BMP-3 is a novel inhibitor of both activin and BMP-4 signaling in Xenopus embryos.
In Xenopus, the biological effects of BMP-3 oppose those of ventralizing BMPs, but the mechanism for this antagonism remains unclear. Here, we demonstrate that BMP-3 is a dorso-anteriorizing factor in Xenopus embryos that interferes with both activin and BMP signaling. BMP-3 acts by binding to ActRIIB, the common type II receptor for these proteins. Once BMP-3 binds to ActRIIB, it cannot be competed off by excess ligand making a receptor complex that is unable to activate R-Smads and transduce signal. Consistent with a model where BMP-3 interferes with activin and BMPs through a shared receptor, we show that overexpression of BMP-3 can only be rescued by co-injection of xActRIIB. Our results identify BMP-3 as a novel antagonist of both activin and BMPs and uncover how some of the diverse developmental processes that are regulated by both activin and BMP signaling can be modulated during embryogenesis.


Novel targets in gastric and esophageal cancer.
Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant chemotherapy, radiotherapy or both have increased the survival of patients with loco-regional disease. However, most patients with GC or EC have advanced disease either at diagnosis or during the follow-up, and despite recent advances, these patients still do poorly. Understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC, including EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into clinical benefit for patients with these common malignancies.


Successive Administration of Streptococcus Type 5 Group A Antigens and S. typhimurium Antigenic Complex Corrects Elevation of Serum Cytokine Concentration and Number of Bone Marrow Stromal Pluripotent Cells in CBA Mice Induced by Each Antigen Separately.
Administration of bacterial antigens to CBA mice induced an increase in serum concentration of virtually all cytokines with a peak in 4 h after administration of S. typhimurium antigens and in 7 h after administration of streptococcus antigens. In 20 h, cytokine concentrations returned to the control level or were slightly below it. In 4 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, we observed a significant decrease in serum concentrations of IFN-γ, IL-10, GM-CSF, IL-12, and TNF-α, in comparison with injection S. typhimurium antigens alone and IL-5, IL-10, GM-CSF, and TNF-α in comparison with injection of streptococcus antigens alone; the concentrations of IL-2 and IFN-γ, in contrast, increased by 1.5 times in this case. In 20 h after administration of S. typhimurium antigens, the number of multipotential stromal cells (MSC) in the bone marrow and their cloning efficiency (ECF-MSC) increased by 4.8 and 4.4 times, respectively, in comparison with the control, while after administration of streptococcus antigens by 2.6 and 2.4 times, respectively. In 20 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, these parameters increased by 3.2 and 2.9 times, respectively, in comparison with the control, i.e. the observed increase in the level of MSC count and ECF-MSC is more consistent with the response of the stromal tissue to streptococcus antigens. Thus, successive administration of two bacterial antigens corrected both serum cytokine profiles and MSC response to administration of each antigen separately, which indicates changeability of the stromal tissue in response to changes in the immune response.


Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia.
In a phase IV trial, 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56(bright) (CD3(-)/16(-)/56(bright)) and CD16(+) (CD3(-)/16(+)/56(+)) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56(bright) NK cell counts and high expression of NKp30 or NKp46 on CD16(+) NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML.


Urbanization and environmental change during the economic transition on the Mongolian Plateau: Hohhot and Ulaanbaatar.
Driven by drastic socioeconomic changes in China and Mongolia, urbanization has become one of the most significant driving forces in the transformation of the Mongolian Plateau in the past 30 years. Using Hohhot and Ulaanbaatar as case studies, we developed a holistic approach to examine the socioeconomic and natural driving forces for urbanization and to investigate the impact on the urban environment. We used a multidisciplinary approach and relied on a variety of data sources to assess the changes of the landscape and environment of the two cities. We detected a rapid urbanization in Hohhot and Ulaanbaatar, both in terms of urban population growth and urban land expansion, from 1990 to 2010, with a much faster speed in 2000-2010. The local geo-physical conditions have constrained the spatial direction of expansion. Ulaanbaatar lagged behind Hohhot for about a decade when measured by indicators of urban population and urban land. Both cities have a degraded urban environment and a growing air pollution epidemic. While Hohhot had worse air pollution than Ulaanbaatar in the early 2000s, the gap between the two cities became smaller after 2010. The research presented here highlights the following as key determinants for urbanization and environmental change: (1) the co-evolution of urbanization, economic development, and environmental change; (2) the urbanization of transitional economies driven by the change of the economic structure, i.e., the development by both manufacturing and tertiary sectors and the change in the primary sector; and (3) the recent institutional changes and increased integration with the global economy.


A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States.
In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'.


Sex differences, activation level, and bilateral electrodermal activity.
The effects of the activation level and subject's sex on bilateral skin conductance measures were studied. Thirty right-handed subjects (15 males and 15 females) were exposed to three types of stimulus conditions: rest-period, verbal task and spatial task. Results showed that no relationship was observed between EDA asymmetry and the increase in the activation level induced by the verbal and the spatial tasks. Males showed both higher SCRs and greater frequency of responses on the left than on the right hand. The direction of electrodermal asymmetry remained constant regardless of the stimulus conditions. It was concluded that sex differences are important in the study of EDA asymmetry and that this asymmetry appeared to depend on peripheral variations.


Early and late ventricular arrhythmias complicating ST-segment elevation myocardial infarction.
Ventricular arrhythmias can be life-threatening complications of ST-segment elevation myocardial infarction (STEMI). To describe the incidence, predictors and in-hospital impact of early ventricular arrhythmia (EVA, occurring<day 2 after STEMI) and late ventricular arrhythmia (LVA, occurring≥day 2 after STEMI) in patients with STEMI. Data from 13,523 patients enrolled in a prospective registry were analysed. Logistic and Cox regressions were performed to identify predictors of EVA, LVA and in-hospital all-cause mortality. Predictors of LVA were used to build a risk score. EVA occurred in 678 patients (5%), whereas 120 patients (0.9%) experienced LVA, at a median timing of 3days after STEMI. EVA was associated with a significantly higher risk of all-cause mortality (hazard ratio: 1.44, 95% confidence interval: 1.17-1.76; P=0.001), whereas no association was observed with LVA (hazard ratio 0.86, 95% confidence interval 0.57-1.28; P=0.45). Multivariable predictors of LVA were: age≥65years; serum creatinine≥85μmol/L on admission; pulse pressure≤45mmHg on admission; presence of a Q wave on admission electrocardiogram; Thrombolysis In Myocardial Infarction flow grade<3 after percutaneous coronary intervention; and left ventricular ejection fraction≤45%. The score derived from these variables allowed the classification of patients into four risk categories: low (0-21); low-to-intermediate (22-34); intermediate-to-high (35-44); and high (≥45). Observed LVA rates were 0.2%, 0.3%, 0.9% and 2.5%, across the four risk categories, respectively. The model demonstrated good discrimination (20-fold cross-validated c-statistic of 0.76) and adequate calibration (Hosmer-Lemeshow P=0.23). EVA is 5-fold more common than LVA in the setting of STEMI, and portends a higher risk of in-hospital all-cause mortality. LVA is mainly associated with the patient's baseline risk profile and surrogate markers of larger infarct size. We developed and internally validated a risk score identifying patients at high risk of LVA for whom early intensive care unit discharge may not be suitable.


Between everyday politics and political elites: transmission and coupling within Westminster's parliamentary e-petitions system.
Popular dissatisfaction with representative democracy has encouraged governments and legislatures worldwide to experiment with democratic innovations. However, despite calls for a 'systemic' approach to the study of democratic engagement and participation, empirical knowledge is limited about the diffusion of democratic innovations within civil society, and, in particular, about the connective mechanisms that bring the 'voice' of citizens to the 'ears' of political elites. This article responds to this gap, presenting original empirical research examining the UK House of Commons' e-petitions system. This research maps public engagement with parliamentary e-petitions across a range of expressive spaces, and highlights the facilitative role of non-institutional intermediaries. However, it also underlines the predominant role of institutional actors in structuring public participation, and shows that effective transmission between the informal public and formal political spheres remains contingent on both 'designed-in powers' of institutional coupling and 'developed practices' of public engagement. Through this analysis, the article makes an important contribution to debates concerning democratic innovations, political participation, and institutional design. The online version contains supplementary material available at 10.1057/s41293-022-00208-9.


Pharmacokinetics of rufloxacin once daily in patients with lower respiratory tract infections.
The pharmacokinetic properties of rufloxacin, a new quinolone antibacterial agent, were evaluated in ten patients with lower respiratory tract infections. Patients were given 400 mg of rufloxacin once a day for seven to nine days. Plasma concentrations of the drug were determined by high-performance liquid chromatography and bioassay at regular intervals during treatment. After the first administration, maximal plasma concentrations were 3.17 +/- 0.36 mg/l (mean +/- SEM) and were reached at 4.2 +/- 0.7 h. At the end of treatment peak plasma concentrations increased to 7.26 +/- 0.52 mg/l. Elimination half-life was 38.2 +/- 2.9 h, with a mean extent of accumulation of 2.96 +/- 0.30. Treatment was well tolerated, with no abnormalities noted during routine laboratory examinations. Two days after the last administration, measurable levels of rufloxacin were still observed in plasma, indicating that the long half-life of rufloxacin assures valuable antibacterial activity even after discontinuation of treatment.


Pathogenic factors in the later pulmonary phase of Angiostrongylus cantonensis-infected rats.
In rats infected with different worm burdens of Angiostrongylus cantonensis, the loss of body weight was proportional to the increasing dose of infection. Body weight was correlated inversely with female worm burden (r = -0.669), the sum of mean numbers of larvae per gram of faeces (LPG) (r = -0.527) and lung weight (r = -0.761). Lung weight was positively correlated with female worm burden (r = 0.785) and the sum of mean numbers of LPG (r = 0.685). On the other hand, in rats infected with larvae developed from gamma-irradiated first-stage larvae (Experiment B) or infected rats treated with the drug ivermectin (Experiment C), body weight was inversely correlated with the sum of mean numbers of LPG (r = -0.798, Experiment B; r = -0.670, Experiment C) and lung weight (r = -0.862, Experiment B; r = -0.812, Experiment C), but not with female worm burden. Furthermore, lung weight was positively correlated with the sum of mean numbers of LPG (r = -0.783, Experiment B; r = 0.899, Experiment C), but not with the female worm burden. From these results, it is concluded that in the later pulmonary phase of infection in rats the pathogenic effects may be closely related to the increasing number of first-stage larvae produced by female worms.


Effect of COVID-19 Quarantine on Voice Handicap Index in Female Classical Singers.
This study aimed to verify the impact of vocal deviation in the quality of life of classical female singers over the quarantine imposed by the COVID-19 pandemic through self-assessments. Fifty five professional classical female singers filled out an online questionnaire including general questions such as identification, age, professional experience time, vocal classification, time of singing, and rehearsal studies. They all answered the protocol Classical Singing Handicap Index, adapted for this research, which analyses three subscales: Disability, Handicap, and Impairment. There was no significant difference in the perceived total handicap index score (40% of 120 points). Regarding the three domains analyzed, Disability was significantly higher than Impairment (P = 0.012). In addition, the correlation with the variables identified that Impairment subscale showed a negative correlation with the variable hours of rehearsal (r = -0.335, P = 0.040). The COVID-19 quarantine does not seem to cause a significant impact on the voice of professional classical female singers probably due to their degree of experience and vocal preparation.


Risk behaviours and prevalence of sexually transmitted infections and HIV in a group of Dominican gay men, other men who have sex with men and transgender women.
The objectives of this study were to estimate the point prevalence of sexually transmitted infection (STI) and to investigate the sexual practices and behaviours associated with STIs in a group of gay men, other men who have sex with men and transgender women (GMT) in the province of La Romana, Dominican Republic. A cross-sectional study of a convenience sample of GMT persons. The study was conducted in the province of La Romana, Dominican Republic, in June-July 2013. Out of 117 GMT persons screened, a total of 100 completed the study. Participants had to be at least 18 years of age, reside in La Romana and have had sex with another man in the preceding 12 months. All participants were interviewed and tested for STI. The main outcome of interest was the detection of any STI (HIV, herpes simplex virus type 2 (HSV-2), syphilis, hepatitis B or C) by serology. Among 100 participants, the median age was 22 years (range 18-65). One-third had consumed illicit drugs the preceding year and only 43% consistently used condoms. Prevalence was 38% for HSV-2, 5% for HIV and 13% for syphilis. There were no cases of hepatitis B or C. Factors associated with the odds of a STI were age >22 years (OR=11.1, 95% CI 3.6 to 34.5), receptive anal intercourse (OR=4.2, 95% CI 1.3 to 13.6) and having ≥2 male sexual partners during the preceding month (OR=4, 95% CI 1.3 to 12.5). In this group of GMT persons, seroprevalence of STI was high, and a number of risk behaviours were associated with STI. These preliminary data will help inform policy and programmes to prevent HIV/STI in GMT persons in the region.


Monitoring sustainable forest management in different jurisdictions.
The concept of sustainable forest management (SFM) requires forest resource managers to monitor and collect information pertaining to their environmental, economic and social impact. There are increasing expectations from a variety of publics (government, customers, and other stakeholders) that forests be demonstrably well-managed, creating incentives for forest managers to design credible systems for assessing their management performance. It is against this background that local, national and international approaches to regulating forest practices have been evolving. This article reviews the different dimensions of governance as they relate to monitoring and information reporting in the forest sector. Specifically, it discusses the changing role of sovereignty, the effects of globalization and the emergence of civil society stakeholders in forestry-related decision-making. Concepts such as sovereignty and globalization have important implications for monitoring forest practices and for defining SFM. Whether SFM standard creation and enforcement involves a sovereign, shared-sovereignty or civil society approach will affect the level and nature of SFM monitoring. As a result, we need to better consider the concept of monitoring appropriate to the scale and intensity of operations, how monitoring and information reporting standards differ between jurisdictions, and what this means for independently verifying SFM at an inter-jurisdictional level.


Knowledge, attitude, barriers, and associated factors of obstetric ultrasound among pregnant women in public hospitals, Ethiopia, 2022: a cross-sectional study.
Obstetric ultrasound is a non-invasive imaging modality that uses sound waves to provide a real-time image of the foetus. Women's knowledge of and attitudes toward ultrasound are suggested to influence their responses, and a variety of barriers also influence their practices. This study aimed to assess the knowledge, attitude, barriers, and associated factors of obstetric ultrasound among pregnant women in public hospitals in Addis Ababa. An institution-based cross-sectional study was conducted on 422 pregnant women from July to August 2021 using systematic random sampling. A structured questionnaire was employed, entered into Epi Info 7.2, and analysed in SPSS 23. Bivariate and multivariate logistic regression was used to identify associated factors. The proportion with good knowledge of obstetric ultrasound was 51.4%, and that with positive attitudes was 70.1%. Women with a degree and above (AOR 2.70; 95% CI 0.21-35.23), government employment (AOR 3.901; 95% CI 1.92-7.90), and previous ultrasound exposure (AOR 1.966; 95% CI 1.24-3.12) were significantly associated with knowledge. Government-employed women (AOR 6.83; 95% CI 2.43-19.18), women with 1000-5000birr in household income (AOR 5.31; 95% CI 2.01-14.03), and women with a history of births with congenital anomalies (AOR 21.07; 95% CI 2.09-21.21) were significantly associated with the attitude toward obstetric ultrasound. Participants in the study expressed a variety of barriers that influenced their practices; long waiting time was the most common (77.3%). Pregnant women's levels of knowledge and attitudes towards obstetric ultrasound were moderately good. However, there were a variety of barriers, including patient privacy, waiting time, handling, and side effects, that influenced the utilisation of ultrasound.


Appendectomy due to lead poisoning: a case-report.
Lead poisoning is a common occupational health hazard in developing countries and many misdiagnoses and malpractices may occur due to unawareness of lead poisoning symptoms. We report a case of occupational lead poisoning in an adult battery worker with abdominal colic who initially underwent appendectomy with removal of normal appendix. Later on he was diagnosed with lead poisoning and was treated appropriately with lead chelator (CaNa2EDTA). Lead poisoning is frequently overlooked as the differential diagnosis of acute abdomen which may result in unnecessary surgery. Appropriate occupational history taking is helpful in making a correct diagnosis. Occupational lead poisoning is a preventable disorder and a serious challenge for the health and labor authorities in developing countries.


Activation of adult mammalian retinal stem cells in vivo via antagonism of BMP and sFRP2.
The adult mammalian retina does not have the capacity to regenerate cells lost due to damage or disease. Therefore, retinal injuries and blinding diseases result in irreversible vision loss. However, retinal stem cells (RSCs), which participate in retinogenesis during development, persist in a quiescent state in the ciliary epithelium (CE) of the adult mammalian eye. Moreover, RSCs retain the ability to generate all retinal cell types when cultured in vitro, including photoreceptors. Therefore, it may be possible to activate endogenous RSCs to induce retinal neurogenesis in vivo and restore vision in the adult mammalian eye. To investigate if endogenous RSCs can be activated, we performed combinatorial intravitreal injections of antagonists to BMP and sFRP2 proteins (two proposed mediators of RSC quiescence in vivo), with or without growth factors FGF and Insulin. We also investigated the effects of chemically-induced N-methyl-N-Nitrosourea (MNU) retinal degeneration on RSC activation, both alone and in combination withthe injected factors. Further, we employed inducible Msx1-CreERT2 genetic lineage labeling of the CE followed by stimulation paradigms to determine if activated endogenous RSCs could migrate into the retina and differentiate into retinal neurons. We found that in vivo antagonism of BMP and sFRP2 proteins induced CE cells in the RSC niche to proliferate and expanded the RSC population. BMP and sFRP2 antagonism also enhanced CE cell proliferation in response to exogenous growth factor stimulation and MNU-induced retinal degeneration. Furthermore, Msx1-CreERT2 genetic lineage tracing revealed that CE cells migrated into the retina following stimulation and/or injury, where they expressed markers of mature photoreceptors and retinal ganglion cells. Together, these results indicate that endogenous adult mammalian RSCs may have latent regenerative potential that can be activated by modulating the RSC niche and hold promise as a means for endogenous retinal cell therapy to repair the retina and improve vision.


The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis.
In this study, we estimate the impact of a recent relapse on physical and mental health in subjects with relapsing-remitting multiple sclerosis (RRMS) using validated patient-reported outcome (PRO) measures. Subjects enrolled in the Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital with RRMS were eligible for enrollment. Subjects with a clinical visit within 45 days of a relapse were identified and divided into groups based on whether the relapse occurred before (recent relapse) (n = 59) or after the visit (pre-relapse) (n = 31). A group of subjects with no relapses was also identified (remission) (n = 336). PRO measures in these three groups were compared. All outcomes were compared using a t test and linear regression controlling for age, disease duration, sex, and EDSS. Subjects with a recent relapse had significantly worse functioning on several physical and mental health scales compared to subjects in remission even after adjusting for potential confounders. Subjects with a recent relapse also showed significant deterioration on PRO measures over 1 year compared to subjects in remission (P < 0.05 for each comparison). Subjects in the pre-relapse group were not significantly different than subjects in remission. Clinical relapses have a measurable effect on PRO in subjects with RRMS.


Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance.
It is important to identify a germline mutation in a patient with an inherited cancer syndrome to allow mutation carriers to be included in cancer surveillance programs, which have been proven to save lives. Many of the mutations identified result in premature termination of translation, and thus in loss-of-function of the encoded mutated protein. However, the significance of a large proportion of the sequence changes reported is unknown. Some of these variants will be associated with a high risk of cancer and have direct clinical consequence. Many criteria can be used to classify variants with unknown significance; most criteria are based on the characteristics of the amino acid change, on segregation data and appearance of the variant, on the presence of the variant in controls, or on functional assays. In inherited cancers, tumor characteristics can also be used to classify variants. It is worthwhile to examine the clinical, morphological and molecular features of a patient, and his or her family, when assessing whether the role of a variant is likely to be neutral or pathogenic. Here we describe the advantages and disadvantages of using the tumor characteristics of patients carrying germline variants of uncertain significance (VUS) in BRCA1, BRCA2, or in one of the mismatch repair (MMR) genes, MLH1, MSH2, or MSH6, to infer pathogenicity.


Family-Involved Mental Health Care Among OEF/OIF Veterans With and Without PTSD Using VHA Administrative Records.
Prior research indicates that veterans are interested in including family members in health care and that family-inclusive mental health treatment can improve treatment outcomes. Consequently, the Veterans Health Administration's (VHA) directive requires providers to offer family-inclusive mental health services to veterans. However, the extent to which veterans engage in family-inclusive mental health services at the VHA remains unclear. Using data from a longitudinal registry of male and female veterans with and without posttraumatic stress disorder, we examined the extent to which veterans included family members in their mental health care and predictors of engagement in family-involved therapy visits using VHA administrative records over a 5-year time span. Of the 1,329 veterans who received mental health care during the study, 8.4% received a family therapy visit-the number of visits per veteran ranged from 1 to 34. Results from logistic regressions indicate that relative to White veterans, Black veterans were 61.0% less likely to receive a family-involved therapy visit. Married veterans or veterans living with a partner, and veterans with poor romantic relationship functioning, were more likely to receive a family-involved therapy visit. These findings indicate that only a small percentage of veterans received a family therapy visit across 5 years. Efforts to understand barriers to family-involved therapy visits and strategies to increase engagement in family-involved visits may improve clinical outcomes and promote patient-centered care.


Different medical expenses incurred by appendiceal cystadenoma in China: Report of three cases.
Appendiceal cystadenoma, the most common type of what has been generally termed 'mucocele' of the appendix, has unique clinical characteristics. In this study, three similar clinical manifestations of appendiceal cystadenoma are presented, with different subsequent management and diverse prognostic outcomes relating to the characteristics of the disease, the wishes of the patients, the medical workers and social factors. In this study, we provide details of three cases of appendiceal cystadenomas.


Mobility and recalcitrance of organo-chromium(III) complexes.
Hexavalent chromium [Cr(VI)] is a major industrial pollutant. Bioremediation of Cr(VI) to Cr(III) is a viable clean-up approach. However, Cr(VI) bioreduction also produces soluble organo-Cr(III) complexes, and little is known about their behavior in the environment. When tested with soil columns, citrate-Cr(III) showed little sorption to soil; malate-Cr(III) had limited partitioning with soil; and histidine-Cr(III) exhibited significant interaction with soil. It appears that the mobility varies depending on the organic ligand. Further, Ralstonia eutropha JMP 134 and Pseudomonas aeruginosa pAO1 readily degraded malate, citrate, and histidine, but not the corresponding organo-Cr(III) complexes. The recalcitrance is not due to toxicity, but the complexes are likely to cause hindrance to enzymes, as malate dehydrogenase and amino acid oxidase could not use malate-Cr(III) and histidine-Cr(III), respectively. The data are in agreement with the reports of soluble organo-Cr(III) complexes in the environment.


Multi-site assessment of soil nitrogen stocks across temperate forests under different thinning intensities, recovery times, and site conditions.
Increasing research interests have been paid to understand the factors controlling soil nitrogen (N) stocks under diverse environmental conditions and forest thinning regimes. This study investigated soil N stocks across 13 temperate forests, each of which received three thinning intensities (unthinned control, 15-30 %, and 30-50 % basal area removals) under varying pre-treatment conditions (altitude, slope, soil pH, soil moisture, stand age, stand density, diameter at breast height, and tree height). The total N stored in the forest floor (L, F, and H layers) and mineral soils (0-10, 10-20, and 20-30 cm) was determined 1, 4, and 7 years after thinning. Given the various site conditions and thinning regimes, a standardized effect size was used to analyze the influences of thinning on N stocks. The N stocks (Mg N ha-1) of the forest floor and at 0-10, 10-20, and 20-30 cm mineral soil depths were 0.02-0.46, 0.32-3.21, 0.29-3.03, and 0.25-2.54 across all studied forests, respectively. The averaged effect sizes indicated decrease in forest floor N stocks and increase in mineral soil N stocks under thinning due to the reduced litterfall and eventual input of thinning residues. Thinning intensity negatively affected the effect sizes for the N stocks (P < 0.05), suggesting that excessively heavy thinning may be inappropriate for retaining forest soil N. However, multimodel inference showed that soil pH (relative importance = 1.00) and stand age (relative importance = 0.42) had the largest influence on the effect sizes for forest floor and mineral soil N stocks. This pattern suggests that the effects of thinning on soil N stocks might vary with pre-treatment conditions, even more than thinning intensities and recovery time; therefore, thinning to manage forest soil N should consider pre-treatment environmental conditions in addition to thinning regime.


The expression of several Cbf genes at the Fr-A2 locus is linked to frost resistance in wheat.
The C-repeat binding factor (Cbf) gene family has been shown to have a critical role in the regulation of low-temperature stress response in Arabidopsis. In Triticum monococcum, a locus carrying a family of Cbf-like genes, orthologs of Arabidopsis Cbf genes, is tightly linked to the frost tolerance locus Fr-A ( m ) 2, representing candidates for the differences in frost tolerance mapped at this locus. In this work we show that several Cbf genes have dramatically different levels of induction after cold exposure in hexaploid wheat. The Cbf-transcription levels differ between substitution and single chromosome recombinant lines carrying different 5A chromosomes or chromosome segments of the chromosome 5A from frost-tolerant and frost-sensitive wheat varieties. When the expression of eight Cbf genes, previously mapped at the Fr-A2 locus was investigated with gene specific primers using real-time RT-PCR, three Cbf sequences (Cbf1A, Cbf1C, Cbf7) showed a significantly higher relative transcription level (more than fourfold change) in lines differing for the Fr-A2 region. Differences in Cbf expression were also associated with a variation in frost tolerance. These results suggest that the amount of some Cbf mRNAs might be a critical factor for determining the level of frost tolerance in wheat.


An examination of the intrapuparial development of Chrysomya albiceps (Wiedemann, 1819) (Calliphoridae: Diptera) at three different temperatures.
The determination of intrapuparial development periods and development times of insects with holometabolous metamorphosis is necessary both in terms of developmental biology and for minimum Post-mortem interval (PMImin) calculations in forensic entomology. In this study, Chrysomya albiceps (Wiedemann, 1819), which is a cosmopolitan species and one of the most rapidly attracted to carrion, was studied. The focus was the intrapuparial development periods of this species at varying temperatures (20, 25, and 30 °C), knowledge which is used in forensic entomology for the estimation of Post-mortem interval (PMI) and is a type of black box. At the specified temperatures, pupae were collected and puparia were dissected hourly; thus, developmental periods were determined, and minimum and maximum starting times of these periods were calculated. With this research, a total of 20 periods, nine of which are new, were determined. The hourly determination of intrapuparial development periods at three different temperatures is the first in the world for this species.


Computer-based virtual reality colonoscopy simulation improves patient-based colonoscopy performance.
Colonoscopy simulators that enable one to perform computer-based virtual colonoscopy now exist. However, data regarding the effectiveness of this virtual training are limited. To determine whether virtual reality simulator training translates into improved patient-based colonoscopy performance. The present study was a prospective controlled trial involving 18 residents between postgraduate years 2 and 4 with no previous colonoscopy experience. These residents were assigned to receive 16 h of virtual reality simulator training or no training. Both groups were evaluated on their first five patient-based colonoscopies. The primary outcome was the number of proctor 'assists' required per colonoscopy. Secondary outcomes included insertion time, depth of insertion, cecal intubation rate, proctor- and nurse-rated competence, and patient-rated pain. The simulator group required significantly fewer proctor assists than the control group (1.94 versus 3.43; P ≤ 0.001), inserted the colonoscope further unassisted (43 cm versus 24 cm; P=0.003) and there was a trend to intubate the cecum more often (26% versus 10%; P=0.06). The simulator group received higher ratings of competence from both the proctors (2.28 versus 1.88 of 5; P=0.02) and the endoscopy nurses (2.56 versus 2.05 of 5; P=0.001). There were no significant differences in proctor-, nurse- or patient-rated pain, or attention to discomfort. Computer-based colonoscopy simulation in the initial stages of training improved novice trainees' patient-based colonoscopy performance.


Free modeling with Rosetta in CASP6.
We describe Rosetta predictions in the Sixth Community-Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP), focusing on the free modeling category. Methods developed since CASP5 are described, and their application to selected targets is discussed. Highlights include improved performance on larger proteins (100-200 residues) and the prediction of a 70-residue alpha-beta protein to near-atomic resolution.


Towards the synthesis of aryl glucuronides as potential heparanase probes. An interesting outcome in the glycosidation of glucuronic acid with 4-hydroxycinnamic acid.
This work describes our preliminary efforts towards the development of aryl glucuronides as potential probes for heparanase. During the course of these initial investigations, attempted glycosidation of methyl 2,3,4-tri-O-acetyl-alpha-D-glucopyranosyluronate trichloroacetimidate with 4-hydroxycinnamic acid gave a complex mixture of four different components. These were identified as the 1-cinnamyl glucuronate ester 13, the cinnamyl linked disaccharide 14, the glucuronate trichloroacetamide 15, and the glucuronyl alpha-fluoride 16. This paper rationalises the formation of each of these products, and reports our efforts in trying to optimise the formation of the alpha-fluoride 16.


Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart.
Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumors. Angiosarcoma of bone is rare and poorly characterized. For angiosarcoma of soft tissue, some pathways seem to be involved in tumor development. Our aim was to evaluate the role of these pathways in angiosarcoma of bone. We collected 37 primary angiosarcomas of bone and used 20 angiosarcomas of soft tissue for comparison. Immunohistochemistry was performed on constructed tissue microarrays to evaluate expression of CDKN2A, TP53, PTEN, BCL2, CDK4, MDM2, cyclin D1, β-catenin, transforming growth factor-β (TGF-β), CD105, phospho-Smad1, phospho-Smad2, hypoxia-inducible factor-1α, plasminogen activator inhibitor type 1 (PAI-1), VEGF, CD117 and glucose transporter--1. PIK3CA was screened for hotspot mutations in 19 angiosarcomas. In nearly 55% of the angiosarcoma of bone, the retinoblastoma (Rb) pathway was affected. Loss of CDKN2A expression was associated with a significantly worse prognosis. No overexpression of TP53 or MDM2 was found, suggesting that the TP53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-β signaling with immunoreactivity for phospho-Smad2 and PAI-1. Although the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be active in both tumor groups, different mechanisms were involved: 41% of angiosarcoma of bone showed a decrease in expression of PTEN, whereas in angiosarcoma of soft tissue overexpression of KIT was found (90%). PIK3CA hotspot mutations were absent. In conclusion, the Rb pathway is involved in tumorigenesis of angiosarcoma of bone. The PI3K/Akt pathway is activated in both angiosarcoma of bone and soft tissue, however, with a different cause; PTEN expression is decreased in angiosarcoma of bone, whereas angiosarcomas of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies. Both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway. However, interference with TGF-β signaling may be specifically relevant in angiosarcoma of bone.


Controlled-release levodopa/carbidopa. II. Sinemet CR4 treatment of response fluctuations in Parkinson's disease.
Sixteen patients with Parkinson's disease and therapeutic response fluctuations entered an open-label trial of a controlled-release carbidopa/levodopa preparation, Sinemet CR4. Sinemet CR4 behaved as a slow release preparation. At the end of 6 weeks CR4 treatment, there was an increase in percent "on" time and mean interdose interval; the number of daily doses and "off" periods were diminished and a slight reduction in the variability of plasma levodopa levels was observed. Overall benefit waned over the next 6 months, despite addition of standard levodopa or Sinemet to overcome the delayed onset of antiparkinsonian effect of CR4 which resulted from prolongation in the Tmax for levodopa. The major benefits of CR4 were reduction in off time and in the number of daily off periods, with fewer levodopa doses per day and prolongation of the interdose interval.


A case of ROS1-rearranged lung adenocarcinoma with osteoblastic bone metastasis.
A 53-year-old woman was referred to our hospital for detailed examination of abnormal chest shadows recognized on CT imaging. Transbronchial lung biopsy of a right S6 nodular shadow led to a diagnosis of lung adenocarcinoma. FDG-PET-CT showed FDG accumulation in the Th11 and L2 vertebral bodies and osteoblastic bone lesions. Since osteoblastic bone metastasis in lung cancer is extremely rare, CT-guided bone biopsy was performed. The tumor was diagnosed as ROS1-rearranged lung adenocarcinoma, for which crizotinib was administered, which led to improvement of both the primary and metastatic lesions. We report here a rare case of ROS1-rearranged lung adenocarcinoma with osteoblastic bone metastasis of lung cancer.


A bad rap: Rap1 signaling and oncogenesis.
In the paper by Ishida et al. in this issue of Cancer Cell, the authors report the results of targeted inactivation of a Rap1-specific GTPase-activating protein (GAP) gene, called SPA-1, in mice. Rap1 hyperactivation was observed in hematopoietic cells, which led over time to features associated with symptoms typical of human myeloid dyslastic and myeloid proliferative diseases. The authors present additional data showing that the level of Rap1 activation is important for regulating myelopoiesis and that, in the right context, can deliver an oncogenic signal.


The root cortex cell hydraulic conductivity is enhanced with increasing chromosome ploidy in wheat.
Wheat (Triticum spp.) root water uptake is enhanced with increasing chromosome ploidy, but the underlying mechanism is unclear. The leaf transpiration rate (E), individual root (Lp(r)) and cortical cell (Lp(c)) hydraulic conductivity, cortical cell volume (V(c)) and transcription levels of two putative plasma intrinsic aquaporin genes (PIPs) were investigated in wheat seedlings with different chromosome ploidy (Triticum monococcum (2X, AA); Triticum dicoccum (4X, BB); Triticum aestivum (6X, AABBDD)). The E, Lp(r) and Lp(c) of wheat increased with increasing ploidy, but the Vc was reduced. Osmotic stress significantly reduced the E, Lp(c), Lp(r), and the relative mRNA content of TaPIP1;2 and TaPIP2;5 in wheat. Under both well-watered and osmotic stress conditions, the Lp(r) was significantly and positively correlated with the E and Lp(c), and the relative mRNA content of TaPIP1;2 and TaPIP2;5 was significantly and positively correlated with Lp(c) and Lp(r), respectively. For well-watered or osmotically stressed wheat plants, the Lp(c) was reduced, but the L(p)(c)/Lp(r) increased with increasing V(c), suggesting that Vc affects root radical water transport. Thus, the increased Lp(c) and transcription levels of TaPIP1;2 and TaPIP2;5 in wheat roots provides insight into the mechanisms underlying enhanced root water uptake with increasing chromosome ploidy during wheat evolution.


Differential expression of the two distinct replication protein A subunits from Cryptosporidium parvum.
Apicomplexan parasites differ from their host by possessing at least two distinct types (long and short) of replication protein A large subunits (RPA1). Different roles for the long and short types of RPA1 proteins have been implied in early biochemical studies, but certain details remained to be elucidated. In the present study, we have found that the Cryptosporidium parvum short-type RPA1 (CpRPA1A) was highly expressed at S-phase in parasites during the early stage of merogony (a cell multiplication process unique to this group of parasites), but otherwise present in the cytosol at a much lower level in other cell-cycle stages. This observation indicates that CpRPA1A is probably responsible for the general DNA replication of the parasite. On the other hand, the long-type CpRPA1B protein was present in a much lower level in the early life cycle stages, but elevated at later stages involved in sexual development, indicating that CpRPA1B may play a role in DNA recombination. Additionally, CpRPA1B could be up-regulated by UV exposure, indicating that this long-type RPA1 is probably involved in DNA repair. Collectively, our data implies that the two RPA1 proteins in C. parvum are performing different roles during DNA replication, repair and recombination in this parasite.


Geographical access to point-of-care testing for hypertensive disorders of pregnancy as an integral part of maternal healthcare in Ghana.
Hypertensive disorders of pregnancy (HDP) are associated with high maternal mortality in Ghana and globally. Evidence shows that there is poor availability of pregnancy-related point-of-care (POC) tests in Ghana's primary healthcare (PHC) clinics (health centre or community-based health planning services facilities). Therefore, we employed geographic information systems to estimate the geographical distribution of and physical accessibility to HDP POC testing services in the Upper East Region (UER), Ghana. We collected data on 100 out of 365 PHC clinics, public hospitals providing HDP testing, PHC clinic type, ownership, and availability of urine dipsticks and blood pressure (BP) devices. We also obtained the geo-located data of the PHC clinics and hospitals using the global positioning system. We employed ArcGIS 10.4 to measure the distance and travel time from the location of each PHC clinic without HDP POC testing services as well as from all locations of each district to the nearest hospital/clinic where the service is available. The travel time was estimated using an assumed motorised tricycle speed of 20 km/hour. We further calculated the spatial distribution of the hospitals/clinics providing HDP POC testing services using the spatial autocorrelation tool in ArcMap, and Stata version 14 for descriptive statistical analysis. Of the 100 participating PHC clinics, POC testing for HDP was available in 19% (14% health centres and 5% community-based health planning services compounds) in addition to the 10 hospitals use as referral points for the service. The findings indicated that the spatial pattern of the distribution of the health facilities providing HDP POC testing was random (z-score = -0.61; p = 0.54). About 17% of the PHC clinics without HDP POC testing service were located > 10 km to the nearest facility offering the service. The mean distance and travel time from PHC clinics without HDP POC testing to a health facility providing the service were 11.4 ± 9.9 km and 31.1 ± 29.2 min respectively. The results suggest that if every 19% of the 365 PHC clinics are offering HDP POC testing in addition to these 10 hospitals identified, then the estimated coverage (health facility-to-women in fertility age ratio) in the UER is 1: 3,869. There is poor physical accessibility to HDP POC testing services from PHC clinics without HDP POC testing in the UER. Mothers who obtain maternal healthcare in about 17% of the PHC clinics travel long distances (> 10 km) to access the service when needed. Hence, there is a need to improve the availability of HDP POC diagnostic tests in Ghana's rural clinics.


An epigenome-wide association study of metabolic syndrome and its components.
The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10-8). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10-9) and waist circumference (P = 5.21 × 10-9). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10-7). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10-8). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.


Successful haploidentical hematopoietic stem cell transplantation (HSCT) and durable engraftment by repeated donor lymphocyte infusions for a Chinese patient with transfusion-dependent hemoglobin (Hb) Hammersmith and massive splenomegaly.
Hemoglobin (Hb) Hammersmith is a rare form of unstable β-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT). A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαβ/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions. Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.


Pentagastrin activation of adenylate cyclase in human gastric biopsy specimens.
Adenylate cyclase activity of human fundic mucosa is log-normally distributed and equally stimulated by pentagastrin and histamine. Cimetidine inhibits the histamine, but not the pentagastrin effect, which is even intensified by H2-receptor blockade. The results indicate that pentagastrin and histamine activate adenylate cyclase via distinct receptors.


Xeroradiographic localization of implanted 125I seeds.
In many instances implanted 125I seeds are shown better by xeroradiography than by conventional film-cassette combinations.


Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial.
Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. ClinicalTrials.gov, NCT02632812 . Registered 14 December 2015.


Characterization and transcription analysis of a cloned sequence derived from a major developmentally regulated mRNA of D. discoideum.
The plasmid pDd 812 contains a portion of a poly(A)+ RNA sequence isolated from developing cells of the cellular slime mold Dictyostelium discoideum (Williams and Lloyd, 1979). The poly(A)+ RNA complementary to this plasmid shows an increase in concentration during the first 4 hr of development followed by a decrease in concentration during the following 4 hr. This RNA is very abundant after 3-4 hr of development, constituting at least 2% of the poly(A)+ RNA population. In this study, we demonstrate that this poly(A)+ RNA is an mRNA sequence by translating the RNA complementary to pDd 812 in a heterologous system. The mRNA directs the synthesis of a major polypeptide of 33,000 daltons and a minor polypeptide of 31,000 daltons. We have used the plasmid DNA immobilized on filters to analyze the transcription of this RNA sequence in isolated nuclei. The amount of transcript synthesized in nuclei isolated at various stages of development which was complementary to pDd 812 changed in the same way as did the cytoplasmic concentration of this RNA--that is, maximal transcription occurred after 3-4 hr of development. Because this result was observed using labeling periods as short as 5 min, we believe that this change is unlikely to reflect a change in the rate of processing of RNA. We interpret these results to indicate that, at least in part, the control of the synthesis of this RNA is at the level of gene transcription.


Alternative extraction methods for Zearalenone: Microwave Assisted Extraction and Accelerated Solvent Extraction.
Zearalenone (ZON) was extracted from wheat and corn by using Microwave Assisted Extraction and Accelerated Solvent Extraction. A factorial design approach was applied to evaluate the influence of the most important extraction parameters such as temperature, time and solvent extraction mixture on fortified cereals. ZON was determined by LC-MS without performing any clean-up after the extraction to better evaluate the extraction efficiency. The selected extraction conditions were tested on samples which had been previously used in an international proficiency test. Applying the selected extraction conditions both alternative extraction procedure provided satisfactory results comparable to the most commonly used method.


Nonmotor symptoms in Parkinson's disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model.
To investigate the psychiatric symptoms accompanying the early phases of Parkinson's disease (PD), we injected adult rats with 10.5 microg 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal striatum. The resulting neurodegeneration led, 12 weeks after injection, to a mild (36%) reduction of striatal dopamine. We tested the behavioral response of sham and 6-OHDA-lesioned animals at different time points after injection to evaluate the onset and progression of behavioral abnormalities. The results showed that such a mild reduction of dopamine levels was associated with a decrease in anxiety-like behavior, an increase in "depression"-like behavior, and a marked change in social behavior. Learning and memory abilities were not affected. Overall, the PD rat model used here displays behavioral alterations having face validity with psychiatric symptoms of the pathology and thus appears to be a valuable tool for investigating the neural bases of the early phases of PD.


Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial.
Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1. In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422. Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups. Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy. National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.


Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease.
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.


Molecular cloning and nucleotide sequence cDNA encoding nucleoside diphosphate kinase of rice (Oryza sativa L.).
We isolated a rice cDNA encoding nucleoside diphosphate kinase (NDK, EC 18.104.22.168). The deduced amino acid sequence of the rice NDK shows highest homology to spinach NDK-I. The rice NDK gene exhibits a strong codon bias (73.8% GC) in the third position of the codon. DNA blot analysis indicated that at least single NDK gene is present in rice genome.


Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis.
To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.


Muscle alkali-soluble protein, carnitine, water and electrolytes in patients with persistent post-operative infection.
The muscle contents of water, electrolytes, creatine, alkali-soluble protein (ASP) and carnitine were determined using percutaneous muscle biopsy technique. Seven patients with prolonged catabolic states and subsequent respiratory failure were studied. Twelve age- and sex-matched healthy subjects were used for comparison. The muscle content of alkali-soluble protein in relation to the content of DNA was less than half of control values, indicating a loss of more than 50% of muscle protein content. The muscle carnitine content was 25.9 +/- 6.5 mumol/g alkali-soluble protein, suggesting a preserved muscle carnitine concentration. Total muscle water was increased by over 20%, mainly due to an increase in extracellular water. Muscle sodium and chloride contents were doubled. The content of magnesium was slightly reduced but muscle potassium was normal. The marked depletion of muscle protein may have contributed to the requirements for artificial ventilation and the difficulties in weaning off the ventilator. The increase in muscle water masks the loss of metabolically active muscle tissue yielding low values for energy expenditure when relating to body weight. The benefit of the use of the ASP/DNA ratio in nutritional assessment is emphasised.


New analysis of the radio source counts.
Luminosity evolution and not density evolution emerges as the dominating influence explaining the radio source counts.


Test-retest stability analysis of resting brain activity revealed by blood oxygen level-dependent functional MRI.
To assess test-retest stability of four functional magnetic resonance imaging (fMRI)-derived resting brain activity metrics: the seed-region-based functional connectivity (SRFC), independent component analysis (ICA)-derived network-based FC (NTFC), regional homogeneity (ReHo), and the amplitude of low frequency fluctuation (ALFF). Simulations were used to assess the sensitivity of SRFC, ReHo, and ALFF to noise interference. Repeat resting blood oxygen level-dependent (BOLD) fMRI were acquired from 32 healthy subjects. The intraclass correlation coefficient (ICC) was used to assess the stability of the four metrics. Random noise yielded small random SRFC, small but consistent ReHo and ALFF. A neighborhood size greater than 20 voxels should be used for calculating ReHo in order to reduce the noise interference. Both the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC)-based SRFC were reproducible in more spatially extended regions than ICA NTFC. The two regional spontaneous brain activity (SBA) measures, ReHo and ALFF, showed test-retest reproducibility in almost the whole gray matter. SRFC, ReHo, and ALFF are robust to random noise interference. The neighborhood size for calculating ReHo should be larger than 20 voxels. ICC > 0.5 and cluster size > 11 should be used to assess the ICC maps for ACC/PCC SRFC, ReHo, and ALFF. BOLD fMRI-based SBA can be reliably measured using ACC/PCC SRFC, ReHo, and ALFF after 2 months.


Characterization of the novel HLA-DRB3*03:37 allele by sequencing-based typing.
HLA-DRB3*03:37 differs from HLA-DRB3*03:01:01:01 by one nucleotide substitution in codon 205 in exon 4.


Hemicrania continua-like headache with leprosy: casual or causal association?
Hemicrania continua is a strictly unilateral, moderate to severe, continuous, indomethacin-responsive primary headache disorder with ipsilateral autonomic cranial symptoms at the time of exacerbations. We describe a 30-year-old woman with a 4-month history of indomethacin-responsive hemicrania continua-like headache and one-month history of mononeuritis multiplex due to leprosy. Indomethacin was successfully weaned off after completion of antileprotic therapy.


Persistence of auditory nerve response and absence of brain-stem response in severe cerebral ischaemia.
Cerebral ischaemia, in which the brain-stem components of the ABP were isoelectric, was accompanied by the paradoxical persistence of the compound action potential of the auditory nerve (wave 1). This ischaemia was induced in cats by reducing mean arterial blood pressure and elevating intracranial pressure, resulting in decreased cerebral perfusion pressure (CPP). This is unexpected since the inner ear is supplied by a branch of an intracranial artery. To study this phenomenon, CPP was manipulated and when average CPP was 13.5 mm Hg, only wave 1 remained. In 7 of 9 experiments, clamping of both common carotid arteries did not abolish wave 1. Experiments with radioactive tracers demonstrated a remaining residual blood flow through the inner ear. This remaining auditory nerve response is probably not due to a very low metabolism of the inner ear or to the cochlea being supplied by anastomoses from the middle ear, supplied by the external carotid artery. The residual cochlear blood flow and the persistent wave 1 can probably be explained in the following way: at low CPPs the smaller intracranial blood vessels collapse so that the brain tissue is not perfused, leading to loss of the brain-stem components of the ABP. However, flow still persists in the larger intracranial arteries. This blood preferentially flows to the cochlea since the intracochlear pressure is slightly below the intracranial pressure due to the presence of the oval and round windows. Thus a sufficient blood flow to the cochlea is maintained, with sparing of wave 1.


[A system for collecting historical professional exposures in the workplace in Piedmont (ESP ALP).]
Background. ARPA Piemonte carries out occupational exposure measurements of chemical agents in workplace environment to support the Occupatonal Health and Safety Units of Local Health Boards for the assessment of the exposure level of dangerous chemical. Data are reported in internal documents, but are not available for other purposes. Objectives. Organize the occupational exposure measures collected by ARPA Piemonte, in order to facilitate their availability, in accordance with the indications of the European Foundation for the Improvement of Living and Working Conditions. Methods. An application in a relational database environment was defined and developed to collect and structure information relating to companies, interventions, tasks and / or monitored sampling points, samples and measurements performed. Results. Data on chemical exposure related to interventions carried out by ARPA Piemonte in the period from 2005 to part of 2020 have been collected in the ESP ALP application. ESP ALP contains information about 161 companies, 193 interventions, 815 sampling points, 3.490 samples and 18.576 measurements and information on companies obtained from the 2011 Census of Economic Activities and the archives of the National Institute for Insurance against Accidents at Work (INAIL). Discussion. We verified the feasibility of retrieving and organizing the information collected in past years in an integrated environment that facilitates its processing and use. Finally, we confirm the usefulness of collaboration between multidisciplinary professionals.


Ultrastructural visualization of low-density lipoproteins during receptor binding and cellular endocytosis.
Human fibroblasts possess surface receptors which have a high affinity for low-density lipoproteins (LDL). However, previous studies have not provided direct ultrastructural visualization of LDL bound to the receptor. To permit direct observation of unlabeled LDL during receptor binding and cellular endocytosis, we examined several fixative regimens which employ lipophilic stains. Staining with tannic acid, an oxidized form of ruthenium red, or potassium ferrocyanide imparted sufficient contrast to individual molecules of LDL to permit high-resolution electron microscopy of receptor binding and endocytosis. The LDL molecule was observed in immediate contact with the receptor and the coated vesicle, indicating that receptor-ligand binding occurs by short-range interactions.


Growth of copper organophosphate nanosheets on graphene oxide to improve fire safety and mechanical strength of epoxy resins.
With the high integration of electronic products in our daily life, high-performance epoxy resins (EP) with excellent flame retardancy, smoke suppression, and mechanical strength are highly desired for applications. In this study, copper organophosphate nanosheets were evenly grown on the surface of graphene oxide (GO) via a self-assembly process based on coordination bonding and electrostatic interactions. The resultant nanohybrid endowed EP with satisfactory flame retardant effect and improved mechanical properties. Incorporating functionalized nanosheets of merely 1 wt% loading, the impact strength of the EP nanocomposites improved by 147% when compared to 1% EP-GO. Additionally, the nanosheets inhibited the smoke and heat release of EP, and the limiting oxygen value of EP-EGOPC reached ∼29%. The mechanism analysis verified that the existence of organophosphate and copper-containing components associated with the physical barrier of GO promoted the hybrid aromatization of the char layer, thereby improving the fire safety of epoxy matrix. This research offers a new interfacial method for designing functional nanosheets with good interface compatibility and high flame-retardant efficiency in polymers.


Radiotherapy and immediate two-stage breast reconstruction with a tissue expander and implant: complications and esthetic results.
To report complications, failure rate, and esthetic results in patients undergoing immediate breast reconstruction with a tissue expander and implant, with or without adjuvant treatment. We reviewed the records of the 77 patients who underwent immediate breast reconstruction with an expander/implant between January 1999 and December 2000. Complications were assessed using the Common Toxicity Criteria, version 2, scale. Esthetic results were assessed by the physician using five criteria. Of the 77 patients, 55 had received adjuvant radiotherapy. The median follow-up was 25 months. Complications appeared to correlate with radiotherapy (14% for nonirradiated patients; 51% for irradiated patients; p = 0.006) and adjuvant chemotherapy (54% with chemotherapy [CHT] vs. 25% without CHT; p = 0.02). Breast reconstruction failed in 21% of patients (9% of nonirradiated patients and 24% of irradiated patients; p = 0.1), and chemotherapy was associated with a worse rate of failure (34% with CHT vs. 6% without CHT, p = 0.005). Adjuvant tamoxifen, however, correlated neither with complications (45% with tamoxifen vs. 39% without; p = 0.15) nor with failure (21% with tamoxifen and 23% without, p = 0.79). Esthetic results were acceptable in 60% of cases. Immediate breast reconstruction with an expander/implant can be considered even for patients requiring adjuvant treatment. However, the complication and failure rates are three times higher after postexpander radiotherapy.


Deciphering the photolysis products and biological concerns of triclosan under UVC and UVA.
Triclosan (TCS) is omnipresent in the environment and has drawn increasing attention due to its potential adverse effects on human health. Direct photolysis of TCS readily occurs, especially in the surface layers of waters that receive abundant ultraviolet radiation during the daytime. However, biological concerns and the identification of toxic products during TCS photolysis have been explored limitedly. Therefore, in the present work, the structural characterization of the photolysis products by UVC and UVA were performed based on the mass spectra and fragmental ions. The results displayed that TCS was more readily eliminated by UVC than UVA, and the product species were completely different when TCS was degraded by UVC and UVA, respectively. Two products, m/z 235 and m/z 252, were produced via reductive dechlorination and nucleophilic substitution with UVC, while three dioxin-like isomer products were generated by dechlorination, cyclization and hydroxylation. Furthermore, the results of biological concerns suggested that the elimination of TCS did not represent the disappearance of biological risks. Specifically, more hazardous and photolysis products were formed during TCS photolysis with ultraviolets. For instance, the dioxin-like isomer products were highly microtoxic and genotoxic, and mildly antiestrogenic. The positive findings highlighted the biological concerns of TCS photolysis by ultraviolet radiation in the aquatic environment.


Gene expression patterns during somatic embryo development and germination in maize Hi II callus cultures.
Gene expression patterns were profiled during somatic embryogenesis in a regeneration-proficient maize hybrid line, Hi II, in an effort to identify genes that might be used as developmental markers or targets to optimize regeneration steps for recovering maize plants from tissue culture. Gene expression profiles were generated from embryogenic calli induced to undergo embryo maturation and germination. Over 1,000 genes in the 12,060 element arrays showed significant time variation during somatic embryo development. A substantial number of genes were downregulated during embryo maturation, largely histone and ribosomal protein genes, which may result from a slowdown in cell proliferation and growth during embryo maturation. The expression of these genes dramatically recovered at germination. Other genes up-regulated during embryo maturation included genes encoding hydrolytic enzymes (nucleases, glucosidases and proteases) and a few storage genes (an alpha-zein and caleosin), which are good candidates for developmental marker genes. Germination is accompanied by the up-regulation of a number of stress response and membrane transporter genes, and, as expected, greening is associated with the up-regulation of many genes encoding photosynthetic and chloroplast components. Thus, some, but not all genes typically associated with zygotic embryogenesis are significantly up or down-regulated during somatic embryogenesis in Hi II maize line regeneration. Although many genes varied in expression throughout somatic embryo development in this study, no statistically significant gene expression changes were detected between total embryogenic callus and callus enriched for transition stage somatic embryos.


Behavior-change interventions to improve antimicrobial stewardship in human health, animal health, and livestock agriculture: A systematic review.
Antimicrobial resistance (AMR) is an economic, food security, and global health threat accelerated by a multitude of factors including the overuse and misuse of antimicrobials in the human health, animal health, and agriculture sectors. Given the rapid emergence and spread of AMR and the relative lack of development of new antimicrobials or alternative therapies, there is a need to develop and implement non-pharmaceutical AMR mitigation policies and interventions that improve antimicrobial stewardship (AMS) practices across all sectors where antimicrobials are used. We conducted a systematic literature review per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify peer-reviewed studies that described behavior-change interventions that aimed to improve AMS and/or reduce inappropriate antimicrobial use (AMU) among human health, animal health, and livestock agriculture stakeholders. We identified 301 total publications- 11 in the animal health sector and 290 in the human health sector-and assessed described interventions using metrics across five thematic areas- (1) AMU, (2) adherence to clinical guidelines, (3) AMS, (4) AMR, and (5) clinical outcomes. The lack of studies describing the animal health sector precluded a meta-analysis. Variation across intervention type, study type, and outcome precluded a meta-analysis for studies describing the human health sector; however, a summary descriptive analysis was conducted. Among studies in the human health sector, 35.7% reported significant (p<0.05) pre- to post-intervention decreases in AMU, 73.7% reported significant improvements in adherence of antimicrobial therapies to clinical guidelines, 45% demonstrated significant improvements in AMS practices, 45.5% reported significant decreases in the proportion of isolates that were resistant to antibiotics or the proportion of patients with drug-resistant infections across 17 antimicrobial-organism combinations. Few studies reported significant changes in clinical outcomes. We did not identify any overarching intervention type nor characteristics associated with successful improvement in AMS, AMR, AMU, adherence, nor clinical outcomes.


Assessment for Predictors of Rise in Hemoglobin A1c During Extended Use of a Closed-Loop Control System.
We assessed predictors of rising hemoglobin A1c (HbA1c) during long-term use of closed-loop control (CLC) in children aged 6-13 years with type 1 diabetes. Participants used a CLC system during a 16-week randomization phase followed by a 12-week extension phase. We compared an "Increased-HbA1c" group (n = 17, ≥0.5% rise in HbA1c between randomization and extension phases) to a "Maintained-Improvement" group (n = 18, had stable or improved HbA1c). The Increased-HbA1c group had higher pre-CLC HbA1c (8.42% ± 0.80 vs. 7.45% ± 0.93, P = 0.002). Contrary to a-priori hypotheses, there were no differences in Δ-height-for-age z-score, a surrogate for a pubertal growth spurt (+0.16 vs. -0.15, P = 0.113), or number of carbohydrate boluses per day, a surrogate for missed boluses (4.4 ± 2.2 vs. 5.2 ± 2.1, P = 0.263). Both groups maintained high rates in closed-loop. Thus, some children exhibit meaningful rise in HbA1c after initial CLC use, likely from multiple contributing factors, and may benefit from added encouragement during ongoing use.


24-month outcomes of an eHealth universal program for students and parents to prevent adolescent alcohol use: A cluster randomized controlled trial in schools.
Parents play a critical role in delaying adolescent initiation of alcohol and other drug use. However, the majority of prevention programs focus on adolescents only. This study tested the acceptability and effectiveness of an eHealth universal program for students and parents to prevent adolescent alcohol use. A cluster randomized controlled trial (RCT) was conducted between 2018 and 2020 with students from one grade level (aged 12-14 years) from 12 Australian secondary schools randomly allocated to the intervention or control conditions. Students accessed a web-based program in class and parents accessed the program online at their convenience. Data were collected via online questionnaires from students (N = 572) and parents (N = 78) at baseline, and 12- and 24- months post baseline. Multilevel, mixed effects regression models were used to analyse student data. More students in the control group reported having at least one standard alcoholic drink and engaging in heavy episodic drinking in the previous 12 months at both 12- and 24-month follow up compared to students in the intervention, however, these differences were not statistically significant. Students in the intervention group reported greater increases in alcohol-related knowledge, compared to the control students. Qualitative data from parents indicated that they found the program useful, however, the number of parents who enrolled in the research study (13.9 %) was low. Parent engagement increased following implementation of an interactive parent/adolescent homework task. Small sample size, low prevalence of alcohol use and parental engagement, and relatively short follow-up period may have contributed to lack of observed intervention effect, other than on alcohol-related knowledge. Parents who engaged with the program found it useful, however, implementation strategies that encourage parent-child interaction and communication may increase parent engagement for future programs.


Mapping combined with principal component analysis identifies excellent lines with increased rice quality.
Quality-related traits are some of the most important traits in rice, and screening and breeding rice lines with excellent quality are common ways for breeders to improve the quality of rice. In this study, we used 151 recombinant inbred lines (RILs) obtained by crossing the northern cultivated japonica rice variety ShenNong265 (SN265) with the southern indica rice variety LuHui99 (LH99) and simplified 18 common rice quality-related traits into 8 independent principal components (PCs) by principal component analysis (PCA). These PCs included peak and hot paste viscosity, chalky grain percentage and chalkiness degree, brown and milled rice recovery, width length rate, cooked taste score, head rice recovery, milled rice width, and cooked comprehensive score factors. Based on the weight ratio of each PC score, the RILs were classified into five types from excellent to poor, and five excellent lines were identified. Compared with SN265, these 5 lines showed better performance regarding the chalky grain percentage and chalkiness degree factor. Moreover, we performed QTL localization on the RIL population and identified 94 QTLs for quality-related traits that formed 6 QTL clusters. In future research, by combining these QTL mapping results, we will be using backcrossing to aggregate excellent traits and achieve quality improvement of SN265.


Sleep in pituitary insufficient patients compared to patients with depression and healthy controls at baseline and after challenge with CRH.
Sleep disturbances are prevalent in both patients with pituitary insufficiency and with depression. The role of corticotropin releasing hormone (CRH), involved in sleep regulation, has not been fully clarified. Pituitary insufficiency is an ideal model for studying sleep-endocrine effects since no consecutive hormone releases and feedback effects occur after hormone administration. 11 male patients with a chronic insufficiency of the anterior pituitary gland (PI) and under stable hormonal substitution were studied during three consecutive nights in the sleep laboratory. The first night served for adapting to laboratory setting, during the second night placebo was administered and during the third night 4 × 50 μg CRH were injected in pulsatile fashion. Sleep parameters were additionally compared with those of 15 healthy male controls (C) and 15 male patients with depression (D). CRH administration was associated with a numerical increase of wake time (115 ± 15 to 131 ± 13 min) and a decrease of REM sleep (89 ± 8 to 80 ± 8 min), REM latency (69 ± 14 to 55 ± 9 min) and slow wave sleep (66 ± 16 to 57 ± 15 min). Yet, none of these changes reached statistical significance. PI showed a worse sleep profile as compared to both control groups, e.g. indicated by a significantly lower sleep efficiency index (PI:0.80 ± 0.03 vs. C:0.94 ± 0.01 vs. D:0.87 ± 0.03). In conclusion sleep-EEG changes after CRH in PI patients resemble those found in in part in patients with depression. Sleep in anterior pituitary insufficiency was impaired despite full hormonal substitution possibly suggesting an alteration of the receptor organisation of brain structures involved in sleep regulation.


Rapid Cycle Deliberate Practice in Healthcare Simulation: a Scoping Review.
Rapid cycle deliberate practice (RCDP) is a type of simulation-based medical education (SBME) where learners cycle between deliberate practice and directed feedback until skill mastery is achieved before progressing to subsequent learning objectives. This scoping review examines and summarizes the literature on RCDP, compares RCDP to other modes of instruction, and identifies knowledge gaps for future research. Of the 1224 articles identified, 23 studies met inclusion criteria. The studies varied in design, RCDP technique implementation strategies, and outcome measures. RCDP is associated with positive outcomes in immediate learner performance. It is unclear if RCDP is superior to traditional simulation.


Comparing the diagnostic ability of inflammatory markers in metabolic syndrome.
Chronic low-grade inflammation contributes to the pathogenesis of the metabolic syndrome (MetS). Although some studies have demonstrated that several standard inflammatory markers provide diagnostic value for MetS, few studies have compared the diagnostic ability of various inflammatory markers. We demonstrated the diagnostic ability of several inflammatory markers in detecting MetS. Complement component 3 (C3), C4, high-sensitivity C-reactive protein (hs-CRP), leukocyte count, neutrophil, lymphocyte and neutrophil-to-lymphocyte ratio (NLR) concentrations were measured in 6312 participants living in Tianjin, China. MetS was defined according to American Heart Association criteria. Adjusted logistic models were used to assess associations between inflammatory markers and MetS. Receiver operating characteristic (ROC) curves were performed to determine the diagnostic values of inflammatory markers for MetS. The adjusted odds ratio (95% CI) of MetS for the highest inflammatory markers (C3, leukocyte, neutrophil, lymphocyte) quintile, when compared to the lowest quintile were 2.68 (2.12-3.38), 2.53 (2.05-3.11), 1.31 (1.06-1.62) and 1.94 (1.60-2.37), respectively. ROC analysis showed that the optimal cut-off values were 101.0mg/dl for C3 (Area under the ROC curve (AUC)=0.68), 5.41×1000cells/mm3 for leukocyte (AUC=0.63), 3.20×1000cells/mm3 for neutrophil (AUC=0.60) and 1.82×1000cells/mm3 for lymphocyte (AUC=0.62). No significant association was observed between the other inflammatory markers and MetS. Among the inflammatory markers assessed in this population, C3 has the strongest diagnostic value in detecting MetS. Further studies are encouraged to determine the efficacy of applying C3 to diagnosis and treatment in the clinical setting.


Effect of food restriction on tissue carnitine concentration in rats.
The effect of feeding different amounts of a standard laboratory pellet diet on tissue carnitine concentration was studied in four groups of rats. Group I was fed ad libitum, whereas food intake was restricted to 25, 20, and 15g protein/kg body weight/day in group II, III, and IV, respectively. The intake of food, protein, energy and carnitine was constant and adjusted to actual body weight in groups 2-4. Six weeks food restriction had no effect on muscle carnitine. Restricted diet caused lowered concentrations of carnitine in serum (group I, fed ad libitum, total 95.0 +/- 13.8, free 80.2 +/- 2.7; group II total 78.4 +/- 8.4, free 56.9 +/- 4.7; group III total 81.7 +/- 8.8, free 66.0 +/- 8.8; and group IV total 73.8 +/- 8.7, free 59.5 +/- 7.6 micromol/l) and urinary carnitine excretion (group I, total 7.1 +/- 3.3, free 6.3 +/- 3.1; group II, total 2.5 +/- 0.7, free 2.2 +/- 0.7; group III, total 1.9 +/- 0.8, free 1.6 +/- 0.8; and group IV, total 1.3 +/- 0.4 free 1.1 +/- 0.3 micromol/day). In contrast, the liver carnitine tended to increase when dietary intake was reduced (group I total 1.1 +/- 0.1, free 1.0 +/- 0.1; group II total 1.5 +/- 0.2, free 1.4 +/- 0.2; group III total 1.3 +/- 0.1, free 1.1 +/- 0.1; and group IV total 1.5 +/- 0.2, free 1.4 +/- 0.2 micromol/g dry wt). The highest liver carnitine concentrations were observed during the lowest dietary intake when also the serum and urine carnitine were lowest. We conclude that the amount of food intake has a direct impact on carnitine concentrations in the liver, serum, and urine while muscle carnitine concentration remains relatively stable despite wide variations in food intake.


Cardiac tamponade in an adolescent female: an unusual manifestation of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) affects approximately 0.6 children per 100,000. The disease is extremely rare in children under 5 years of age and is diagnosed predominantly in adolescent females. Children tend to present with more severe multisystem involvement than adults. Pericarditis occurs in approximately 25% of patients with SLE in all age groups. Progression to tamponade is extremely uncommon in the pediatric population. In the current report, an adolescent girl is diagnosed with SLE after presenting with signs and symptoms consistent with cardiac tamponade. A review of other pediatric patients with a similar presentation is also included.


Synergistic effect of Kalpaamruthaa on antiarthritic and antiinflammatory properties--its mechanism of action.
The present study was designed to evaluate the antiinflammatory properties of Kalpaamruthaa (KA) a modified indigenous Siddha formulation constituting Semecarpus anacardium nut milk extract (SA), Emblica officinalis (EO) and honey in acute and chronic antiinflammatory studies. A dose of 150 mg/kg b.wt. of SA and KA were used for the present studies. The effect of KA was compared with standard drug diclofenac sodium. It was observed that the drug KA exhibited enhanced effect on antiinflammatory and antiarthritic properties than sole SA treatment and the collective effect of KA might be due to the combined interactions of the phytochemicals such as flavonoids, tannins and other compounds such as vitamin c present in KA.


Acute mannitol intoxication in a patient with normal renal function.
A young, previously healthy patient with multiple trauma mistakenly received 400 grams of mannitol over a 3-hour period. The laboratory report of hyponatremia prompted treatment with hypertonic saline before the hyperosmolar state was recognized. The osmolal gap was 118. Mannitol intoxication in a patient without preexisting renal failure is unusual. Identification of an abnormal osmolal gap and recognition of the hyperosmolar state is discussed.


Downregulation of miR-16 promotes growth and motility by targeting HDGF in non-small cell lung cancer cells.
MicroRNAs play important roles in the development and progression of non-small cell lung cancer (NSCLC). miR-16 functions as a tumor-suppressor and is inhibited in several malignancies. Herein, we validated that miR-16 is downregulated in NSCLC tissue samples and cell lines. Ectopic expression of miR-16 significantly inhibited cell proliferation and colony formation. Moreover, miR-16 suppressed cell migration and invasion in NSCLC cells. Hepatoma-derived growth factor (HDGF) was found to be a direct target of miR-16 in NSCLC cell lines. Rescue experiments showed that the suppressive effect of miR-16 on cell proliferation, colony formation, migration, and invasion is partially mediated by inhibiting HDGF expression. This study indicates that miR-16 might be associated with NSCLC progression, and suggests an essential role for miR-16 in NSCLC.


Molecular cloning and characterization of a grapevine (Vitis vinifera L.) serotonin N-acetyltransferase (VvSNAT2) gene involved in plant defense.
Melatonin is a ubiquitous molecule and exists across kingdoms. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. A number of studies have been conducted on the melatonin content and exogenous melatonin treatment of grapevine (Vitis vinifera L.). However, key genes or enzymes of the melatonin biosynthetic pathway remain unclear. In this study, we cloned and identified the gene encoding serotonin N-acetyltransferase (SNAT) in grapevine (VvSNAT2). The VvSNAT2 protein was identified from a collection of 30 members of the grapevine GCN5-related N-acetyltransferase (GNAT) superfamily. Phylogenetic and protein sublocalization analyses showed that the candidate gene VvGNAT16 is VvSNAT2. Characterization of VvSNAT2 showed that its enzymatic activity is highest at a pH of 8.8 and a temperature of 45 °C. Analysis of enzyme kinetics showed the values of Km and Vmax of VvSNAT2 using serotonin were 392.5 μM and 836 pmol/min/mg protein, respectively. The expression of VvSNAT2 was induced by melatonin treatment and pathogen inoculation. Overexpression of VvSNAT2 in Arabidopsis resulted in greater accumulation of melatonin and chlorophyll and enhanced resistance to powdery mildew in the transgenic plants compared with the wild type (WT). Additionally, our data showed that the marker genes in the salicylic acid (SA) signaling pathway were expressed to higher levels in the transgenic plants compared with the WT. The VvSNAT2 gene was cloned and identified in grapevine for the first time. Our results indicate that VvSNAT2 overexpression activates the SA and JA signaling pathways; however, the SA pathway plays a central role in VvSNAT2-mediated plant defense.