Regional and global strategies of MNEs: Revisiting Rugman & Verbeke (2004).
We describe the extent to which the world's largest companies (in terms of revenues), achieve sales around the globe, and have been able to penetrate markets outside of their home region. We try to answer the following question: Has there been a recent increase in the world's largest firms achieving a global sales orientation, meaning a balanced, global distribution of sales? Rugman & Verbeke (2004) found that few of the 2002 Fortune Global 500 (Fortune Magazine 2002) firms, accounting for over 90% of the world's stock of FDI, actually had a global sales orientation. A majority of multinational enterprises (MNEs) were home-region oriented, suggesting that much work on corporate globalization was normative, rather than accurately describing reality. We present the equivalent data for the 2017 Fortune Global 500 (Fortune Magazine 2017) list. Our data confirm that many large firms are still home-region oriented, but to a lesser extent than before, with 36 MNEs (up from only nine in the 2002 list), now having widely distributed sales across the world's core economic regions. The question arises whether this relative increase in the number of MNEs with a global sales orientation holds any normative value for the firms that presently do not have such a sales distribution.


Osteometric analysis of sexual dimorphism in the sternal end of the rib.
Although there have been a number of radiological studies of the entire anterior thorax, no attempt has been made to establish a method of sex determination based on direct metrical analysis of an isolated rib. The present study attempts to determine sex from the sternal end of the fourth rib. The sample (144 males, 86 females) was obtained from individuals of known age, sex, and race autopsied at a medical examiner's office. Three measurements (height, width, and sternal articular pit depth) were taken from each bone. The sample was divided into three groups: young, old, and the combined total and analyzed by means of stepwise discriminant function statistics. It was found that the accuracy of sex determination varied from 82% in the young and 89% in the old groups to 83% for the combined group. However, when a discriminant function formula developed for a different age group was used the accuracy of correct assessment diminished considerably. It was, therefore, concluded that sexual dimorphism can be detected by metrical analysis from the teens to the 70s and this dimorphism increases with age.


The genetic basis for inactivation of Wnt pathway in human osteosarcoma.
Osteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma. aCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, β-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples. KEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no β-catenin protein was detected in the nucleus. β-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall survival of human osteosarcoma patients. Frequent deletions of Wnt and other Wnt signaling pathway genes suggest that the Wnt signaling pathway is genetically inactivated in human osteosarcoma.


Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity.
Depending on the cellular context, Ras can activate characteristic effectors by mechanisms still poorly understood. Promotion by galectin-1 of Ras activation of Raf-1 but not of phosphoinositide 3-kinase (PI3-K) is one such mechanism. In this report, we describe a mechanism controlling selectivity of K-Ras4B (K-Ras), the most important Ras oncoprotein. We show that galectin-3 acts as a selective binding partner of activated K-Ras. Galectin-3 co-immunoprecipitated significantly better with K-Ras-GTP than with K-Ras-GDP, H-Ras, or N-Ras and colocalized with green fluorescent protein-K-Ras(G12V), not with green fluorescent protein-H-Ras(G12V), in the cell membrane. Co-transfectants of K-Ras/galectin-3, but not of H-Ras/galectin-3, exhibited enhanced and prolonged epidermal growth factor-stimulated increases in Ras-GTP, Raf-1 activity, and PI3-K activity. Extracellular signal-regulated kinase (ERK) activity, however, was attenuated in K-Ras/galectin-3 and in K-Ras(G12V)/galectin-3 co-transfectants. Galectin-3 antisense RNA inhibited the epidermal growth factor-stimulated increase in K-Ras-GTP but enhanced ERK activation and augmented K-Ras(G12V) transformation activity. Thus, unlike galectin-1, which prolongs Ras activation of ERK and inhibits PI3-K, K-Ras-GTP/galectin-3 interactions promote, in addition to PI3-K and Raf-1 activation, a third inhibitory signal that attenuates active ERK. These experiments established a novel and specific mechanism controlling the duration and selectivity of signals of active K-Ras, which is extremely important in many human tumors.


Intravitreal triamcinolone acetonide as treatment of ischemic ophthalmopathy.
To describe the clinical course of a patient receiving repeated intravitreal injections of triamcinolone acetonide (25 mg) as treatment of ischemic ophthalmopathy. A 70-year-old patient with Waldenström disease presented with progressive iris neovascularization, vitreous hemorrhage, and ocular hypotony due to ischemic ophthalmopathy. Visual acuity was 0.05. Within 2.5 years, he received three intravitreal injections of 25 mg of triamcinolone acetonide. Additionally, penetrating keratoplasty and synechiolysis were performed during the follow-up. After each intravitreal injection, visual acuity and intraocular pressure increased, iris neovascularization regressed, and vitreous haze cleared up. Intravitreal triamcinolone acetonide may induce regression of iris neovascularization, increase intraocular pressure, and improve visual acuity in eyes presenting with ocular hypotony, vitreous hemorrhage, and progressive intraocular neovascularization due to ischemic ophthalmopathy.


The cost of not breastfeeding in Southeast Asia.
Rates of exclusive breastfeeding are slowly increasing, but remain suboptimal globally despite the health and economic benefits. This study estimates the costs of not breastfeeding across seven countries in Southeast Asia and presents a cost-benefit analysis of a modeled comprehensive breastfeeding strategy in Viet Nam, based on a large programme. There have been very few such studies previously for low- and middle-income countries. The estimates used published data on disease prevalence and breastfeeding patterns for the seven countries, supplemented by information on healthcare costs from representative institutions. Modelling of costs of not breastfeeding used estimated effects obtained from systematic reviews and meta-analyses. Modelling of cost-benefit for Viet Nam used programme data on costs combined with effects from a large-scale cluster randomized breastfeeding promotion intervention with controls. This study found that over 12 400 preventable child and maternal deaths per year in the seven countries could be attributed to inadequate breastfeeding. The economic benefits associated with potential improvements in cognition alone, through higher IQ and earnings, total $1.6 billion annually. The loss exceeds 0.5% of Gross National Income in the country with the lowest exclusive breastfeeding rate (Thailand). The potential savings in health care treatment costs ($0.3 billion annually) from reducing the incidence of diarrhoea and pneumonia could help offset the cost of breastfeeding promotion. Based on the data available and authors' assumptions, investing in a national breastfeeding promotion strategy in Viet Nam could result in preventing 200 child deaths per year and generate monetary benefits of US$2.39 for every US$1, or a 139% return on investment. These encouraging results suggest that there are feasible and affordable opportunities to accelerate progress towards achieving the Global Nutrition Target for exclusive breastfeeding by 2025.


Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease: facts and uncertainties underlying the causal link between animal and human diseases.
Following an outbreak of bovine spongiform encephalopathy (BSE) in dairy cows in the United Kingdom (UK), 153 definite and probable human cases of new variant Creutzfeldt-Jakob disease (nvCJD) have been reported, almost exclusively in the UK. Although exposure to the BSE agent is the most plausible interpretation for the occurrence of nvCJD, the causal link between the BSE prion and nvCJD is still debated. This review discusses the pros and cons of nvCJD as a separate nosographic entity, the scientific basis for a correlation between BSE and nvCJD, the validity of the current diagnostic criteria for CJD and nvCJD, the contribution of epidemiology to the detection of a causal relation between BSE and nvCJD, and the present and future directions of the epidemiological research on BSE, CJD and nvCJD.


Crystal structure of (E)-1,2-diferrocenyl-1,2-bis(furan-2-yl)ethene.
The title compound, [Fe2(C5H5)2(C20H14O2)], is the product of a new synthetic route towards tetra-aryl/hetaryl-substituted ethenes that reduces the occurrence of side-products. In the crystal, the mol-ecule is centrosymmetric and the cyclo-penta-dienyl (Cp) rings are nearly coplanar and aligned slightly closer to a staggered conformation than to an eclipsed one. The ethene plane is tilted by 32.40 (18)° with respect to that of the substituted Cp ring and by 63.19 (19)° with respect to that of the furan ring. C-H⋯π inter-actions link the mol-ecules into a three-dimensional supramolecular framework.


Psychological impact of genetic testing for Huntington's disease: an update of the literature.
Genetic testing has been available for Huntington's disease for longer than any other adult onset genetic disorder. The discovery of the genetic mutation causing Huntington's disease made possible the use of predictive testing to identify currently unaffected carriers. Concerns have been raised that predictive testing may lead to an increase in deaths by suicide among identified carriers, and these concerns set in motion research to assess the psychological impact of predictive testing for Huntington's disease. This review article provides an overview of the literature and draws implications for clinical practice. About 10%-20% of people at risk request testing when approached by registries or testing centres. Most of the evidence suggests that non-carriers and carriers differ significantly in terms of short term, but not long term, general psychological distress. Adjustment to results was found to depend more on psychological adjustment before testing than the testing result itself. Although risk factors for psychological sequelae have been identified, few adverse events have been described and no obvious contraindications for testing people at risk have been identified. The psychological impact of testing may depend on whether testing was based on linkage analysis or mutation detection. Cohorts enrolled in mutation detection programmes have higher levels of depression before and after testing, compared with people who sought genetic testing when linkage analysis was available. There is evidence that people who choose to be tested are psychologically selected for a favourable response to testing. The impact of testing on people in settings where less intensive counselling protocols and eligibility criteria are used is unknown, and genetic testing is therefore best offered as part of comprehensive specialist counselling.


Institutional commitment and aging among allied health care professionals in the British National Health Service.
Because of a perceived decline in staff morale, the UK National Health Service has begun to routinely assess the extent to which commitment to the National Health Service may aid staff retention. While a number of studies have investigated the role of employee commitment in relation to staff turnover, no research to date has empirically tested if staff commitment to the NHS could protect job satisfaction from the effects of high job demands, and if this varies according to age. Using latent variable path analysis, this novel study examined this question among a national sample of Healthcare Professionals Allied to Medicine in the National Health Service. The results indicate that the negative effects of high job demands on job satisfaction were fully mediated by commitment to the National Health Service, but age mattered. Among the over 45s and over 55s, commitment to the National Health Service acted as an effective buffer against the negative effects of job demands on job satisfaction, but this effect was not as strong among the 35-44 age group. The broader policy implications of these findings are that age sensitive policies to support NHS workforce retention are needed. Also, pro-social institutions who employ Healthcare Professionals Allied to Medicine should develop policies for inspiring commitment to that institution, as it could help them with the demands of the job, and may even encourage more skilled workers to work longer.


Noviceware: a model for learning the software development process.
Students and nursing faculty without formal computer science training can collaborate within an independent study structure to assist the student in gaining experience with the fundamentals of software development. The systems development life cycle approach provides an essential map to structure such independent studies. This article describes the development within an academic setting of a computerized research management system. The software builds a database of research case demographic data and data from a 65-item tool used in scoring videotapes of caregiver-infant interactions. For students and faculty contemplating similar projects, recommendations about planning software development experiences and securing hardware, software, and expert resources are provided.


The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma.
Immune checkpoint inhibitors have been tried for several thoracic malignancies; however, their application as a neoadjuvant therapy in esophageal squamous cell carcinoma (ESCC) has not been studied. We evaluated the feasibility and safety of esophagectomy and total lymphadenectomy after neoadjuvant chemoradiation therapy with pembrolizumab. Between 2017 and 2018, 38 patients who received the neoadjuvant therapy followed by radical esophagectomy and total lymphadenectomy for ESCC were analyzed. Twenty-two patients received conventional neoadjuvant chemoradiation therapy (Group 1), and sixteen patients received neoadjuvant chemoradiation therapy with pembrolizumab in clinical trial (Group 2). Two groups were compared retrospectively. The basic characteristics of age, clinical stage, location and methods of operation were not different between the two groups. The pathologic stages were higher in Group 2, but the difference was not statistically significant. The operative outcomes, i.e., operation time, blood loss, and numbers of dissected lymph nodes in the thorax, neck, and abdomen were comparable. Complications, including pulmonary complications and anastomotic leakage, were also comparable. The rate of recurrent laryngeal nerve palsy was also comparable between the two groups (31.8% vs. 18.8%, P=0.469). Operative mortalities developed in 2 patients [0 vs. 2 (12.5%), P=0.171] due to acute respiratory distress syndrome (ARDS). Radical esophagectomy for esophageal squamous cell carcinoma after neoadjuvant chemoradiation therapy with pembrolizumab may not increase the operative risk or reduce the quality of radical dissection including lymphadenectomy. The risk of ARDS after neoadjuvant neoadjuvant chemoradiation therapy with pembrolizumab has to be studied in the further analysis.


A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients.
brain metastasis is a common cause of mortality in cancer patients, and associated with poor prognosis. Our objective was to develop a clinically relevant animal model by transplanting human biopsy spheroids derived from metastatic lesions into brains of immunodeficient rats. nine different patient brain metastases from four different primary cancers were implanted into brains of immunodeficient rats. The xenografts were compared with patient tumours by magnetic resonance imaging, histochemistry, immunohistochemistry and DNA copy number analysis. after transplantation, tumour growth was achieved in seven out of nine human brain metastases. Spheroids derived from four of the metastases initiated in the rat brains were further serially transplanted into new animals and a 100% tumour take was observed during second passage. Three of the biopsies were implanted subcutaneously, where no tumour take was observed. The animal brain metastases exhibited similar radiological features as observed clinically. Histological comparisons between the primary tumours from the patients, the patient brain metastases and the derived xenografts showed striking similarities in histology and growth patterns. Also, immunohistochemistry showed a strong marker expression similarity between the patient tumours and the corresponding xenografts. DNA copy number analysis between the brain metastases, and the corresponding xenografts revealed strong similarities in gains and losses of chromosomal content. we have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system.


The role of mitogen- and stress-activated protein kinase 1 and 2 in chronic skin inflammation in mice.
Mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) are two kinases phosphorylated by both ERK1/2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1/2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1/2 knockout mice and wild-type mice. MSK1/2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-α (TNF-α), IL-1β and IL-6 at both mRNA and protein levels in MSK1/2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1/2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1/2 knockout mice. Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.


The Bordetella bfe system: growth and transcriptional response to siderophores, catechols, and neuroendocrine catecholamines.
Ferric enterobactin utilization by Bordetella bronchiseptica and Bordetella pertussis requires the BfeA outer membrane receptor. Under iron-depleted growth conditions, transcription of bfeA is activated by the BfeR regulator by a mechanism requiring the siderophore enterobactin. In this study, enterobactin-inducible bfeA transcription was shown to be TonB independent. To determine whether other siderophores or nonsiderophore catechols could be utilized by the Bfe system, various compounds were tested for the abilities to promote the growth of iron-starved B. bronchiseptica and induce bfeA transcription. The BfeA receptor transported ferric salmochelin, corynebactin, and the synthetic siderophores TRENCAM and MECAM. Salmochelin and MECAM induced bfeA transcription in iron-starved Bordetella cells, but induction by corynebactin and TRENCAM was minimal. The neuroendocrine catecholamines epinephrine, norepinephrine, and dopamine exhibited a remarkable capacity to induce transcription of bfeA. Norepinephrine treatment of B. bronchiseptica resulted in BfeR-dependent bfeA transcription, elevated BfeA receptor production, and growth stimulation. Pyrocatechol, carbidopa, and isoproterenol were similarly strong inducers of bfeA transcription, whereas tyramine and 3,4-dihydroxymandelic acid demonstrated low inducing activity. The results indicate that the inducer structure requires a catechol group for function and that the ability to induce bfeA transcription does not necessarily correlate with the ability to stimulate bacterial growth. The expanded range of catechol siderophores transported by the BfeA receptor demonstrates the potential versatility of the Bordetella Bfe iron retrieval system. The finding that catecholamine neurotransmitters activate bfeA transcription and promote growth suggests that Bordetella cells can perceive and may benefit from neuroendocrine catecholamines on the respiratory epithelium.


Lipid content and fatty acid composition of the digital cushion of bulls offered different amounts of linseed.
Previous research suggests that the digital cushion, a shock-absorbing structure in the claw, plays an important role in protecting cattle from lameness. This study aimed to assess the degree to which nutritional factors influence the composition of the digital cushion. This involved quantifying lipid content and fatty acid composition differences in digital cushion tissue from cattle offered diets with different amounts of linseed. Forty-six bulls were allocated to 1 of 4 treatments, which were applied for an average of 140 +/- 27 d during the finishing period. The treatments consisted of a linseed supplement offered once daily on top of the basal diet (grass silage:concentrate) at 0, 400, 800, or 1,200 g of supplement/animal per day. For each treatment, the concentrate offered was adjusted to ensure that total estimated ME intake was constant across treatments. Target BW at slaughter was 540 kg. Legs were collected in 3 batches after 120, 147 and 185 d on experiment. Six samples of the digital cushion were dissected from the right lateral hind claw of each animal. Lipids were extracted and expressed as a proportion of fresh tissue, and fatty acid composition of the digital cushion was determined by gas chromatography. Data were analyzed by ANOVA, with diet, location within the digital cushion, and their interactions as fixed effects and fat content (grams per 100 g of tissue) as a covariate. Linear or quadratic contrasts were examined. The lipid content of digital cushion tissue differed between sampling locations (P < 0.001) but did not vary by treatment. There were quadratic responses to increasing linseed supplementation for several fatty acids. Although the overall proportion of C18:3n-3 (the most abundant fatty acid in linseed) did not differ (P < 0.33) by treatment, there was a quadratic influence of diet on total PUFA concentration (P = 0.003) and a linear increase in C18:3n-3 as a proportion of total PUFA (P = 0.01) in the digital cushion. This work demonstrates that dietary fatty acid composition influences the concentration of fatty acids incorporated in the digital cushion of cattle. Based on the large number of quadratic responses among the fatty acids, it appears there is a threshold amount of fatty acid incorporation in the digital cushion.


The efficacy of divergence hitchhiking in generating genomic islands during ecological speciation.
Genes under divergent selection flow less readily between populations than other loci. This observation has led to verbal "divergence hitchhiking" models of speciation in which decreased interpopulation gene flow surrounding loci under divergent selection can generate large regions of differentiation within the genome (genomic islands). The efficacy of this model in promoting speciation depends on the size of the region affected by divergence hitchhiking. Empirical evidence is mixed, with examples of both large and small genomic islands. To address these empirical discrepancies and to formalize the theory, we present mathematical models of divergence hitchhiking, which examine neutral differentiation around selected sites. For a single locus under selection, regions of differentiation do not extend far along a chromosome away from a selected site unless both effective population sizes and migration rates are low. When multiple loci are considered, regions of differentiation can be larger. However, with many loci under selection, genome-wide divergence occurs and genomic islands are erased. The results show that divergence hitchhiking can generate large regions of differentiation, but that the conditions under which this occurs are limited. Thus, speciation may often require multifarious selection acting on many, isolated and physically unlinked genes. How hitchhiking promotes further adaptive divergence warrants consideration.


Selective X-ray contrast enhancement of the spleen of living mice mediated by gold nanorods.
Gold nanomaterials (AuNPs) represent a promising new class of contrast agents for X-ray computed tomographic (CT) imaging in both research and clinical settings. These materials exhibit superior X-ray absorption properties compared with other iodinated agents, and thus require lower injection doses. Gold is nonimmunogenic and therefore contributes to safety profile in living specimens. Unfortunately, most reports on the use of AuNPs as X-ray CT enhancers only demonstrate marginal enhancement of the intended anatomical structure. In this study, we demonstrate the dramatic properties of gold nanorods (GNR) to serve as robust X-ray CT contrast-enhancing agent for selective imaging of the spleen. These organ-specific uptake properties were delineated by performing longitudinal CT imaging of living mice that were dosed with GNR at 2 day intervals. Rapid uptake in spleen was noted within 12 h of first systemic administration with a change in contrast enhancement of 90 Hounsfield units (ΔHU = 90) and with two subsequent injections a total contrast enhancement of over 200 HU was observed. The resulting images provide excellent contrast that will enable the detailed anatomical visualization and study of a range of pre-clinical models of spleen disease including infection and cancer.


Parenting and the Adjustment of Children Born to Gay Fathers Through Surrogacy.
Findings are presented on a study of 40 gay father families created through surrogacy and a comparison group of 55 lesbian mother families created through donor insemination with a child aged 3-9 years. Standardized interview, observational and questionnaire measures of stigmatization, quality of parent-child relationships, and children's adjustment were administered to parents, children, and teachers. Children in both family types showed high levels of adjustment with lower levels of children's internalizing problems reported by gay fathers. Irrespective of family type, children whose parents perceived greater stigmatization and children who experienced higher levels of negative parenting showed higher levels of parent-reported externalizing problems. The findings contribute to theoretical understanding of the role of family structure and family processes in child adjustment.


Governing sex workers in Timor Leste.
This paper argues that international security forces in Timor Leste depend upon civilian partners in HIV/AIDs "knowledge networks" to monitor prostitutes' disease status. These networks produce mobile expertise, techniques of government and forms of personhood that facilitate international government of distant populations without overt coercion. HIV/AIDs experts promote techniques of peer education, empowerment and community mobilisation to construct women who sell sex as health conscious sex workers. Such techniques make impoverished women responsible for their disease status, obscuring the political and economic contexts that produced that status. In the militarised context of Timor Leste, knowledge of the sexual conduct of sub-populations labelled high risk circulates among global HIV/AIDs knowledge networks, confirming their expert status while obscuring the sexual harm produced by military intervention. HIV/AIDs knowledge networks have recently begun to build Timorese sex worker organisations by contracting an Australian sex worker NGO to train a Timorese NGO tasked with building sex worker identity and community. Such efforts fail to address the needs and priorities of the women supposedly empowered. The paper engages theories of global knowledge networks, mobile technologies of government, and governmentality to analyse policy documents, reports, programmes, official statements, speeches, and journalistic accounts regarding prostitution in Timor Leste.


Use of membrane filters to facilitate the recovery of virus from aqueous suspensions.
Influenza virus was recovered from aqueous suspensions by means of membrane filters. Separation of virus from bacterial mixtures was achieved and virus was recovered free from bacteria. Technics developed for this application of the use of membrane filters were presented. These technics were extended to the successful isolation of Asian influenza virus from clinical specimens made available for use in the study.


Motor development in children at risk of autism: a follow-up study of infant siblings.
Recently, evidence of poor or atypical motor skills in autism spectrum disorder has led some to argue that motor impairment is a core feature of the condition. The current study uses a longitudinal prospective design to assess the development of motor skills of 20 children at increased risk of developing autism spectrum disorder, who were recruited and tested at 9 and 40 months of age, on the basis of having an older sibling diagnosed with the condition. All children completed a range of motor, face processing, IQ and diagnostic assessments at a follow-up visit (aged 5-7 years), providing a detailed profile of development in this group from a number of standardised, parental report and experimental measures. A higher proportion of children than expected demonstrated motor difficulties at the follow-up visit and those highlighted by parental report as having poor motor skills as infants and toddlers were also more likely to have lower face processing scores and elevated autism-related social symptoms at 5-7 years, despite having similar IQ levels. These data lend support to the argument that early motor difficulties may be a risk factor for later motor impairment as well as differences in social communication and cognition, traits that are related to autism spectrum disorder.


[Food insecurity in Brazilian families with children under five years of age].
This article analyzes food insecurity and hunger in Brazilian families with children under five years of age. This was a nationally representative cross-sectional study using data from the National Demographic and Health Survey on Women and Children (PNDS-2006), in which the outcome variable was moderate to severe food insecurity, measured by the Brazilian Food Insecurity Scale (EBIA). Prevalence estimates and prevalence ratios were generated with 95% confidence intervals. The results showed a high prevalence of moderate to severe food insecurity, concentrated in the North and Northeast regions (30.7%), in economic classes D and E (34%), and in beneficiaries of conditional cash transfer programs (36.5%). Multivariate analysis showed that the socioeconomic relative risks (beneficiaries of conditional cash transfers), regional relative risks (North and Northeast regions), and economic relative risks (classes D and E) were 1.8, 2.0 and 2.4, respectively. Aggregation of the three risks showed 48% of families with moderate to severe food insecurity, meaning that adults and children were going hungry during the three months preceding the survey.


Sciatic nerve regeneration by using collagen type I hydrogel containing naringin.
In the present study, collagen hydrogel containing naringin was fabricated, characterized and used as the scaffold for peripheral nerve damage treatment. The collagen was dissolved in acetic acid, naringin added to the collagen solution, and cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide powder (EDC; 0.10 mM) to form the hydrogel. The microstructure, swelling behavior, biodegradation, and cyto/hemocompatibility of the fabricated hydrogels were assessed. Finally, the healing efficacy of the prepared collagen hydrogel loaded with naringin on the sciatic nerve crush injury was assessed in the animal model. The characterization results showed that the fabricated hydrogels have a porous structure containing interconnected pores with the average pore size of 90 µm. The degradation results demonstrated that about 70% of the primary weight of the naringin loaded hydrogel had been lost after 4 weeks of storage in PBS. The in vitro study showed that the proliferation of Schwann cells on the collagen/naringin hydrogel was higher than the control group (tissue culture plate) at both 48 and 72 h after cell seeding and even significantly higher than pure collagen 72 h after cell seeding (*p < 0.005, **p < 0.001). The animal study implied that the sciatic functional index reached to -22.13 ± 3.00 at the end of 60th days post-implantation which was statistically significant (p < 0.05) compared with the negative control (injury without the treatment) (-82.60 ± 1.06), and the pure collagen hydrogel (-59.80 ± 3.20) groups. The hot plate latency test, the compound muscle action potential, and wet weight-loss of the gastrocnemius muscle evaluation confirmed the positive effect of the prepared hydrogels on the healing process of the induced nerve injury. In the final, the histopathologic examinations depicted that the collagen/naringin hydrogel group reduced all the histological changes induced from the nerve injury and showed more resemblance to the normal sciatic nerve, with well-arranged fibers and intact myelin sheath. The overall results implied that the prepared collagen/naringin hydrogel can be utilized as a sophisticated alternative to healing peripheral nerve damages.


Predictors of response to sildenafil citrate following radiation therapy for prostate cancer.
Phosphodiesterase type 5 inhibitor (PDE5) use is a treatment strategy for prostate cancer patients with post-radiation therapy (RT) erectile dysfunction (ED). To define the predictors of sildenafil response in men treated with RT for prostate cancer. International Index of Erectile Function (IIEF). Patients were enrolled prospectively if they met the following criteria: (i) either a three-dimensional conformal external beam (EBRT) or brachytherapy (BT) with or without androgen deprivation (AD) for prostate cancer; (ii) self-reported ability to have sexual intercourse prior to RT; (iii) experienced onset of ED following RT; (iv) candidates for sildenafil citrate use; (v) followed-up periodically; and (vi) completed the IIEF at least 12 months after RT. Failure to respond to sildenafil was defined as IIEF-erectile function (EF) domain score of <22. One hundred fifty-two patients met all the criteria: 110 in the EBRT group and 42 in the BT group. Mean age was 62 years. The mean follow-up was 38 months. Mean radiation dose for EBRT was 78 Gy and for BT was 101 Gy. Thirty-five patients received AD, 25% of EBRT, and 62% of BT patients. Sixty-one percent of the patients receiving AD had exposure only pre-RT, whereas 39% had pre- and post-RT AD exposure. The mean duration of AD was 4.6 months. Post-RT IIEF-EF domain score at >24 months was 17. Successful response to sildenafil occurred in 68% of men at 12 months after RT, 50% at 24 months, and 36% at 36 months. On multivariable analysis, predictors of failure to respond to sildenafil were: older age, longer time after RT, AD > 4 months duration, and RT dose > 85 Gy. Modality of radiation delivery was not predictive of sildenafil failure. A steady decrease in sildenafil response was seen with increasing duration after RT. Several factors were predictive of sildenafil failure.


Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease.
Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis.


Short range ordering in the modified honeycomb lattice compound SrHo(2)O(4).
The low temperature behaviour of single crystalline SrHo(2)O(4) has been characterized by dc magnetic susceptibility, heat capacity, and neutron scattering experiments. Our results show that despite the lack of magnetic long-ranged ordering in the presence of strong antiferromagnetic correlations, SrHo(2)O(4) does not order down to 1.8 K. Elastic neutron scattering experiments show prominent magnetic diffuse scattering correlated with a broad feature in the dc susceptibility at T = 4 K, indicative of magnetic short-ranged ordering of the Ho(3) spins. Inelastic neutron scattering shows the presence of five crystal field levels up to 80 K in energy, in agreement with the integration of the magnetic specific heat component yielding Rln5 entropy release. The magnetic short-ranged ordering is fitted to a nearest neighbour interaction model with good agreement.


Prospective investigation of a PTSD personality typology among individuals with personality disorders.
This study investigated the replicability of a previously proposed personality typology of posttraumatic stress disorder (PTSD, and explored stability of cluster membership over a 6-month period. Participants with current PTSD (n = 156) were drawn from the Collaborative Longitudinal Personality Disorders Study (CLPS). The CLPS project tracked a large sample of individuals who met criteria for 1 of 4 target diagnoses (borderline, schizotypal, avoidant, and obsessive-compulsive) and a contrast group of individuals who met criteria for depression but no personality disorder. A cluster analysis using scales from the Schedule of Nonadaptive and Adaptive Personality yielded 3 clusters: "internalizing," "externalizing," and "low pathology." Using K-means cluster analysis, the results did not replicate previous work. Using Ward's method, the hypothesized 3-cluster structure was confirmed at baseline but did not demonstrate temporal stability at 6 months.


Effect of human glutathione S-transferases on glutathione-dependent inactivation of cytochrome P450-dependent reactive intermediates of diclofenac.
Idiosyncratic adverse drug reactions due to the anti-inflammatory drug diclofenac have been proposed to be caused by the generation of reactive acyl glucuronides and oxidative metabolites. For the oxidative metabolism of diclofenac by cytochromes P450 at least five different reactive intermediates have been proposed previously based on structural identification of their corresponding GSH-conjugates. In the present study, the ability of four human glutathione S-transferases (hGSTs) to catalyze the GSH-conjugation of the different reactive intermediates formed by P450s was investigated. Addition of pooled human liver cytosol and recombinant hGSTA1-1, hGSTM1-1, and hGSTP1-1 to incubations of diclofenac with human liver microsomes or purified CYP102A1M11 L437N as a model system significantly increased total GSH-conjugation. The strongest increase of total GSH-conjugation was observed by adding hGSTP1-1, whereas hGSTM1-1 and hGSTA1-1 showed lower activity. Addition of hGSTT1-1 only showed a minor effect. When considering the effects of hGSTs on GSH-conjugation of the different quinoneimines of diclofenac, it was found that hGSTP1-1 showed the highest activity in GSH-conjugation of the quinoneimine derived from 5-hydroxydiclofenac (5-OH-DF). hGSTM1-1 showed the highest activity in inactivation of the quinoneimine derived from 4'-hydroxydiclofenac (4'-OH-DF). Separate incubations with 5-OH-DF and 4'-OH-DF as substrates confirmed these results. hGSTs also catalyzed GSH-conjugation of the o-iminemethide formed by oxidative decarboxylation of diclofenac as well as the substitution of one of the chlorine atoms of DF by GSH. hGSTP1-1 showed the highest activity for the formation of these minor GSH-conjugates. These results suggest that hGSTs may play an important role in the inactivation of DF quinoneimines and its minor reactive intermediates especially in stress conditions when tissue levels of GSH are decreased.


Impact of immune system stimulation on the ileal nutrient digestibility and utilisation of methionine plus cysteine intake for whole-body protein deposition in growing pigs.
The impact of immune system stimulation (ISS) on the ileal nutrient digestibility and utilisation of dietary methionine plus cysteine (SAA) intake for whole-body protein deposition (PD) was evaluated in growing pigs. For this purpose, sixty barrows were used in two experiments: thirty-six pigs in Expt I and twenty-four pigs in Expt II. Pigs were feed restricted and assigned to five levels of dietary SAA allowance (three and two levels in Expt I and II, respectively) from SAA-limiting diets. Following adaptation, pigs at each dietary SAA level were injected with either increasing amounts of Escherichia coli lipopolysaccharide (ISS+; eight and six pigs per dietary SAA level in Expt I and II, respectively) or saline (ISS - ; four and six pigs in Expt I and II, respectively) while measuring the whole-body nitrogen (N) balance. After N-balance observations, pigs were euthanised, organs were removed and ileal digesta were collected for determining nutrient digestibility. Ileal digestibility of gross energy, crude protein and amino acids was not affected by ISS (P>0·20). ISS reduced PD at all levels of dietary SAA intake (P< 0·01). The linear relationship between daily dietary SAA intake and PD observed at the three lowest dietary SAA intake levels indicated that ISS increased extrapolated maintenance SAA requirements (P< 0·05), but had no effect on the partial efficiency of the utilisation of dietary SAA intake for PD (P>0·20). Physiological and metabolic changes associated with systemic ISS had no effect on the ileal digestibility of nutrients per se, but altered SAA requirements for PD in growing pigs.


A systematic approach to diagnosis of cystic brain lesions.
Brain metastasis is the most common intracranial tumor in adults. The incidence of brain metastasis is rising with the increase in survival of cancer patients. Magnetic resonance imaging with contrast enhancement is the imaging procedure of choice to diagnose and characterize brain metastases. Multiple lesions with marked vasogenic edema and mass effect are typically seen in patients with brain metastases. The classical appearance of a metastasis is a solid enhancing mass with well-defined margins and extensive edema. Occasionally, central necrosis produces a ring enhancing mass. Here, we report a case of Non Small Cell Lung Cancer with multiple ring enhancing lesions in brain, and the approach to diagnosis of such patients.


Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: the increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens.
The carcinogens to which humans are exposed are normally in the form of complex mixtures, and much effort has gone into determining the nature of the most significant carcinogenic components in these mixtures and their mechanisms of action. Essential to achieving this aim in exposed populations is the use of biomarkers, which can characterize the chemical nature of the carcinogens involved and identify key biological effects that result from the exposure. DNA adducts are particularly appropriate as biomarkers in the case of genotoxic carcinogens as they indicate the biologically effective dose of the genotoxin in the target tissue under study. This review considers in particular the use of mass spectrometry (MS), which is having an increasing role in the determination of DNA adducts. Compared to other existing DNA damage detection methods, such as 32P-postlabeling, HPLC-fluorescence or electrochemical detection, immunoassay-based techniques and modified Comet assays, MS provides improved structural characterization of adducts. Greater selectivity in the analyses is achieved by the use of tandem MS with selected reaction monitoring or constant neutral loss of ions. Use of capillary/nano liquid chromatography and micro/nano electrospray ionization improves the analytical sensitivity and higher throughput may be obtained by the use of online-column switching. The application of microfluidics technology offers exciting new possibilities for interfacing sample preparation to the mass spectrometer. Despite these improvements in the use of MS for adduct detection, the main current requirement is to validate these methods both analytically and in molecular epidemiology studies. More knowledge of the stability of stored samples is required. Development of sensitive mass spectrometric DNA adductomic screening systems, and of long-term biomarkers (e.g., phosphotriester adducts that are not repaired efficiently) seems important areas for the future assessment of the effects of human exposure to environmental genotoxins, together with studies of dose-response relationships at low doses.


Mast Cells Exert Anti-Inflammatory Effects in an IL10-/- Model of Spontaneous Colitis.
Mast cells are well established as divergent modulators of inflammation and immunosuppression, but their role in inflammatory bowel disease (IBD) remains to be fully defined. While previous studies have demonstrated a proinflammatory role for mast cells in acute models of chemical colitis, more recent investigations have shown that mast cell deficiency can exacerbate inflammation in spontaneous colitis models, thus suggesting a potential anti-inflammatory role of mast cells in IBD. Here, we tested the hypothesis that in chronic, spontaneous colitis, mast cells are protective. We compared colitis and intestinal barrier function in IL10-/- mice to mast cell deficient/IL10-/- (double knockout (DKO): KitWsh/Wsh × IL10-/-) mice. Compared with IL10-/- mice, DKO mice exhibited more severe colitis as assessed by increased colitis scores, mucosal hypertrophy, intestinal permeability, and colonic cytokine production. PCR array analyses demonstrated enhanced expression of numerous cytokine and chemokine genes and downregulation of anti-inflammatory genes (e.g., Tgfb2, Bmp2, Bmp4, Bmp6, and Bmp7) in the colonic mucosa of DKO mice. Systemic reconstitution of DKO mice with bone marrow-derived mast cells resulted in significant amelioration of IL10-/--mediated colitis and intestinal barrier injury. Together, the results presented here demonstrate that mast cells exert anti-inflammatory properties in an established model of chronic, spontaneous IBD. Given the previously established proinflammatory role of mast cells in acute chemical colitis models, the present findings provide new insight into the divergent roles of mast cells in modulating inflammation during different stages of colitis. Further investigation of the mechanism of the anti-inflammatory role of the mast cells may elucidate novel therapies.


Cognitive factors associated with adherence to oral antiestrogen therapy: results from the cognition in the study of tamoxifen and raloxifene (Co-STAR) study.
Little is known about the cognitive factors associated with adherence to antiestrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral antiestrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled nondemented participants ≥65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol ≥80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2 ± 4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were nonadherent. In adjusted analyses, the odds of nonadherence were lower for those with better scores on verbal memory [OR (95% confidence interval): 0.75 (0.62-0.92)]. Larger relative deficits in verbal memory compared with verbal fluency were also associated with nonadherence [1.28 (1.08-1.51)]. Among nondemented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence.


Synthesis and utilization of E. coli-encapsulated PEG-based microdroplet using a microfluidic chip for biological application.
We report herein an effective strategy for encapsulating Escherichia coli in polyethylene glycol diacrylate (PEGDA) microdroplets using a microfluidic device and chemical polymerization. PEGDA was employed as a reactant due to the biocompatibility, high porosity, and hydrophilic property. The uniform size and shape of microdroplets are obtained in a single-step process using microfluidic device. The size of microdroplets can be controlled through the changing continuous flow rate. The combination of microdroplet generation and chemical polymerization techniques provide unique environment to produce non-toxic ways of fabricating microorganism-encapsulated hydrogel microbeads. Due to these unique properties of micro-sized hydrogel microbeads, the encapsulated E. coli can maintain viability inside of microbeads and green fluorescent protein (GFP) and red fluorescent protein (RFP) genes are efficiently expressed inside of microbeads after isopropyl-β-D-thiogalactopyranoside induction, suggesting that there is no low-molecular weight substrate transfer limitation inside of microbeads. Furthermore, non-toxic, gentle, and outstanding biocompatibility of microbeads, the encapsulated E. coli can be used in various applications including biotransformation, biosensing, bioremediation, and engineering of artificial cells.


The Diagnostic Accuracy of Clinical Diagnostic Tests for Thoracic Outlet Syndrome.
Clinical Scenario: Thoracic outlet syndrome is quite challenging to diagnose. Currently, there are myriad diagnostic procedures used in the diagnosis of all types of thoracic outlet syndrome. However, controversy exists over which diagnostic procedures produce accurate findings. Can clinical diagnostic tests accurately diagnose patients presenting with symptoms of thoracic outlet syndrome? Summary of Key Findings: A thorough literature search returned 6 possible studies; 3 studies met the inclusion criteria and were included. Two studies supported the use of clinical diagnostic tests for the diagnosis of thoracic outlet syndrome. One study reported high false-positive rates among clinical diagnostic tests for thoracic outlet syndrome. One study reported that clinical diagnostic test findings correlate to provocative positioned magnetic resonance imaging findings. Clinical Bottom Line: There is moderate evidence to support the use of the Halstead maneuver (also known as the costoclavicular maneuver or exaggerated military brace test), Wright's test, Cyriax Release test, and supraclavicular pressure test to have good diagnostic accuracy for the provocation of symptoms in patients presenting with upper extremity pathology. However, these clinical diagnostic tests do not appear to allow for the differential diagnosis of thoracic outlet syndrome exclusively. The use of the Adson's test and Roos test should be discontinued for the differential diagnosis of thoracic outlet syndrome. Strength of Recommendation: Grade B evidence exists to support the accuracy of the Halstead maneuver, Wright's test, Cyriax Release test, and supraclavicular pressure test for the diagnosis of upper extremity pathology in general. Grade C evidence exists for the use of these clinical diagnostic tests to exclusively diagnose thoracic outlet syndrome.


Decoding the diagnostic potential of T cell repertoires in peripheral blood of patients from amnestic mild cognitive impairment to Alzheimer's disease.
Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder and is the most common etiological cause of dementia. Consequently, it has severe burden on its patients and on their caregivers and represents a global health concern. Clinical investigations have indicated that a dysregulation of peripheral T cell immune homeostasis may be involved in the pathogenesis of AD, as well as in the early stages of AD, characterized by mild cognitive impairment (MCI). However, the characteristics and concomitant feasibility of the use of T-cell receptor (TCR) typing for disease diagnosis remains largely unknown. We employed a high-throughput sequencing and multidimensional bioinformatics analyses for the identification of TCR repertoires present in peripheral blood samples of 10 patients with amnestic MCI (aMCI), 10 patients with AD, and 10 healthy controls (HCs). Based on the characteristics of the TCR repertoires in the amount and diversity of combinations of V-J, the spectrum of immune defense, and differentially expressed genes (DEGs), single and specific TCR profiles were observed in the patient samples of aMCI and AD compared to profiles of HCs. In particular, the diversity of TCR clonotypes manifested a pattern of "decreased first and then increased" pattern during the progression from aMCI to AD, a pattern that was not observed in HC samples. Additionally, a total of 46 and 35 amino acid CDR3 sequences with consistent and reverse expressive abundance with diversity of TCR clonotypes were identified, respectively. Taken together, we provide novel and essential preliminary evidence demonstrating the presence of diversity of T cell repertoires from differentially expressed V-J gene segments and amino acid clonotypes using peripheral blood samples from patients with AD, aMCI, and from HC. Such findings have the potential to reveal potential mechanisms through which aMCI progresses to AD and provide a reference for the future development of immune-related diagnoses and therapies for AD.


Antimicrobial susceptibility survey of Pseudomonas aeruginosa strains isolated from clinical sources.
A two-year prospective study of 554 Pseudomonas aeruginosa isolates was recovered from various clinical sources throughout Trinidad, and their resistance patterns to antipseudomonal antimicrobial agents were determined. Of the 554 P. aeruginosa isolates, 20.6% (114/554) were community isolates, 17.3% (96/554) from the intensive care unit (ICU), 10.1% (56/554) from the nursery, and the remaining 52% (288/554) were from other hospital inpatient services. Respiratory tract infections were the predominant source of P. aeruginosa isolates from the ICU--46.9% (45/96)--and nursery--21.4% (12/56), whereas wounds were the principal source of P. aeruginosa from the surgical services--77.0% (141/183). Community isolates of P. aeruginosa were predominantly from ear--100% (51/51)--and urinary tract infections--35.5%, (33/93). The overall prevalence of resistance was low for both hospital isolates (13.9%) and community isolates (3.8%). All community isolates were fully sensitive to four of the nine antimicrobials tested. Resistance rates among community strains ranged from 2.6% (ciprofloxacin and ceftazidime) to 12.3% for piperacillin. All isolates from hospital were fully sensitive to imipenem, but resistance rates for the other drugs ranged between 2.5% and 27.3%. The study showed that the overall resistance pattern of P. aeruginosa was relatively low. This is an encouraging observation but invites caution since resistance to the newly introduced drug, cefepime, has now emerged within the hospital environment and may present serious therapeutic problems within the near future. Policies governing the use of antimicrobials in many institutions are lacking. Such policies must be instituted in order to limit the spread of resistance and also to reduce the emergence of resistance to newly commissioned drugs within the country.


The irritable bowel syndrome. A clinical review and ethical considerations.
The irritable bowel syndrome (IBS) is clinically characterized by a wide variety of symptoms, including dyspepsia, flatulence, nausea, cramping abdominal pain, constipation and/or diarrhea, and nonspecific symptoms, probably reflecting autonomic nervous system overreactivity. Physiologically, the colonic motor abnormality is characterized by an altered slow-wave rhythm, quantitative differences from normal in the repetitive contraction pattern of the rectosigmoid area, and increased colonic muscle responsiveness to hormones such as cholecystokinin and pentagastrin. The diagnosis of IBS involves practical and ethical considerations as well as the need for decisive reassurance of the patient through judicious examination. Treatment of IBS requires a thoughtful and sensitive approach to the patient, recognition of IBS as an important clinical problem, regularization of bowel function, relief of the abdominal discomfort, and intelligent emotional support.


Construction and identification of recombinant adenovirus carrying human TIMP-1shRNA gene.
The aim of this study was to construct the recombinant adenovirus carrying human TIMP-1shRNA gene expression system for preliminary identification to lay the foundation for the further study of gene therapy. Using the Adeno-X system, the recombinant adenovirus plasmid pAdeno-X green fluorescent protein (GFP)-tissue inhibitor of metalloprotease (TIMP)-1 small hairpin (1shRNA) was constructed by including the target gene fragment of the TIMP-1shRNA shuttle plasmid pShuttle2-GFP-TIMP-1shRNA and the backbone plasmid pAdeno-X by homologous recombination in Escherichia coli. Recombinant plasmids were transfected into HEK293A cells to package the recombinant adenovirus rvAdeno-XGFP-TIMP-1shRNA. The recombinant adenovirus was identified by polymerase chain reaction, and the viral titer and infection efficiency were detected using GFP. Polymerase chain reaction and restriction endonuclease digestion demonstrated that rvAdeno-XGFP-TIMP-1shRNA had been successfully constructed, which has a strong ability to infect the kidney. The TIMP-1shRNA adenovirus expression vector was successfully constructed using homologous recombination methods.


Localization of a mutant gene for cleft palate and ankyloglossia in an X-linked Icelandic family.
Common congenital malformations such as cleft lip and cleft palate are in most cases multifactorial in origin, involving both environmental and genetic components. Molecular biology techniques have enabled the successful chromosomal localization of many mutant genes from disorders that exhibit simple Mendelian segregation, whether autosomally dominant (e.g., Huntington's disease), autosomal recessive (e.g., cystic fibrosis), or X-linked (e.g., Duchenne muscular dystrophy). Studying the genetic aspect of multifactorial disorders is more complex. It requires a model family or families within which the common multifactorial phenotype is displayed as a single gene defect. Such a model has been recently exploited in the form of a large Icelandic family (over 280 members) exhibiting X-linked secondary cleft palate (CP) and ankyloglossia (A) (tongue-tied) as a single gene mutation. Using this family and the large bank of well-characterized DNA probes available for the human X chromosome, the gene for CP + A was localized by linkage analysis to Xq13-q21.1 (LOD score = 3.07, linked to anonymous probe DXYS1). Further fine mapping, using other X probes from this region (confirmed by analysis of DNA from a deletion cell-line) has placed the gene between markers DXYS12 and DXS17 (LOD score = 4.1) at Xq21.3-q22. The approximate distance between these two probes is 5 centimorgans (cM), equivalent to approximately 5 million base pairs. Now that the limits of genetic linkage have been fully tested and there are two markers flanking the defect locus, strategies are being pursued to clone the gene responsible.(ABSTRACT TRUNCATED AT 250 WORDS)


Double-exposure to acute stress and chronic family stress is associated with immune changes in children with asthma.
To understand how psychological stress heightens risk for asthma flare-ups, we examined the relationship between acute stress, chronic family stress, and the production of asthma-related cytokines. Seventy-one children with asthma and 76 medically healthy children completed interviews regarding life stress, and peripheral blood samples were collected. After mononuclear cells had been mitogenically stimulated, production of the cytokines interleukin (IL)-4, IL-5, IL-13, and IFN-gamma was measured. All measurements were repeated every 6 months for 2 years. Children reported on their asthma symptoms for 14 days after each study visit. Children with asthma who had higher levels of chronic family stress showed increased production of IL-4, IL-5, and IFN-gamma at times when they had experienced an acute event compared with times when they had not. These stress-related changes did not occur in asthmatic children with lower levels of chronic family stress, or in healthy controls. The combination of acute and chronic stress was also associated with increased asthma symptoms. These findings suggest that acute negative life events have a particularly strong impact among a subgroup of children with asthma who are under high chronic family stress. The heightened inflammatory profile in this group suggests an explanation for why children experiencing life stressors are at greater risk for asthma exacerbations.


Effect of Body Position on Epsicleral Venous Pressure in Healthy Subjects.
The mechanism of IOP change during a body position change is poorly understood. In this study, we investigated changes in episcleral venous pressure (EVP) between two body positions, sitting and inclined, and compared this with changes in IOP. This study was a prospective, comparative case series of 43 eyes of 24 healthy volunteers. IOP was measured using a pneumatonometer in the seated position. EVP was then measured in a selected episcleral vein by using an automated, slit-lamp-mounted venomanometer. Thirty minutes later, the subject was placed in an inclined position with the neck extended and the head resting on the chin rest of the slit lamp. After 5 minutes, IOP and EVP in the same vein were remeasured. EVP in the inclined position was compared with EVP in the seated position, and the change in IOP was compared with the change in EVP. Statistical significance was determined using generalized estimating equation models. Mean IOP increased from 11.4 ± 3.0 mm Hg (mean ± SD) in the sitting position to 13.1 ± 3.4 mm Hg in the inclined position (P < 0.001). Mean EVP increased from 6.4 ± 1.4 mm Hg in the sitting position to 7.8 ± 1.7 mm Hg in the inclined position (P < 0.001). The postural rise in IOP was not different from the rise in EVP (P = 0.18). In the inclined position, IOP and EVP are higher than they are in the sitting position. The posture-induced rise in IOP can be attributed to an increase in EVP.


Identification and characterization of Bahia Grande, Reed Ranch and Muir Springs viruses, related members of the family Rhabdoviridae with widespread distribution in the United States.
Sixteen virus isolates with similar biological characteristics were obtained from salt-marsh mosquitoes collected in south Texas in 1974. When compared antigenically, these and 13 other isolates from mosquitoes collected between 1972 and 1979 in west Texas, New Mexico, Louisiana, Colorado and North Dakota were shown to be related but not identical. Three distinct serotypes were determined: Bahia Grande (prototype strain TB4-1054), Reed Ranch (TB4-222) and Muir Springs (76V-23524). When examined by electron microscopy, these three viruses were shown to be rhabdoviruses. Structural analysis of the prototype strain of Bahia Grande virus from Texas revealed five proteins. Comparative oligonucleotide fingerprint maps showed 51 to 86% sharing of the large oligonucleotides between Bahia Grande virus (strain TB4-1054) and 11 other antigenically related isolates but not with Muir Springs virus (strain 76V-23524), an antigenically distinct isolate from mosquitoes collected in Colorado. A serological survey for antibody to Bahia Grande virus showed that humans, cattle, sheep, reptiles and wild mammals from south Texas had neutralizing antibodies to this virus.


Complementary prognostic value of cystatin C, N-terminal pro-B-type natriuretic Peptide and cardiac troponin T in patients with acute heart failure.
The aims of this study were to compare the prognostic value of cystatin C over creatinine and the Modification of Diet in Renal Disease (MDRD) equation and to evaluate whether it provides complementary information to cardiac biomarkers in the risk stratification of an unselected cohort of patients with acute heart failure. Consecutive hospitalized patients with established diagnoses of acute heart failure were prospectively studied. Blood samples were collected on hospital arrival to determine cystatin C, cardiac troponin T, and N-terminal-pro-brain natriuretic peptide. Clinical follow-up was obtained, and the occurrence of mortality and/or heart failure readmission was registered. One hundred thirty-eight patients (median age 74 years, interquartile range 67 to 80; 54% men) were studied. During a median follow-up period of 261 days (interquartile range 161 to 449), 60 patients (43.5%) presented with adverse events. After multivariate adjustment, cystatin C, N-terminal-pro-brain natriuretic peptide, cardiac troponin T, New York Heart Association functional class III or IV, and diabetes mellitus were identified as independent predictors of mortality and/or heart failure readmission. In contrast to creatinine and the MDRD equation, the highest cystatin C tertile (>1.50 mg/L) was a significant independent risk factor for adverse events (hazard ratio 3.08, 95% confidence interval 1.54 to 6.14, p = 0.004). A multimarker approach combining cardiac troponin T, N-terminal-pro-brain natriuretic peptide, and cystatin C improved risk stratification further, showing that patients with 2 (hazard ratio 2.37, 95% confidence interval 1.10 to 5.71) or 3 (hazard ratio 3.64, 95% confidence interval 1.55 to 8.56) elevated biomarkers had a higher risk for adverse events than patients with no elevated biomarkers (p for trend = 0.015). In conclusion, in this unselected cohort, cystatin C was a stronger predictor of adverse events than conventional measures of kidney function. In addition, cystatin C offered complementary prognostic information to cardiac biomarkers and could help clinicians perform more accurate risk stratification of patients with acute heart failure.


[Bladder with non-coordinated voiding: urodynamics and clinical correlations].
25 children (female) with urodynamically proven non-coordinated voiding were followed prospectively. The objective was to study the changes of urodynamic pattern and its clinical correlation after voiding reeducation and pharmacological treatment. All patients presented with urinary tract infections and voiding disfunction symptoms. 5 children had vesicoureteral reflux on voiding cystography and 10 patients had established scars on DMSA scan at initial presentation. Urodynamic study showed constriction of the urinary sphincter during voiding and increase of post-voiding residual urine volume in all children, with bladder instability 20 (80%). Treatment consisted of voiding reeducation, anticholinergics, antibiotic prophylaxis and muscle relaxants. The mean of follow-up was 22 months. Clinical remission occurred prior to urodynamic remission in all girls. Clinical recurrence was observed in 2 girls after cessation of treatment prior to normalization of urodynamic pattern. Non-coordinated voiding should be diagnosed and treated at pediatric age to avoid its possible progression to renal failure in other period of life.


Peptidyl fluorescent chemosensors for the detection of divalent copper.
Fluorescent organic chemosensors for the detection of divalent copper with high selectivity and sensitivity are the subject of intense research in the recent years. Structurally, ionophore and fluorophore are two essential parts determining the resultant performance of the chemosensor. While much work has been focused on designing highly selective ligands, little attention has been paid to the possible influence of ionophore-fluorophore interaction on their properties in metal ion binding. We studied here fluorescent chemosensors based on the Gly-His peptidyl motif and found that the functionality of the chemosensors was greatly influenced by the spatial alignment of the fluorophore in the molecules. In Gly-His-Lys(Dns) (1), the dansyl group is on a side branch and does not interact with copper, while in Dpr(Dns)-His-Lys (2), the dansyl group is also on a side branch but the close placement allows it to directly participate in the binding with copper ions. Therefore, although dansyl can signal the binding event in both molecules, the mechanisms involved are quite different, and this difference resulted in different sensing performance, e.g., the selectivity. Even more strikingly, the dansyl group in Dns-Gly-His-Gly (3) exhibited a profound effect on the molecular complexation. The binding constant decreased, and binding mode was affected since only 1:1 binding was observed while in side-branch-labeled ligands, a 2:1 binding may also be involved. In contrast to those side-chain-labeled ligands, molecule 3 is extremely simple in structure and possesses superior detecting qualities such as selectivity, molecular sensitivity, and applicability in a wide range of pH.


[Professional development: the mission (II)].
In the second part of this generic article whose purpose is to analyze what is a mission statement of an organization, the author concentrates on two fundamental points: what are the bases upon which a mission statement is constructed from a strategic perspective and what are the functions and advantages of a mission statement. With respect to this first basis, the author points out that an organization's function should be based on sound business criteria; that a mission statement should harmonize with the organizational milieu, reflect the values of the organization's professional staff while paying attention to special interest groups; and focus on professional know-how and on what works well and makes sense for the client. Concerning this second aspect, this article deals with maintaining the integrity of an organization, motivating professionals or utilizing a mission statement as a means of control.


Human Salmonella clinical isolates distinct from those of animal origin.
The global trend toward intensive livestock production has led to significant public health risks and industry-associated losses due to an increased incidence of disease and contamination of livestock-derived food products. A potential factor contributing to these health concerns is the prospect that selective pressure within a particular host may give rise to bacterial strain variants that exhibit enhanced fitness in the present host relative to that in the parental host from which the strain was derived. Here, we assessed 184 Salmonella enterica human and animal clinical isolates for their virulence capacities in mice and for the presence of the Salmonella virulence plasmid encoding the SpvB actin cytotoxin required for systemic survival and Pef fimbriae, implicated in adherence to the murine intestinal epithelium. All (21 of 21) serovar Typhimurium clinical isolates derived from animals were virulent in mice, whereas many (16 of 41) serovar Typhimurium isolates derived from human salmonellosis patients lacked this capacity. Additionally, many (10 of 29) serovar Typhimurium isolates derived from gastroenteritis patients did not possess the Salmonella virulence plasmid, in contrast to all animal and human bacteremia isolates tested. Lastly, among serovar Typhimurium isolates that harbored the Salmonella virulence plasmid, 6 of 31 derived from human salmonellosis patients were avirulent in mice, which is in contrast to the virulent phenotype exhibited by all the animal isolates examined. These studies suggest that Salmonella isolates derived from human salmonellosis patients are distinct from those of animal origin. The characterization of these bacterial strain variants may provide insight into their relative pathogenicities as well as into the development of treatment and prophylactic strategies for salmonellosis.


Organ-preserving approach via radiotherapy for small cell carcinoma of the bladder: an analysis based on the Japanese Radiation Oncology Study Group (JROSG) survey.
Small cell carcinoma of the bladder is extremely rare, accounting for <1% of all malignant tumours in the urinary tract. Thus, no standard therapy modality for this malignancy has been established. This study aimed to retrospectively analyse the clinical outcomes associated with definitive radiotherapy for small cell carcinoma of the bladder. A questionnaire-based survey of patients with pathologically proven small cell carcinoma of the bladder treated with definitive radiation therapy between 1990 and 2010 was conducted by the Japanese Radiation Oncology Study Group. The clinical records of 12 eligible patients were collected from nine institutions. The median age of the patients was 70.5 years (range: 44-87 years), and the median follow-up period was 27.3 months (range: 3.3-117.8 months). The median prescribed dose was 60 Gy (range: 50.0-61.0 Gy), and a median of 2.0 Gy (range: 1.2-2.0 Gy) was administered per fraction. Systemic chemotherapy combined with radiotherapy was performed in eight cases (66.7%). The 3- and 5-year overall survival rates were 50.0% and 33.3%, respectively. And the 3- and 5-year local control rates were 66.7% and 55.6%, respectively. Chemotherapy significantly improved overall survival and relapse-free survival (P = 0.006 and 0.001, respectively). No serious adverse events occurred in the observation period. All patients who achieved local control maintained functional bladders. In conclusion, radiotherapy is a potential local treatment option and has an important role in maintaining quality of life. Systemic chemotherapy combined with local radiotherapy seems to be effective in improving survival.


High folate and low vitamin B12 status during pregnancy is associated with gestational diabetes mellitus.
B-vitamins and homocysteine may contribute to the development of gestational diabetes mellitus (GDM), but existing studies are inconsistent. We examined the cross-sectional associations of plasma folate, vitamins B6, B12, and homocysteine concentrations with GDM and glycemia in a sample of multi-ethnic Asian pregnant women. Plasma concentrations of folate, vitamins B6, B12, homocysteine and glucose were measured at 26-weeks' gestation in 913 pregnant women. GDM was diagnosed using the 1999 World Health Organization criteria. Associations were examined with linear or logistic regression, adjusted for confounders and stratified by ethnicity. Higher plasma folate was associated with higher 2-h glucose and higher odds of GDM [0.15 (0.02, 0.23) per 1-SD increment in folate, OR 1.29 (1.00, 1.60)], mainly among Indian mothers. Higher plasma vitamin B12 and homocysteine were associated with lower fasting and 2-h glucose, and lower odds of GDM [-0.04 (-0.07, -0.01) per 1-SD increment in B12 and -0.09 (-0.18, -0.003) respectively, OR: 0.81 (0.68, 0.97); -0.05 (-0.08, -0.02) per 1-SD increment in homocysteine and -0.12 (-0.21, -0.02) respectively, OR: 0.76 (0.62, 0.92)]. The highest odds of GDM were observed among women with combined vitamin B12 insufficiency and high folate concentration [OR: 1.97 (1.05, 3.68)]. An association between higher vitamin B6 and higher 2-h glucose shifted towards null adjusting for other B-vitamins. Higher maternal folate coupled with vitamin B12 insufficiency was associated with higher GDM risk. This finding has potential implications for antenatal supplement recommendations but will require confirmation in future studies.


Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials.
To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee. Systematic review and meta-analysis of randomised placebo controlled trials. 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years. Change in overall intensity of pain. Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31). NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.


Transport and retention of selected engineered nanoparticles by porous media in the presence of a biofilm.
Column experiments were conducted to investigate the transport of aqueous C60 (aqu-nC60), fullerol, silver nanoparticles (NPs) coated with polyvinylpyrrolidone (Ag-PVP) and stabilized by citrate (Ag-CIT) in biofilm-laden porous media. Gram-negative Pseudomonas aeruginosa (PA) and Gram-positive Bacillus cereus (BC) biofilm-laden glass beads were selected to represent the bacterial interfaces NPs might encounter in the natural aquatic environment. The biomass distribution, extracellular polymeric substances (EPS) components, electrokinetic property, and hydrophobicity of these interfaces were characterized, and the hydrophobicity was found to correlate with the quantity of proteins in EPS. The retention of NPs on glass beads coated with bovine serum albumin (BSA) and alginate were also studied. Except for Ag-PVP, the affinity of NPs for porous medium, indicated by attachment efficiency α, increased in the presence of biofilms, BSA and alginate. For hydrophobic aqu-nC60, the larger the proteins/polysaccharides ratio, the larger the α, suggesting the hydrophobic interaction determines the attachment of aqu-nC60 to the collector surface. Uncharged PVP stabilized Ag-PVP by steric repulsion, and the attachment to glass beads was not enhanced by biofilm. The presence of divalent ion Ca(2+) significantly hydrophobized biofilm, BSA, and alginate-coated glass beads and further retarded the mobility of aqu-nC60, fullerol, and Ag-CIT; while Ag-PVP was again sterically stabilized.


Free fructose is conformationally locked.
Fructose has been examined under isolation conditions using a combination of UV ultrafast laser vaporization and Fourier-transform microwave (FT-MW) spectroscopy. The rotational spectra for the parent, all (six) monosubstituted (13)C species, and two single D species reveal unambiguously that the free hexoketose is conformationally locked in a single dominant β-pyranose structure. This six-membered-chair skeleton adopts a (2)C(5) configuration (equivalent to (1)C(4) in aldoses). The free-molecule structure sharply contrasts with the furanose form observed in biochemically relevant polysaccharides, like sucrose. The structure of free fructose has been determined experimentally using substitution and effective structures. The enhanced stability of the observed conformation is primarily attributed to a cooperative network of five intramolecular O-H···O hydrogen bonds and stabilization of both endo and exo anomeric effects. Breaking a single intramolecular hydrogen bond destabilizes the free molecule by more than 10 kJ mol(-1). The structural results are compared to ribose, recently examined with rotational resolution, where six different conformations coexist with similar conformational energies. In addition, several DFT and ab initio methods and basis sets are benchmarked with the experimental data.


Injectable collagen hydrogel combines human umbilical cord mesenchymal stem cells to promote endometrial regeneration in rats with thin endometrium.
The regeneration of thin endometrium still remains as a great challenge in the field of reproductive medicine. Stem cells-based therapy has been considered as a promising strategy for the restoration of thin endometrium. However, the low transplantation and retention rate of stem cells and loss of stemness due to in vitro expansion limits the therapeutic efficacy. In our study, we combined collagen hydrogel and human umbilical cord mesenchymal stem cells (uMSCs) for improving the regeneration of thin endometrium, by using the potent pluripotency and low immunogenicity of uMSCs and collagen hydrogel that promotes the anchorage and proliferation of stem cells. Results showed that collagen hydrogel has favorable biocompatibility and the capacity to enhance the cell viability and expression of stemness-associated genes (including organic cation/carnitine transporter4 (Oct-4), Nanog homeobox (Nanog) and SRY-box transcription factor 2 (SOX2)) of uMSCs. The combination of collagen hydrogel and uMSCs prolonged the retention time of the constructs in the uterine cavity and improved endometrial thickness compared with uMSCs alone, leading to increase the fertility of the rats with thin endometrium. These highlighted therapeutic prospects of collagen hydrogel combined with uMSCs for the minimally invasive therapy of thin endometrium in the clinic.


Is local anesthesia or oral analgesics necessary after mini-laparoscopic functional surgery in children and young adults?: A prospective randomized trial.
This prospective, randomized, single-blind trial was to determine if local anesthesia or oral analgesics reduce postoperative pain after mini-laparoscopic functional surgery. One hundred fifteen patients who underwent mini-laparoscopic herniorrhaphy or varicocelectomy were assigned randomly to receive wound infiltration with xylocaine, regular oral analgesics, or a placebo after the procedures. Visual analog pain scores owing to carbon-dioxide irritation and trocar wounds were recorded 2 hours, 1 day, and 1 week after surgery. Levels of pain were measured by a visual analog pain scale. Patients' age, type of procedure, pressure of gas insufflated, length of procedure, dosage of oral/parenteral analgesics, and trocar-related complications were evaluated. There were no significant differences between groups in the mean pain scores over trocar wounds 2 hours, 1 day, and 1 week after mini-laparoscopic procedures, respectively. There were no significant differences between groups in satisfaction of pain control regimens. Patients who received local anesthesia required fewer on demand meperidine injections than others. Local anesthesia and routine oral analgesic did not significantly reduce postoperative pain after mini-laparoscopic surgeries in children and young adults.


The inflammatory effects of 2 ppm NO2 on the airways of healthy subjects.
Nitrogen dioxide (NO2) is a free radical and a common oxidant in polluted air. Here we present data on the time course of inflammation after NO2 exposure, as reflected in bronchial biopsy and airway lavage specimens. Healthy, nonsmoking subjects were exposed to air or 2 ppm NO2 for 4 h in random order on separate occasions. Endobronchial biopsies, bronchial washing (BW), and bronchoalveolar lavage (BAL) were done at 1.5 h (n = 15) or 6 h (n = 15) after exposure. In BW, exposure to NO2 induced a 1.5-fold increase in interleukin-8 (IL-8) (p < 0.05) at 1.5 h and a 2.5-fold increase in neutrophils (p < 0.01) at 6 h. In BAL fluid (BALF), small increases were observed in CD45RO+ lymphocytes, B-cells, and natural killer (NK) cells only. Immunohistologic examination of bronchial biopsy specimens showed no signs of upregulation of adhesion molecules, and failed to reveal any significant changes in inflammatory cells at either time point after NO2 exposure. In summary, NO2 induced a neutrophilic inflammation in the airways that was detectable in BW at 6 h after NO2 exposure. The increase in neutrophils could be related to the enhanced IL-8 secretion observed at 1.5 h after exposure. The absence of adhesion-molecule upregulation or cellular inflammation in mucosal biopsy specimens indicates that the major site of inflammation following exposure to NO2 may be in the smaller airways and not in the alveoli.


Further Characterization of the Mitigation of Radiation Lethality by Protective Wounding.
There continues to be a major effort in the United States to develop mitigators for the treatment of mass casualties that received high-intensity acute ionizing radiation exposures from the detonation of an improvised nuclear device during a radiological terrorist attack. The ideal countermeasure should be effective when administered after exposure, and over a wide range of absorbed doses. We have previously shown that the administration of a subcutaneous incision of a defined length, if administered within minutes after irradiation, protected young adult female C57BL/6 mice against radiation-induced lethality, and increased survival after total-body exposure to an LD50/30 X-ray dose from 50% to over 90%. We refer to this approach as "protective wounding". In this article, we report on our efforts to further optimize, characterize and demonstrate the validity of the protective wounding response by comparing the response of female and male mice, varying the radiation dose, the size of the wound, and the timing of wounding with respect to administration of the radiation dose. Both male and female mice that received a subcutaneous incision after irradiation were significantly protected from radiation lethality. We observed that the extent of protection against lethality after an LD50/30 X-ray dose was independent of the size of the subcutaneous cut, and that a 3 mm subcutaneous incision is effective at enhancing the survival of mice exposed to a broad range of radiation doses (LD15-LD100). Over the range of 6.2-6.7 Gy, the increase in survival observed in mice that received an incision was associated with an enhanced recovery of hematopoiesis. The enhanced rate of recovery of hematopoiesis was preceded by an increase in the production of a select group of cytokines. Thus, a thorough knowledge of the timing of the cytokine cascade after wounding could aid in the development of novel pharmacological radiation countermeasures that can be administered several days after the actual radiation exposure.


Phosphate uptake restriction, phosphate export, and polyphosphate synthesis contribute synergistically to cellular proliferation and survival.
Phosphate (Pi) is a macronutrient, and Pi homeostasis is essential for life. Pi homeostasis has been intensively studied; however, many questions remain, even at the cellular level. Using Schizosaccharomyces pombe, we sought to better understand cellular Pi homeostasis and showed that three Pi regulators with SPX domains, Xpr1/Spx2, Pqr1, and the VTC complex synergistically contribute to Pi homeostasis to support cell proliferation and survival. SPX domains bind to inositol pyrophosphate and modulate activities of Pi-related proteins. Xpr1 is a plasma membrane protein and its Pi-exporting activity has been demonstrated in metazoan orthologs, but not in fungi. We first found that S. pombe Xpr1 is a Pi exporter, activity of which is regulated and accelerated in the mutants of Pqr1 and the VTC complex. Pqr1 is the ubiquitin ligase downregulating the Pi importers, Pho84 and Pho842. The VTC complex synthesizes polyphosphate in vacuoles. Triple deletion of Xpr1, Pqr1, and Vtc4, the catalytic core of the VTC complex, was nearly lethal in normal medium but survivable at lower [Pi]. All double-deletion mutants of the three genes were viable at normal Pi, but Δpqr1Δxpr1 showed severe viability loss at high [Pi], accompanied by hyper-elevation of cellular total Pi and free Pi. This study suggests that the three cellular processes, restriction of Pi uptake, Pi export, and polyP synthesis, contribute synergistically to cell proliferation through maintenance of Pi homeostasis, leading to the hypothesis that cooperation between Pqr1, Xpr1, and the VTC complex protects the cytoplasm and/or the nucleus from lethal elevation of free Pi.


Evaluation of clinical competence: the gap between expectation and performance.
To evaluate a 3-year experience with the Objective Structured Clinical Examinations (OSCEs) and to compare faculty expectations with resident performance. Descriptive analysis of measures of resident performance. Community-based pediatric residency program in Michigan. One hundred twenty-six pediatric residents at all levels of training. The three examinations consisted of 36 to 42 5-minute stations, testing skills in physical examination, history, counseling, telephone management, and test interpretation. A committee of faculty and chief residents predetermined minimum pass levels for each resident level. Results were compared with other indices of resident performance. There was evidence for content, construct, and concurrent validity, as well as a high degree of reliability. However, 40% to 96% of residents scored below the minimum pass levels for their levels. In each examination, third-year residents had the highest failure rates, yet they scored well on the American Board of Pediatrics in-training examination and on their monthly clinical evaluations. Furthermore, for residents at all levels, the scores reflecting application of data were significantly lower than those assessing data gathering. The gaps between expectations and performance, and between data gathering and application, have important implications for institutional educational philosophy, suggesting a shift toward more clinically oriented and learner-directed strategies in the design of instructional and evaluation methods.


Characterization of a potent varicella-zoster virus-encoded trans-repressor.
Using a transient expression assay in Vero cells, we have shown that the protein product from gene 61 of varicella-zoster virus (VZV) can repress the function of the VZV encoded trans-activators on putative viral immediate-early, early, and late gene promoters. The repression is exerted at the transcriptional level and requires functional gene 61 protein. This trans-repressor is the herpes simplex type 1 ICP0 (a trans-activator) homolog, as defined by gene location, the sharing of a cysteine-rich putative zinc-binding finger in the amino-terminal region, and limited amino acid homology. Open reading frame 61 (ORF61)-mediated trans-repression appears to be specific for VZV-encoded trans-activators in that it has no effect on simian virus 40 and Rous sarcoma virus promoters. Moreover, it does not inhibit trans-activation of the human T-lymphotropic virus type I and human immunodeficiency virus long terminal repeats by tax and tat genes, respectively. We constructed plasmids with mutations in ORF61 and tested them for their ability to inhibit trans-activator (VZV genes 4 and 62)-mediated activation of the viral thymidine kinase promoter-chloramphenicol acetyltransferase construct. Mutants containing interruptions in ORF61 lost their trans-repressing ability, as demonstrated at both the protein and steady-state RNA levels. These results suggest that the ORF61 protein product can mediate down-regulation of VZV gene expression.


Puberty and the family formation process in Sudan: age-at-menarche differential fecundity hypothesis revisited.
This paper revisits and extends an inquiry on the age-at-menarche differential fecundity hypothesis. Earlier studies have interpreted the difference in the onset of female pubertal maturation as indicative of biological differences in fecundity between early and late menarcheal women. Using the WFS data for Sudan, the authors address the entire reproductive life of the women in terms of their transition from one parity to the next, as well as the speed with which birth intervals are closed, as a way to infer biological fecundity among the women. The study concludes that there is little evidence that early menarcheal women are more fecund than their late puberty counterparts.


Design of monolimb using finite element modelling and statistics-based Taguchi method.
Monolimb is a transtibial prosthesis having the socket and shank molded into one piece of thermoplastic material. If properly designed, the shank of a monolimb can have a controlled deflection during walking which simulates the ankle joint motions to some extent. However, there is no clear guidance for the design of monolimb considering the dilemma between shank flexibility and structural integrity. Finite element analysis was used to simulate structural tests based on ISO10328 on monolimbs of different configurations. Statistics-based Taguchi method was employed to identify the significance of each design factor in controlling the deformation and stress within monolimbs. The design factors considered were the thickness of the thermoplastics, anteroposterior and medialateral dimensions of the elliptical shank, and depth of the posterior seam line. By progressively fine-tuning the design factors, the monolimb configuration was optimized giving offering appropriate flexibilities of the shank and would not structurally fail in normal uses. Experimental structural test was used to validate the finite element model. Anteroposterior dimension of the shank was shown to be the most important design factor determining the peak von Mises stress values, deformation and dorsiflexion angles of monolimbs. Depth of seam line appears much less important than the other three factors. A monolimb fulfilling the design requirements was suggested. Experimental test results reasonably matched with the finite element results. Finite element analysis and Taguchi method was shown to be an effective method in optimizing the structural design of prostheses. Further prosthetic design can be facilitated based on the degree of importance of the design factors on the structural behavior of the prosthesis. Gait analysis of amputees using the suggested monolimb design is needed in the future.