Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected pulmonary embolism.
This clinical policy focuses on critical issues in the evaluation and management of patients with signs or symptoms of pulmonary embolism (PE). A MEDLINE search for clinical trials published from January 1995 through April 2001 was performed using the key words "pulmonary embolus" with limits of "clinical investigations" and "clinical policies." Subcommittee members and expert peer reviewers also supplied articles with direct bearing on the policy. This policy focuses on 2 major areas of current interest and/or controversy: (1) diagnostic: utility of D -dimer, ventilation-perfusion scanning, and spiral computed tomography angiogram in the evaluation of PE; and (2) therapeutic: indications for fibrinolytic therapy. Recommendations for patient management are provided for each 1 of these topics based on strength of evidence (Level A, B, or C). Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies based on preliminary, inconclusive, or conflicting evidence, or based on panel consensus. This guideline is intended for physicians working in emergency departments or chest pain evaluation units.


Does the ultrasonic cleaning medium affect the adhesion of resin cement to feldspathic ceramic?
To evaluate the effect of different cleaning media on the adhesion of resin cement to feldspathic ceramic after etching. The cementation surfaces of ceramic blocks (N = 20, n = 5 per group) were etched with 10% hydrofluoric acid (HF) gel for 20 s and rinsed for 60 s. They were then randomly assigned to 4 groups: G1: air-water spray+drying (control); G2: ultrasonic cleaning in distilled water for 4 min+drying; G3: ultrasonic cleaning in 99.5% acetone for 4 min+drying; G4: ultrasonic cleaning in 70% alcohol for 4 min+drying. The ceramic blocks were silanized and cemented (RelyX ARC) to the composite blocks. Subsequently, the microtensile bond strength test (µTBS) was performed. In addition, EDS analysis was made to assess the elemental composition of the conditioned and cleaned ceramic surfaces. A significantly higher mean µTBS was obtained when specimens had been ultrasonically cleaned in distilled water (G2: 18.8 ± 0.4 MPa) (p < 0.05) compared to other groups (G1: 16.6 ± 0.5; G3: 16.1 ± 0.9; G4: 15.8 ± 1.4) (one-way ANOVA). EDS analysis indicated the presence of F- only in G1. Dissolved precipitates after HF etching were removed by ultrasonic cleaning. Cleaning the HF-etched ceramic surface ultrasonically in distilled water is recommended, instead of rinsing it with air-water spray only.


Differential exercise effects on quality of life and health-related quality of life in older adults: a randomized controlled trial.
Maintaining quality of life (QOL) and physical and mental health status are important outcomes throughout the aging process. Although cross-sectional studies suggest a relationship between global QOL and physical activity, it is unclear whether such a relationship exists as a function of exercise training. We examined the effects of two exercise intervention arms on health-related quality of life (HRQOL) and global QOL. Low-active, older adults (n = 179) were randomly assigned to either a 12-month aerobic walking group or a strengthening and flexibility group. HRQOL and QOL were measured at baseline, 6, and 12 months. There was a significant group by time effect on QOL [F(2,176) = 3.11, p = 0.047, η (2) = 0.03]. There was also a significant overall group by time effect for HRQOL [F(4,174) = 2.46, p = 0.047, η (2) = 0.05], which was explained by the significant group by time interaction for mental health status (p = 0.041, η (2) = 0.02) favoring the walking condition. Further analyses using latent class analysis revealed three classes of individuals with differential patterns of change in QOL and HRQOL across time. These classes reflected no change, declines, and improvements in these constructs across time. Walking appears to enhance the mental aspect of HRQOL and global QOL when compared to a non-aerobic intervention. Additionally, the patterns of change in QOL and HRQOL were not linear over time. Our findings are in contrast to previous reports that these outcomes change a little or not at all in randomized trials.


COLOSTOMY CLOSURE: RISK FACTORS FOR COMPLICATIONS.
: The restoration of intestinal continuity is an elective procedure that is not free of complications; on the contrary, many studies have proven a high level of morbidity and mortality. It is multifactorial, and has factors inherent to the patients and to the surgical technique. : To identify epidemiological features of patients that underwent ostomy closure analyzing the information about the surgical procedure and its arising complications. : It was realized a retrospective analysis of medical records of patients who underwent ostomy closure over a period of seven years (2009-2015). : A total of 39 patients were included, 53.8% male and 46.2% female, with mean age of 52.4 years. Hartmann´s procedure and ileostomy were the mainly reasons for restoration of intestinal continuity, representing together 87%. Termino-terminal anastomosis was performed in 71.8% of cases, by using mainly the manual technique. 25.6% developed complications, highlighting anastomotic leakage; there were three deaths (7.6%). The surgical time, the necessity of ICU and blood transfusion significantly related to post-operative complications. : It was found that the majority of the patients were male, with an average age of 52 years. It was observed that the surgical time, the necessity of blood transfusion and ICU were factors significantly associated with complications.


Translation and psychometric assessment of the Persian version of the Rhodes Index of Nausea, Vomiting and Retching (INVR) scale for the assessment of chemotherapy-induced nausea and vomiting.
No tools are available to assess or measure the experience of chemotherapy-induced nausea and vomiting (CINV) for Persian/Farsi speakers. The purpose of this study is to translate the Rhodes Index of Nausea, Vomiting and Retching (INVR) scale for use with Persian-speaking cancer patients. A sample of 94 cancer patients were recruited from a cancer research centre in Mashhad-Iran. A standard two phase process of scale translation and validation was conducted. In phase I, standard 'forward-backward' translation procedure was used to translate the original version of the INVR questionnaire into Persian. The translated questionnaire was reviewed and revised and a Persian version of the scale was produced. In the second phase, a multiphase instrumentation study describing the internal consistency and test-retest reliability of the translated version was conducted. The inter-item correlation measured by Cronbach's alpha was 0.88. Test/re-test reliability was measured by the weighted kappa and was between 0.63 and 0.79, indicating 'substantial agreement' and stability between the initial and subsequent administrations for each item. These results demonstrate that the Persian version of the INVR is acceptable for use among Iranian cancer patients. Researchers could use this study as a model for future translation and application of psychometric instrumentation.


Evidence for the Cytoplasmic Localization of the L-α-Glycerophosphate Oxidase in Members of the "Mycoplasma mycoides Cluster".
Members of the "Mycoplasma mycoides cluster" are important animal pathogens causing diseases including contagious bovine pleuropneumonia and contagious caprine pleuropneumonia, which are of utmost importance in Africa or Asia. Even if all existing vaccines have shortcomings, vaccination of herds is still considered the best way to fight mycoplasma diseases, especially with the recent and dramatic increase of antimicrobial resistance observed in many mycoplasma species. A new generation of vaccines will benefit from a better understanding of the pathogenesis of mycoplasmas, which is very patchy up to now. In particular, surface-exposed virulence traits are likely to induce a protective immune response when formulated in a vaccine. The candidate virulence factor L-α-glycerophosphate oxidase (GlpO), shared by many mycoplasmas including Mycoplasma pneumoniae, was suggested to be a surface-exposed enzyme in Mycoplasma mycoides subsp. mycoides responsible for the production of hydrogen peroxide directly into the host cells. We produced a glpO isogenic mutant GM12::YCpMmyc1.1-ΔglpO using in-yeast synthetic genomics tools including the tandem-repeat endonuclease cleavage (TREC) technique followed by the back-transplantation of the engineered genome into a mycoplasma recipient cell. GlpO localization in the mutant and its parental strain was assessed using scanning electron microscopy (SEM). We obtained conflicting results and this led us to re-evaluate the localization of GlpO using a combination of in silico and in vitro techniques, such as Triton X-114 fractionation or tryptic shaving followed by immunoblotting. Our in vitro results unambiguously support the finding that GlpO is a cytoplasmic protein throughout the "Mycoplasma mycoides cluster." Thus, the use of GlpO as a candidate vaccine antigen is unlikely to induce a protective immune response.


Magnetic domain-wall racetrack memory.
Recent developments in the controlled movement of domain walls in magnetic nanowires by short pulses of spin-polarized current give promise of a nonvolatile memory device with the high performance and reliability of conventional solid-state memory but at the low cost of conventional magnetic disk drive storage. The racetrack memory described in this review comprises an array of magnetic nanowires arranged horizontally or vertically on a silicon chip. Individual spintronic reading and writing nanodevices are used to modify or read a train of approximately 10 to 100 domain walls, which store a series of data bits in each nanowire. This racetrack memory is an example of the move toward innately three-dimensional microelectronic devices.


'Is anybody listening?' The experiences of widowhood for older Australian women.
This paper discusses preliminary findings from participants in the baseline survey of the Australian Longitudinal Study on Women's Health (Women's Health Australia: WHA) who reported their marital status as widowed. A total of 12,624 women, aged 70-75 years, completed a self-administered 260-item questionnaire, and 4335 of these women were widowed. Many of these women provided additional qualitative comments about their health, social and financial circumstances after the death of their spouse. This paper presents a thematic analysis of the qualitative comments and builds on the findings of the quantitative analysis of baseline data. The aims of this part of the study are to examine the short- and long-term effects of widowhood on the health and wellbeing of older women and to explore the process of change they experience after the death of a spouse. Preliminary findings suggest that, as a key life event, widowhood has an initial negative impact on the health and wellbeing of older women, but in the long term it may be accompanied by a positive shift into a new life phase.


Cardiometabolic and psychological effects of dual-release hydrocortisone: a cross-over study.
Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15-20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (-1.23 kg, P = 0.006) and BMI (-0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.


Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms.
How scaffold proteins control information flow in signaling pathways is poorly understood: Do they simply tether components, or do they precisely orient and activate them? We found that the yeast mitogen-activated protein (MAP) kinase scaffold Ste5 is tolerant to major stereochemical perturbations; heterologous protein interactions could functionally replace native kinase recruitment interactions, indicating that simple tethering is largely sufficient for scaffold-mediated signaling. Moreover, by engineering a scaffold that tethers a unique kinase set, we could create a synthetic MAP kinase pathway with non-natural input-output properties. These findings demonstrate that scaffolds are highly flexible organizing factors that can facilitate pathway evolution and engineering.


Effectiveness of Dance Movement Therapy in the Treatment of Adults With Depression: A Systematic Review With Meta-Analyses.
Background: Depression is the largest cause of mental ill health worldwide. Although interventions such as Dance Movement Therapy (DMT) may offer interesting and acceptable treatment options, current clinical guidelines do not include these interventions in their recommendations mainly because of what is perceived as insufficient research evidence. The 2015 Cochrane review on DMT for depression includes only three studies leading to inconclusive results. In a small and underfunded field such as DMT, expensive multi-centered Randomized Controlled Trials (RCTs) are as yet rare. It is therefore, necessary to not only capture evidence from RCTs, but to also look beyond such designs in order to identify and assess the range of current evidence. Methods: We therefore conducted a systematic review of studies that aimed to explore the effectiveness in the use of DMT with people with depression. This led to a qualitative narrative synthesis. We also performed meta-analyses that calculated the effect size for all included studies, studies with RCT designs only, followed by a subgroup analysis and a sensitivity analysis. In all meta-analyses a random effects model was used with Standardized Mean Differences (SMD) to accommodate for the heterogeneity of studies and outcome measures. Results: From the 817 studies reviewed, eight studies were identified as meeting our inclusion criteria. Three hundred and fifty one people with depression (mild to severe) participated, 192 of whom attended DMT groups while receiving treatment as usual (TAU) and 159 received TAU only. Qualitative findings suggest there was a decrease in depression scores in favor of DMT groups in all studies. Subgroup analysis performed on depression scores before and 3 months after the completion of DMT groups suggested changes in favor of the DMT groups. When sensitivity analysis was performed, RCTs at high risk of bias were excluded, leaving only studies with adult clients up to the age of 65. In these studies, the highest effect size was found favoring DMT plus TAU for adults with depression, when compared to TAU only. Conclusions: Based on studies with moderate to high quality, we concluded that DMT is an effective intervention in the treatment of adults with depression. Furthermore, by drawing on a wide range of designs with diverse quality, we were able to compile a comprehensive picture of relevant trends relating to the use of DMT in the treatment of depression. Despite the fact that there remains a paucity of high-quality studies, the results have relevance to both policy-making and clinical practice, and become a platform for further research.


No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.
Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy. We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.


Diurnal Variations in Vascular Endothelial Vasodilation Are Influenced by Chronotype in Healthy Humans.
Introduction: The time of day when cardiovascular events are most likely to occur is thought to be aligned with the circadian rhythm of physiological variables. Chronotype has been shown to influence the time of day when cardiovascular events happen, with early chronotypes reported to be more susceptible in the morning and late chronotypes in the evening. However, no studies have investigated the influence of chronotype on physiological variables responsible for cardiovascular regulation in healthy individuals. Methods: 312 individuals completed the Munich ChronoType Questionnaire to assess chronotype. Twenty participants were randomly selected to continue into the main study. In a repeated-measures experiment, participants were tested between 08:00 and 10:00 h and again between 18:00 and 20:00 h. Measurements of mean arterial pressure, heart rate and vascular endothelial vasodilation via flow-mediated dilatation (FMD) were obtained at each session. Results: Individual diurnal differences in mean arterial pressure and heart rate show no significant relationship with chronotype. Diurnal differences in FMD showed a significant correlation (p = 0.010), driven by a clear significant relationship in the evening and not the morning (p < 0.001). Conclusion: These preliminary data indicate that chronotype influences the diurnal variation of endothelial vasodilation measured using flow-mediated dilatation. Furthermore, we show that the influence of chronotype is much stronger in the evening, highlighting an increased susceptibility for later types. These findings are consistent with the diurnal rhythm in cardiovascular events and uncover potential mechanisms of local mediators that may underpin the influence of chronotype in the onset of these events.


Comparison of Computed Tomography derived Fractional Flow Reserve to invasive Fractional Flow Reserve in Diagnosis of Functional Coronary Stenosis: A Meta-Analysis.
Computed Tomography derived Fractional Flow Reserve (CTFFR) is an emerging non-invasive imaging modality to assess functional significance of coronary stenosis. We performed a meta-analysis to compare the diagnostic performance of CTFFR to invasive Fractional Flow reserve (FFR). Electronic search was performed to identify relevant articles. Pooled Estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-) and diagnostic odds ratio (DOR) with corresponding 95% confidence intervals (CI) were calculated at the patient level as well as the individual vessel level using hierarchical logistic regression, summary receiver operating characteristic (SROC) curve and area under the curve were estimated. Our search yielded 559 articles and of these 17 studies was included in the analysis. A total of 2,191 vessels in 1294 patients were analyzed. Pooled estimates of sensitivity, specificity, LR+, LR- and DOR with corresponding 95% CI at per-patient level were 83% (79-87), 72% (68-76), 3.0 (2.6-3.5), 0.23 (0.18-0.29) and 13 (9-18) respectively. Pooled estimates of sensitivity, specificity, LR+, LR- and DOR with corresponding 95% CI at per-vessel level were 85% (83-88), 76% (74-79), 3.6 (3.3-4.0), 0.19 (0.16-0.22) and 19 (15-24). The area under the SROC curve was 0.89 for both per patient level and at the per vessel level. In our meta-analysis, CTFFR demonstrated good diagnostic performance in identifying functionally significant coronary artery stenosis compared to the FFR.


Caregiver's difficulty paying child's healthcare bills and bullying victimization of adolescents with physical disabilities.
Guided by the ecological systems perspective, the objective of the study was to examine whether caregivers' difficulty paying their child's health-care bills is associated with bullying victimization directly and indirectly through the mediating mechanisms of caregivers' frustration, adolescents' internalizing problems, and social difficulty focusing on adolescents with physical disabilities. The 2019 National Survey of Children's Health dataset, which collected data on adolescents' and caregivers' demographic characteristics and health and well-being, was used. The study sample consisted of 368 caregivers of adolescents, 12-17 years of age with physical disabilities. No direct association between caregivers' difficulty paying their child's health-care bills and bullying victimization was found. However, caregivers' frustration and adolescents' internalizing problems were shown to have an indirect association with bullying victimization, which was mediated by difficulty making friends. In addition, adolescents' difficulty making friends was positively associated with bullying victimization. Practitioners working with adolescents with physical disabilities are encouraged to foster collaborative processes across various ecological systems of the adolescent and family to address caregivers' frustration and promote positive social and emotional development of the adolescent with physical disabilities, which can decrease their risk of bullying victimization.


Pattern of spread and prognosis in lower limb-onset ALS.
Our objective was to establish the pattern of spread in lower limb-onset ALS (contra- versus ipsi-lateral) and its contribution to prognosis within a multivariate model. Pattern of spread was established in 109 sporadic ALS patients with lower limb-onset, prospectively recorded in Oxford and Sheffield tertiary clinics from 2001 to 2008. Survival analysis was by univariate Kaplan-Meier log-rank and multivariate Cox proportional hazards. Variables studied were time to next limb progression, site of next progression, age at symptom onset, gender, diagnostic latency and use of riluzole. Initial progression was either to the contralateral leg (76%) or ipsilateral arm (24%). Factors independently affecting survival were time to next limb progression, age at symptom onset, and diagnostic latency. Time to progression as a prognostic factor was independent of initial direction of spread. In a regression analysis of the deceased, overall survival from symptom onset approximated to two years plus the time interval for initial spread. In conclusion, rate of progression in lower limb-onset ALS is not influenced by whether initial spread is to the contralateral limb or ipsilateral arm. The time interval to this initial spread is a powerful factor in predicting overall survival, and could be used to facilitate decision-making and effective care planning.


Impact of b-value on estimates of apparent fibre density.
Recent advances in diffusion magnetic resonance imaging (dMRI) analysis techniques have improved our understanding of fibre-specific variations in white matter microstructure. Increasingly, studies are adopting multi-shell dMRI acquisitions to improve the robustness of dMRI-based inferences. However, the impact of b-value choice on the estimation of dMRI measures such as apparent fibre density (AFD) derived from spherical deconvolution is not known. Here, we investigate the impact of b-value sampling scheme on estimates of AFD. First, we performed simulations to assess the correspondence between AFD and simulated intra-axonal signal fraction across multiple b-value sampling schemes. We then studied the impact of sampling scheme on the relationship between AFD and age in a developmental population (n = 78) aged 8-18 (mean = 12.4, SD = 2.9 years) using hierarchical clustering and whole brain fixel-based analyses. Multi-shell dMRI data were collected at 3.0T using ultra-strong gradients (300 mT/m), using 6 diffusion-weighted shells ranging from b = 0 to 6,000 s/mm2 . Simulations revealed that the correspondence between estimated AFD and simulated intra-axonal signal fraction was improved with high b-value shells due to increased suppression of the extra-axonal signal. These results were supported by in vivo data, as sensitivity to developmental age-relationships was improved with increasing b-value (b = 6,000 s/mm2 , median R2 = .34; b = 4,000 s/mm2 , median R2 = .29; b = 2,400 s/mm2 , median R2 = .21; b = 1,200 s/mm2 , median R2 = .17) in a tract-specific fashion. Overall, estimates of AFD and age-related microstructural development were better characterised at high diffusion-weightings due to improved correspondence with intra-axonal properties.


C-Med 100, a hot water extract of Uncaria tomentosa, prolongs lymphocyte survival in vivo.
Water extracts of the bark of Uncaria tomentosa, a vine indigenous to South America, has been used for generations as an "immuno modulator". To understand the basis of this immuno modulatory effect we fed mice in their drinking water with C-Med 100, which is a commercially available water extract from Uncaria tomentosa. We found a dose-dependent increase in spleen cell numbers in the supplemented mice, but the proportions of B cells, T cells, NK cells, granulocytes, and memory lymphocytes were normal. However, there were no detectable changes of the lymphoid architecture of the spleen even after long-term treatment. Further, when C-Med 100 treatment was interrupted the cellularity returned to normal level within four weeks. The increased number of lymphocytes was most likely not due to increased production because C-Med 100 did not have any significant effect on precursor cells nor on the accumulation of recent thymic emigrants in the spleen. We conclude that accumulation is most likely due to prolonged cell survival, because adoptive transfer experiments demonstrated that C-Med 100 treatment significantly prolonged lymphocyte survival in peripheral lymphoid organs, without increasing their proliferation rate. Since the accumulation was reversible and without detectable pathological effects, these results suggest the use of C-Med 100 as a potential agent for clinically accelerating the recovery of patients from leukopenia.


Emergent chirality in the electric polarization texture of titanate superlattices.
Chirality is a geometrical property by which an object is not superimposable onto its mirror image, thereby imparting a handedness. Chirality determines many important properties in nature-from the strength of the weak interactions according to the electroweak theory in particle physics to the binding of enzymes with naturally occurring amino acids or sugars, reactions that are fundamental for life. In condensed matter physics, the prediction of topologically protected magnetic skyrmions and related spin textures in chiral magnets has stimulated significant research. If the magnetic dipoles were replaced by their electrical counterparts, then electrically controllable chiral devices could be designed. Complex oxide BaTiO3/SrTiO3 nanocomposites and PbTiO3/SrTiO3 superlattices are perfect candidates, since "polar vortices," in which a continuous rotation of ferroelectric polarization spontaneously forms, have been recently discovered. Using resonant soft X-ray diffraction, we report the observation of a strong circular dichroism from the interaction between circularly polarized light and the chiral electric polarization texture that emerges in PbTiO3/SrTiO3 superlattices. This hallmark of chirality is explained by a helical rotation of electric polarization that second-principles simulations predict to reside within complex 3D polarization textures comprising ordered topological line defects. The handedness of the texture can be topologically characterized by the sign of the helicity number of the chiral line defects. This coupling between the optical and novel polar properties could be exploited to encode chiral signatures into photon or electron beams for information processing.


Invasive Bacterial Infections in Infants Younger Than 60 Days With Skin and Soft Tissue Infections.
The objective of this study was to describe the frequency of invasive bacterial infections (IBIs) in young infants with skin and soft tissue infections (SSTIs) and the impact of IBI evaluation on disposition, length of stay (LOS), and cost. This retrospective (2009-2014) cohort study used data from 35 children's hospitals in the Pediatric Health Information System. We included infants younger than 60 days who presented to an emergency department (ED) with SSTI. Invasive bacterial infection was defined as bacteremia/sepsis, bone/joint infection, or bacterial meningitis. Readmission and return ED visits within 30 days were evaluated to identify missed IBIs for infants. A total of 2734 infants were included (median age, 33 days; interquartile range [IQR], 21-44); 62% were hospitalized. Invasive bacterial infection was identified in 2%: bacteremia (1.8%), osteomyelitis (0.1%), and bacterial meningitis (0.1%). Hospitalization occurred in 78% of infants with blood cultures, 95% with cerebrospinal fluid cultures, and 23% without cultures. Median hospitalization LOS was 2 days (IQR, 1-3). Median cost was US $4943 for infants with cerebrospinal fluid cultures (IQR, US $3475-6780) compared with US $419 (IQR, US $215-1149) for infants without IBI evaluations (P < 0.001). Five infants (0.2%) returned to the ED within 30 days with new IBI diagnoses (4 bacteremia, 1 meningitis). Invasive bacterial infection occurs infrequently in infants younger than 60 days who present to children's hospital EDs with SSTI. Bacteremia is the most common IBI. More extensive evaluation for IBI is associated with increased rate of admission, LOS, and cost. Further studies are needed to evaluate the safety of a limited IBI evaluation in young infants with SSTI.


Autoimmune features in metabolic liver disease: a single-center experience and review of the literature.
Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of non-alcoholic fatty liver disease associated with the metabolic syndrome. The existence of autoimmune features in NASH has been reported, but its significance remains unclear. We herein report the autoantibody profile of 54 patients with histologically proven NASH and further determined the development of autoimmunity in three different murine NASH models (monosodium glutamate, CDAA (choline-deficient L-amino acid-defined), and TSOD (Tsumura Suzuki, Obese Diabetes)) at 48 weeks of age. Forty-eight percent (26/54) of NASH cases were positive for antinuclear (ANA) or antimitochondrial antibody and manifested histological signs of overlap with autoimmune hepatitis and primary biliary cirrhosis, respectively. These patients were significantly older (60 ± 10 versus 50 ± 16 years), more frequently women (81 % versus 43 %), and with more severe portal inflammatory infiltrate compared with patients without autoimmunity. In one third of mice, regardless of the model, we observed a marked lymphoid infiltrate with non-suppurative cholangitis, and several cases were ANA-positive, but none AMA-positive. Our data suggest that autoimmunity may share some pathogenetic traits with the chronic inflammation of NASH, possibly related to advanced age.


Palmatine attenuates osteoclast differentiation and function through inhibition of receptor activator of nuclear factor-κb ligand expression in osteoblast cells.
Osteoclasts are the only cell type capable of resorbing mineralized bone, and they act under the control of numerous cytokines produced by supporting cells such as osteoblasts and stromal cells. Among cytokines, receptor activator of nuclear factor-κB ligand (RANKL) was found to be a key osteoclastogenetic molecule that directly binds to its cognate receptor, RANK, on osteoclast precursor cells. In turn, RANKL, which is an essential factor for differentiation and activation of osteoclasts, is one of the major targets of anti-resorptive agents. In this study, we found that palmatine, an isoquinoline alkaloid originally isolated from Coptis chinensis, had an inhibitory effect on osteoclast differentiation and function in vitro. Palmatine inhibited osteoclast formation in the co-culture system with mouse bone marrow cells (BMC) and osteoblasts in the presence of 10 nM 1α,25-(OH)(2)D(3). Palmatine did not affect osteoclast formation induced by RANKL in the BMC cultures. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that palmatine significantly inhibited the expression of 1α,25-(OH)(2)D(3)-induced expression of RANKL mRNAs in stromal cells without loss of cell viability. Moreover, palmatine suppressed resorption pit formation by mature osteoclasts on dentin slices and induced disruption of actin ring formation in mature osteoclasts with an impact on cell viability. Taken together, these results suggest that palmatine attenuates osteoclast differentiation through inhibition of RANKL expression in osteoblast cells, and its inhibitory effect on bone resorption is due to its disruptive effect on actin rings in mature osteoclasts. Therefore, palmatine might be an ideal candidate as an anti-resorptive agent for the prevention and treatment of bone disorders such as osteoporosis.


Prions, prionoids and pathogenic proteins in Alzheimer disease.
Like patients with prion disease, Alzheimer patients suffer from a fatal, progressive form of dementia. There is growing evidence that amyloid-β (Aβ) aggregates may be transmissible similar to prions, at least under extreme experimental conditions. However, unlike mice infected with prion protein (PrP) prions, those inoculated with Aβ do not die. The transmission of Aβ and PrP thus differs conspicuously in the neurological effects they induce in their hosts, the difference being no less than a matter of life and death. Far from being a mere academic nuance, this distinction between Aβ and PrP begs the crucial questions of what, exactly, controls prion toxicity and how prion toxicity relates to prion infectivity.


ADA5/SPT20 links the ADA and SPT genes, which are involved in yeast transcription.
In this report we described the cloning and characterization of ADA5, a gene identified by resistance to GAL4-VP16-mediated toxicity. ADA5 binds directly to the VP16 activation domain but not to a transcriptionally defective VP16 double point mutant. Double mutants with mutations in ada5 and other genes (ada2 or ada3) isolated by resistance to GAL4-VP16 grow like ada5 single mutants, suggesting that ADA5 is in the same pathway as the other ADA genes. Further, ADA5 cofractionates and coprecipitates with ADA3. However, an ada5 deletion mutant exhibits a broader spectrum of phenotypes than mutants with null mutations in the other ADA genes. Most interestingly, ADA5 is identical to SPT20 (S.M. Roberts and F. Winston, Mol. Cell. Biol. 16: 3206-3213, 1996), showing that it shares phenotypes with the ADA and SPT family of genes. Of the other SPT genes tested, mutants with mutations in SPT7 and, strikingly, SPT15 (encoding the TATA-binding protein) show resistance to GAL4-VP16. We present a speculative pathway of transcriptional activation involving the ADA2-ADA3-GCN5-ADA5 complex and the TATA-binding protein.


ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms.
Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.


Psychometric properties of the processes of change scale for smoking cessation in UK adolescents.
The transtheoretical model (TTM) proposes that individuals move stage and hence change behaviour through the use of processes of change (POC)--cognitive, emotional and behavioural activities related to the target behaviour. This study was a test of the psychometric properties of the POC scale. The sample consisted of year 9 students from 26 schools who completed a computer-based version of the POC questionnaire on up to three occasions. There were 1,160 former and current smokers who completed the questionnaire on the first occasion, 978 on the second, and 836 on the third occasion. Confirmatory factor analysis was used to explore three alternative factor structures. Cronbach alpha and test-retest reliability coefficients were examined. Construct validity was examined by calculating POC means for each stage and testing differences between means using analysis of variance. The TTM-hypothesised second-order factor that clustered ten primary factors into experiential and behavioural processes fitted the data reasonably, though an alternative model, removing the second-order factors, was a significantly improved fit. Cronbach alpha coefficients were reasonable except for two processes. Test-retest reliabilities were modest. Experiential processes showed differences across precontemplation to preparation, but differences between preparation, action, and maintenance were slight. Behavioural processes showed linear differences between stages, though helping relationships was not different across stages. There is evidence of some specific difficulties with the POC questionnaire that may be overcome with some reformulation. The POC questionnaire shows evidence of adequate factorial validity, sufficient to allow its use in future predictive testing.


A Critical Period for the Development of Schizophrenia-Like Pathology by Aberrant Postnatal Neurogenesis.
Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neurodevelopmental processing in the pathophysiological progress of schizophrenia has not been well investigated. Here in this study, by using the rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, we aimed to examine whether the postnatal neurogenesis might be involved in the development of schizophrenia-like pathology. Through the comprehensive behavioral analyses of multiple core symptoms of schizophrenia at different developmental stages (6-, 9-, and 12-weeks after birth) of the affected offspring, we found a delayed onset of schizophrenia-like behaviors in poly (I:C) animals through the development. Meanwhile, there is an age-dependent alteration of postnatal neurogenesis in the poly (I:C) animals along different development stages by which the aberrant dendritic elaboration functionally correlated with the schizophrenia-like symptoms in 9-week-old of age for the animals. Interestingly, increase in the neurogenesis during a critical period of neurodevelopment exacerbates the schizophrenia-like pathology. Conversely, temporal suppression of aberrant postnatal neurogenesis during the same period of neurodevelopment ameliorates the occurrence of schizophrenia-like symptoms. Together, these findings strongly suggested the aberrant dendritic growth of postnatal neurogenesis during the critical time window of development is essential for controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic.


Heterogeneity of sialoglycoproteins purified from normal and malignant cells.
We have identified previously a group of sialoglycoproteins with an apparent molecular weight of 110,000, which appear homogeneous by sodium dodecyl sulfate:polyacrylamide gel electrophoresis but exhibit isoelectric point heterogeneity by two-dimensional polyacrylamide gel electrophoresis. This technique demonstrated that there are multiple glycoproteins of similar molecular weight which differ between normal cells and transformants. We have now purified glycoproteins by concanavalin A:Sepharose chromatography and preparative polyacrylamide gel electrophoresis from both a nontumorigenic normal mouse fibroblast line, A31, and a highly malignant nonimmunogenic transformant, 3T12T. Differences in the isoelectric point distribution of the sialoglycoproteins which were observed between the normal and transformed two-dimensional gel patterns using crude membranes could also be demonstrated with the purified glycoproteins. Treatment of the isolated sialoglycoproteins with neuraminidase to remove sialic acid resulted in significant isoelectric point shifts but did not eliminate all of the heterogeneity. Even following neuraminidase treatment, the purified glycoprotein fraction upon isoelectric focusing showed differences in patterns between normal and transformed cells. Preliminary characterization of the alterations seen in the two cell lines are presented and show decreased fucose and increased sialic acid in transformed cell glycoprotein.


Upper and lower limb motor axons demonstrate differential excitability and accommodation to strong hyperpolarizing currents during induced hyperthermia.
Length-dependent peripheral neuropathy typically involves the insidious onset of sensory loss in the lower limbs before later progressing proximally. Recent evidence proposes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels as dysfunctional in rodent models of peripheral neuropathy, and therefore differential expression of HCN channels in the lower limbs was hypothesized as a pathophysiological mechanism accounting for the pattern of symptomatology within this study. We studied six healthy participants, using motor axon excitability including strong and long [-70% and -100% hyperpolarizing threshold electrotonus (TEh)] hyperpolarizing currents to preferably study HCN channel function from the median and tibial nerves from high (40%) and low (20%) threshold. This was recorded at normothermia (~32°C) and then repeated during hyperthermia (~40°C) as an artificial hyperpolarizing axon stress. Significant differences between recovery cycle, superexcitability, accommodation to small depolarizing currents, and alterations in late stages of the inward-rectifying currents of strongest (-70% and -100% TEh) currents were observed in the lower limbs during hyperthermia. We demonstrate differences in late IH current flow, which implies higher expression of HCN channel isoforms. The findings also indicate their potential inference in the symptomatology of length-dependent peripheral neuropathies and may be a unique target for minimizing symptomatology and pathogenesis in acquired disease. NEW & NOTEWORTHY This study demonstrates nerve excitability differences between the upper and lower limbs during hyperthermia, an experimentally induced axonal stress. The findings indicate that there is differential expression of slow hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms between the upper and lower limbs, which was demonstrated through strong, long hyperpolarizing currents during hyperthermia. Such mechanisms may underlie postural control but render the lower limbs susceptible to dysfunction in disease states.


Challenges in the prenatal and post-natal diagnosis of mediastinal cystic hygroma: a case report.
Cystic hygroma is a benign congenital neoplasm that mostly presents as a soft-tissue mass in the posterior triangle of the neck. Pure mediastinal lesions are uncommon; the vast majority are asymptomatic and are an incidental finding in adulthood. The diagnosis is often made intra- or postoperatively. Prenatal identification is exceptional and post-natal diagnosis also proves challenging. We report one such case that was mistaken for other entities in both the prenatal and immediate post-natal period. Initial and follow-up antenatal ultrasound scans demonstrated a multicystic lesion in the left chest, and the mother was counselled about the possibility of her baby having a congenital diaphragmatic hernia. Initial post-natal chest radiographs were reported as normal. An echocardiogram and thoracic computed tomography scan confirmed a complex multiloculated cystic mediastinal mass. The working diagnoses were of a mediastinal teratoma or congenital cystic adenomatous malformation. At operation, the lesion was compressed by the left lung and was found to be close to the left phrenic nerve, which was carefully identified and preserved. After excision, histopathological examination of the mass confirmed the diagnosis of cystic hygroma. Postoperative dyspnoea was observed secondary to paradoxical movement of the left hemidiaphragm and probable left phrenic neuropraxia. This settled conservatively with excellent recovery. Despite the fact that isolated intrathoracic cystic hygroma is a rare entity, it needs to be considered in the differential diagnosis of foetal and neonatal mediastinal masses, particularly for juxtadiaphragmatic lesions. The phrenic nerve is not identifiable on prenatal ultrasound imaging, and it is therefore understandable that a mass close to the diaphragm may be mistaken for a congenital diaphragmatic hernia because of the location, morphology and potential phrenic nerve compression. Post-natal diagnosis may also be misleading as many mediastinal cystic masses have similar appearances on imaging. Therefore, as well as cystic architecture, special consideration needs to be given to the anatomical location and effect on local structures.


The Chlamydomonas Genome Project, version 6: Reference assemblies for mating-type plus and minus strains reveal extensive structural mutation in the laboratory.
Five versions of the Chlamydomonas reinhardtii reference genome have been produced over the last two decades. Here we present version 6, bringing significant advances in assembly quality and structural annotations. PacBio-based chromosome-level assemblies for two laboratory strains, CC-503 and CC-4532, provide resources for the plus and minus mating-type alleles. We corrected major misassemblies in previous versions and validated our assemblies via linkage analyses. Contiguity increased over ten-fold and >80% of filled gaps are within genes. We used Iso-Seq and deep RNA-seq datasets to improve structural annotations, and updated gene symbols and textual annotation of functionally characterized genes via extensive manual curation. We discovered that the cell wall-less classical reference strain CC-503 exhibits genomic instability potentially caused by deletion of the helicase RECQ3, with major structural mutations identified that affect >100 genes. We therefore present the CC-4532 assembly as the primary reference, although this strain also carries unique structural mutations and is experiencing rapid proliferation of a Gypsy retrotransposon. We expect all laboratory strains to harbor gene-disrupting mutations, which should be considered when interpreting and comparing experimental results. Collectively, the resources presented here herald a new era of Chlamydomonas genomics and will provide the foundation for continued research in this important reference organism.


CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma.
Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255-66. ©2018 AACR.


Outer, inner and planar polarity in the Arabidopsis root.
Plant roots control uptake of water and nutrients and cope with environmental challenges. The root epidermis provides the first selective interface for nutrient absorption, while the endodermis produces the main apoplastic diffusion barrier in the form of a structure called the Casparian strip. The positioning of root hairs on epidermal cells, and of the Casparian strip around endodermal cells, requires asymmetries along cellular axes (cell polarity). Cell polarity is termed planar polarity, when coordinated within the plane of a given tissue layer. Here, we review recent molecular advances towards understanding both the polar positioning of the proteo-lipid membrane domain instructing root hair initiation, and the cytoskeletal, trafficking and polar tethering requirements of proteins at outer or inner plasma membrane domains. Finally, we highlight progress towards understanding mechanisms of Casparian strip formation and underlying endodermal cell polarity.


Mechanistically linking age-related diseases and dietary carbohydrate via autophagy and the ubiquitin proteolytic systems.
Epidemiological data indicate that consuming diets that deliver sugar to the blood rapidly (called high glycemic index, GI) is associated with enhanced risk for age-related diseases such as cardiovascular disease, type 2 diabetes, cataract and age-related macular degeneration (AMD). These debilities are associated with accumulation of toxic protein aggregates as observed in other protein precipitation or amyloid diseases including Alzheimer, Parkinson and Huntington diseases and encephalopathies. Barriers to recommending lower-GI diets to promote health include the absence of established intracellular biochemical mechanisms that link high-GI diets to compromised homeostasis. The data herein corroborate the epidemiological findings and provide platforms to elucidate additional mechanistic aspects of salutary effects of consuming diets of different GIs. They are also useful for testing drugs, including autophagy enhancers, glycemia regulators, or nutraceuticals, which can be exploited to extend health.


High prevalence of multiple syndemic conditions associated with sexual risk behavior and HIV infection among a large sample of Spanish- and Portuguese-speaking men who have sex with men in Latin America.
The HIV epidemic in Latin America is highly concentrated in men who have sex with men (MSM). In the United States, multiple co-occurring psychosocial conditions have been shown to act as intertwined epidemics to potentiate HIV transmission among MSM. To date, no study has examined the role of syndemics and condomless sex among MSM in Latin America. In 2012, an online survey was conducted among members of the largest social/sexual networking website for MSM in Latin America. Participants were asked about demographics, sexual behaviors, HIV/STI diagnoses, and psychosocial well-being, including depression, suicidal ideation, hazardous alcohol use, hard drug use during sex, history of childhood/adolescent sexual abuse, intimate partner violence, and sexual compulsivity. Multivariable logistic generalized estimation equations were used to assess the relationship of syndemic factors and (1) engagement in higher risk condomless anal sex and (2) self-report of prior HIV diagnosis. Among 24,274 survey respondents, 74.6 % of the sample had at least one syndemic factor. In an additive model, syndemics were associated with increased odds of higher risk condomless anal sex, ranging from adjusted odds ratio of 1.31 (95 % CI 1.20, 1.43) for one syndemic factor to 4.06 (95 % CI 3.25, 5.09) for 6/7 syndemic factors. Similarly, syndemics were associated with increased odds of HIV infection (p < .0001). This study provides initial evidence that intertwined syndemics increase HIV risk behavior and HIV infection among MSM in Latin America. In the Latin American context, comprehensive HIV prevention interventions for MSM should be developed and tested that simultaneously address co-occurring psychosocial conditions and HIV risk.


Intramembrane ionic protein-lipid interaction regulates integrin structure and function.
Protein transmembrane domains (TMDs) are generally hydrophobic, but our bioinformatics analysis shows that many TMDs contain basic residues at terminal regions. Physiological functions of these membrane-snorkeling basic residues are largely unclear. Here, we show that a membrane-snorkeling Lys residue in integrin αLβ2 (also known as lymphocyte function-associated antigen 1 [LFA-1]) regulates transmembrane heterodimer formation and integrin adhesion through ionic interplay with acidic phospholipids and calcium ions (Ca2+) in T cells. The amino group of the conserved Lys ionically interacts with the phosphate group of acidic phospholipids to stabilize αLβ2 transmembrane association, thus keeping the integrin at low-affinity conformation. Intracellular Ca2+ uses its charge to directly disrupt this ionic interaction, leading to the transmembrane separation and the subsequent extracellular domain extension to increase adhesion activity. This Ca2+-mediated regulation is independent on the canonical Ca2+ signaling or integrin inside-out signaling. Our work therefore showcases the importance of intramembrane ionic protein-lipid interaction and provides a new mechanism of integrin activation.


Management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures.
Long-term bisphosphonate use has often been associated with atypical femoral fractures. These fractures evolve from incomplete femoral fractures. A previous study demonstrated that the presence of a radiolucent line in an incomplete fracture can indicate a high risk of progression to complete fracture. The aim of this study is to present a management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. Specific study questions include the following: (1) Is there a difference in the prognosis of these fractures based on the presence or absence of a radiolucent fracture line? (2) Can treatment with teriparatide assist in clinical/radiographic healing of these incomplete fractures? (3) Is there a characteristic biochemical profile in these patients? We retrospectively examined all femur radiographs ordered by the metabolic bone disease service at our hospital between July 1, 2006 and July 1, 2011 and identified 10 patients with a total of 14 incomplete fractures. Nine patients received bisphosphonates for a mean duration of 10 ± 5 years (range, 4-17). The mean follow-up since the time of diagnosis was 20 ± 11 months (range, 6-36 months). Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and pharmacologic therapy. All five of these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only two of these were treated successfully with conservative management including teriparatide. Six of the eight patients with a radiolucent line elected for surgical prophylaxis after 3 months of conservative management, whereas one patient underwent surgical prophylaxis without a trial of conservative management. Regarding the biochemical profiles, bone turnover markers for our patient cohort were in the lower quartile. Fractures without a radiolucent line appear to respond to conservative management and not require surgical prophylaxis. Teriparatide treatment may hold promise in promoting healing of these fractures.


Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy.
Accumulation of α-synuclein (α-syn) in the brain is a pathogenic feature and also a causative factor of Parkinson disease. Isorhynchophylline (IsoRhy) is a major tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.)Jacks (Gouteng in Chinese), which has been used for the treatment of neurological diseases in East Asia for centuries. Here we report a novel function of IsoRhy as a neuronal autophagy inducer. IsoRhy induced autophagy in different neuronal cell lines, including N2a, SH-SY5Y and PC12 cells, and also in primary cortical neurons. Furthermore, IsoRhy induced autophagy in the fat bodies of Drosophila. IsoRhy promoted clearance of wild-type, A53T and A30P α-syn monomers, α-syn oligomers and α-syn/synphilin-1 aggresomes in neuronal cells via the autophagy-lysosome pathway. More importantly, IsoRhy was able to decrease the expression levels of wild-type and A53T α-syn protein in differentiated human dopaminergic neurons. Notably, IsoRhy-induced autophagy was independent of the mTOR pathway but dependent on the function of Beclin 1. Taken together, data from this study raise the possibility that oxindole alkaloid derivatives may serve as a means to stimulate autophagy in neuronal cells, thereby exerting preventive and therapeutic values against neurodegenerative diseases such as Parkinson disease by reducing pathogenic protein aggregates in neurons.


Lower Serum Zinc and Higher CRP Strongly Predict Prenatal Depression and Physio-somatic Symptoms, Which All Together Predict Postnatal Depressive Symptoms.
Pregnancy and delivery are associated with activation of immune-inflammatory pathways which may prime parturients to develop postnatal depression. There are, however, few data on the associations between immune-inflammatory pathways and prenatal depression and physio-somatic symptoms. This study examined the associations between serum zinc, C-reactive protein (CRP), and haptoglobin at the end of term and prenatal physio-somatic symptoms (fatigue, back pain, muscle pain, dyspepsia, obstipation) and prenatal and postnatal depressive and anxiety symptoms as measured using the Edinburgh Postnatal Depression Scale (EPDS), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HAMD), and Spielberger's State Anxiety Inventory (STAI). Zinc and haptoglobin were significantly lower and CRP increased at the end of term as compared with non-pregnant women. Prenatal depression was predicted by lower zinc and lifetime history of depression, anxiety, and premenstrual tension syndrome (PMS). The latter histories were also significantly and inversely related to lower zinc. The severity of prenatal EDPS, HAMD, BDI, STAI, and physio-somatic symptoms was predicted by fatigue in the first and second trimesters, a positive life history of depression, anxiety, and PMS, and lower zinc and higher CRP. Postnatal depressive symptoms are predicted by prenatal depression, physio-somatic symptoms, zinc and CRP. Prenatal depressive and physio-somatic symptoms have an immune-inflammatory pathophysiology, while postnatal depressive symptoms are highly predicted by prenatal immune activation, prenatal depression, and a lifetime history of depression and PMS. Previous episodes of depression, anxiety disorders, and PMS may prime pregnant females to develop prenatal and postnatal depressive symptoms via activated immune pathways.


Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to common and discrete local effects whilst AdipoR2 promotes additional systemic effects.
Hypoadiponectinemia and adiponectin resistance are implicated in the aetiology of obesity-related cardiometabolic disorders, hence represent a potential therapeutic axis. Here we characterised the effects of in vivo electrotransfer-mediated overexpression of the adiponectin receptors, AdipoR1 or AdipoR2, into tibialis anterior muscle (TAM) of lean or obese mice. In lean mice, TAM-specific overexpression of AdipoR1 (TAMR1) or AdipoR2 (TAMR2) increased phosphorylation of AMPK, AKT and ERK and expression of the insulin responsive glucose transporter glut4. In contrast, only TAMR2 increased pparα and a target gene acox1. These effects were decreased in obese mice despite no reduction in circulating adiponectin levels. TAMR2 also increased expression of adipoQ in TAM of lean and obese mice. Furthermore, in obese mice TAMR2 promoted systemic effects including; decreased weight gain; reduced epididymal fat mass and inflammation; increased epididymal adipoQ expression; increased circulating adiponectin. Collectively, these results demonstrate that AdipoR1 and AdipoR2 exhibit overlapping and distinct effects in skeletal muscle consistent with enhanced adiponectin sensitivity but these appear insufficient to ameliorate established obesity-induced adiponectin resistance. We also identify systemic effects upon TAMR2 in obese mice and postulate these are mediated by altered myokine production. Further studies are warranted to investigate this possibility which may reveal novel therapeutic approaches.


Altered functional response to risky choice in HIV infection.
Risky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making. This study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored. Although there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions. This study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.


Safety climate and mindful safety practices in the oil and gas industry.
The existence of a positive association between safety climate and the safety behavior of sharp-end workers in high-risk organizations is supported by a considerable body of research. Previous research has primarily analyzed two components of safety behavior, namely safety compliance and safety participation. The present study extends previous research by looking into the relationship between safety climate and another component of safety behavior, namely mindful safety practices. Mindful safety practices are defined as the ability to be aware of critical factors in the environment and to act appropriately when dangers arise. Regression analysis was used to examine whether mindful safety practices are, like compliance and participation, promoted by a positive safety climate, in a questionnaire-based study of 5712 sharp-end workers in the oil and gas industry. The analysis revealed that a positive safety climate promotes mindful safety practices. The regression model accounted for roughly 31% of the variance in mindful safety practices. The most important safety climate factor was safety leadership. The findings clearly demonstrate that mindful safety practices are highly context-dependent, hence, manageable and susceptible to change. In order to improve safety climate in a direction which is favorable for mindful safety practices, the results demonstrate that it is important to give the fundamental features of safety climate high priority and in particular that of safety leadership.


Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein.
To enhance the effectiveness of diet in lowering cholesterol, recommendations of the Adult Treatment Panel III of the National Cholesterol Education Program emphasize diets low in saturated fat together with plant sterols and viscous fibers, and the American Heart Association supports the use of soy protein and nuts. To determine whether a diet containing all of these recommended food components leads to cholesterol reduction comparable with that of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Randomized controlled trial conducted between October and December 2002. Forty-six healthy, hyperlipidemic adults (25 men and 21 postmenopausal women) with a mean (SE) age of 59 (1) years and body mass index of 27.6 (0.5), recruited from a Canadian hospital-affiliated nutrition research center and the community. Participants were randomly assigned to undergo 1 of 3 interventions on an outpatient basis for 1 month: a diet very low in saturated fat, based on milled whole-wheat cereals and low-fat dairy foods (n = 16; control); the same diet plus lovastatin, 20 mg/d (n = 14); or a diet high in plant sterols (1.0 g/1000 kcal), soy protein (21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (n = 16; dietary portfolio). Lipid and C-reactive protein levels, obtained from fasting blood samples; blood pressure; and body weight; measured at weeks 0, 2, and 4 and compared among the 3 treatment groups. The control, statin, and dietary portfolio groups had mean (SE) decreases in low-density lipoprotein cholesterol of 8.0% (2.1%) (P =.002), 30.9% (3.6%) (P<.001), and 28.6% (3.2%) (P<.001), respectively. Respective reductions in C-reactive protein were 10.0% (8.6%) (P =.27), 33.3% (8.3%) (P =.002), and 28.2% (10.8%) (P =.02). The significant reductions in the statin and dietary portfolio groups were all significantly different from changes in the control group. There were no significant differences in efficacy between the statin and dietary portfolio treatments. In this study, diversifying cholesterol-lowering components in the same dietary portfolio increased the effectiveness of diet as a treatment of hypercholesterolemia.


Optical imaging of individual biomolecules in densely packed clusters.
Recent advances in fluorescence super-resolution microscopy have allowed subcellular features and synthetic nanostructures down to 10-20 nm in size to be imaged. However, the direct optical observation of individual molecular targets (∼5 nm) in a densely packed biomolecular cluster remains a challenge. Here, we show that such discrete molecular imaging is possible using DNA-PAINT (points accumulation for imaging in nanoscale topography)-a super-resolution fluorescence microscopy technique that exploits programmable transient oligonucleotide hybridization-on synthetic DNA nanostructures. We examined the effects of a high photon count, high blinking statistics and an appropriate blinking duty cycle on imaging quality, and developed a software-based drift correction method that achieves <1 nm residual drift (root mean squared) over hours. This allowed us to image a densely packed triangular lattice pattern with ∼5 nm point-to-point distance and to analyse the DNA origami structural offset with ångström-level precision (2 Å) from single-molecule studies. By combining the approach with multiplexed exchange-PAINT imaging, we further demonstrated an optical nanodisplay with 5 × 5 nm pixel size and three distinct colours with <1 nm cross-channel registration accuracy.


Scattering from an elliptical cylinder by using the vectorial complex ray model.
The vectorial complex ray model (VCRM) is applied to the light scattering of an elliptical cylinder illuminated by a plane wave. In the VCRM, all waves are described by vectorial complex rays, and the scattering intensities are computed by the superposition of the complex amplitudes of the vectorial rays. The significant merit of this approach is that the wave properties are integrated in the ray model such that the divergence/convergence of the wave each time it encounters a dioptric surface is deduced by the wavefront curvature equation, and the phase shifts due to the focal lines are determined directly by the curvature of the wavefront. The approach is particularly suitable for a large cylinder with an elliptical cross section.


Insights from the complete chloroplast genome into the evolution of Sesamum indicum L.
Sesame (Sesamum indicum L.) is one of the oldest oilseed crops. In order to investigate the evolutionary characters according to the Sesame Genome Project, apart from sequencing its nuclear genome, we sequenced the complete chloroplast genome of S. indicum cv. Yuzhi 11 (white seeded) using Illumina and 454 sequencing. Comparisons of chloroplast genomes between S. indicum and the 18 other higher plants were then analyzed. The chloroplast genome of cv. Yuzhi 11 contains 153,338 bp and a total of 114 unique genes (KC569603). The number of chloroplast genes in sesame is the same as that in Nicotiana tabacum, Vitis vinifera and Platanus occidentalis. The variation in the length of the large single-copy (LSC) regions and inverted repeats (IR) in sesame compared to 18 other higher plant species was the main contributor to size variation in the cp genome in these species. The 77 functional chloroplast genes, except for ycf1 and ycf2, were highly conserved. The deletion of the cp ycf1 gene sequence in cp genomes may be due either to its transfer to the nuclear genome, as has occurred in sesame, or direct deletion, as has occurred in Panax ginseng and Cucumis sativus. The sesame ycf2 gene is only 5,721 bp in length and has lost about 1,179 bp. Nucleotides 1-585 of ycf2 when queried in BLAST had hits in the sesame draft genome. Five repeats (R10, R12, R13, R14 and R17) were unique to the sesame chloroplast genome. We also found that IR contraction/expansion in the cp genome alters its rate of evolution. Chloroplast genes and repeats display the signature of convergent evolution in sesame and other species. These findings provide a foundation for further investigation of cp genome evolution in Sesamum and other higher plants.


EarlyCDT-Lung: an immunobiomarker test as an aid to early detection of lung cancer.
Recent publications have reported the technical and clinical validation of EarlyCDT-Lung, an autoantibody test which detected elevated autoantibodies in 40% of lung cancers at diagnosis. This manuscript reports the results of EarlyCDT-Lung run on four new (postvalidation) data sets. The following four cohorts of patients (n = 574) with newly diagnosed lung cancer were identified: group 1 (n = 122), 100% small cell lung cancer (SCLC); group 2 (n = 249), 97% non-small cell lung cancer (NSCLC); group 3 (n = 122), 100% NSCLC; group 4 (n = 81), 62% NSCLC. Serum samples were obtained after diagnosis, prior to any anticancer treatment. Autoantibody levels were measured against a panel of six tumor-related antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1, and SOX2) in the EarlyCDT-Lung panel and previously established cutoffs applied. In groups 2, 3, and 4, patients were individually matched by gender, age, and smoking history to a control individual with no history of malignant disease. Assay sensitivity was tested in relation to cancer type and stage, and in the matched normals to demographic variables. The autoantibody panel showed sensitivity/specificity of 57%/n.d (not done) for SCLC in group 1, 34%/87% for NSCLC in group 2, 31% and 84% for NSCLC in group 3, and 35%/89% for NSCLC and 43%/89% for SCLC in group 4. There was no significant difference in positivity of EarlyCDT-Lung and different lung cancer stages. These studies confirm the value of an autoantibody assay, EarlyCDT-Lung, as an aid to detecting lung cancer in patients at high risk of the disease.


Lyme borreliosis: host responses to Borrelia burgdorferi.
The chronic inflammatory condition that develops after infection by B. burgdorferi is a complex process resulting from host responses to a limited number of organisms. Amplification mechanisms driven by potent proinflammatory molecules, i.e., IL-1, may explain the vigorous response to a paucity of organisms. Spirochete dissemination to distant locations involves adherence to and penetration across endothelium and may be facilitated by host responses that increase vessel permeability. The apparent lack of tissue tropism in Lyme disease is reflected in the organism's ability to adhere to different eucaryotic cell types in vitro and the wide distribution of B. burgdorferi in various organs of infected humans and experimentally infected animals. While phagocytosis and complement activation have been observed in vitro, the specific immune response that develops in humans is inefficient in eradicating the organisms, which may possess some mechanism(s) to evade this response. There is significant evidence for host autoreactivity based on antigenic cross-reactivity between the 41-kDa flagellar subunit and stress proteins of the spirochetes and endogenous host cell components. Although the outer surface proteins appear to be suitable candidates as targets for vaccination in animal studies, fundamental differences in the immune response to spirochetal components may preclude their use in humans.


β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.
This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.


Salvage of the limb in the treatment of malignant pelvic tumors.
From 1970 through 1985, at the Mayo Clinic, sixty patients had operative treatment, with salvage of the limb, for a primary malignant tumor of the pelvis. Chondrosarcoma, osteosarcoma, and fibrosarcoma were common diagnoses. There were twenty-three iliosacral, twenty-five acetabular, and twelve ischiopubic lesions. Most of the resections were done with a wide margin and disruption of femorosacral continuity. Reconstruction included ten iliosacral, fourteen iliofemoral, and three ischiofemoral arthrodeses, and approximately 50 per cent of the procedures resulted in fusion. The average length of follow-up exceeded five years. Seventeen per cent of the patients, primarily those in whom an iliosacral lesion extended into the sacrum or along the spinal column, had a local recurrence. Twenty-one patients (37 per cent) had metastasis. The best functional results were seen after resections in which femorosacral continuity was maintained or reconstructed. If satisfactory margins can be achieved by the excision of a pelvic tumor, salvage of the limb is justified from both an oncological and a functional standpoint.


Chromosomal localization of the gene for Gaucher disease.
The structural gene for human GBA has been assigned to chromosome 1 using somatic cell hybridization techniques for gene mapping. The human enzyme was detected in mouse RAG cell-human fibroblast cell hybrids by a sensitive double antibody immunoprecipitation assay using a mouse anti-human GBA antibody. No cross-reactivity between mouse beta-glucosidase and human GBA or GBN was observed. For the initial assignment, fifty-two primary, secondary, and tertiary man-mouse hybrids lines, derived from three separate fusion experiments, were analyzed for human GBA and enzyme markers for the human chromosomes. Without exception, the presence of human GBA in these hybrid clones was correlated with the presence of human chromosome 1 or its enzymatic markers, PGM1 and FH. All other human chromosomes were eliminated by the independent segregation of GBA and their respective enzyme markers and/or chromosomes. Using a RAG-human fibroblast line with a mouse-human rearrangement of human chromosome 1, the locus for GBA was limited to the region 1p11 leads to 1qter. Further regional localization was obtained using subclones of hybrids derived from the fusion of a human fibroblast line, 46,XX,del(1)(pter leads to q42:), with mouse RAG fibroblasts. All hybrid subclones containing a normal chromosome 1 were positive for GBA. In contrast, subclones with a single deleted chromosome 1 were negative for GBA by immunoprecipitation and by the natural substrate assays. These results further localized the gene for GBA to the narrow region, 1q42 leads to 1qter.


What's Ideal? A case study exploring handoff routines in practice.
Handoffs of care in the healthcare system between responsible providers have traditionally been conceptualized and studied at the point of patient transfer. Thus, clinical practice and associated information systems are designed with the concept of the handoff as a solitary event. This viewpoint does not consider the routine activities necessary for a successful handoff. We propose expanding the analysis of the handoff beyond the single point of transfer to include a routine of interrelated activities leading up to the transfer of responsibility. We used this expanded definition of handoffs to identify exceptions from standard practice as identified by ideal-type handoff routines. We used an ethnographic case method to study handoffs in an interventional cardiology unit in a Midwestern community hospital. This involved examining handoffs and their supporting routines. We conducted thematic analysis of the handoffs using NVivo, a qualitative software analysis program. These analyses include categorization of the types and causes of differences in practice and exceptions from ideal-type handoffs. Observed handoffs that took place within the clinical unit did not consistently align with the ideal-type routine, yet this variation did not necessarily lead to exceptions. However, for handoffs between clinical units, although more likely to follow the ideal-type routine, differences from the standardized routine more often led to exceptions. We found that problems with performing the routine activities leading up to the handoff and the context in which the handoff occurred affected whether the handoff was successful. Considering the handoff as a routine rather than simply the point of transition gives broader insight about how care transitions function. Such consideration helps clinicians better understand how variations occur and how differences from ideal-type handoffs can lead to potential exceptions such as missing information. This analysis can be used to develop information systems that better support handoffs.


Long-term healthy lifestyle patterns and tooth loss studied in a Swedish cohort of middle-aged and older people.
The promotion of a healthy lifestyle has become an issue of public health importance in the context of ageing populations and increasing prevalence of chronic diseases. (i) To estimate changes in use of fluoridated tooth paste, use of tooth picks, smoking and alcohol consumption and (ii) to examine whether experience with incident or prevalent tooth loss predict healthy lifestyle transitions from age 50 to 70. In 1992, 6346 individuals born in 1942 agreed to participate in a prospective cohort study and 3585 completed follow-up questionnaires in 1997, 2002, 2007 and 2012. Statistical analyses were conducted by chi-square statistics, Cochran's Q and logistic regression. In total, 15.7% and 74.0% reported incident (tooth loss only in 2012) and prevalent tooth loss (tooth loss in 1992 and 2012). Significant differences occurred between the 1992 and 2012 prevalence of using toothpicks (from 48.3% to 69.1%), smoking (from 26.9% to 10.1%) and alcohol consumption (from 41.5% to 50.5%), 29% and 15.6% increased use of toothpicks and alcohol consumption, whereas 15.5% stopped daily smoking. Increased use of fluoridated tooth paste, smoking cessation and failure to increase use of toothpicks was associated with prevalent tooth loss between age 50 and 70. This study revealed positive and negative trends in oral health behaviours over a 20-year period in persons aged 50 at baseline. Mixed support was obtained for the assumption that oral health promoting lifestyle transitions follow experience with tooth loss. Older people with tooth loss experience could benefit from targeted counselling aimed at coping with oral diseases.


Pembrolizumab for the first-line treatment of non-small cell lung cancer.
Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field. Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and -189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created. Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.


Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans.
The major fungal pathogen Candida albicans can occupy diverse microenvironments in its human host. During colonization of the gastrointestinal or urogenital tracts, mucosal surfaces, bloodstream, and internal organs, C. albicans thrives in niches that differ with respect to available nutrients and local environmental stresses. Although most studies are performed on glucose-grown cells, changes in carbon source dramatically affect cell wall architecture, stress responses, and drug resistance. We show that growth on the physiologically relevant carboxylic acid, lactate, has a significant impact on the C. albicans cell wall proteome and secretome. The regulation of cell wall structural proteins (e.g. Cht1, Phr1, Phr2, Pir1) correlated with extensive cell wall remodeling in lactate-grown cells and with their increased resistance to stresses and antifungal drugs, compared with glucose-grown cells. Moreover, changes in other proteins (e.g. Als2, Gca1, Phr1, Sap9) correlated with the increased adherence and biofilm formation of lactate-grown cells. We identified mating and pheromone-regulated proteins that were exclusive to lactate-grown cells (e.g. Op4, Pga31, Pry1, Scw4, Yps7) as well as mucosa-specific and other niche-specific factors such as Lip4, Pga4, Plb5, and Sap7. The analysis of the corresponding null mutants confirmed that many of these proteins contribute to C. albicans adherence, stress, and antifungal drug resistance. Therefore, the cell wall proteome and secretome display considerable plasticity in response to carbon source. This plasticity influences important fitness and virulence attributes known to modulate the behavior of C. albicans in different host microenvironments during infection.


Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model.
A disturbed process of gonadal formation and maintenance may result in testicular dysgenesis syndrome or disorders of sex development (DSDs), with an increased germ cell cancer (GCC) risk. Early diagnosis and treatment requires the identification of relevant risk factors and initial pathologic stages. To evaluate current knowledge and novel insights regarding GCC risk in patients with DSDs, with the aim of providing a model for clinical use. A Medline search was conducted to identify all original and review articles assessing the aetiology of GCC, GCC risk in DSD patients, new predictive markers related to GCC, and possible clinical scenarios related to GCC and DSDs. Embryonic development is controlled by orchestrated patterns of gene and subsequent protein expression. Knowledge of these networks is essential to understand the mechanisms of disturbed development including GCC formation. GCCs are subdivided into seminomas and nonseminomas, and they all arise from embryonic germ cells that have failed to mature appropriately. The precursor is known as carcinoma in situ (also referred to as testicular intratubular neoplasia and intratubular germ cell neoplasia unclassified) in a testicular microenvironment and gonadoblastoma in a dysgenetic/ovarian microenvironment. GCCs mimic embryonic development, resulting in the identification of diagnostic markers (eg, OCT3/4, SRY [sex determining region Y]-box 2 [SOX2], and [sex determining region Y]-box 17 [SOX17]). Novel insights indicate a subtle interplay of specific single nucleotide polymorphisms, environmental factors, and epigenetic aberrations in the aetiology of GCCs. A genvironmental model combining these factors is presented, proposed as a guideline for clinical management by an experienced multidisciplinary team. The goal is individualised treatment including preservation of gonadal function (if possible) and prevention of malignant transformation. A hypothesis is presented in which combined interactions of epigenetic and environmental parameters affect embryonic gonadal development, resulting in delayed/blocked germ cell maturation that determines the risk for GCC formation. Current and future possibilities for early detection of GCCs in risk populations and follow-up in a clinical setting are discussed. This review analyses current knowledge about the underlying networks that relate to the development of a germ cell cancer in the context of a disorder of sex development. A combined effect of epigenetic and environmental factors is identified in the pathogenesis, and a model is proposed to apply this knowledge to clinical practice.


NTP Toxicology and Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
Tetrachloroethylene is used primarily as a dry cleaning agent, an industrial solvent for fats, oils, tars, rubber, and gums, and a metal degreasing agent. Tetrachloroethylene had antihelminthic uses, particularly for hookworms (1.6-8 g/60 kg), and was formerly used in combination with some grain protectants and fumigants. Toxicology and carcinogenesis studies of tetrachloroethylene (99.9% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 103 weeks. The exposure concentrations used (0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to tetrachloroethylene at 100-1,600 ppm for 6 hours per day, 5 days per week. During the 13-week studies, 1,600 ppm tetrachloroethylene was lethal to 20%-70% of the rats and mice and reduced the final body weights of survivors. In rats, tetrachloroethylene at 200-800 ppm caused minimal to mild hepatic congestion. In dosed male and female mice, minimal to mild hepatic leukocytic infiltration, centrilobular necrosis, bile stasis (400-1,600 ppm), and mitotic alteration (200-1,600 ppm) were produced. Tetrachloroethylene exposure also caused minimal renal tubular cell karyomegaly in mice at concentrations as low as 200 ppm. During the 2-year studies, exposure to tetrachloroethylene did not consistently affect body weight gains in either rats or mice. Exposure at 400 ppm tetrachloroethylene reduced the survival of male rats (control, 23/50; low dose, 20/50; high dose, 12/50). This reduced survival may have been related to an increased incidence of mononuclear cell leukemia. Tetrachloroethylene at both exposure concentrations reduced the survival of male mice (46/50; 25/50; 32/50), whereas exposure at 200 ppm reduced female mouse survival (36/50; 31/50; 19/50). Early deaths in mice may have been related to the development of hepatocellular carcinomas. Both concentrations of tetrachloroethylene were associated with increased incidences of mononuclear cell leukemia in male rats (28/50; 37/50; 37/50). In female rats, tetrachloroethylene increased the incidence of leukemia (18/50; 30/50; 29/50) and decreased the time to occurrence of the disease. Tetrachloroethylene produced renal tubular cell karyomegaly in male and female rats, renal tubular cell hyperplasia in male rats, and renal tubular cell adenomas or adenocarcinomas (combined) in male rats (1/49; 3/49; 4/50). The incidence of the renal tubular cell tumors was not statistically significant; these uncommon tumors have been consistently found at low incidences in male rats in other 2-year studies of chlorinated ethanes and ethylenes. One low dose male rat had a kidney lipoma, and another had a nephroblastoma. Four high dose male and two high dose female rats had gliomas of the brain, whereas one control male and one control female had this tumor. In male and female mice, tetrachloroethylene caused dose-related increases in the incidences of hepatocellular neoplasms. In males, tetrachloroethylene at 200 ppm increased the incidence of hepatocellular adenomas (11/49; 8/49; 18/50) and at both concentrations increased the incidence of hepatocellular carcinomas (7/49; 25/49; 26/50). In female mice, tetrachloroethylene at both concentrations increased the incidences of hepatocellular carcinomas (1/48; 13/50; 36/50). Tetrachloroethylene also produced renal tubular cell karyomegaly in both sexes of mice, and one low dose male mouse had a tubular cell adenocarcinoma. In these inhalation studies, there were no neoplastic changes in the respiratory tracts of either species, but there was an increase in the incidence of squamous metaplasia in the nasal cavities in dosed male rats (0/50; 5/50; 5/50). Tetrachloroethylene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of male Syrian hamster or male Sprague-Dawley rat liver S9. Tetrachloroethylene was not mutagenic in was not mutagenic in L5178Y/TK± mouse lymphoma cells with or without metabolic activation and did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. Tetrachloroethylene did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of metabolic activation. An audit of the experimental data was conducted for these 2-year studies on tetrachloroethylene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenicity of tetrachloroethylene for male F344/N rats as shown by an increased incidence of mononuclear cell leukemia and uncommon renal tubular cell neoplasms. There was some evidence of carcinogenicity of tetrachloroethylene for female F344/N rats as shown by increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenicity for B6C3F1 mice as shown by increased incidences of both hepatocellular adenomas and carcinomas in males and of hepatocellular carcinomas in females. Synonyms: carbon bichloride; carbon dichloride; ethylene tetrachloride; per; perc; perchlor; perchlorethylene; perchloroethylene; perk; tetrachlorethylene; 1,1,2,2-tetrachloroethylene Trade names: Ankilostin; Antisal 1; Dee-Solv; Didakene; Dow-Per; ENT 1860; Fedel-Un; Nema; Perclene; Percosolv; Perklone; PerSec; Tetlen; Tetracap; Tetraleno; Tetravec; Tetroguer; Tetropil