Irradiation of intense characteristic x-rays from weakly ionized linear molybdenum plasma.
In the plasma flash x-ray generator, a high-voltage main condenser of approximately 200 nF is charged up to 55 kV by a power supply, and electric charges in the condenser are discharged to an x-ray tube after triggering the cathode electrode. The flash x-rays are then produced. The x-ray tube is a demountable triode that is connected to a turbo molecular pump with a pressure of approximately 1 mPa. As electron flows from the cathode electrode are roughly converged to a rod molybdenum target of 2.0 mm in diameter by the electric field in the x-ray tube, weakly ionized linear plasma, which consists of molybdenum ions and electrons, forms by target evaporation. At a charging voltage of 55 kV, the maximum tube voltage was almost equal to the charging voltage of the main condenser, and the peak current was about 20 kA. When the charging voltage was increased, the linear plasma formed, and the K-series characteristic x-ray intensities increased. The K lines were quite sharp and intense, and hardly any bremsstrahlung rays were detected. The x-ray pulse widths were approximately 700 ns, and the time-integrated x-ray intensity had a value of approximately 35 micro C/kg at 1.0 m from the x-ray source with a charging voltage of 50 kV.


Comparative vascular and renal tubular effects of angiotensin II receptor blockers combined with a thiazide diuretic in humans.
The goal of this study was to investigate whether angiotensin II receptor blockers (ARBs) induce a comparable blockade of AT1 receptors in the vasculature and in the kidney when the renin-angiotensin system is activated by a thiazide diuretic. Thirty individuals participated in this randomized, controlled, single-blind study. The blood pressure and renal hemodynamic and tubular responses to a 1-h infusion of exogenous angiotensin II (Ang II 3 ng/kg per min) were investigated before and 24 h after a 7-day administration of either irbesartan 300 mg alone or in association with 12.5 or 25 mg hydrochlorothiazide (HCTZ). Irbesartan 300/25 mg was also compared with losartan 100 mg, valsartan 160 mg, and olmesartan 20 mg all in association with 25 mg HCTZ. Each participant received two treatments with a 1-week washout period between treatments. The blood pressure response to Ang II was blocked by more than 90% with irbesartan alone or in association with HCTZ and with olmesartan/HCTZ and by nearly 60% with valsartan/HCTZ and losartan/HCTZ (P < 0.05). In the kidney, Ang II reduced renal plasma flow by 36% at baseline (P < 0.001). Irbesartan +/- HCTZ and olmesartan/HCTZ blocked the renal hemodynamic response to Ang II nearly completely, whereas valsartan/HCTZ and losartan/HCTZ only blunted this effect by 34 and 45%, respectively. At the tubular level, Ang II significantly reduced urinary volume (-84%) and urinary sodium excretion (-65%) (P < 0.01). These tubular effects of Ang II were only partially blunted by the administration of ARBs. These data demonstrate that ARBs prescribed at their recommended doses do not block renal tubular AT1 receptors as effectively as vascular receptors do. This observation may account for the need of higher doses of ARB for renal protection. Moreover, our results confirm that there are significant differences between ARBs in their capacity to induce a sustained vascular and tubular blockade of Ang II receptors.


Understanding Internal Migration: A Research Note Providing an Assessment of Migration Selection With Genetic Data.
Migration is selective, resulting in inequalities between migrants and nonmigrants. However, investigating migration selection is empirically challenging because combined pre- and post-migration data are rarely available. We propose an alternative approach to assessing internal migration selection by integrating genetic data, enabling an investigation of migration selection with cross-sectional data collected post-migration. Using data from the UK Biobank, we utilized standard tools from statistical genetics to conduct a genome-wide association study (GWAS) for migration distance. We then calculated genetic correlations to compare GWAS results for migration with those for other characteristics. Given that individual genetics are determined at conception, these analyses allow a unique exploration of the association between pre-migration characteristics and migration. Results are generally consistent with the healthy migrant literature: genetics correlated with longer migration distance are associated with higher socioeconomic status and better health. We also extended the analysis to 53 traits and found novel correlations between migration and several physical health, mental health, personality, and sociodemographic traits.


Contemporary diagnosis and treatment of conduct disorder in youth.
Conduct disorder (CD) is characterized by repetitive and persistent antisocial behaviors, being among the most frequently reported reasons of referral in youth. CD is a highly heterogeneous disorder, with possible specifiers defined according to age at onset, Limited Prosocial Emotions (LPE) otherwise known as Callous-Unemotional (CU) traits, Emotional Dysregulation (ED), and patterns of comorbidity, each with its own specific developmental trajectories. The authors review the evidence from published literature on the clinical presentations, diagnostic procedures, psychotherapeutic and psychoeducational approaches, and pharmacological interventions from RCT and naturalistic studies in youth. Evidence from studies including youths with LPE/CU traits, ED and aggression are also reviewed, as response moderators. Due to its clinical heterogeneity, relevant subtypes of CD should be carefully characterized to gain reliable information on prognosis and treatments. Thus, disentangling this broad category in subtypes is crucial as a first step in diagnosis. Psychosocial interventions are the first option, possibly improving LPE/CU traits and ED, especially if implemented early during development. Instead, limited information, based on low-quality studies, supports pharmacological options. Second-generation antipsychotics, mood stabilizers, and stimulants are first-line medications, according to different target symptoms, such as aggression and emotional reactivity. Developmental pathways including ADHD suggest a specific role of psychostimulants.


Deuterium-depleted water (DDW) inhibits the proliferation and migration of nasopharyngeal carcinoma cells in vitro.
Recent studies have demonstrated that natural water that has 65% of the deuterium concentration depleted, can exhibit anti-tumor properties. However, the anti-tumor effects of DDW on various nasopharyngeal carcinoma (NPC) cells have not previously been reported. In the present study, NPC cell lines and normal preosteoblast MC3T3-E1 cells were grown in RPMI1640 media containing different deuterium concentrations (50-150 ppm). The effects of DDW on the proliferation and migration of NPC and MC3T3-E1 cells were investigated using the MTT, plate colony formation, and Transwell assays, as well as Boyden chamber arrays, flow cytometry (FCM), western blot and immunofluorescence. We found that DDW was an effective inhibitor of NPC cell proliferation, plated colony formation, migration and invasion. In contrast, the growth of normal preosteoblast MC3T3-E1 cells was promoted when they were cultured in the presence of DDW. Cell cycle analysis revealed that DDW caused cell cycle arrest in the G1/S transition, reduced the number of cells in the S phase and significantly increased the population of cells in the G1 phase in NPC cells. Western blot analysis revealed that treatment with DDW significantly increased the expression of NADPH:quinone oxidoreductase-1 (NQO1), while immunofluorescence assay analysis revealed that treatment with DDW decreased the expression of PCNA and matrix metalloproteinase 9 (MMP9) in NPC cells. These results demonstrated that DDW is a novel, non-toxic adjuvant therapeutic agent that suppresses NPC cell proliferation, migration, and invasion by inducing the expression of NQO1 and causing cell cycle arrest, as well as decreasing PCNA and MMP9 expression.


[An experimental study on the neurotoxicity of 2-octanone and 2-hexanol, a metabolite of n-hexane].
An electrophysiological study of the neurotoxicity of 2-octanone (an analogue of methyl n-butyl ketone) and 2-hexanol (a metabolite of n-hexane) was conducted on rats as a part of the study to determine the specific molecular arrangement required for the development of peripheral neuropathy. The compound 2-octanone or 2-hexanol was administered subcutaneously in the daily dose of 400 mg/kg of each compound into the back of seven rats, weighing 290 g, 5 days per week for a period of 21 weeks. Animals treated with 2-octanone for 21 weeks failed to exhibit apparent clinical and neurophysiological evidence except a slight inhibition of weight gain and narcotic effects after treatment with the compound. The same doses of 2-hexanol for 21 weeks caused hypersalivation, gait disturbances, crossing phenomena of hind limbs and a failure of normal growth. Retardation of the conduction velocity in the motor and sensory nerve fibers and the prolonged motor latencies of the tail nerves (distal part) began to appear at the 14th week of the experiment when 9.6 g in the total dose had been given to each animal. These changes were intensified in the subsequent course of the experiment. Our previous experiments and the present results showed that n-hexane barely produced peripheral neuropathy in doses over 10.5 g, and that 2-hexanone (MBK), 2,5-hexanediol or 2,5-hexanedione never failed to produce a neuropathy even in doses less than 9.6 g of each compound. The above results suggest that the neurotoxic potency of 2-hexanol is greater than that of n-hexane but less than that of MBK, 2,5-hexanediol or 2,5-hexanedione.


The intravitreal penetration of orally administered ciprofloxacin in humans.
To evaluate the penetration of ciprofloxacin, a new wide-spectrum oral antibiotic, into the vitreous, ciprofloxacin was administered orally to 21 patients who were scheduled to undergo vitreal surgery. Seven patients received 750 mg ciprofloxacin 4 hr before surgery (group I), seven patients received this dose 8 hr before surgery (group II), and seven patients received two 750-mg doses of oral ciprofloxacin every 12 hr. The last dose was administered 12 hr before surgery (group III). Vitreous and blood samples were collected simultaneously and assayed for ciprofloxacin concentrations by bioassay and high-performance liquid chromatography.


A human Fab-based immunoconjugate specific for the LMP1 extracellular domain inhibits nasopharyngeal carcinoma growth in vitro and in vivo.
Nasopharyngeal carcinoma (NPC) is a major cause of cancer-related death in Southeast Asia and China. Metastasis and relapse are the primary cause of morbidity and mortality in NPC. Recent evidence suggests that the Epstein-Barr virus latent membrane protein 1 (LMP1) is exclusively expressed in most NPC and is a potential target for biotherapy. In this study, we successfully prepared a novel human antibody Fab (HLEAFab) against LMP1 extracellular domain, which was subsequently conjugated with mitomycin C (MMC), thus forming an immunoconjugate (HLEAFab-MMC). The effects of HLEAFab-MMC on proliferation and apoptosis in NPC cell lines HNE2/LMP1 and the inhibition rate of growth of NPC xenografts in nude mice were examined. The inhibition rate of HNE2/LMP1 cell proliferation was the highest for HLEAFab-MMC (76%) compared with MMC (31%) and HLEAFab (22%) at a concentration of 200 nmol/L and showed dose-dependent fashion. The apoptosis rate of HNE2/LMP1 cell lines was 13.88% in HLEAFab-MMC group, 3.04% in MMC group, 2.78% in HLEAFab group, and 2.10% in negative control group at the same concentration, respectively. In vivo, the inhibition rate of growth of NPC xenografts in nude mice was 55.1% in HLEAFab-MMC group, 26.5% in MMC group, and 5.64% in HLEAFab group. In summary, our findings show that HLEAFab-MMC is a unique immunoconjugate with the potential as a novel therapeutic agent in the treatment of LMP1-expressing NPC.


Cancer dormancy: role of cyclin-dependent kinase inhibitors in induction of cell cycle arrest mediated via membrane IgM.
Anti-idiotype (anti-Id) antibody can induce tumor dormancy in a murine B lymphoma, BCL1, by its ability to induce cell cycle arrest and apoptosis (negative signaling). In human B lymphoma, there is accumulating evidence that the antitumor effect of anti-Id or several other B cell-reactive antibodies relates to their ability to act as agonists rather than conventional effector antibodies. In this study, we sought to elucidate the role of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors in anti-IgM-induced cell cycle arrest to better understand the mechanisms underlying cancer dormancy. To accomplish this, we have performed in vitro studies with a human lymphoma cell line (Daudi) because its response to anti-Id (or anti-IgM) is similar to that of a BCL1 cell line, more reagents are available, and the results would be particularly pertinent to therapy of human B cell lymphomas. Our results show that cross-linking of membrane IgM on Daudi cells induces an arrest late in G1 and prevents pRb from becoming phosphorylated. The G1 arrest is correlated with an induction of the CDK inhibitor p21 and reduced CDK2 activity, although the level of CDK2 protein was not changed. Coprecipitation of CDK2 with p21 in anti-IgM-treated cells and the unchanged level of cyclin E suggest that p21 is responsible for the reduction of CDK2 activity and therefore blockade of the cell cycle. The induction of p21 was not accompanied by changes in p53 levels. As a result of the G1 block, cyclin A levels sharply declined by 24 h after anti-IgM treatment. There was no evidence for involvement of CDK4 or CDK6 in the blockade. These results provide evidence that membrane IgM cross-linking on Daudi cells induces expression of p21 and a subsequent inhibition of the cyclin E-CDK2 kinase complex resulting in a block to pRb phosphorylation and cell cycle arrest late in G1.


Genomic analysis of antigenically related avian paramyxoviruses.
Six avian paramyxoviruses isolated from wild and domestic ducks in the United States, Hong Kong and Japan were characterized antigenically and genetically. All viruses examined were shown to be antigenically closely related. Oligonucleotide patterns of duck/Miss/334 and duck/Miss/406 were apparently distinguishable from those of duck/Miss/116 and duck/Miss/320 isolated in the same area of the United States. On the other hand, two viruses isolated from a domestic duck in Hong Kong (duck/Hong Kong/D3/75) and from a domestic duck in Japan (duck/Tokyo/41/78) were genetically very similar to that of duck/Miss/116, suggesting that these three viruses represent a genetically homogeneous group and may be of the same origin.


Genetic characterization of atypical Mansonella (Mansonella) ozzardi microfilariae in human blood samples from northeastern Peru.
DNA sequence comparisons are useful for characterizing proposed new parasite species or strains. Microfilariae with an atypical arrangement of nuclei behind the cephalic space have been recently described in human blood samples from the Amazon region of Peru. Three blood specimens containing atypical microfilariae were genetically characterized using three DNA markers (5S ribosomal DNA, 12S ribosomal DNA, and cytochrome oxidase I). All atypical microfilariae were clustered into the Mansonella group and indistinguishable from M. ozzardi based on these DNA markers.


Genetic and phenotypically flexible components of seasonal variation in immune function.
Animals cope with seasonal variation in environmental factors by adjustments of physiology and life history. When seasonal variation is partly predictable, such adjustments can be based on a genetic component or be phenotypically flexible. Animals have to allocate limited resources over different demands, including immune function. Accordingly, immune traits could change seasonally, and such changes could have a genetic component that differs between environments. We tested this hypothesis in genotypically distinct groups of a widespread songbird, the stonechat (Saxicola torquata). We compared variation in immunity during 1 year in long-distance migrants, short-distance migrants, tropical residents and hybrids in a common garden environment. Additionally, we investigated phenotypically flexible responses to temperature by applying different temperature regimes to one group. We assessed constitutive immunity by measuring hemagglutination, hemolysis, haptoglobin and bactericidal ability against Escherichia coli and Staphylococcus aureus. Genotypic groups differed in patterns of variation of all measured immune indices except haptoglobin. Hybrids differed from, but were rarely intermediate to, parental subspecies. Temperature treatment only influenced patterns of hemolysis and bactericidal ability against E. coli. We conclude that seasonal variation in constitutive immunity has a genetic component, that heredity does not follow simple Mendelian rules, and that some immune measures are relatively rigid while others are more flexible. Furthermore, our results support the idea that seasonal variability in constitutive immunity is associated with variability in environment and annual-cycle demands. This study stresses the importance of considering seasonal variation in immune function in relation to the ecology and life history of the organism of interest.


AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress.
CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury in the lung and other organs. Treg cells require mitochondrial metabolism to exert their function, but how Treg cells adapt their metabolic programs to sustain and optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMP-activated protein kinase (AMPK) to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during acute lung injury caused by influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In the lung during viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking DNA methylation with AMPK function and mitochondrial metabolism. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.


Anaerobic pathogens associated with OSA may contribute to pathophysiology via amino-acid depletion.
The human microbiome is linked to multiple metabolic disorders such as obesity and diabetes. Obstructive sleep apnoea (OSA) is a common sleep disorder with several metabolic risk factors. We investigated the associations between the gut microbiome composition and function, and measures of OSA severity in participants from a prospective community-based cohort study: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Bacterial-Wide Association Analysis (BWAS) of gut microbiome measured via metagenomics with OSA measures was performed adjusting for clinical, lifestyle and co-morbidities. This was followed by functional analysis of the OSA-enriched bacteria. We utilized additional metabolomic and transcriptomic associations to suggest possible mechanisms explaining the microbiome effects on OSA. Several uncommon anaerobic human pathogens were associated with OSA severity. These belong to the Lachnospira, Actinomyces, Kingella and Eubacterium genera. Functional analysis revealed enrichment in 49 processes including many anaerobic-related ones. Severe OSA was associated with the depletion of the amino acids glycine and glutamine in the blood, yet neither diet nor gene expression revealed any changes in the production or consumption of these amino acids. We show anaerobic bacterial communities to be a novel component of OSA pathophysiology. These are established in the oxygen-poor environments characteristic of OSA. We hypothesize that these bacteria deplete certain amino acids required for normal human homeostasis and muscle tone, contributing to OSA phenotypes. Future work should test this hypothesis as well as consider diagnostics via anaerobic bacteria detection and possible interventions via antibiotics and amino-acid supplementation. Described in methods.


Maternal adverse childhood experiences on child growth and development in rural Pakistan: An observational cohort study.
Maternal adverse childhood experiences (ACEs) have significant impacts on the next generation with links to negative birth outcomes, impaired cognitive development, and increased socioemotional problems in children. However, not all types or levels of adversity are similarly deleterious and research from diverse contexts is needed to better understand why and how intergenerational transmission of adversity occurs. We examined the role of maternal ACEs on children's growth, cognitive, and socioemotional development at 36 months postpartum in rural Pakistan. We used data from 877 mother-child dyads in the Bachpan Cohort, a birth cohort study. Maternal ACEs were captured using an adapted version of the ACE-International Questionnaire. Outcomes at 36 months of age included child growth using the WHO growth z-scores, fine motor and receptive language development assessed with the Bayley Scales of Infant and Toddler Development, and socioemotional and behavioral development measured with the Ages and Stages Questionnaire: Socioemotional and Strengths and Difficulties Questionnaire. To estimate the associations between maternal ACEs and child outcomes, we used multivariable generalized linear models with inverse probability weights to account for sampling and loss to follow-up. Over half of mothers in our sample (58%) experienced at least one ACE. Emotional abuse, physical abuse, and emotional neglect were the most commonly reported ACEs. We found null relationships between the number of maternal ACEs and child growth. Maternal ACEs were associated with higher fine motor and receptive language development and worse socioemotional and behavioral outcomes. Maternal ACE domains had similarly varying relationships with child outcomes. Our findings highlight the complexity of intergenerational associations between maternal ACEs and children's growth and development. Further work is necessary to examine these relationships across cultural contexts and identify moderating factors to mitigate potential negative intergenerational effects.


Measurement of the pro-hormone of brain type natriuretic peptide (proBNP): methodological considerations and pathophysiological relevance.
Recent studies demonstrated that large amounts of the pro-hormone peptide of brain natriuretic peptide (proBNP) can be detected in plasma of healthy subjects and in particular of patients with heart failure. As a result, a great part of B-type natriuretic peptides measured in patients with cardio-vascular disease may be devoid of biological activity. These findings stimulated the set up of specific immunoassay methods for the measurement of the intact proBNP peptide. The aim of this review article is to discuss the methodological characteristics and the possible clinical relevance of specific immunoassay methods for the measurement of the proBNP peptide. From an analytical point of view, a fully automated immunoassay of proBNP has some theoretical advantages (e.g., a more stable molecule with higher molecular weight than the derived peptides) compared to the active hormone BNP. Recent studies supported the concept that the precursor proBNP might be actually considered a circulating prohormone, which can be cleaved by specific plasma proteases in BNP, the active hormone, and NT-proBNP, an inactive peptide. The peripheral processing of circulating proBNP could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening new perspectives in the treatment of heart failure (e.g., by studying drugs inducing the cleavage of the prohormone into active BNP). Furthermore, as a future perspective, the specific assay in the same plasma sample of the intact precursor proBNP and of the biologically active peptide BNP, could allow a more accurate estimation of the production/secretion of B-type related peptides from cardiomyocytes and of the global cardiac endocrine function.


Interplay of Vitamin D, Unfolded Protein Response, and Iron Metabolism in Neuroblastoma Cells: A Therapeutic Approach in Neurodegenerative Conditions.
Vitamin D3 (VD) is crucial for various cell functions, including gene regulation, antioxidant defense, and neural health. Neurodegenerative conditions are closely linked to the unfolded protein response (UPR), a mechanism reacting to endoplasmic reticulum (ER) stress. Iron metabolism is intricately associated with UPR and neurodegeneration. This study used SH-SY5Y neuroblastoma cells to investigate the relationship between UPR, iron metabolism, and VD. Different sequences of treatments (pre- and post-treatments) were applied using VD and thapsigargin (Tg), and various methods were used for evaluation, including real-time qPCR, Western blotting, ELISA, and iron content analysis. The findings indicate that VD affects UPR pathways, cytokine release, and iron-related genes, potentially offering anti-inflammatory benefits. It also influences iron transporters and storage proteins, helping to maintain cellular iron balance. Furthermore, pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) were impacting UPR activation in cells. VD also influenced fractalkine (CX3CL1) gene expression and secretion, suggesting its potential as a therapeutic agent for addressing neuroinflammation and iron dysregulation. This research provides insights into the intricate connections among VD, UPR, and iron metabolism in SH-SY5Y neuroblastoma cells, with implications for future investigations and potential therapeutic approaches in neurodegenerative diseases characterized by UPR dysregulation and iron accumulation.


[Effect of natriuretic factor on sodium secretion in the small intestine].
In dogs with Tiri-Vella fistula, the natriuretic factor increases the secretion of the intestinal fluid and its content of sodium. In rats with increased content of natriuretic factor, the water and sodium absorption diminishes in the intestine whereas the secretion of 22Na into the intestine lumen is increased.


Probing single-cell micromechanics in vivo: the microrheology of C. elegans developing embryos.
Cells are not directly accessible in vivo and therefore their mechanical properties cannot be measured by methods that require a direct contact between probe and cell. Here, we introduce a novel in vivo assay based on particle tracking microrheology whereby the extent and time-lag dependence of the mean squared displacements of thermally excited nanoparticles embedded within the cytoplasm of developing embryos reflect local viscoelastic properties. As a proof of principle, we probe local viscoelastic properties of the cytoplasm of developing Caenorhabditis elegans embryos. Our results indicate that unlike differentiated cells, the cytoplasm of these embryos does not exhibit measurable elasticity, but is highly viscous. Furthermore, the viscosity of the cytoplasm does not vary along the anterior-posterior axis of the embryo during the first cell division. These results support the hypothesis that the asymmetric positioning of the mitotic spindle stems from an asymmetric distribution of elementary force generators as opposed to asymmetric viscosity of the cytoplasm.


Hemostatic prophylaxis and colonoscopy outcomes for patients with bleeding disorders: A retrospective cohort study and review of the literature.
Hemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence-based guidelines are needed to determine optimal HP strategies. To determine outcomes of HP for PWBD undergoing colonoscopy. We undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center. During the study period, 73 PWBD (58 with milder phenotypes: haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test). The low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low-risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high-risk intervention is required. Further studies are needed to determine optimal evidence-based HP strategies for PWBD undergoing colonoscopy.


The experience of cash transfers in alleviating childhood poverty in South Africa: mothers' experiences of the Child Support Grant.
Cash transfer (CT) programmes are increasingly being used as policy instruments to address child poverty and child health outcomes in developing countries. As the largest cash-transfer programme in Africa, the South African Child Support Grant (CSG) provides an important opportunity to further understand how a CT of its kind works in a developing country context. We explored the experiences and views of CSG recipients and non-recipients from four diverse settings in South Africa. Four major themes emerged from the data: barriers to accessing the CSG; how the CSG is utilised and the ways in which it makes a difference; the mechanisms for supplementing the CSG; and the impact of not receiving the grant. Findings show that administrative factors continue to be the greatest barrier to CSG receipt, pointing to the need for further improvements in managing queues, waiting times and coordination between departments for applicants trying to submit their applications. Many recipients, especially those where the grant was the only source of income, acknowledged the importance of the CSG, while also emphasising its inadequacy. To maximise their impact, CT programmes such as the CSG need to be fully funded and form part of a broader basket of poverty alleviation strategies.


Health access and status of adolescents and young adults using youth employment and training programs in an urban environment.
To describe the health status and access to healthcare of adolescents and young adults disconnected from traditional education and work settings. The health status of these disconnected youth is largely unknown, although it is suspected to be quite poor. Most information about the health of youth in the United States relies on school-based samples. In-person interviews with 1037 adolescents and young adults (aged 16-24 years) enrolled in an employment and training program in Baltimore were used to measure access to health services and health status in four domains: violent behavior, mental health, substance use, and reproductive health. Differences in healthcare access and health status by age and gender were examined. In addition, youth in the employment and training sample are compared with Baltimore youth in school and of comparable ages, as measured by the Youth Risk Behavior Surveillance System. Nearly 50% of young adults in the employment and training program were found to lack health insurance, and about 20% reported a time when they needed medical care but did not receive it. Youth in the program exhibited notable health status concerns, often exceeding the risk prevalence of students in school. In particular, adolescents and young adults disconnected from traditional employment and work settings were more likely to be in physical fights, to smoke cigarettes, and to use marijuana than their in-school counterparts. In-school youth were more likely to have considered harming themselves and to have made a suicide plan in the last year. Given high levels of health risk among youth disconnected from traditional education and work settings, adolescent health providers must increasingly pay attention to integrating health promotion and disease prevention strategies into youth employment and training programs, where sizable numbers of these youth can be reached.


[Beta-endorphin and beta-lipotropin in the pathogenesis of obesity].
The blood beta-endorphin and beta-lipotropin content was studied by radioimmunoassay in patients with obesity of different degree and healthy subjects with normal body weights. It was shown that the blood beta-endorphin concentration rises depending on the body weight growth, promoting the intensified insulin secretion and obesity development. beta-Lipotropin level was significantly augmented in patients with the 3d and 4th stages of obesity. The intensified beta-lipotropin secretion, stimulating lipolysis, may be considered as a compensatory mechanism, tending to return to normal fat metabolism in the originated pathological conditions. Comparison of beta-endorphin and beta-lipotropin levels in the blood of obese patients suggests that obesity is not only marked by hormonal disorders, producing obesity progression but also by the formation of adaptive mechanisms, directed at compensation of the pathological process.


Jugular venous hemodynamic changes with aging.
Cerebral venous outflow insufficiency via the internal jugular vein (IJV) is associated with several neurological disorders. However, a normal reference set of IJV hemodynamic parameters derived from a large, healthy population over a wide range of age has, until now, been lacking. Color-coded duplex sonography was performed on the IJVs of 349 subjects (55.60 ± 17.49,16 to 89 y; 167 M/182 F). With increasing age, increased lumen area and decreased time-averaged mean velocity of bilateral IJV and a decreased proportion of total flow volume, drainage in the left IJV were found. The frequency of left jugular venous reflux (JVR) also increased with aging. We report IJV hemodynamic parameters across a large population, which could be used as a normal reference for clinical and research purposes. Furthermore, we found a decreased proportion of venous drainage, increased JVR prevalence, dilated lumen and slowed flow velocity in the left IJV, all of which suggest increased left IJV outflow impedance with aging.


Is dimerization a common feature in thioredoxins? The case of thioredoxin from Litopenaeus vannamei.
The quaternary structure of the redox protein thioredoxin (Trx) has been debated. For bacterial Trx, there is no question regarding its monomeric state. In humans and other eukaryotes, the presence of a cysteine residue at the crystallographic symmetry axis points to the relevance of dimer formation in solution and in vivo. Crystallographic data for shrimp thioredoxin (LvTrx) obtained under different redox conditions reveal a dimeric arrangement mediated by a disulfide bond through residue Cys73 and other hydrophobic interactions located in the crystallographic interface, as reported for human Trx. Through the analysis of five mutants located at the crystallographic interface, this study provides structural and biochemical evidence for the existence in solution of monomeric and dimeric populations of wild-type LvTrx and five mutants. Based on the results of biochemical assays, SAXS studies and the crystallographic structures of three of the studied mutants (Cys73Ser, Asp60Ser and Trp31Ala), it is clear that the Cys73 residue is essential for dimerization. However, its mutation to Ser produces an enzyme which has similar redox activity in vitro to the wild type. A putative regulatory function of dimerization is proposed based on structural analysis. Nonetheless, the biological role of LvTrx dimerization needs to be experimentally unveiled. Additionally, the findings of this work reopen the discussion regarding the existence of similar behaviour in human thioredoxin, which shares a Cys at position 73 with LvTrx, a structural feature that is also present in some Trxs from vertebrates and crustaceans.


Splenectomy and extravascular platelet destruction in thrombotic thrombocytopenic purpura.
Intravascular platelet deposition has been considered an essential pathophysiologic mechanism in thrombotic thrombocytopenic purpura. Splenectomy resulted in prompt and sustained hematologic improvement in a patient with the chronic form of the disease. The response to splenectomy, normal plasma levels of secretable platelet proteins, and phagocytosis of erythrocyte fragments and platelets by splenic macrophages demonstrated by electron microscopy suggest that platelet destruction may occasionally be predominantly extravascular in this disease.


High sensitivity optical measurement of skin gloss.
We demonstrate a low-cost optical method for measuring the gloss properties with improved sensitivity in the low gloss regime, relevant for skin gloss properties. The gloss estimation method is based on, on the one hand, the slope of the intensity gradient in the transition regime between specular and diffuse reflection and on the other on the sum over the intensities of pixels above threshold, derived from a camera image obtained using unpolarized white light illumination. We demonstrate the improved sensitivity of the two proposed methods using Monte Carlo simulations and experiments performed on ISO gloss calibration standards with an optical prototype. The performance and linearity of the method was compared with different professional gloss measurement devices based on the ratio of specular to diffuse intensity. We demonstrate the feasibility for in-vivo skin gloss measurements by quantifying the temporal evolution of skin gloss after application of standard paraffin cream bases on skin. The presented method opens new possibilities in the fields of cosmetology and dermatopharmacology for measuring the skin gloss and resorption kinetics and the pharmacodynamics of various external agents.


Immunogenicity, protective efficacy and safety of a recombinant DNA vaccine encoding truncated Plasmodium yoelii sporozoite asparagine-rich protein 1 (PySAP1).
Although great efforts have been undertaken for the development of malaria vaccines, no completely effective malaria vaccines are available yet. Despite being clinically silent, the pre-erythrocytic stage is considered an ideal target for the development of malaria vaccines. Sporozoite asparagine-rich protein 1 (SAP1) is a sporozoite-localized protein that regulates the expression of UIS (upregulated in infectious sporozoites) genes, which are essential for the infectivity of sporozoites. In this study, a recombinant DNA vaccine encoding a predicted antigenic determinant region of Plasmodium yoelii SAP1 (PySAP1) was constructed. Immunization of mice with this DNA vaccine construct resulted in significant elevation of cytokines such as IFN-γ, IL-2, IL-4 and IL-10, and total IgG as compared with control groups immunized with either the empty DNA vector or saline. After challenge with sporozoites, the group receiving the DNA vaccine showed delayed development of parasitemia and prolonged survival time compared with the control group. The DNA vaccine provided partial protection against P. yoelii 17XL infection, with an overall protection rate of 20%. In addition, the DNA vaccine did not show integration into the host genome. Further studies of SAP1 are needed to test whether it can be used as subunit vaccine candidate.


Induced minisatellite germline mutations in herring gulls (Larus argentatus) living near steel mills.
Despite widespread industrial release of genotoxic contaminants, little is understood of their role in inducing germline mutations in natural populations. We used multilocus DNA fingerprinting to quantify germline minisatellite mutations in families of herring gulls (Larus argentatus) in three nesting categories: (a) near cities with large steel mills operating coking ovens; (b) near cities without steel mills; and (c) in rural locations removed from point sources of contamination. Gulls nesting near integrated steel mills showed significantly higher mutation rates than gulls from rural locations (Fisher's exact, P=0.0004); urban sites without steel mills fell midway between steel and rural sites (difference from rural; Fisher's exact, P=0.19). Distance of the nesting location of herring gulls from the steel industries' coking ovens was negatively correlated with minisatellite mutation rate demonstrating significant risk for induced germline mutations in cities with steel operations (Kendall Tau; tau=0.119; P<0.0001).


Amino terminal hydrophobic import signals target the p14(ARF) tumor suppressor to the mitochondria.
The p14(ARF) tumor suppressor is frequently targeted for inactivation in many human cancers and in individuals predisposed to cutaneous melanoma. The functions of p14(ARF) are closely linked with its subcellular distribution. Nucleolar p14(ARF) dampens ribosome biosynthesis and nucleoplasmic forms of p14(ARF) activate the p53 pathway and induce cell cycle arrest. p14(ARF) can also be recruited to mitochondria where it interacts with many mitochondrial proteins, including Bcl-x(L) and p32 to induce cell death. It has been suggested that the movement of p14(ARF) to mitochondria requires its interaction with p32, but we now show that the ARF-p32 interaction is not necessary for the accumulation of p14(ARF) in mitochondria. Instead, highly hydrophobic domains within the amino-terminal half of p14(ARF) act as mitochondrial import sequences. We suggest that once this hydrophobic pocket is exposed, possibly in a stimulus-dependent manner, it accelerates the mitochondrial import of p14(ARF). This allows the interaction of p14(ARF) with mitochondrial proteins, including p32 and enables p53-independent cell death.


Socioeconomic differences in smoking in an urban Swedish population. The bias introduced by non-participation in a mailed questionnaire.
Stockholm Health of the Population Study is a cross-sectional study carried out from 1984-85. Postal questionnaires, telephone interviews and health interviews were used to get information from a sample of 5,199 persons, 18-64 years of age, on health status, risk exposures, healthcare consumption and social factors. Non-participation with respect to the postal questionnaire was 36.8%. With subsequent telephone interviews and an invitation to a health interview, non-participation was reduced to 17.8%. The estimated prevalence of daily smoking increased from 36.1% to 38.7. The non-responders had a higher prevalence of daily smoking in all sub-groups. This effect of the efforts to reduce non-participation differed socially. The prevalence of smoking for men, 40-64 years of age, who were reached by telephone was 60.3%. Male professionals and intermediate non-manual workers, 40-64 years of age reached by telephone had a prevalence of smoking, which was twice as high as for the responders of the questionnaire (62.5 and 26.8%, respectively). In the younger age-group, non-responders had the same socioeconomic pattern in smoking as the responders. Independent of socioeconomic group, there was a tendency of ill or disabled smokers to respond more quickly than healthy smokers. Using a postal questionnaire with a high non-response rate might lead to an overestimation of socioeconomic differences and an underestimation of smoking prevalence.


Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a disease pathogenetically and clinically similar to that caused by the 654G-A mutation (familial amyloidosis of the Finnish type).
Familial amyloidosis of the Finnish type (FAF, Finnish hereditary amyloidosis) is caused by a 654G-A mutation in the gelsolin gene on chromosome 9 resulting in the expression of mutant Asn-187 gelsolin which is abnormally proteolytically processed generating amyloidogenic fragments that polymerize into amyloid fibrils. We have recently shown that in a Danish and a Czech family with a clinical syndrome similar to FAF, including corneal lattice dystrophy, cranial neuropathy and skin changes, the disease is caused by another mutation at the same position, namely 654G-T predicting a Try-for-Asp substitution at 187 in secreted gelsolin. To undertake a closer examination of the Danish subtype of FAF and report immunohistochemical and biochemical findings. Immunostaining of plasma gelsolin isolated from heterozygous FAF of the Danish subtype revealed a pattern similar to that found in FAF-Asn 187. The > 60 kDa gelsolin species contain an epitope characteristic of the amyloid forming region as revealed by an amyloid specific antibody, whereas the approximately 50 kDa fragments are devoid of it. Compared with the wild-type gelsolin peptide (Asp-187), the corresponding mutant peptide (Tyr-187) showed dramatically increased fibrillogenicity as revealed by quantitative thioflavine-T based fluorimetry; ultrastructurally, amyloid-like fibrils were formed by the mutant peptide. Immunohistochemistry showed that antibodies directed against residues 231-242 of secreted gelsolin, representing the carboxy terminus of the sequence forming the amyloid protein (residues 173-243) laid down in the tissues in a fibrillar form in FAF, specifically labelled the amyloid deposited in rectum and skin in the Danish (654G-T) subtype. The 654G-T mutation in the gelsolin gene gives rise to an amyloid disease clinically and pathogenetically similar to that caused by the 654G-A mutation.


Robust damping control of mobile manipulators.
A novel robust control technique, robust damping control (RDC), is introduced. An RDC controller is further developed for the motion control of a mobile manipulator subject to kinematic constraints. The knowledge of dynamic parameters of the mobile manipulator is assumed to be completely unknown. The proposed RDC controller is capable of disturbance-rejection in the presence of unknown bounded disturbance, without requiring the knowledge of its bound. The stability of the closed-loop system is guaranteed. The controller has a simple structure and can be easily implemented in applications. Experimental tests on a 2-DOF robotic manipulator illustrate that the proposed control is significantly better than conventional robust control.


Male genes: X-pelled or X-cluded?
Two recent studies by Parisi et al. and Ranz et al., catalogue sex differences in gene expression across the whole genome of the fruit fly Drosophila melanogaster. Both report striking associations of sex-biased gene expression with the X chromosome. Genes with male-biased expression are depauperate on the X chromosome, whereas genes with female-biased expression show weaker evidence of being in excess. A number of evolutionary hypotheses for the expulsion or exclusion of male-biased genes from the X chromosome have been suggested. None is entirely consistent with the available evidence.


Polydopamine-Modified Zeolite Imidazole Framework Drug Delivery System for Photothermal Chemotherapy of Hepatocellular Carcinoma.
Metal-organic frameworks (MOFs) are promising drug-delivering platforms for their intrinsic capability of loading and releasing different cargoes. To further extend their biomedical practices, the development of collaborative MOF systems with good biocompatibility and synergistic efficacy is essential. Herein, the near-infrared and pH dual-response collaborative zeolitic imidazolate framework-8 (ZIF-8) platform SOR@ZIF-8@PDA (SZP) was constructed, in which the chemotherapeutic drug sorafenib (SOR) was encapsulated in ZIF-8 and via polydopamine (PDA) coating on ZIF-8 by hierarchical self-assembly. PDA coating serves as a photothermal agent for PPT while reducing the toxicity of ZIF-8. SZP achieves intelligent release of therapeutic drugs by responding to the lower pH of the tumor microenvironment and thermal stimulation generated by near-infrared light irradiation. In addition, under light irradiation, SZP could effectively realize treatment of cancer cells through synergistic chemo-photothermal therapy, as evidenced by the enhanced cell apoptosis, inhibited tumor cell proliferation and migration. This collaborative MOFs system showed excellent biocompatibility and antitumor ability in vivo on a mouse HepG2 tumor model. Our results demonstrated that PDA-modified MOFs exhibited a fantastic good development prospect in biomedical applications.


Fast reversibility of glucose-induced desensitization in rat pancreatic islets. Evidence for an involvement of ionic fluxes.
The present study was done to achieve a better understanding of the role of ionic flux alterations in glucose-induced desensitization of pancreatic beta-cells. Moreover, we investigated the reversibility of glucose-induced desensitization after different times of exposure to high glucose to ascertain the time necessary for desensitization reversal and to determine whether it depends on the length of high glucose exposure. Glucose desensitization was obtained by incubating rat pancreatic islets for 6 h in CMRL medium containing 16.7 mmol/l glucose. At the end of this period, insulin release, 86Rb efflux, and 45Ca uptake were measured in parallel experiments. In islets cultured at 16.7 mmol/l glucose, maximal glucose-induced insulin release was reduced (848 +/- 97 pg x islet-1 x 30 min-1) in comparison to islets incubated at 5.5 mmol/l glucose (1,436 +/- 144, n = 7, P < 0.01). In contrast, insulin content was similar in the two groups, being 41.0 +/- 2.7 and 47.8 +/- 2.2 ng/islet in islets exposed to 16.7 or 5.5 mmol/l glucose, respectively (P = 0.167). The effect of glucose on both 86Rb efflux and 45Ca uptake was also significantly reduced in 16.7 mmol/l glucose-cultured islets. 86Rb efflux was inhibited only 19 +/- 4% in islets cultured at high glucose with respect to 56 +/- 7% in control islets (n = 5, P < 0.001). 45Ca uptake was 10.5 +/- 1.7 pmol/islet (mean +/- SE, n = 9) in islets cultured at high glucose with respect to 19.7 +/- 2.4 pmol/islet in control islets (P < 0.001). In contrast, the effect of glyburide (10 micromol/l) on insulin release, 86Rb efflux, and 45Ca uptake was similar in islets exposed to 5.5 or 16.7 mmol/l glucose. All the abnormalities observed in islets cultured at 16.7 mmol/l glucose were promptly and simultaneously reversible after islets were transferred in culture medium at 5.5 mmol/l glucose; both insulin secretion and glucose effects on 86Rb efflux and 45Ca uptake returned to values similar to control islets within 5 min. Also, islets exposed to high glucose for a longer period (24 h) recovered from both secretory and ionic abnormalities after 5 min of incubation in CMRL medium at 5.5 mmol/l glucose. Reversal from glucose desensitization was slower (45 - 60 min) when islets were incubated at 5.5 mmol/l glucose in Krebs-Ringer HEPES buffer instead of CMRL medium. The present data suggest that ion flux and consequent membrane-potential changes play a key role in the mechanism leading to glucose-induced desensitization of pancreatic beta-cells. Because a normal response to glyburide was observed in islets exposed to high glucose, a proximal signal defect for closure of K+ channels rather than an intrinsic defect in the channel is likely.


WITHDRAWN: Home-based support for disadvantaged teenage mothers.
Babies born to socio-economically disadvantaged mothers are at higher risk of injury, abuse or neglect and health problems than babies born to more affluent mothers; disadvantaged teenage mothers are at particular risk of adverse outcomes. Home-visiting programs are thought to improve outcomes for both mothers and children, largely through advice and support. To assess the effectiveness of home-visiting programmes for women who have recently given birth and who are socially or economically disadvantaged. The following electronic databases were searched: CENTRAL (2006, Issue 3); MEDLINE (1966 to March 2006); EMBASE (1980 to week 12 2006); CINAHL (1982 to March week 4 2006); PsycINFO (1872 to March week 4 2006); ASSIA (1987 to March 2006); LILACS (1982 to March 2006); and Sociological Abstracts (1963 to March 2006). Grey literature was also be searched using ZETOC (1993 to March 2006); Dissertation Abstracts International (late 1960s to 2006); and SIGLE (1980 to March 2006). Communication with published authors about ongoing or unpublished research was also undertaken. Included studies were randomised controlled trials investigating the efficacy of home visiting directed at teenage mothers. Titles and abstracts identified in the search were independently assessed for eligibility by two review authors (EC and JP or CB). Data were extracted and entered into RevMan (EC, JP and CB), synthesised and presented in both written and graphical form (forest plots). Outcomes included in this review were established at the protocol stage by an international steering group. The review did not report on all outcomes reported in included studies. Five studies with 1838 participants were included in this review. Data from single studies provided support for the effectiveness of home visiting on some outcomes, but the evidence overall provided only limited support for the effectiveness of home visiting as a means of improving the range of maternal and child outcomes considered in this review. This review suggests there is only limited evidence that home-visiting programmes of the kind described in this review can impact positively on the quality of parenting of teenage mothers or on child development outcomes for their offspring. For reasons discussed in the review, this does not amount to a conclusion that home-visiting programmes are ineffective but indicates a need to think carefully about the problems that home visiting might influence and about improvements in the conduct and reporting of outcome studies in this area.