Expenditures and use of wraparound health insurance for employed people with disabilities.
The Affordable Care Act (ACA) provides health insurance to many working-age adults with disabilities, but we do not expect the new coverage or existing insurance options to fully meet their employment-related health care needs. Wraparound services have the potential to foster employment among people with disabilities. We use Massachusetts, which implemented health care reform in 2006, as a case study to estimate the wraparound health care expenditures and use for workers with disabilities. We identified a group of employed, working-age people with disabilities whose primary health insurance is Medicare or private insurance and who use the Medicaid Buy-In Program for wraparound coverage. We analyzed claims to estimate expenditures and use. Wraparound expenditures averaged $427 per member per month. Community-based services for both mental and non-mental health, which are generally not covered by Medicare or private insurance, accounted for 63% of all expenditures. The number who used community-based services was low, but the expenditures were high. The majority of the remaining expenditures were for services usually covered by primary insurance including: inpatient and outpatient, pharmacy and professional services. Expenditures were higher for people with Medicare compared to private insurance. This case study suggests that, from a total program cost perspective, wraparound demand is greatest for community-based services. From a member utilization perspective, the demand is greatest for coverage that alleviates out-of-pocket costs for services provided by primary insurance. Additional analysis is needed to further assess the design options for wraparound programs and their feasibility.


Human parasitic protozoan infection to infertility: a systematic review.
Protozoan parasitic diseases are endemic in many countries worldwide, especially in developing countries, where infertility is a major burden. It has been reported that such infections may cause infertility through impairment in male and female reproductive systems. We searched Medline, PubMed, and Scopus databases and Google scholar to identify the potentially relevant studies on protozoan parasitic infections and their implications in human and animal model infertility. Literature described that some of the protozoan parasites such as Trichomonas vaginalis may cause deformities of the genital tract, cervical neoplasia, and tubal and atypical pelvic inflammations in women and also non-gonoccocal urethritis, asthenozoospermia, and teratozoospermia in men. Toxopalasma gondii could cause endometritis, impaired folliculogenesis, ovarian and uterine atrophy, adrenal hypertrophy, vasculitis, and cessation of estrus cycling in female and also decrease in semen quality, concentration, and motility in male. Trypanosoma cruzi inhibits cell division in embryos and impairs normal implantation and development of placenta. Decrease in gestation rate, infection of hormone-producing glands, parasite invasion of the placenta, and overproduction of inflammatory cytokines in the oviducts and uterine horns are other possible mechanisms induced by Trypanosoma cruzi to infertility. Plasmodium spp. and Trypanosoma brucei spp. cause damage in pituitary gland, hormonal disorders, and decreased semen quality. Entamoeba histolytica infection leads to pelvic pain, salpingitis, tubo-ovarian abscess, and genital ulcers. Cutaneous and visceral leishmaniasis can induce genital lesion, testicular amyloidosis, inflammation of epididymis, prostatitis, and sperm abnormality in human and animals. In addition, some epidemiological studies have reported that rates of protozoan infections in infertile patients are higher than healthy controls. The current review indicates that protozoan parasitic infections may be an important cause of infertility. Given the widespread prevalence of parasitic protozoa diseases worldwide, we suggest further studies to better understanding of relationship between such infections and infertility.


A method for the direct measurement of electronic site populations in a molecular aggregate using two-dimensional electronic-vibrational spectroscopy.
Two dimensional electronic spectroscopy has proved to be a valuable experimental technique to reveal electronic excitation dynamics in photosynthetic pigment-protein complexes, nanoscale semiconductors, organic photovoltaic materials, and many other types of systems. It does not, however, provide direct information concerning the spatial structure and dynamics of excitons. 2D infrared spectroscopy has become a widely used tool for studying structural dynamics but is incapable of directly providing information concerning electronic excited states. 2D electronic-vibrational (2DEV) spectroscopy provides a link between these domains, directly connecting the electronic excitation with the vibrational structure of the system under study. In this work, we derive response functions for the 2DEV spectrum of a molecular dimer and propose a method by which 2DEV spectra could be used to directly measure the electronic site populations as a function of time following the initial electronic excitation. We present results from the response function simulations which show that our proposed approach is substantially valid. This method provides, to our knowledge, the first direct experimental method for measuring the electronic excited state dynamics in the spatial domain, on the molecular scale.


Early Weight Bearing of Calcaneal Fractures Treated by Intraoperative 3D-Fluoroscopy and Locked-Screw Plate Fixation.
Operative therapy of intraarticular fractures of the calcaneus is an established surgical standard. The aim is an accurate reduction of the fracture with reconstruction of Boehler's angle, length, axis and subtalar joint surface. Intraoperative 3D-fluoroscopy with the Siremobil Iso-C 3D(R) mobile C-arm system is a valuable assistant for accurate reconstruction of these anatomical structures. Remaining incongruities can be recognized and corrected intraoperatively. The achieved reduction can be fixed by the advantages of an internal fixator (locked-screw plate interface). In the period of October 2002 until April 2007 we operated 136 patients with intraarticular fractures of the calcaneus by means of anatomical reduction, and internal plate fixator under intraoperative control of 3D-fluoroscopy. All patients were supplied with an orthesis after the operation which allowed weight bearing of 10 kg for 12 weeks for the patients operated between October 2002 and October 2004 (Group A). Transient local osteoporosis was observed in all X-Rays at follow-up after an average of 8,6 months. Therefore we changed our postoperative treatment plan for the patients operated between November 2004 and April 2007 (Group B). Weight bearing started with 20 KG after 6 weeks, was increased to 40 KG after 8 weeks and full weight bearing was allowed after 10 weeks for these patients. In no case a secondary dislocation of the fracture was seen. No bone graft was used. At follow up the average American Foot and Ankle Society Score (AOFAS) were 81 for Group_A, compared to 84 for Group B, treated with earlier weight bearing. Autologous bone graft was not necessary even if weight bearing was started after a period of six weeks postoperatively. The combination of 3D-fluoroscopy with locked internal fixation showed promising results. If the rate of patients developing subtalar arthrosis will decrease by this management will have to be shown in long term follow up.


Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts.
In around 50% of all human cancers the tumor suppressor p53 is mutated. It is generally assumed that in the remaining tumors the wild-type p53 protein is functionally impaired. The two main inhibitors of p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed in wild-type p53 tumors. Whereas the main activity of hMDM2 is to degrade p53 protein, its close homolog hMDMX does not degrade p53, but it represses its transcriptional activity. Here we study the role of hMDMX in the neoplastic transformation of human fibroblasts and embryonic retinoblasts, since a high number of retinoblastomas contain elevated hMDMX levels. We made use of an in vitro transformation model using a retroviral system of RNA interference and gene overexpression in primary human fibroblasts and embryonic retinoblasts. Consecutive knockdown of RB and p53, overexpression of SV40-small t, oncogenic HRasV12 and HA-hMDMX resulted in a number of stable cell lines representing different stages of the transformation process, enabling a comparison between loss of p53 and hMDMX overexpression. The cell lines were tested in various assays to assess their oncogenic potential. Both p53-knockdown and hMDMX overexpression accelerated proliferation and prevented growth suppression induced by introduction of oncogenic Ras, which was required for anchorage-independent growth and the ability to form tumors in vivo. Furthermore, we found that hMDMX overexpression represses basal p53 activity to some extent. Transformed fibroblasts with very high levels of hMDMX became largely resistant to the p53 reactivating drug Nutlin-3. The Nutlin-3 response of hMDMX transformed retinoblasts was intact and resembled that of retinoblastoma cell lines. Our studies show that hMDMX has the essential properties of an oncogene. Its constitutive expression contributes to the oncogenic phenotype of transformed human cells. Its main function appears to be p53 inactivation. Therefore, developing new drugs targeting hMDMX is a valid approach to obtain new treatments for a subset of human tumors expressing wild-type p53.


The genetics of coronary heart disease: the contribution of twin studies.
Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.


Cavernous Sinus Involvement by Pituitary Adenomas: Clinical Implications and Outcomes of Endoscopic Endonasal Resection.
Background Parasellar invasion of pituitary adenomas (PAs) into the cavernous sinus (CS) is common. The management of the CS component of PA remains controversial. Objective The objective of this study was to analyze CS involvement in PA treated with endoscopic endonasal approaches, including incidence, surgical risks, surgical strategies, long-term outcomes, and our treatment algorithm. Methods We reviewed a series of 176 surgically treated PA with particular attention to CS involvement and whether the CS tumor was approached medial or lateral to the internal carotid artery. Results The median duration of follow-up was 36 months. Macroadenomas and nonfunctional adenomas represented 77 and 60% of cases, respectively. CS invasion was documented in 23% of cases. CS involvement was associated with a significantly diminished odds of gross total resection (47 vs. 86%, odds ratio [OR]: 5.2) and increased the need for subsequent intervention (4 vs. 40%, OR: 14.4). Hormonal remission was achieved in 15% of hormonally active tumors. Rates of surgical complication were similar regardless of CS involvement. Conclusion Our tailored strategy beginning with a medial approach and adding lateral exposure as needed resulted in good outcomes with low morbidity in nonfunctional adenomas. Functional adenomas involving the CS were associated with low rates of hormonal remission necessitating higher rates of additional treatment.


Kidney protection by pretreatment with free radical scavengers and allopurinol: renal function at recirculation after warm ischaemia in rabbits.
Renal function and morphology were studied before and after 60 min of renal ischaemia and contralateral nephrectomy in five groups of rabbits. The animals were pretreated with superoxide dismutase, catalase, allopurinol or mannitol. One group was not pretreated and served as a control. A moderate transient increase in serum creatinine concentration was observed in the control rabbits, while a significantly less pronounced increase was noted after pretreatment with superoxide dismutase, catalase and mannitol. Pretreatment with allopurinol did not significantly reduce the postoperative increase in serum creatinine and sodium excretion, but the urine osmolality returned to normal more rapidly than in the control group. The appearance under the light microscope of kidney tissue taken from surviving rabbits was found to be normal irrespective of pretreatment. Severe tubular necrosis was observed in the kidneys from rabbits that died during the observation period.


Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes.
In this report, we describe a novel activation antigen that appears very early after T cell activation and is absent in resting lymphocytes, through which agonistic proliferative signals can be triggered by mAb binding. It has been designated as activation inducer molecule (AIM) and is a disulphide-linked heterodimeric structure containing two polypeptide chains of Mr 33,000 and 27,000. The expression of AIM can be induced by different activation stimuli such as PMA, PHA, or anti-CD3 mAb, but not by the Ca2+ ionophore A23187, and it precedes the expression of other activation molecules such as 4F2 or the IL-2-R. Once AIM antigens are expressed on lymphocytes after stimulation with submitogenic doses of PMA, the binding of anti-AIM mAbs triggers a strong proliferative response. Furthermore, a comitogenic effect of the anti-AIM mAbs is exerted in the presence of either PHA or anti-CD3 mAb. The activation of lymphocytes through AIM antigens induces both IL-2 and IL-2-R receptor synthesis and is inhibited by anti-IL-2-R mAbs.


Human pathogens associated with the blacklegged tick Ixodes scapularis: a systematic review.
The blacklegged tick Ixodes scapularis transmits Borrelia burgdorferi (sensu stricto) in eastern North America; however, the agent of Lyme disease is not the sole pathogen harbored by the blacklegged tick. The blacklegged tick is expanding its range into areas of southern Canada such as Ontario, an area where exposure to blacklegged tick bites and tick-borne pathogens is increasing. We performed a systematic review to evaluate the public health risks posed by expanding blacklegged tick populations and their associated pathogens. We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for conducting our systematic review. We searched Ovid MEDLINE, Embase, BIOSIS, Scopus and Environment Complete databases for studies published from 2000 through 2015, using subject headings and keywords that included "Ixodes scapularis", "Rickettsia", "Borrelia", "Anaplasma", "Babesia" and "pathogen." Two reviewers screened titles and abstracts against eligibility criteria (i.e. studies that included field-collected blacklegged ticks and studies that did not focus solely on B. burgdorferi) and performed quality assessments on eligible studies. Seventy-eight studies were included in the final review, 72 were from the US and eight were from Canada (two studies included blacklegged ticks from both countries). Sixty-four (82%) studies met ≥ 75% of the quality assessment criteria. Blacklegged ticks harbored 91 distinct taxa, 16 of these are tick-transmitted human pathogens, including species of Anaplasma, Babesia, Bartonella, Borrelia, Ehrlichia, Rickettsia, Theileria and Flavivirus. Organism richness was highest in the Northeast (Connecticut, New York) and Upper Midwest US (Wisconsin); however, organism richness was dependent on sampling effort. The primary tick-borne pathogens of public health concern in Ontario, due to the geographic proximity or historical detection in Ontario, are Anaplasma phagocytophilum, Babesia microti, B. burgdorferi, Borrelia miyamotoi, deer tick virus and Ehrlichia muris-like sp. Aside from B. burgdorferi and to a much lesser concern A. phagocytophilum, these pathogens are not immediate concerns to public health in Ontario; rather they represent future threats as the distribution of vectors and pathogens continue to proliferate. Our review is the first systematic assessment of the literature on the human pathogens associated with the blacklegged tick. As Lyme disease awareness continues to increase, it is an opportune time to document the full spectrum of human pathogens transmittable by blacklegged ticks.


Effects of growth-promoting agents and season on blood metabolites and body temperature in heifers.
To assess the efficacy of growth-promoting agents among seasons, triiodothyronine (T3), thyroxine (T4), plasma urea nitrogen (PUN), IGF-I, and tympanic temperature (TT) were measured in summer and winter studies. Heifers (n = 9/pen) were allotted to 12 pens in both December and June. Pens were assigned to 1 of 6 growth promotant treatments: control (no growth promotant), estrogenic implant (E), trenbolone acetate implant (TBA), E + TBA (ET), melengestrol acetate (MGA), and ET + MGA (ETM). Blood samples were collected from 4 heifers per pen per study on d 0, 28, 56, and 84 via jugular puncture. Near the midpoint of both studies, TT were obtained from the heifers. There was a season by sample day interaction for all blood metabolites (P < 0.05). During the winter, IGF-I levels peaked on d 28, whereas T3, T4, and PUN peaked on d 56. In the summer, IGF-I levels increased from d 0 to 28 and remained elevated throughout the study. Season by growth promotant interactions (P < 0.05) indicated that in the winter ET increased T3, whereas TBA alone decreased both T3 and T4, compared with control, or ET, and ETM treatment groups. Across seasons, treatments ET and ETM increased (P < 0.05) IGF-I and decreased (P < 0.05) PUN. However, E, TBA, and MGA alone had no effect on IGF-I or PUN concentrations. The maximum TT was greater (P < 0.01) in the summer than in the winter, whereas the minimum TT was lower (P < 0.01) in the summer. Mean TT did not differ among growth-promoting treatments. However, in the summer and over both seasons, the maximum TT was lower (P < 0.05) in E-, MGA-, and ETM-treated heifers. Although limited growth promotant by season interactions existed, changes in blood metabolite levels resulting from the use of growth promotants do not appear to influence seasonal changes in body temperature as measured by TT.


Variable epidemic histories of hepatitis C virus genotype 2 infection in West Africa and Cameroon.
It has recently been suggested that HCV genotype 2 (HCV-2) was more recently introduced to Cameroon (Middle Africa) than West African countries. In order to explore the relationships among HCV-2 strains from Cameroon and West Africa, and to estimate the epidemic history of each lineage, a recently-developed Bayesian evolutionary analysis approach was used. The estimated date of the most recent common ancestor (MRCA) of the Cameroon HCV-2 strains, 1630 (95% highest posterior density interval: 1470-1760) was slightly more recent than that of West Africa, 1540 (95% highest posterior density interval: 1380-1680). Estimates of epidemic history indicate significant differences between the two strains. HCV-2 appears to have spread relatively slowly within the West African population from 1630 to 1900, whilst the Cameroon lineages exhibit rapid, exponential spread from 1920 to 1960. This comparative genetic analysis indicates that Cameroon HCV-2 strains are derived from West African strains and that HCV-2 has undergone radically different epidemiological histories in the two regions.


Glycogen Synthase Kinase 3 (GSK-3)-mediated Phosphorylation of Uracil N-Glycosylase 2 (UNG2) Facilitates the Repair of Floxuridine-induced DNA Lesions and Promotes Cell Survival.
Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. However, the mechanisms by which UNG2 is regulated remain unclear. Several phosphorylation sites within the N-terminal regulatory domain of UNG2 have been identified, although the effects of these modifications on UNG2 function have not been fully explored, nor have the identities of the kinases involved been determined. Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event. We also show that mutating Thr60 or Ser64 to Ala increases the half-life of UNG2, reduces the rate of in vitro uracil excision, and slows UNG2 dissociation from chromatin after DNA replication. Using an UNG2-deficient ovarian cancer cell line that is hypersensitive to floxuridine, we show that GSK-3 phosphorylation facilitates UNG2-dependent repair of floxuridine-induced DNA lesions and promotes tumor cell survival following exposure to this agent. These data suggest that GSK-3 regulates UNG2 and promotes DNA damage repair.


Intensity-modulated radiotherapy for prostate cancer.
Radiation therapy (RT) is a curative treatment modality for localized prostate cancer. Over the past two decades, advances in technology and imaging have considerably changed RT in prostate cancer treatment. Treatment has evolved from 2-dimensional (2D) planning using X-ray fields based on pelvic bony landmarks to 3-dimensional (3D) conformal RT (CRT) which uses computed tomography (CT) based planning. Despite improvements with 3D-CRT, dose distributions often remained suboptimal with portions of the rectum and bladder receiving unacceptably high doses. In more recent years, intensity-modulated radiation therapy (IMRT) has become the standard of care to deliver external beam RT. IMRT uses multiple radiation beams of different shapes and intensities delivered from a wide range of angles to 'paint' the radiation dose onto the tumor. IMRT allows for a higher dose of radiation to be delivered to the prostate while reducing dose to surrounding organs. Multiple clinical trials have demonstrated improved cancer outcomes with dose escalation, but toxicities using 3D-CRT and escalated doses have been problematic. IMRT is a method to deliver dose escalated RT with more conformal dose distributions than 3D-CRT and has been associated with improved toxicity profiles. IMRT also appears to be the safest method to deliver hypofractionated RT and pelvic lymph node radiation. The purpose of this review is to summarize the technical aspects of IMRT planning and delivery, and to review the literature supporting the use of IMRT for prostate cancer.


Consumption of onion juice modulates oxidative stress and attenuates the risk of bone disorders in middle-aged and post-menopausal healthy subjects.
Osteoporosis is a chronic inflammatory condition that is characterized by the loss of bone mineral density (BMD). The current study was undertaken to evaluate the impact of onion juice intake on the bone mineral density (BMD) and bone loss in corroboration with antioxidant effects in human (in vivo) as well as inhibitory effects on the differentiation of osteoclasts in the cell line (in vitro). For in vitro studies, the RAW 264.7 (osteoclast progenitor) cells were used to examine the anti-osteoclastogenic effect of onion. In the case of in vivo studies, twenty-four subjects were divided into two groups and advised to intake 100 mL of onion juice or placebo for 8 weeks. Anthropometric measurements and blood samples were collected at the initial, 2(nd), 6(th), 8(th) and 10(th) week. The result of in vitro studies indicated that onion extract would effectively inhibit the osteoclastogenesis and its differentiation. Significant changes in the levels of alkaline phosphatase (ALP), free radicals, total antioxidant capacity (TEAC) and various antioxidants were observed in onion administered subjects. The BMD of three postmenopausal women was also found to be mildly improved on supplementation with onion juice. Onion juice consumption showed a positive modulatory effect on the bone loss and BMD by improving antioxidant activities and thus can be recommended for treating various bone-related disorders, especially osteoporosis.


An observation of Clostridium perfringens in Greater Sage-Grouse.
Mortality due to infectious diseases is seldom reported in the Greater Sage-Grouse (Centrocercus urophasianus). A case of necrotic enteritis associated with Clostridium perfringens type A is described in a free-ranging adult male sage-grouse in eastern Oregon. Clostridial enteritis is known to cause outbreaks of mortality in various domestic and wild birds, and should be considered as a potential cause of mortality in sage-grouse populations.


Parenting style and cultural influences on overweight children's attraction to physical activity.
To investigate the associations among parenting style, gender, Chinese culture, and overweight children's attraction to physical activity. A total of 104 parents with overweight children were recruited from six primary schools in Hong Kong, China. Only overweight children in grades 3 through 6 (8 to 12 years of age) were invited to participate. Overweight children were defined and identified using the international cut-off points stratified by sex and age. Questionnaires were used to assess Children's Attraction to Physical Activity (CAPA), perceived competence, and parental socialization influences. Parental influence, especially father's role modeling, was significantly related to attraction to physical activity in overweight Chinese children. Perceived physical competence was also an important correlate of an overweight child's attraction to physical activity. Gender differences in CAPA were not significant among the Chinese overweight children. However, gender differences were observed in the relationship between parent physical activity orientation and CAPA. In addition to a child's perceived competence, father's role modeling can provide additional and significant influence with regard to overweight children's attraction to physical activity. Differences in cultural orientation toward body weight should be considered when explaining overweight children's physical activity.


Knowledge, Attitudes, Practices and Beliefs about Medical Male Circumcision (MMC) among a Sample of Health Care Providers in Haiti.
Haiti has the highest number of people living with HIV infection in the Caribbean/Latin America region. Medical male circumcision (MMC) has been recommended to help prevent the spread of HIV. We sought to assess knowledge, attitudes, practices and beliefs about MMC among a sample of health care providers in Haiti. A convenience sample of 153 health care providers at the GHESKIO Centers in Haiti responded to an exploratory survey that collected information on several topics relevant to health providers about MMC. Descriptive statistics were calculated for the responses and multivariable logistic regression was conducted to determine opinions of health care providers about the best age to perform MMC on males. Bayesian network analysis and sensitivity analysis were done to identify the minimum level of change required to increase the acceptability of performing MMC at age less than 1 year. The sample consisted of medical doctors (31.0%), nurses (49.0%), and other health care professionals (20.0%). Approximately 76% showed willingness to offer MMC services if they received training. Seventy-six percent believed that their male patients would accept circumcision, and 59% believed infancy was the best age for MMC. More than 90% of participants said that MMC would reduce STIs. Physicians and nurses who were willing to offer MMC if provided with adequate training were 2.5 (1.15-5.71) times as likely to choose the best age to perform MMC as less than one year. Finally, if the joint probability of choosing "the best age to perform MMC" as one year or older and having the mistaken belief that "MMC prevents HIV entirely" is reduced by 63% then the probability of finding that performing MMC at less than one year acceptable to health care providers is increased by 35%. Participants demonstrated high levels of knowledge and positive attitudes towards MMC. Although this study suggests that circumcision is acceptable among certain health providers in Haiti, studies with larger and more representative samples are needed to confirm this finding.


Cancer prevention in Africa: liver cancer.
Hepatocellular carcinoma is a common cancer in Africa. The risk factors are well known and avoidable in most cases (hepatitis B, hepatitis C, aflatoxin and alcohol). Vaccination against hepatitis B and the fight against aflatoxin are efficient contributions to the fight against liver cancer. The costly nature of these measures in Africa is an impediment to the fight against liver cancer in Africa.


Effect of fluoride intoxication on endometrial apoptosis and lipid peroxidation in rats: role of vitamins E and C.
Fluoride is a strong, hard anion and cumulative toxic agent. The effect of fluoride intoxication on lipid peroxidation in endometrial tissue and the protective effects of combinations of vitamins E and C in rats were studied. Additionally, the apoptotic changes in endometrial tissue were examined. Experimental groups were as follows: control group; a group treated with 100 mg/l fluoride (F group); and a group treated with 100 mg/l fluoride plus vitamins E and C (F+Vit group). The F and F+Vit groups were treated orally with fluoride for 30 days. Vitamins E and C were injected simultaneously at doses of 50 mg/kg day i.m. and 20 mg/kg day body weight i.p. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick and labeling (TUNEL) method. Malondialdehyde (MDA) levels were determined in uterine tissue of rats. Fluoride caused a significant increase in MDA levels (an important marker of lipid peroxidation) in the fluoride group compared with the controls (p<0.05). Vitamins E and C significantly reduced the fluoride-induced lipid peroxidation in the F+Vit group compared with the F group (p<0.05). Diffuse apoptosis in glandular epithelium and stromal cells was found in endometrial tissues of F treated rats by TUNEL method. The severity of these lesions was reduced by the administration of vitamins. From these results, it can be concluded that subchronic fluoride administration causes endometrial apoptosis, and lipid peroxidation may be a molecular mechanism involved in fluoride-induced toxicity. Furthermore, treatment with a combination of vitamins E and C reduced endometrial apoptosis caused by fluoride.


Imaging and therapeutic applications of zinc(ii)-dipicolylamine molecular probes for anionic biomembranes.
This feature article describes the development of synthetic zinc(ii)-dipicolylamine (ZnDPA) receptors as selective targeting agents for anionic membranes in cell culture and living subjects. There is a strong connection between anionic cell surface charge and disease, and ZnDPA probes have been employed extensively for molecular imaging and targeted therapeutics. Fluorescence and nuclear imaging applications include detection of diseases such as cancer, neurodegeneration, arthritis, and microbial infection, and also quantification of cell death caused by therapy. Therapeutic applications include selective targeting of cytotoxic agents and drug delivery systems, photodynamic inactivation, and modulation of the immune system. The article concludes with a summary of expected future directions.


Family planning in genitourinary medicine: an opportunistic service?
To evaluate and serve the need for contraception in those not using conventional sources of family planning services. South London outpatient genitourinary medicine department at King's College Hospital. Prospective study of 200 women seen consecutively in the clinic by the same doctor (LM) during 1993. Women at risk of unwanted pregnancy were identified, and offered immediate contraceptive provision or referral. 15 women (7.5%) were using no contraception, despite being sexually active and not wishing to conceive; of these two presented with an unwanted pregnancy. A further 23 women (11.5%) were not using their chosen contraception effectively, and another 20 women were unclear about contraceptive methods and wanted advice. Young women were most at risk; 14% of those aged 25 years and under were using no contraception. Eight women wished to defer contraceptive advice; of these four defaulted from follow up. Eighteen women (9%) wanted immediate contraceptive supplies. Ten of 18 returned a follow up questionnaire; all these women were satisfied with the contraceptive advice service received. Absent or ineffective contraception is common in women attending an inner city genitourinary medicine clinic. Immediate provision of contraceptive education, advice and supplies is welcomed by patients.


Nutrition, microRNAs, and Human Health.
MicroRNAs (miRs) hybridize with complementary sequences in mRNA and silence genes by destabilizing mRNA or preventing translation of mRNA. Over 60% of human protein-coding genes are regulated by miRs, and 1881 high-confidence miRs are encoded in the human genome. Evidence suggests that miRs not only are synthesized endogenously, but also might be obtained from dietary sources, and that food compounds alter the expression of endogenous miR genes. The main food matrices for studies of biological activity of dietary miRs include plant foods and cow milk. Encapsulation of miRs in exosomes and exosome-like particles confers protection against RNA degradation and creates a pathway for intestinal and vascular endothelial transport by endocytosis, as well as delivery to peripheral tissues. Evidence suggests that the amount of miRs absorbed from nutritionally relevant quantities of foods is sufficient to elicit biological effects, and that endogenous synthesis of miRs is insufficient to compensate for dietary miR depletion and rescue wild-type phenotypes. In addition, nutrition alters the expression of endogenous miR genes, thereby compounding the effects of nutrition-miR interactions in gene regulation and disease diagnosis in liquid biopsies. For example, food components and dietary preferences may modulate serum miR profiles that may influence biological processes. The complex crosstalk between nutrition, miRs, and gene targets poses a challenge to gene network analysis and studies of human disease. Novel pipelines and databases have been developed recently, including a dietary miR database for archiving reported miRs in 15 dietary resources. miRs derived from diet and endogenous synthesis have been implicated in physiologic and pathologic conditions, including those linked with nutrition and metabolism. In fact, several miRs are actively regulated in response to overnutrition and tissue inflammation, and are involved in facilitating the development of chronic inflammation by modulating tissue-infiltrated immune cell function.


Measurement of the extinction coefficients of magnetic fluids.
A novel spectral transmittance approach for measuring the extinction coefficient of magnetic fluids is proposed. The measuring principle and accuracy of the approach are analysed. Experiments are conducted to measure the extinction coefficient of magnetic fluids with different particle volume fractions. The relative uncertainty of experimental data is less than 1.8%. The experimental results indicate that the extinction coefficient of magnetic fluids increases with increase of the volume fraction of suspended magnetic nanoparticles and the optical properties of the particle material have a significant effect on the extinction coefficient of the magnetic fluids.


Chronic constipation: new diagnostic and treatment approaches.
Chronic constipation is a highly prevalent disorder that affects approximately 15% of the US population. Chronic constipation refers to patients who have had symptoms for more than 6 months. In clinical practice, chronic constipation is often used interchangeably with the term functional constipation. This is best defined using the Rome III criteria, which involves an evaluation of stool frequency in addition to symptoms of straining, feelings of incomplete evacuation, and the need to use manual maneuvers to assist with stool evacuation. Symptoms can be burdensome, leading to a reduction in patients' quality of life. As a national healthcare issue, chronic constipation is also important because it imposes a significant economic impact on the healthcare system. A number of treatment options are currently available, both over-the-counter and by prescription, although not all patients respond to these therapies. This review will focus on new medical treatment options for the management of chronic constipation, and the safety and efficacy of these agents will be reviewed. In addition, the efficacy of new diagnostic tests to evaluate colonic motility and anorectal function are described.


Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women.
Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women. Normal weight and overweight women without diabetes (N = 108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non-pregnant.Insulin sensitivity and β-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry. Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r2 = 0.11; Spearman r = -0.47; p = 0.007) and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002). Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion. Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity.


Haematoma evacuation in cerebellar intracerebral haemorrhage: systematic review.
Guidelines regarding recommendations for surgical treatment of spontaneous cerebellar intracerebral haemorrhage (ICH) differ. We aimed to systematically review the literature to assess treatment strategies and outcomes. We searched PubMed and Embase between 1970 and 2019 for randomised or otherwise controlled studies and observational cohort studies. We included studies according to predefined selection criteria and assessed their quality according to the Newcastle-Ottawa Scale (NOS) and risk of bias according to a predefined scale. We assessed case fatality and functional outcome in patients treated conservatively or with haematoma evacuation. Favourable functional outcome was defined as a modified Rankin Scale score of 0-2 or a Glasgow Outcome Scale score of 4-5. We included 41 observational cohort studies describing 2062 patients (40% female) with spontaneous cerebellar ICH. A total of 1171 patients (57%) underwent haematoma evacuation. Ten studies described a cohort of surgically treated patients (n=533) and 31 cohorts with both surgically and conservatively treated patients (n=638 and n=891, respectively). There were no randomised clinical trials nor studies comparing outcome between the groups after adjustment for differences in baseline characteristics. The median NOS score (IQR) was 5 (4-6) out of 8 points and the bias score was 2 (1-3) out of 8, indicative of high risk of bias. Case fatality at discharge was 21% (95% CI 17% to 25%) after conservative treatment and 24% (95% CI 19% to 29%) after haematoma evacuation. At ≥6 months after conservative treatment, case fatality was 30% (95% CI 25% to 30%) and favourable functional outcome was 45% (95% CI 40% to 50%) and after haematoma evacuation, case fatality was 34% (95% CI 30% to 38%) and 42% (95% CI 37% to 47%). Controlled studies on the effect of neurosurgical treatment in patients with spontaneous cerebellar ICH are lacking, and the risk of bias in published series is high. Due to substantial differences in patient characteristics between conservatively and surgically treated patients, and high variability in treatment indications, a meaningful comparison in outcomes could not be made. There is no good published evidence to support treatment recommendations and controlled, preferably randomised studies are warranted in order to formulate evidence-based treatment guidelines for patients with cerebellar ICH.


Nervous system development and regeneration in freshwater planarians.
Planarians have a long history in the fields of developmental and regenerative biology. These animals have also sparked interest in neuroscience due to their neuroanatomy, spectrum of simple behaviors, and especially, their almost unparalleled ability to generate new neurons after any type of injury. Research in adult planarians has revealed that neuronal subtypes homologous to those found in vertebrates are generated from stem cells throughout their lives. This feat is recapitulated after head amputation, wherein animals are capable of regenerating whole brains and regaining complete neural function. In this review, we summarize early studies on the anatomy and function of the planarian nervous system and discuss our present knowledge of the molecular mechanisms governing neurogenesis in planarians. Modern studies demonstrate that the transcriptional programs underlying neuronal specification are conserved in these remarkable organisms. Thus, planarians are outstanding models to investigate questions about how stem cells can replace neurons in vivo. WIREs Dev Biol 2017, 6:e266. doi: 10.1002/wdev.266 For further resources related to this article, please visit the WIREs website.


Whatever you want: Inconsistent results are the rule, not the exception, in the study of primate brain evolution.
Primate brains differ in size and architecture. Hypotheses to explain this variation are numerous and many tests have been carried out. However, after body size has been accounted for there is little left to explain. The proposed explanatory variables for the residual variation are many and covary, both with each other and with body size. Further, the data sets used in analyses have been small, especially in light of the many proposed predictors. Here we report the complete list of models that results from exhaustively combining six commonly used predictors of brain and neocortex size. This provides an overview of how the output from standard statistical analyses changes when the inclusion of different predictors is altered. By using both the most commonly tested brain data set and the inclusion of new data we show that the choice of included variables fundamentally changes the conclusions as to what drives primate brain evolution. Our analyses thus reveal why studies have had troubles replicating earlier results and instead have come to such different conclusions. Although our results are somewhat disheartening, they highlight the importance of scientific rigor when trying to answer difficult questions. It is our position that there is currently no empirical justification to highlight any particular hypotheses, of those adaptive hypotheses we have examined here, as the main determinant of primate brain evolution.


Republished: 'Warm-Up Angina': harnessing the benefits of exercise and myocardial ischaemia.
The phenomenon of warm-up angina was first noted over 200 years ago. It describes the curious observation whereby exercise-induced ischaemia on second effort is significantly reduced or even abolished if separated from first effort by a brief rest period. However, the precise mechanism via which this cardio-protection occurs remains uncertain. Three possible explanations for reduced myocardial ischaemia on second effort include: first, an improvement in myocardial perfusion; second, increased myocardial resistance to ischaemia similar to ischaemic preconditioning; and third, reduced cardiac work through better ventricular-vascular coupling. Obtaining accurate coronary physiological measurements in the catheter laboratory throughout exercise demands a complex research protocol. In the 1980s, studies into warm-up angina relied on great cardiac vein thermo-dilution to estimate coronary blood flow. This technique has subsequently been shown to be inaccurate. However exercise physiology in the catheter laboratory has recently been resurrected with the advent of coronary artery wires that allow continuous measurement of distal coronary artery pressure and blood flow velocity. This review summarises the intriguing historical background to warm-up angina, and provides a concise critique of the important studies investigating mechanisms behind this captivating cardio-protective phenomenon.


Intravoxel Incoherent Motion Protocol Evaluation and Data Quality in Normal and Malignant Liver Tissue and Comparison to the Literature.
Although intravoxel incoherent motion (IVIM) becomes more and more popular, there is currently no clear consensus on the number and distribution of b-values to use. In this work, we (1) tested and evaluated the data quality of a 25-b-value IVIM protocol in patients with malignant liver lesions and normal liver tissue as a standard of reference, (2) calculated an optimal b-value distribution and compared with the standard of reference, and (3) compared the 25-b-value protocol with other proposed protocols in the literature. Intravoxel incoherent motion imaging with 25 b-values was performed at 3 T in a total of 15 patients with malignant liver lesions. Reference IVIM parameter maps were calculated in tumor and normal liver tissue. With these parameters, optimal IVIM protocols with reduced numbers of b-values were calculated. These optimal IVIM protocols were again applied to calculate new IVIM parameter maps that were compared with the reference parameter maps by calculating mean relative errors. In addition, 35 other IVIM protocols, as found in literature, were compared in a similar way with the 25-b-value protocol serving as a standard of reference. The mean relative error depends on the number of b-values and their distribution. In tumor tissue, the error is higher and more variable than in normal-appearing liver tissue. The largest errors occur in tumor tissue and in the protocols having low numbers of b-values in the IVIM protocols. In the calculated optimal IVIM protocols, the mean relative errors decreased by 40% or more when the number of b-values included increased from 4 to 16. The mean relative errors in the protocols adapted from the literature vary substantially between the various b-value distributions. One optimized 16-b-value protocol, which was found in literature, reduced the average relative error by 80% when compared with 4- and 5-b-value protocols listed in literature. Including more b-values and applying an optimized b-value distribution significantly reduces errors in the IVIM parameter estimates, thereby increasing its accuracy.This effect is even more pronounced in inhomogeneous tumor compared with that in normal liver tissue. However, when restrictions in acquisition time or patient-related factors apply, a minimum of 16 b-values should be considered for reliable results.


Comparison of the prevalence of reversible airways obstruction in rural and urban Zimbabwean children.
The prevalence of reversible airways obstruction has been assessed in children in three areas in Zimbabwe--northern Harare (high socioeconomic class urban children), southern Harare (low socio-economic class urban children), and Wedza Communal Land (rural children from peasant families). Peak expiratory flow (PEF) was measured before and after six minutes' free running in 2055 Zimbabwean primary school children aged 7-9 years. Height and weight were measured and nutritional state expressed as a percentage of the 50th centile for age (Tanner-Whitehouse standards). Reversible airways obstruction was deemed to be present when peak expiratory flow was below the 2.5th centile for height before exercise and rose by more than 15% after inhalation of salbutamol and when it fell by 15% or more after exercise and rose again after salbutamol. The prevalence of reversible airways obstruction was 5.8% (95% confidence interval 4.1-7.5%) in northern Harare (n = 726); 3.1% (1.8-4.5%) in southern Harare (n = 642), and 0.1% (0.0-0.4%) in Wedza (n = 687). In northern Harare, the only study area in which white children were found, the prevalence of reversible airways obstruction was similar in white (5.3%, 10/188) and black (5.9%, 32/538) children. Indicators of nutritional state also showed no significant differences between white and black children in northern Harare but were lower in southern Harare and lower still in Wedza. Urban living and higher material standards of living appear to be associated with a higher prevalence of reversible airways obstruction in children in Zimbabwe.


Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics.
Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels. SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males. Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation.


Statistics for the nonstatistician: Part II.
Part I of this two-part article provides a foundation of statistical terms and analyses for clinicians who are not statisticians. Types of data, how data are distributed and described, hypothesis testing, statistical significance, sample size determination, and the statistical analysis of interval scale (numeric) data were reviewed. Some data are presented not as interval data, but as named categories, also called nominal or categorical data. Part II reviews statistical tests and terms that are used when analyzing nominal data, data that do not resemble a normal, bell-shaped curve when plotted on the x- and y-axes, linear and logistic regression analysis, and survival analyses. A comprehensive algorithm of appropriate statistical analysis determined by the type, number, and distribution of collected variables also is provided.


Genomic Integration of High-Risk HPV Alters Gene Expression in Oropharyngeal Squamous Cell Carcinoma.
High-risk HPV (hrHPV) is the leading etiologic factor in oropharyngeal cancer. HPV-positive oropharyngeal tumors generally respond well to therapy, with complete recovery in approximately 80% of patients. However, it remains unclear why some patients are nonresponsive to treatment, with 20% of patients recurring within 5 years. In this study, viral factors were examined for possible clues to differences in tumor behavior. Oropharynx tumors that responded well to therapy were compared with those that persisted and recurred. Viral oncogene alternate transcripts were assessed, and cellular sites of viral integration were mapped and sequenced. Effects of integration on gene expression were assessed by transcript analysis at the integration sites. All of the tumors demonstrated active viral oncogenesis, indicated by expression of HPV E6 and E7 oncogenes and alternate E6 splicing. In the responsive tumors, HPV integration occurred exclusively in intergenic chromosome regions, except for one tumor with viral integration into TP63. Each recurrent tumor exhibited complex HPV integration patterns into cancer-associated genes, including TNFRSF13B, SCN2A, SH2B1, UBE2V2, SMOC1, NFIA, and SEMA6D Disrupted cellular transcripts were identified in the region of integration in four of the seven affected genes. Integration of transcriptionally active hrHPV into cellular intergenic regions associates with tumor behavior by altering gene expression. Mol Cancer Res; 14(10); 941-52. ©2016 AACR.


Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus.
Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013. Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year. Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973). Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.


The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1.
Angiopoietins are ligands of the endothelial cell tyrosine kinase receptor Tie2. Angiopoietin-1 (Ang-1) is widely expressed in human normal adult tissues and promotes blood vessel maturation and stabilization by inducing Tie2 receptor phosphorylation. In contrast, the antagonistic ligand Angiopoietin-2 (Ang-2) is up-regulated by hypoxia, expressed only at sites of vascular remodeling and plays a crucial role in destabilizing vessels for normal or pathological angiogenesis. Ang-2 expression is tightly regulated at transcriptional and post-transcriptional levels. To characterize the regulatory sequences of the human Ang-2 gene we cloned a fragment of around 8.5 kb upstream of the Ang-2 coding sequence and analyzed the luciferase reporter activity of constructs of various lengths in endothelial and non-endothelial cells. We isolated a minimal promoter sequence sufficient to promote significant Ang-2 non-cell type specific transcription. Moreover, we identified sequences conferring endothelial specificity. Indeed, sequence analysis of the fragment revealed the presence of several potential binding sites for specific endothelial regulatory factors like GATA or Ets. Using GATA-2 and Ets-1 co-transfection and overexpression assay, we showed that these two factors are able to induce Ang-2 promoter activation. We also show that hypoxic regulation of Ang-2 is HIF-dependent and demonstrate that HIF-1alpha binds in human microvascular endothelial cells (HMVEC) to an evolutionary conserved Hypoxia-Responsive Element (HRE) located in the first intron of the Ang-2 gene. In conclusion, our study provides new elements in favor of HIF involvement in Ang-2 hypoxic regulation and identifies Ets-1 and particularly GATA-2 as central factors in endothelial specific Ang-2 expression.


Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial.
To assess the cost effectiveness of giving tranexamic acid (TXA) to bleeding trauma patients in low, middle and high income settings. The CRASH-2 trial showed that TXA administration reduces the risk of death in bleeding trauma patients with a small but statistically significant increase in non-intensive care stay. A Markov model was used to assess the cost effectiveness of TXA in Tanzania, India and the United Kingdom (UK). The health outcome was the number of life years gained (LYs). Two costs were considered: the cost of administering TXA and the cost of additional days in hospital. Cost data were obtained from hospitals, World Health Organization (WHO) database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions. Administering TXA to bleeding trauma patients within three hours of injury saved an estimated 372, 315 and 755 LYs per 1,000 trauma patients in Tanzania, India and the UK respectively. The cost of giving TXA to 1,000 patients was $17,483 in Tanzania, $19,550 in India and $30,830 in the UK. The incremental cost of giving TXA versus not giving TXA was $18,025 in Tanzania, $20,670 in India and $48,002 in the UK. The estimated incremental cost per LY gained of administering TXA is $48, $66 and $64 in Tanzania, India and the UK respectively. Early administration of TXA to bleeding trauma patients is likely to be highly cost effective in low, middle and high income settings. This paper uses data collected by the CRASH 2 trial: Controlled-Trials.com ISRCTN86750102, Clinicaltrials.govNCT00375258 and South African Clinical Trial Register DOH-27-0607-1919.


High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis.
Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.


[Adolescence and reproduction in Brazil: the heterogeneity of social profiles].
This study aims to estimate the prevalence of adolescent pregnancy (AP) in three Brazilian cities Salvador, Rio de Janeiro, and Porto Alegre and to examine the profiles of pregnant girls and their partners in relation to pregnancy outcomes. Data for a retrospective assessment of AP were collected using an interview-based household survey applied to a stratified sample of males and females aged 18-24. A total of 4,634 individuals were interviewed (85.2 % of the eligible individuals). 21.4% of males and 29.5% of females aged 20-24 reported AP, but few such pregnancies had taken place before age 15 (0.6% and 1.6%). Pregnancy between adolescent partners was reported by 55.1% of males and 27.9% of females. 79.8% of the latter became pregnant while involved in a stable relationship with an older partner. AP levels varied inversely to schooling and income levels. 72.2% of females and 34.5% of males carried their first AP to completion, and more cases of induced abortion were reported by male partners in pregnancies (41.3%) than by females (15.3%). With the birth of the first child, 25.0% of women interrupted their studies temporarily and 17.3% definitively. However, 42.1% of primiparous mothers were already outside school before pregnancy.


Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial.
A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher's exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).


Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function.
The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras-expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation.


Evaluation of Pseudo-Haptic Interactions with Soft Objects in Virtual Environments.
This paper proposes a pseudo-haptic feedback method conveying simulated soft surface stiffness information through a visual interface. The method exploits a combination of two feedback techniques, namely visual feedback of soft surface deformation and control of the indenter avatar speed, to convey stiffness information of a simulated surface of a soft object in virtual environments. The proposed method was effective in distinguishing different sizes of virtual hard nodules integrated into the simulated soft bodies. To further improve the interactive experience, the approach was extended creating a multi-point pseudo-haptic feedback system. A comparison with regards to (a) nodule detection sensitivity and (b) elapsed time as performance indicators in hard nodule detection experiments to a tablet computer incorporating vibration feedback was conducted. The multi-point pseudo-haptic interaction is shown to be more time-efficient than the single-point pseudo-haptic interaction. It is noted that multi-point pseudo-haptic feedback performs similarly well when compared to a vibration-based feedback method based on both performance measures elapsed time and nodule detection sensitivity. This proves that the proposed method can be used to convey detailed haptic information for virtual environmental tasks, even subtle ones, using either a computer mouse or a pressure sensitive device as an input device. This pseudo-haptic feedback method provides an opportunity for low-cost simulation of objects with soft surfaces and hard inclusions, as, for example, occurring in ever more realistic video games with increasing emphasis on interaction with the physical environment and minimally invasive surgery in the form of soft tissue organs with embedded cancer nodules. Hence, the method can be used in many low-budget applications where haptic sensation is required, such as surgeon training or video games, either using desktop computers or portable devices, showing reasonably high fidelity in conveying stiffness perception to the user.


Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D.
Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras(G12D)-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in Kras(G12D) mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies.


Resolving the ancestry of Austronesian-speaking populations.
There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The "out-of-Taiwan" model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.


A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults.
There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro. A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting. CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue. Current Controlled Trials number ISRCTN38002730.


[GIPC: a new target for therapy in pancreatic adenocarcinoma?].
GIPC is highly expressed in human pancreatic adenocarcinoma and is a central protein for the stability of IGF-1R in pancreatic adenocarcinoma cell lines (15). The goal of this study was to prove the importance of GIPC in vivo and to evaluate possible therapeutic strategies that target this protein and its PDZ domain. In vivo effects of GIPC knockout were studied after lentiviral transduction of luciferase-expressing MiaPaCa2 pancreatic cancer cells with shRNA against GIPC; growth characteristics were monitored with bioluminiscence. Knockdown of GIPC led to a significant inhibition of pancreatic tumor cell growth in vivo in different mouse models. To test a possible therapeutic approach, the PDZ domain of GIPC was targeted by a short peptide composed of the amino acid sequence PSQSSSEA. This octapeptide was designed based on the C-terminal binding motif of GAIP. Targeting GIPC with this peptide inhibited the association between IGF-1R and GIPC. The subsequent downregulation of IGF-1R decreased proliferation in vitro and in vivo. In conclusion, our findings suggest that targeting GIPC and its PDZ domain-mediated interaction with the tyrosine kinase receptor IGF-1R could be a promising new treatment option for pancreatic cancer.


Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures.
RecQ helicases are a widely conserved family of ATP-dependent motors with diverse roles in nearly every aspect of bacterial and eukaryotic genome maintenance. However, the physical mechanisms by which RecQ helicases recognize and process specific DNA replication and repair intermediates are largely unknown. Here, we solved crystal structures of the human RECQ1 helicase in complexes with tailed-duplex DNA and ssDNA. The structures map the interactions of the ssDNA tail and the branch point along the helicase and Zn-binding domains, which, together with reported structures of other helicases, define the catalytic stages of helicase action. We also identify a strand-separating pin, which (uniquely in RECQ1) is buttressed by the protein dimer interface. A duplex DNA-binding surface on the C-terminal domain is shown to play a role in DNA unwinding, strand annealing, and Holliday junction (HJ) branch migration. We have combined EM and analytical ultracentrifugation approaches to show that RECQ1 can form what appears to be a flat, homotetrameric complex and propose that RECQ1 tetramers are involved in HJ recognition. This tetrameric arrangement suggests a platform for coordinated activity at the advancing and receding duplexes of an HJ during branch migration.


Carcinogenesis Bioassay of Butyl Benzyl Phthalate (CAS No. 85-68-7) in F344/N Rats and B6C3F1 Mice (Feed Study).
A carcinogenesis bioassay of butyl benzyl phthalate, a plasticizer for vinyl chloride plastics, was accomplished by feeding diets containing 6,000 or 12,000 ppm of the phthalate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 28 to 103 weeks. Mean body weights of dosed female rats and mice of each sex were lower than those of the control animals throughout most of the study. After week 14, an increasing number of dosed male rats died as a result of an unexplained internal hemorrhaging, and all surviving male rats were killed at week 29 to 30. Because of compound-related mortality, butyl benzyl phthalate was not adequately tested for carcinogenicity in male F344/N rats. Mononuclear cell leukemias occurred at a statistically significant (P=0.011) increased incidence in the high-dose group of female rats when compared with the control group and with a significantly (P=0.006) increasing trend (controls 7/49, 14%; low-dose 7/49, 14%; high-dose 18/50, 36%). The incidence in the high-dose group and the overall trend remained statistically significant (P=0.008 and P=0.019) when compared with the historical incidence for F344/N female rats with leukemia at this laboratory (77/ 399, 19%). Further, this leukoproliferation was generally characterized by splenomegaly and often by hepatomegaly. Administration of butyl benzyl phthalate was not associated with increased incidences of any type of tumor among male or female mice. Tumor rates were decreased in female rats for fibroadenomas of the mammary glands (20/49, 14/49, 9/50) and in male mice for lymphomas of the hematopoietic system (13/50, 11/49, 4/50) and for alveolar/bronchiolar adenomas or carcinomas (17/50, 11/49, 8/50). Under the conditions of this bioassay, butyl benzyl phthalate was probably carcinogenic for female F344/N rats, causing an increased incidence of mononuclear cell leukemias. The male F344/N rat study was considered inadequate for evaluation due to compound-related toxicity and early mortality. Butyl benzyl phthalate was not carcinogenic for B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate Study Female Rats: Positive Male Mice: Negative Female Mice: Negative Synonyms: BBP; benzyl butyl phthalate; phthalic acid; benzyl butyl ester; Santicizer 160


Synthesis and characterization of biomimetic hydroxyapatite/sepiolite nanocomposites.
Natural fibrous sepiolite with a high surface area, negative surface charge and porous structure is promising for hydroxyapatite (HAp) mineralization since the clay is naturally abundant and biocompatible. In this paper, the use of fibrous sepiolite as a template for growth of HAp nanocrystals was reported for the first time. Carbonated HAp nanorods with dimensions of 20-60 nm in length and 10-20 nm in diameter were successfully grown on the sepiolite surface with a preferred orientation to the c-axis. The critical nucleus radius of HAp in the presence of natural sepiolite was estimated as 0.296-0.312 nm. Strong acid-activation increased the specific surface area of the sepiolite by 205% and also transformed the sepiolite to silica fiber with an elastic modulus being 395% of the original value. The novel HAp/acid-activated sepiolite biocomposite has a specific surface area of 182 m2 g(-1) and an elastic modulus of over 20 GPa, considerably higher than those of the HAp synthesized without sepiolite. Such hierarchically assembled HAp/sepiolite biocomposites with controlled size and improved modulus open a new way to expand the applications of naturally abundant clays in biological load-bearing devices.


Emergency department waiting times: Do the raw data tell the whole story?
To determine whether there are real differences in emergency department (ED) performance between Australian states and territories. Cross-sectional analysis of 2009-10 attendances at an ED contributing to the Australian non-admitted patient ED care database. The main outcome measure was difference in waiting time across triage categories. There were more than 5.8 million ED attendances. Raw ED waiting times varied by a range of factors including jurisdiction, triage category, geographic location and hospital peer group. All variables were significant in a model designed to test the effect of jurisdiction on ED waiting times, including triage category, hospital peer group, patient socioeconomic status and patient remoteness. When the interaction between triage category and jurisdiction entered the model, it was found to have a significant effect on ED waiting times (P<0.001) and triage was also significant (P<0.001). Jurisdiction was no longer statistically significant (P=0.248 using all triage categories and 0.063 using only Australian Triage Scale 2 and 3). Although the Council of Australian Governments has adopted raw measures for its key ED performance indicators, raw waiting time statistics are misleading. There are no consistent differences in ED waiting times between states and territories after other factors are accounted for. WHAT IS KNOWN ABOUT THE TOPIC? The length of time patients wait to be treated after presenting at an ED is routinely used to measure ED performance. In national health agreements with the federal government, each state and territory in Australia is expected to meet waiting time performance targets for the five ED triage categories. The raw data indicate differences in performance between states and territories. WHAT DOES THIS PAPER ADD? Measuring ED performance using raw data gives misleading results. There are no consistent differences in ED waiting times between the states and territories after other factors are taken into account. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Judgements regarding differences in performance across states and territories for triage waiting times need to take into account the mix of patients and the mix of hospitals.


Design aspects of calibration studies in nutrition, with analysis of missing data in linear measurement error models.
Motivated by an example in nutritional epidemiology, we investigate some design and analysis aspects of linear measurement error models with missing surrogate data. The specific problem investigated consists of an initial large sample in which the response (a food frequency questionnaire, FFQ) is observed and then a smaller calibration study in which replicates of the error prone predictor are observed (food records or recalls, FR). The difference between our analysis and most of the measurement error model literature is that, in our study, the selection into the calibration study can depend on the value of the response. Rationale for this type of design is given. Two major problems are investigated. In the design of a calibration study, one has the option of larger sample sizes and fewer replicates or smaller sample sizes and more replicates. Somewhat surprisingly, neither strategy is uniformly preferable in cases of practical interest. The answers depend on the instrument used (recalls or records) and the parameters of interest. The second problem investigated is one of analysis. In the usual linear model with no missing data, method of moments estimates and normal-theory maximum likelihood estimates are approximately equivalent, with the former method in most use because it can be calculated easily and explicitly. Both estimates are valid without any distributional assumptions. In contrast, in the missing data problem under consideration, only the moments estimate is distribution-free, but the maximum likelihood estimate has at least 50% greater precision in practical situations when normality obtains. Implications for the design of nutritional calibration studies are discussed.


[The proliferative potential of human pituitary macroadenomas on the basis of morphometric analysis of nucleolus organizer regions].
Cell kinetic information is an important adjuvant to histological typing and grading of human brain tumours. In the current study detection of the proliferating potential of adenomas was attempted using silver colloid technique for argyrophilic protein associated with nucleolar organizer regions (AgNORs). The expression of nucleolar organizer regions was assessed on paraffin sections in 28 pituitary macroadenomas which included all the main types. Nucleolar organiser regions have been quantified with computer-aided image analysis system in order to evaluate the mean area of AgNORs and their number relative to an internal reference, the number and areas of clusters of AgNORs and the area of the nucleus. In the pituitary macroadenomas there were 1.48 +/- 0.30 (mean +/- SEM) AgNORs per cell nucleus and corrected values were 1.66 +/- 0.27 (mean +/- SEM) AgNORs. The mean nucleus area was 867.18 +/- 203.91 pixels. The mean AgNORs size was 54.50 +/- 34.80 pixels. Correlation of nucleus area/AgNORs area was: r = 0.7085. On the number of the AgNORs it was possible to distinguish 3 subgroups of macroadenoma with different proliferative potential: low < = 1.367 (1.479); medium 1.367-1.733 (1.479-1.864) and high > 1.733 (1.864) AgNORs per cell nucleus and corrected number of AgNORs per cell nucleus respectively. Thus, this method provides useful information about the proliferative potential of human pituitary adenoma.


First Report of Pepper yellow leaf curl Indonesia virus in Ageratum conyzoides in Indonesia.
Ageratum conyzoides L. plants affected with yellow vein disease were collected from Magelang, Bandung, and Purwokerto locations in Indonesia during 2001. A. conyzoides is a naturally occurring weed that is found in and around fields of cultivated pepper (Capsicum annuum L.) and tomato (Lycopersicon esculentum L.). It is frequently found with symptoms of yellow vein disease and the abundance of whiteflies on the affected plants suggested the possible involvement of a geminivirus. Total nucleic acids were extracted from nine samples collected from these locations of A. conyzoides-affected plants exhibiting yellow vein disease and amplified using PCR with geminivirus DNA-A-specific designed primers (virion-sense primer 5'-GAGCTCTTAGCCGCCTGAATGTTC-3'; complementary-sense primer 5'-GAGCTCGTCAGATGTTAAGACCTAC-3') (1). A PCR-amplified product of approximately 2.7 kbp was obtained from each sample. Five independent sequences were cloned and sequenced from each sample. Sequence analysis showed that five of nine samples were Ageratum yellow vein virus (one each from Bandung and Purwokerto and three from Magelang) and the remaining four samples (two samples each from Bandung and Purwokerto) were a strain of Pepper yellow leaf curl Indonesia virus (PepYLCIDV). Full-length DNA-A of PepYLCIDV from systemic A. coniziodes was amplified using PCR with additional primers designed at only one restriction site (BamHI) (5'-GGATCCGCTTGTTCATCCTTTTCCAG-3'/5'-GGATCCCACATCTTTGGTTAGTGGAGGGTG-3') and cloned. Three independent clones obtained were sequenced and analyzed. The sequence of a full-length DNA-A component was determined (2,760 bases, GenBank Accession No. AB267838). PCR using degenerate primers (DNABLC1: 5'-GTVAATGGRGTDCACTTCTG-3'; DNABLC2: 5'-RGTDCACTTCTGYARGATGC-3', DNABLV2: 5'-GAGTAGTAGTGBAKGTTGCA-3') of begomovirus DNA-B component (2), five independent clones were obtained and sequenced. Primers designed to amplify a full-length B component were constructed around a unique restriction site (BamHI) (5'-GGATCCCCTCATTCCTTTTGCGGAG-3'/5'-GGATCCACAGAGGAAAACTCGCAAGGC-3'). A PCR product was obtained from A. conyzoides samples and three independent clones were sequenced and analyzed. A full-length sequence of a begomovirus B component was determined (2,746 bases, GenBank Accession No. AB267839). Five open reading frames (ORF) were found in DNA-A and two in DNA-B. The DNA-A and DNA-B had a common region (CR) (74% nucleotide sequence identity) that comprised approximately 160 nucleotides. The DNA-A and DNA-B had an identical 31-base stem loop region in the CR. In addition, DNA-A and DNA-B had the highest nucleotide sequence identity (93%) with those of PepYLCIDV (GenBank Accession Nos. AB267834 and AB267835), suggesting it is a strain of PepYLCIDV, which is widely prevalent in Indonesia. To our knowledge, this is the first report of PepYLCIDV isolated from A. conyzoides plants affected with yellow vein disease. References: (1) R. W. Briddon and P. G. Markham. Mol. Biotechnol. 1:202, 1994. (2) S. K. Green et al. Plant Dis. 85:1286, 2001.


High-throughput trapping of secretory pathway genes in mouse embryonic stem cells.
High-throughput gene trapping is a random approach for inducing insertional mutations across the mouse genome. This approach uses gene trap vectors that simultaneously inactivate and report the expression of the trapped gene at the insertion site, and provide a DNA tag for the rapid identification of the disrupted gene. Gene trapping has been used by both public and private institutions to produce libraries of embryonic stem (ES) cells harboring mutations in single genes. Presently, approximately 66% of the protein coding genes in the mouse genome have been disrupted by gene trap insertions. Among these, however, genes encoding signal peptides or transmembrane domains (secretory genes) are underrepresented because they are not susceptible to conventional trapping methods. Here, we describe a high-throughput gene trapping strategy that effectively targets secretory genes. We used this strategy to assemble a library of ES cells harboring mutations in 716 unique secretory genes, of which 61% were not trapped by conventional trapping, indicating that the two strategies are complementary. The trapped ES cell lines, which can be ordered from the International Gene Trap Consortium (http://www.genetrap.org), are freely available to the scientific community.


More than just talk: the framing of transactional sex and its implications for vulnerability to HIV in Lesotho, Madagascar and South Africa.
'Transactional sex' was regarded by the mid-1990s as an important determinant of HIV transmission, particularly in sub-Saharan Africa. Little attention has been paid to what the terms used to denote transactional sex suggest about how it is understood. This study provides a nuanced set of descriptions of the meaning of transactional sex in three settings. Furthermore, we discuss how discourses around transactional sex suggest linkages to processes of globalization and hold implications for vulnerability to HIV. The analysis in this article is based on three case studies conducted as part of a multi-country research project that investigated linkages between economic globalization and HIV. In this analysis, we contextualize and contrast the 'talk' about transactional sex through the following research methods in three study sites: descriptions revealed through semi-structured interviews with garment workers in Lesotho; focus groups with young women and men in Antananarivo, Madagascar; and focus groups and in-depth interviews with young women and men in Mbekweni, South Africa. Participants' talk about transactional sex reveals two themes: (1) 'The politics of differentiation' reflects how participants used language to demarcate identities, and distance themselves from contextually-based marginalized identities; and (2) 'Gender, agency and power' describes how participants frame gendered-power within the context of transactional sex practices, and reflects on the limitations to women's power as sexual agents in these exchanges. Talk about transactional sex in our study settings supports the assertion that emerging transactional sexual practices are linked with processes of globalization tied to consumerism. By focusing on 'talk' about transactional sex, we locate definitions of transactional sex, and how terms used to describe transactional sex are morally framed for people within their local context. We take advantage of an opportunity to comparatively explore such talk across three different study sites, and contribute to a better understanding of both emerging sexual practices and their implications for HIV vulnerability. Our work underlines that transactional sex needs to be reflected as it is perceived: something very different from, but of at least equal concern to, formal sex work in the efforts to curb HIV transmission.


Development, food intake, and ethinylestradiol influence hepatic triglyceride lipase and LDL-receptor mRNA levels in rats.
The influence of development and ethinylestradiol on low density lipoprotein (LDL)-receptor mRNA and hepatic triglyceride lipase (HTGL) activity and mRNA levels was studied in rat liver and intestine. Intestinal LDL-receptor mRNA levels are maximal in the perinatal period, whereas liver LDL-receptor and HTGL mRNA levels are highest after weaning in adult life. All mRNA levels reach a maximum between day 15 and 20 when rats still consume a lipid-rich diet, and increase twofold during weaning. Liver and intestinal LDL-receptor mRNA levels are not influenced by ovariectomy, but increase after ethinylestradiol treatment. Liver LDL-receptor mRNA shows a dose-dependent increase after ethinylestradiol and a sevenfold rise in liver LDL-receptor mRNA is attained with a dose of 2000 micrograms/day. Intestinal LDL-receptor mRNA increases slightly more than twofold after ethinylestradiol and this increase is not dose-dependent. Changes in LDL-receptor mRNA are independent of changes in food intake induced by ethinylestradiol treatment, since they are still observed after pair-feeding. The ethinylestradiol-induced increases in LDL-receptor mRNA levels are reflected by decreased serum apoB levels. HTGL mRNA levels increase after ovariectomy and show a dose-dependent decrease after ethinylestradiol. Pair-feeding abolishes the increase seen after ovariectomy, while the estrogen-mediated decrease is attenuated. These alterations in HTGL mRNA are reflected by similar changes in liver HTGL activity.(ABSTRACT TRUNCATED AT 250 WORDS)


SU-E-T-452: Impact of Abdominal Compression on the Tumor Motion in the Treatment of NSCLC Using Stereotactic Body Radiosurgery.
Involuntary motion of the tumor during the treatment of NSCLC using stereotactic body radiosurgery presents its own unique challenges. In this study, we quantify the impact of abdominal compression technique to minimize tumor motion as a function of location of tumor in a patient. 25 patients (5 in each lung lobe viz. RUL, RML, RLL, LUL and LLL) were retrospectively analyzed. A 4DCT study encompassing the tumor was used on a 16 slice GE CT scanner along with Varian RPM gating system. The images were retrospectively binned in 10 phases. The motion of tumor was analyzed phase by phase in transverse, sagittal & coronal projections of the 3D image. This gave us 2 values for anterior-posterior, superior-inferior and lateral-medial motions each and was averaged out. Analysis of data reveals that the motion (mean ± 1SD) in the superior-inferior direction was 1.8 ± 0.9, 4.2±2.8, 7.4±2.3, 1.5±0.8, 3.1±2.8 mm for tumors located in RUL, RML, RLL, LUL and LLL, respectively. Along the anterior-posterior direction the respective values were 2.5 ± 1.9, 2.4 ± 1.1, 2.7 ± 1.3, 1.4 ± 0.2 and 1.8 ± 1 mm. Similarly, along the lateral direction, the respective values were 2.1 ± 1.1, 1.9 ± 1.1, 1.6 ± 1.3, 1.1 ± 0.3 and 1.8 ± 0.7 mm. When the data was analyzed removing the location of the tumor in the thorax, the median displacement along the superior-inferior, anterior-posterior, lateral direction was 2.3, 1.6 and 1.5 mm, respectively while the respective maximum value were 9.2, 5 & 3.8 mm. The use of abdominal compression provides a simple inexpensive yet easily tolerable device to control the motion of the tumor in the management of NSCLC for SBRT treatments. This will allows the treatment of the tumor without resorting to complex and time consuming gated treatments.