mean the difference between success and failure. Moreover, we discuss on the most important and groundbreaking techniques to approach a CTO. Finally, considering the greater risk of coronary perforation related to a CTO procedure compared to routine PCI, we describe which are best strategy and devices for treating coronary perforations and other major complications.


CT-guided piriformis muscle injection for the treatment of piriformis syndrome.
Piriformis syndrome is a rare neuromuscular disorder that occurs when the piriformis muscle compresses or irritates the sciatic nerve. The treatment of piriformis syndrome includes injections into the piriformis muscle around the sciatic nerve. These invasive approaches have been used with various techniques to increase the safety of the procedure. Computed tomography (CT)-guided injection of the piriformis muscle and the clinical outcome of the patients are discussed. The authors presented 10 consecutive patients that underwent CT-guided piriformis injection between March and December 2007. Three patients had a history of a severe fall on the buttocks, one had gluteal abscess formation following deep intramuscular injection, and another one had a habit of prolonged sitting on the carpet. Etiology was not identified in the other patients. Main complaints of the patients were pain and numbness in the legs. Hypesthesia was the major neurological finding. Magnetic resonance imaging (MRI) and electromyography (EMG) were performed in all patients. Nine patients had full and sustained recovery of their symptoms after piriformis injection. Only the patient who had gluteal abscess formation following deep intramuscular injection showed moderate improvement. Another patient was operated on in the 6th month after piriformis injection due to an extruded disc herniation. CT-guided piriformis injection is a safe and effective method in the treatment of piriformis syndrome.


Improving syphilis screening in deceased organ donors.
Current U.S. policy requires screening of all deceased organ donors for syphilis infection. To date, information on syphilis test performance in this population is limited. All donors with a positive rapid plasma reagin (RPR) and matched donors with negative RPR who were evaluated by one organ procurement organization from January 1, 2000, to September 30, 2012, were retrospectively tested, using retained, residual serum, with two alternate RPR tests and four treponemal-specific tests: A fluorescent treponemal antibody absorption test, a microhemagglutination test, a chemiluminescence immunoassay (CLIA), and a Treponema pallidum particle agglutination (TP-PA) test. Thirty-two of 3,555 (0.9%) potential deceased organ donors screened during the study period showed a positive RPR; 61 RPR-negative matched donor samples were studied as well. Thirteen (40.6%) of the RPR-positive donors were found to be false-positive based on confirmatory TP-PA. As compared to TP-PA, the sensitivity of the fluorescent treponemal antibody absorption, microhemagglutination, and CLIA was 87.5%, 91.7% and 100%, respectively. The CLIA and TP-PA results were 100% concordant. Only 17 (53.1%) of the RPR-positive donors had a total of 46 organs recovered for transplantation. Current screening of deceased organ donors by RPR yields a significant number of false-positive results. Use of alternative tests or the routine use of confirmatory tests may reduce the frequency of false-positive results in deceased organ donors.


Advancement in protein inference from shotgun proteomics using peptide detectability.
A major challenge in shotgun proteomics has been the assignment of identified peptides to the proteins from which they originate, referred to as the protein inference problem. Redundant and homologous protein sequences present a challenge in being correctly identified, as a set of peptides may in many cases represent multiple proteins. One simple solution to this problem is the assignment of the smallest number of proteins that explains the identified peptides. However, it is not certain that a natural system should be accurately represented using this minimalist approach. In this paper, we propose a reformulation of the protein inference problem by utilizing the recently introduced concept of peptide detectability. We also propose a heuristic algorithm to solve this problem and evaluate its performance on synthetic and real proteomics data. In comparison to a greedy implementation of the minimum protein set algorithm, our solution that incorporates peptide detectability performs favorably.


Altered jejunal potassium (Rb+) transport in piglet rotavirus enteritis.
To determine the mechanisms of K+ loss in viral diarrhea, K+ fluxes (estimated by tracer Rb+ flows) across piglet jejunum in Ussing chambers were determined. Normal jejunum was characterized by an indomethacin-sensitive short-circuit current and a small K+ secretory flow. Rotavirus-infected gut secreted K+ at high rates, probably resulting from increased prostaglandin generation because secretion was abolished by indomethacin. Tissues pretreated with indomethacin responded to 8-bromoadenosine 3',5'-cyclic monophosphate acid and 16,16-dimethyl-prostaglandin E2 with K+ secretion. The secretory response in rotavirus-infected jejunum was no greater than that in normal tissue. Serosal addition of Ca2+ ionophore A23187 caused K+ secretion in normal but not rotavirus-infected jejunum. To inhibit the basolateral uptake of K+ and reduce the driving force for secretion, ouabain was added to the bath. Ouabain unmasked a K+ absorptive process in normal intestine, which was not seen in rotavirus-infected tissue. K+ absorption was inhibited by 3-(cyanomethyl)-2-methyl-8-(phenyl-methoxy)imidazo (1,2 alpha)pyridine (Sch-28080) and omeprazole. We speculate that the high fecal K+ losses observed in human rotavirus enteritis might be caused by an imbalance between K+ secretion and an impaired apical K+ absorptive mechanism in the crypt-type epithelium.


Incorporation of biotinylated SP-A into rat lung surfactant layer, type II cells, and clara cells.
The goal of this study was to compare the functions of Clara and type II cells during alveolar clearance and recycling of surfactant protein (SP) A, a secretory product of both cell types. We examined the incorporation of instilled biotinylated SP-A (bSP-A) into rat lung type II and Clara cells as a measure of clearance and recycling of the protein. Ultrastructural localization of bSP-A was accomplished by an electron-microscopic immunogold technique at 7, 30, and 120 min after intratracheal instillation. Localization of bSP-A was quantitatively evaluated within extracellular surfactant components (lipid-rich forms: myelin figures, vesicles, and tubular myelin; and lipid-poor hypophase) and in compartments of type II and Clara cells. bSP-A was incorporated into myelinic and vesicular forms of extracellular surfactant, but tubular myelin and hypophase had little bSP-A. Lamellar bodies of type II cells demonstrated a significant time-dependent increase in their incorporation of bSP-A. There was a concentration of bSP-A in the secretory granules and mitochondria of Clara cells, but no Clara cell compartment showed a pattern of time-dependent change in immunolabeling. Our immunolabeling data demonstrated a time-dependent movement of exogenous SP-A from extracellular components into type II cells and their secretory granules. Clara cells did not demonstrate a time-dependent incorporation of bSP-A into their secretory granules during the period of this study. If Clara cells recycle SP-A, they must reach a steady state very quickly or very slowly.


Email fraud: The search for psychological predictors of susceptibility.
Decisions that we make about email legitimacy can result in a pernicious threat to security of both individuals and organisations. Yet user response to phishing emails is far from uniform; some respond while others do not. What is the source of this diversity in decision-making? From a psychological perspective, we consider cognitive and situational influences that might explain why certain users are more susceptible than others. Alongside an email judgment task employed as a proxy for fraud susceptibility, 224 participants completed a range of cognitive tasks. In addition, we manipulated time pressure for email legitimacy judgments. We identify cognitive reflection and sensation seeking as significant, albeit modest, predictors of susceptibility. Further to this, participants asked to make quicker responses made more judgment errors. We conclude there are cognitive signatures that partially contribute to email fraud susceptibility, with implications for efforts to limit online security breaches and train secure behaviors.


Genetic inhibition of the atypical kinase Wee1 selectively drives apoptosis of p53 inactive tumor cells.
Tumorigenesis is the result of genomic or epigenomic insults and subsequent loss of the proper mechanisms to respond to these alterations leading to unscheduled growth. Tumors arising from these mutations often have altered cell cycles that offer proliferative advantages and lead to the accumulation of additional mutations that can lead to more aggressive phenotypes. Nevertheless, tumor cells must still adhere to the basic tenets of the cell cycle program to ensure their survival by DNA duplication, chromosomal segregation and cytokinesis. The atypical tyrosine kinase Wee1 plays a key role in regulating the cell cycle at the DNA synthesis and mitotic checkpoints via phosphorylation and subsequent inactivation of cyclin-dependent kinases (CDKs) in both healthy and tumorigenic cells. To assess the role of Wee1 in tumor cell proliferation we performed small interfering RNA (siRNA) experiments in a panel of diverse cell lines derived from various tissue origins. We also tested the hypothesis that any potential effects would be as a result of the kinase activity of Wee1 by siRNA rescue studies with wild-type or kinase-dead versions of Wee1. We find that, in general, cells with wild-type p53 activity are not susceptible to loss of Wee1 protein via siRNA. However, Wee1 siRNA treatment in tumor cells with an inherent loss of p53 activity results in a deregulated cell cycle that causes simultaneous DNA synthesis and premature mitosis and that these effects are kinase dependent. These cumulative effects lead to potent inhibition of cellular proliferation and ultimately caspase-dependent apoptosis in the absence of co-treatment with cytotoxic agents. These results suggest that, while Wee1 acts as a tumor suppressor in the context of normal cell growth and its functional loss can be compensated by p53-dependent DNA damage repairing mechanisms, specific inhibition of Wee1 has deleterious effects on the proliferation and survival of p53 inactive tumors. In total, targeting the atypical kinase Wee1 with an siRNA-based therapeutic or a selective ATP competitive small molecule inhibitor would be a feasible approach to targeting p53 inactive tumors in the clinic.


[Long-term study of anthracycline-induced cardiomyopathy in children and adolescents].
In order to detect changes in cardiac function, electrocardiographic, echocardiographic and radiologic studies were performed in 71 patients (age 1-26 yrs) who had been treated at the University Children's Hospital Berlin because of malignant diseases according to protocols of the DAL/GPO and had received anthracyclines (doxorubicin or daunorubicin) at cumulative doses up to 480 mg/m2 (median 280 mg/m2). Clinically overt cardiomyopathy was observed in one girl and required transient administration of digoxin. In 2 patients echocardiographic changes led to a reduction of the scheduled anthracycline doses. No patient died from congestive heart failure. During treatment, an increase in the cardiothoracic index was observed in 14 children, and in 16 the ECG showed pathological findings. A decrease in contractility to 25% or less as detected by ultrasound was seen in 15 patients. More than 50% of patients developed echocardiographical signs indicating an impairment of myocardial function. However, persistent changes were only found in 1 patient after discontinuation of treatment. Long-term echocardiographic follow-up studies for 4-48 months (median 14 months) after completion of anthracycline therapy were performed in 18 patients and the findings compared to matched-pair controls. The observed M-mode parameters were completely normal, and the ejection fractions calculated from the two-dimensional ultrasound investigations were in the normal range but slightly diminished compared to controls. Cardiac ultrasound is a non-invasive, reproducible and tolerable procedure for early detection of an anthracycline cardiomyopathy. In our patients, time of occurrence and the extent of pathological changes were not associated with the cumulative applied anthracycline doses.(ABSTRACT TRUNCATED AT 250 WORDS)


Occurrence of fibrous sodium aluminumtetrafluoride particles in potrooms of the primary aluminum industry.
Inorganic fibrous particles have been found in the work environment of the primary aluminum industry. Based on scanning electron microscopic analysis, the concentrations ranged from 9 to 720 fibers/cc. The fibers were generally thinner than 0.1 micron in diameter and shorter than 5 microns. By electron microscopy, energy dispersive X-ray microanalysis, and selected area electron diffraction the fibers were identified as sodium aluminumtetrafluoride.


Evaluation of a Mobile Phone-Based Microscope for Screening of Schistosoma haematobium Infection in Rural Ghana.
AbstractSchistosomiasis affects over 170 million people in Africa. Here we compare a novel, low-cost mobile phone microscope to a conventional light microscope for the label-free diagnosis of Schistosoma haematobium infections in a rural Ghanaian school setting. We tested the performance of our handheld microscope using 60 slides that were randomly chosen from an ongoing epidemiologic study in school-aged children. The mobile phone microscope had a sensitivity of 72.1% (95% confidence interval [CI]: 56.1-84.2), specificity of 100% (95% CI: 75.9-100), positive predictive value of 100% (95% CI: 86.3-100), and a negative predictive value of 57.1% (95% CI: 37.4-75.0). With its modest sensitivity and high specificity, this handheld and cost-effective mobile phone-based microscope is a stepping-stone toward developing a powerful tool in clinical and public health settings where there is limited access to conventional laboratory diagnostic support.


Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype.
The gene coding for arylformamidase (Afmid, also known as kynurenine formamidase) was inactivated in mice through the removal of a shared bidirectional promoter region regulating expression of the Afmid and thymidine kinase (Tk) genes. Afmid/Tk -deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system. Afmid-catalyzed hydrolysis of N-formyl-kynurenine is a key step in tryptophan metabolism and biosynthesis of kynurenine-derived products including kynurenic acid, quinolinic acid, nicotinamide, NAD, and NADP. A disruption of these pathways is implicated in neurotoxicity and immunotoxicity. In wild-type (WT) mice, Afmid-specific activity (as measured by formyl-kynurenine hydrolysis) was 2-fold higher in the liver than in the kidney. Formyl-kynurenine hydrolysis was reduced by approximately 50% in mice heterozygous (HZ) for Afmid/Tk and almost completely eliminated in Afmid/Tk knockout (KO) mice. However, there was 13% residual formyl-kynurenine hydrolysis in the kidney of KO mice, suggesting the existence of a formamidase other than Afmid. Liver and kidney levels of nicotinamide plus NAD/NADP remained the same in WT, HZ and KO mice. Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine. Gradual kidney deterioration and subsequent failure in KO mice is consistent with high levels of tissue-specific Afmid expression in the kidney of WT but not KO mice. On this basis, the most significant function of the kynurenine pathway and Afmid in mice may be in eliminating toxic metabolites and to a lesser extent in providing intermediates for other processes.


Breastfeeding progression in late preterm infants from birth to one month.
This study aimed to describe and compare breastfeeding progression, infants' feeding behaviours, maternal feeding difficulties, and mothers' usage of breastfeeding interventions for singleton late preterm (LPT) and term infants. A further aim was to identify associated factors for exclusive breastfeeding at breast at 1 month in LPT infants. This was a cohort study where mothers of LPT infants from a neonatal unit (n = 60), LPT infants from a maternity unit (n = 62), and term infants from a maternity unit (n = 269) answered a questionnaire approximately 1 month after delivery. Findings showed no significant differences in exclusive breastfeeding at breasts between LPT infants admitted to the neonatal unit compared with the maternity unit, during the first week at home (38% vs. 48%), or at 1 month of age (52% vs. 50%). Term infants were more likely to be exclusively breastfed at the breast (86% and 74%, p < 0.05) compared with LPT infants. Multiple regression analysis showed that usage of a nipple shield, not feeding breast milk exclusively during the first week at home, or feeding less than 10 times per day at 1 month were statistically significant for not exclusively breastfeed at the breast. A protective factor was the mothers' experience of having an abundance of milk during the first week at home. In conclusion, LPT infants are less likely to be exclusively breastfed at the breast than term infants, highlighting the need for further research to guide interventions aimed at optimising exclusive breastfeeding rates.


Nocardioides panacihumi sp. nov., isolated from soil of a ginseng field.
A novel bacterial strain designated Gsoil 616(T) was isolated from a soil sample of a ginseng field in Pocheon province (South Korea) and was characterized taxonomically by using a polyphasic approach. The isolate was Gram-positive, strictly aerobic, non-motile, non-spore-forming and rod- or coccoid-shaped. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the genus Nocardioides in the family Nocardioidaceae but was clearly separated from established species of this genus. The 16S rRNA gene sequence similarities between strain Gsoil 616(T) and the type strains of Nocardioides species with validly published names ranged from 91.8 to 96.1 %. The G+C content of the genomic DNA was 73 mol%. Phenotypic and chemotaxonomic data [major menaquinone MK-8(H(4)) and major fatty acid iso-C(16 : 0)] supported the affiliation of strain Gsoil 616(T) to the genus Nocardioides. However, the results of physiological and biochemical tests allowed phenotypic differentiation of the isolate from other Nocardioides species. Therefore, strain Gsoil 616(T) represented a novel species within the genus Nocardioides, for which the name Nocardioides panacihumi sp. nov. is proposed. The type strain is Gsoil 616(T) (=KCTC 19187(T) =DSM 18660(T)).


Elevated cardiac troponin T levels in critically ill patients with sepsis.
It is known that troponin elevations have prognostic importance in critically ill patients. We examined whether cardiac troponin T elevations are independently associated with in-hospital, short-term (30 days), and long-term (3 years) mortality in intensive care unit (ICU) patients admitted with sepsis, severe sepsis, and septic shock after adjusting for the severity of disease with the Acute Physiology, Age and Chronic Health Evaluation III system. We studied the Mayo Clinic's Acute Physiology, Age and Chronic Health Evaluation III database and cardiac troponin T levels from patients admitted consecutively to the medical ICU. Between January 2001 and December 2006, 926 patients with sepsis had cardiac troponin T measured at ICU admission. In-hospital, short-term, and long-term all-cause mortality were determined. Among study patients, 645 (69.7%) had elevated cardiac troponin T levels and 281 (30.3%) had undetectable cardiac troponin T. During hospitalization, 15% of the patients with troponin T <0.01 ng/mL died compared with 31.9% of those with troponin T ≥ 0.01 ng/mL (P < .0001). At 30 days, mortality was 31% and 17% in patients with and without elevations, respectively (P < .0001). The Kaplan-Meier probability of survival at 1-, 2-, and 3-year follow-ups was 68.1%, 56.3%, and 46.8% with troponin T ≥ 0.01 ng/mL, respectively, and 76.4%, 69.1%, and 62.0% with troponin T <0.01 μg/L, respectively (P < .0001). After adjustment for severity of disease and baseline characteristics, cardiac troponin T levels remained associated with in-hospital and short-term mortality but not with long-term mortality. In patients with sepsis who are admitted to an ICU, cardiac troponin T elevations are independently associated with in-hospital and short-term mortality but not long-term mortality.


[Differing aspects of human dignity in intensive medicine].
Human dignity often is used as an ethical category in medical judgement of current medical and intensive care decisions. The short history of the intensive care medicine, however, demonstrates a certain drift in the use of the term "human dignity". Parallel to the more pronounced patient autonomy, articulated in patient testaments, therapeutic decisions of current intensive care medicine individualize therapeutic approaches, instead of preferentially maximizing life span.


Management of COVID-19 in patients after liver transplantation: Beijing working party for liver transplantation.
Annually, around 850 liver transplantation is performed in Beijing, China. Recently, the new coronavirus pneumonia (COVID-19) caused by 2019 novel coronavirus (2019-nCoV) has affected nearly 200 countries worldwide. 2019-nCov can cause severe lung disease, multiple-organ damage, and significant mortalities. Liver transplant recipients, because of long-term oral immunosuppressant effects, may be more susceptible to 2019-nCoV infection and have a worse prognosis than the general population. It is urgent to set up guidelines for the prevention, diagnosis, and treatment of COVID-19 in liver transplant recipients. In this article, we reviewed the clinical aspects of 2019-nCoV infection, characteristics of liver transplant recipients, immunosuppressant usage, and potential drug interactions to provide recommendations to clinical staff managing liver transplant recipients during the COVID-19 epidemic.


Guidance to employers on integrating e-cigarettes/electronic nicotine delivery systems into tobacco worksite policy.
In recent years, new products have entered the marketplace that complicate decisions about tobacco control policies and prevention in the workplace. These products, called electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems, most often deliver nicotine as an aerosol for inhalation, without combustion of tobacco. This new mode of nicotine delivery raises several questions about the safety of the product for the user, the effects of secondhand exposure, how the public use of these products should be handled within tobacco-free and smoke-free air policies, and how their use affects tobacco cessation programs, wellness incentives, and other initiatives to prevent and control tobacco use. In this article, we provide a background on e-cigarettes and then outline key policy recommendations for employers on how the use of these new devices should be managed within worksite tobacco prevention programs and control policies.


Nebulised water as a bronchoconstricting challenge in infancy.
The pulmonary response to inhalation challenge with nebulised distilled water was measured in 100 sedated infants with a history of wheeze. Lung function was measured by total body plethysmography. Satisfactory results were obtained in 88 infants. Fifty one were considered to have responded by developing a greater than 20% decrease in specific conductance (sGaw) after nebulised water. Thirty two of these infants had previously been challenged with nebulised saline before but only one showed a greater than 20% decrease in sGaw after saline. Twenty infants who developed signs of bronchoconstriction after challenge with nebulised water were rechallenged 20 minutes later. After the initial challenge a fall in sGaw of greater than 20% was found in 19 of the 20. After a second challenge with nebulised water only 15 (75%) showed a 20% or greater decrease in sGaw. Nine of the 20 infants remained sedated and were rechallenged for a third time. Eight showed a greater than 20% decrease in sGaw. This study indicates that approximately 60% of infants with a history of wheeze will bronchoconstrict in response to inhaled nebulised water and that up to 75% show no evidence of a subsequent refractory period to inhaled water challenge.


Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia.
The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL.


Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage.
Although cyclin-dependent kinase 2 (Cdk2) controls the G1/S transition and promotes DNA replication, it is dispensable for cell cycle progression due to redundancy with Cdk1. Yet Cdk2 also has non-redundant functions that can be revealed in certain genetic backgrounds and it was reported to promote the G2/M DNA damage response checkpoint in TP53 (p53)-deficient cancer cells. However, in p53-proficient cells subjected to DNA damage, Cdk2 is inactivated by the CDK inhibitor p21. We therefore investigated whether Cdk2 differentially affects checkpoint responses in p53-proficient and deficient cell lines. We show that, independently of p53 status, Cdk2 stimulates the ATR/Chk1 pathway and is required for an efficient DNA replication checkpoint response. In contrast, Cdk2 is not required for a sustained DNA damage response and G2 arrest. Rather, eliminating Cdk2 delays S/G2 progression after DNA damage and accelerates appearance of early markers of cell cycle exit. Notably, Cdk2 knockdown leads to down-regulation of Cdk6, which we show is a non-redundant pRb kinase whose elimination compromises cell cycle progression. Our data reinforce the notion that Cdk2 is a key p21 target in the DNA damage response whose inactivation promotes exit from the cell cycle in G2.


Comparative Evaluation of Efficacy of Platelet-Rich Fibrin and Hank's Balanced Salt Solution as a Storage Medium for Avulsed Teeth: An In Vitro Study.
To compare the efficacy of platelet-rich fibrin (PRF) and Hank's balanced salt solution (HBSS) in the preservation of the periodontal ligament (PDL) cells viability of avulsed teeth. A total of 30 non-carious third molars with healthy periodontium, indicated for extraction for orthodontic reasons or chronic pericoronitis, were selected for the study. Samples were divided into four groups: one standard group and one experimental group in addition to two control groups (positive and negative). The positive and negative control group corresponded to immediate and 2-hour dry time respectively. The experimental teeth were bench dried for 40 minutes and then immersed in one of the two storage media: HBSS (standard storage media) and PRF (experimental storage media) for 45 minutes. The teeth in each group were treated with dispase II and collagenase for 30 minutes and later centrifuged for 4 minutes at 1000 rpm. The supernatant was removed with sterile micropipette, the cells were labeled with 0.4% trypan blue, and the number of viable PDL cells was counted with a hemocytometer under a light microscope. One-way Kruskal-Wallis test and Mann-Whitney U test with Boneferroni correction were used for statistical analysis. Results did not demonstrate any statistically significant differences in the viability of PDL cells between the groups with standard and experimental storage media. Group 1 showed a statistically significant difference of mean compared to Groups 2, 3 and 4. When Group 2 was compared with Groups 3 and 4, a P-value>0.05 suggested no statistical significance. Within the parameters of this study, HBSS and PRF demonstrated a similar number of viable PDL cells. Hence, PRF could be a used as a good substitute of HBSS as a storage media for avulsed teeth.


Species integrity in trees.
From California sequoia, to Australian eucalyptus, to the outstanding diversity of Amazonian forests, trees are fundamental to many processes in ecology and evolution. Trees define the communities that they inhabit, are host to a multiplicity of other organisms and can determine the ecological dynamics of other plants and animals. Trees are also at the heart of major patterns of biodiversity such as the latitudinal gradient of species diversity and thus are important systems for studying the origin of new plant species. Although the role of trees in community assembly and ecological succession is partially understood, the origin of tree diversity remains largely opaque. For instance, the relative importance of differing habitats and phenologies as barriers to hybridization between closely related species is still largely uncharacterized in trees. Consequently, we know very little about the origin of trees species and their integrity. Similarly, studies on the interplay between speciation and tree community assembly are in their infancy and so are studies on how processes like forest maturation modifies the context in which reproductive isolation evolves. In this issue of Molecular Ecology, Lindtke et al. (2014) and Lagache et al. (2014) overcome some traditional difficulties in studying mating systems and sexual isolation in the iconic oaks and poplars, providing novel insights about the integrity of tree species and on how ecology leads to variation in selection on reproductive isolation over time and space.


Soy isoflavones in nutritionally relevant amounts have varied nutrigenomic effects on adipose tissue.
Soy consumption has been suggested to afford protection from cardiovascular disease (CVD). Indeed, accumulated albeit controversial evidence suggests that daily consumption of ≥25 g of soy protein with its associated phytochemicals intact can improve lipid profiles in hypercholesterolemic humans. However, the belief that soy foods and supplements positively impact human health has become increasingly controversial among the general public because of the reported estrogenic activities of soy isoflavones. In this study, we investigated the nutrigenomic actions of soy isoflavones (in nutritionally-relevant amounts) with a specific focus on the adipose tissue, due to its pivotal role in cardiometabolism. Young C57BL/6 mice were maintained for eight weeks under two different diet regimes: (1) purified control diet; or (2) purified control diet supplemented with 0.45 g% soybean dry purified extract (a genistein/daidzein mix). Soy isoflavones increased plasma total cholesterol concentrations and decreased triglyceride ones. Circulating leptin levels was also increased by soy consumption. Differentially expressed genes in adipose tissue were classified according to their role(s) in cellular or metabolic pathways. Our data show that soy isoflavones, administered in nutritionally-relevant amounts, have diverse nutrigenomic effects on adipose tissue. Taking into account the moderate average exposure to such molecules, their impact on cardiovascular health needs to be further investigated to resolve the issue of whether soy consumption does indeed increase or decrease cardiovascular risk.


Locally trained piecewise linear classifiers.
We describe a versatile technique for designing computer algorithms for separating multiple-dimensional data (feature vectors) into two classes. We refer to these algorithms as classifiers. Our classifiers achieve nearly Bayes-minimum error rates while requiring relatively small amounts of memory. Our design procedure finds a set of close-opposed pairs of clusters of data. From these pairs the procedure generates a piecewise-linear approximation of the Bayes-optimum decision surface. A window training procedure on each linear segment of the approximation provides great flexibility of design over a wide range of class densities. The data consumed in the training of each segment are restricted to just those data lying near that segment, which makes possible the construction of efficient data bases for the training process. Interactive simplification of the classifier is facilitated by an adjacency matrix and an incidence matrix. The adjacency matrix describes the interrelationships of the linear segments {£i}. The incidence matrix describes the interrelationships among the polyhedrons formed by the hyperplanes containing {£i}. We exploit switching theory to minimize the decision logic.


Winter-to-summer changes in the composition and single-cell activity of near-surface Arctic prokaryotes.
We collected surface samples in Franklin Bay (Western Arctic) from ice-covered to ice-free conditions, to determine seasonal changes in the identity and in situ activity of the prokaryotic assemblages. Catalysed reported fluorescence in situ hybridization was used to quantify the abundance of different groups, and combined with microautoradiography to determine the fraction of active cells taking up three substrates: glucose, amino acids and ATP. In surface waters, Archaea accounted for 16% of the total cell count in winter, but decreased to almost undetectable levels in summer, when Bacteria made up 97% of the total cell count. Alphaproteobacteria were the most abundant group followed by Bacteroidetes (average of 34% and 14% of total cell counts respectively). Some bacterial groups appearing in low abundances (< 10% of total cell counts), such as Betaproteobacteria, Roseobacter and Gammaproteobacteria, showed a high percentage of active cells. By contrast, more abundant groups, such as SAR11 or Bacteroidetes, had a lower percentage of active cells in the uptake of the substrates tested. Archaea showed low heterotrophic activity throughout the year. In comparison with temperate oceans, the percentage of active Bacteria in the uptake of the substrates was relatively high, even during the winter season.


Culture on a 3,4-dihydroxy-l-phenylalanine-coated surface promotes the osteogenic differentiation of human mesenchymal stem cells.
The culture surface can affect the in vitro differentiation of stem cells. In this study, we investigated whether modifying the culture surface with 3,4-dihydroxy-l-phenylalanine (DOPA), an element of mussel adhesion protein, could enhance the in vitro osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMMSCs). hBMMSCs cultured on DOPA-coated plates exhibited better cell adhesion and spreading compared with noncoated conventional tissue culture plates. The DOPA coated did not affect the apoptosis or viability of the cultured hBMMSCs. Also, hBMMSCs cultured on DOPA-coated plates exhibited a higher degree of osteogenic differentiation than did hBMMSCs cultured on noncoated plates, as evaluated with alkaline phosphate (ALP) activity, calcium content, and the mRNA expression of runt-related transcription factor 2, ALP, and osteocalcin. Further, hBMMSCs cultured on DOPA-coated plates demonstrated a higher capability of ectopic bone formation in vivo following implantation in the subcutaneous space of athymic mice compared with hBMMSCs cultured on noncoated plates, as evaluated with microcomputer topography analysis and histomorphometry. These results indicate that modifying the culture surface with DOPA can enhance the in vitro osteogenic differentiation of hBMMSCs.


Atrial myxoma in a patient with hypertrophic cardiomyopathy.
Atrial myxoma is the most common primary cardiac tumor. Patients with atrial myxoma typically present with obstructive, embolic, or systemic symptoms; asymptomatic presentation is very rare. To our knowledge, isolated association of atrial myxoma with hypertrophic cardiomyopathy has been reported only once in the English-language medical literature. We report the case of an asymptomatic 71-year-old woman with known hypertrophic cardiomyopathy in whom a left atrial mass was incidentally identified on cardiac magnetic resonance images. After surgical excision of the mass and partial excision of the left atrial septum, histopathologic analysis confirmed the diagnosis of atrial myxoma. The patient was placed on preventive implantable cardioverter-defibrillator therapy and remained asymptomatic. The management of asymptomatic cardiac myxoma is a topic of debate, because no reports definitively favor either conservative or surgical measures.


Vulvovaginectomy and neo-urethrostomy for treatment of haemangiosarcoma of the vulva and vagina.
Vulvovaginectomy and neo-urethrostomy were performed in a 9-year-old German shepherd dog following a diagnosis of infiltrative vulvar and vestibulovaginal haemangiosarcoma. The dog was presented for intermittent vulvar haemorrhage over a 3-month period. On examination the vulva and vestibulovagina were distended and firm. Vaginal discharge and fine needle aspiration cytology detected anaplastic cells. Haemangiosarcoma was diagnosed on biopsy. A new urethral opening was created in the floor of the vagina allowing resection of the vulva and caudal vestibulovagina. Urinary continence was preserved and healing was without complications.


Single-sweep laser writing of 3D-waveguide devices.
We report on a method to create multiple waveguides simultaneously in 3D in fused silica. A combination of adaptive beam shaping with femtosecond laser writing is used to write two waveguides with changing separation and depth. The method is based on a programmable phase modulator and a dynamic variation of the phase-pattern during the writing process. The depth difference can be dynamically varied by changing a chirp parameter of the applied phase grating pattern. It can be employed in various photonic devices such as couplers, splitters and interferometers. Here we demonstrate splitters with both outputs ending in different depth.


China's factory floors: an industrial hygienist's view.
Determinants of workplace health and safety in China, including work organization, composition of the workforce, production regimens, lack of independent worker representation, and the status of government regulatory enforcement, are described and analyzed. The findings of reports of nongovernmental organizations and media articles are summarized. Key markers of working conditions in export-sector factories, i.e., accident and safety program compliance rates, chemical and noise exposures, and machine guarding issues, are analyzed. Four factors for improving workplace health and safety are proposed: 1) employer commitment and implementation of effective health and safety programs on a plant level; 2) Chinese government enforcement of regulations; 3) meaningful involvement of workers in plant health and safety programs; and 4) continued involvement of international professionals and "civil society" both to pressure multinational corporations and the Chinese government and to provide technical assistance and resources for building the capacity of employers, workers, and government agencies to improve factory working conditions in the world's fastest growing economy.


Helminths as an alternative therapy for intestinal diseases.
Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity, altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings, such as inflammatory bowel disease (IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies, we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use, but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs, since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease, such as the importance of the specific species of helminths used, appropriate dosing regimens, optimal timing of treatment, the role of host genetics, diet, environment, and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method, especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.


Protection against 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine cytotoxicity and DNA adduct formation in human prostate by glutathione S-transferase P1.
The prostate has been identified as a target for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced carcinogenesis. Humans are exposed to PhIP through ingestion of well-done cooked meats, and there is evidence from epidemiological studies that implicates red meat consumption in prostate carcinogenesis. The alpha and pi class isoforms of glutathione S-transferases (GSTs) have been shown to inhibit adduction of activated PhIP metabolites to DNA in cell-free systems. In humans, silencing of GST pi(GSTP1) through CpG island hypermethylation is found in nearly all prostate carcinomas and is believed to be an early event in prostate carcinogenesis. We hypothesized that suppressed GSTP1 expression in prostate cells would increase their vulnerability to cytotoxicity and DNA adduct formation mediated by activated PhIP metabolites. To test this hypothesis, the human prostate adenocarcinoma cell line, LNCaP, which contains a silenced GSTP1 gene, was genetically modified to constitutively express high levels of GSTP1. Both LNCaP and LNCaP-GSTP1 cells exposed to N-OH-PhIP, but not parent PhIP, for 24 h showed a dose-dependent decrease in cell viability. GSTP1-overexpressing cells had LC50s 30-40% higher than cells transfected with the vector alone. PhIP-DNA adducts isolated from LNCaP-derived cells and primary human prostate tissue cultures exposed to N-OH-PhIP were analyzed by liquid chromatography/electrospray ionization mass spectrometry. Primary cultures of human prostate tissue and LNCaP-GSTP1 cells had approximately 50% lower adduct levels than parental LNCaP and vector control cells. Bioactivation assays using LNCaP cytosols showed that enzymatic activation of N-OH-PhIP to a DNA binding species was dependent on ATP and could be inhibited by recombinant human GSTP1 in the presence of glutathione. This evidence confirms that N-OH-PhIP can be bioactivated to a DNA binding species in human prostate and human prostate-derived cells. These observations provide the basis for using LNCaP and LNCaP-GSTP1 cells as a model system for studying the role of this enzyme in protection against N-OH-PhIP induced DNA damage in prostate carcinogenesis. Loss of GSTP1 expression in human prostate may, therefore, enhance its susceptibility to carcinogenic insult by compounds such as N-OH-PhIP. Conversely, induction of GSTs in early-stage prostate carcinogenesis may be a useful protective strategy.


A distorted circadian clock causes early flowering and temperature-dependent variation in spike development in the Eps-3Am mutant of einkorn wheat.
Viable circadian clocks help organisms to synchronize their development with daily and seasonal changes, thereby providing both evolutionary fitness and advantage from an agricultural perspective. A high-resolution mapping approach combined with mutant analysis revealed a cereal ortholog of Arabidopsis thaliana LUX ARRHYTHMO/PHYTOCLOCK 1 (LUX/PCL1) as a promising candidate for the earliness per se 3 (Eps-3A(m)) locus in einkorn wheat (Triticum monococcum L.). Using delayed fluorescence measurements it was shown that Eps-3A(m) containing einkorn wheat accession KT3-5 had a distorted circadian clock. The hypothesis was subsequently confirmed by performing a time course study on central and output circadian clock genes, which showed arrhythmic transcript patterns in KT3-5 under constant ambient conditions, i.e., constant light and temperature. It was also demonstrated that variation in spikelet number between wild-type and mutants is sensitive to temperature, becoming negligible at 25°. These observations lead us to propose that the distorted clock is causative for both early flowering and variation in spike size and spikelet number, and that having a dysfunctional LUX could have neutral, or even positive, effects in warmer climates. To test the latter hypothesis we ascertained sequence variation of LUX in a range of wheat germplasm. We observed a higher variation in the LUX sequence among accessions coming from the warmer climate and a unique in-frame mutation in early-flowering Chinese T. turgidum cultivar 'Tsing Hua no. 559.' Our results emphasize the importance of the circadian clock in temperate cereals as a promising target for adaptation to new environments.


Evaluation of the psychometric performance of the SCOFF questionnaire in a Mexican young adult sample.
To examine the psychometric performance of the SCOFF, a brief screening instrument for eating disorders (ED). Mexican university applicants (n= 3594, 55.7% female, M age= 18.1 years) completed self-report measures and a health screen. Confirmatory factor analyses revealed one factor for females. However a bifactor model fits better for males and females. Reliability was lower for females (KR20 = .49) than males (KR20 = .59). More females (24.2%) presented risk for ED (SCOFF > 2) than males (11.2%). Nomological validity indicated that risk for ED in young women was associated with demographic (e.g., parental education), psychological (e.g., depression, weight management efficacy), physical (e.g., BMI), and social (e.g., family conflict) indicators in conceptually coherent ways. Fewer variables were significant for males. Although the SCOFF may be a useful ED screen in Mexico, further research must examine its criterion validity, sensitivity, and specificity.