IL8 Expression Is Associated with Prostate Cancer Aggressiveness and Androgen Receptor Loss in Primary and Metastatic Prostate Cancer.
Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1β, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating that AR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease. IMPLICATIONS: IL8 expression is repressed by AR and is associated with prostate cancer aggressiveness and AR loss in metastatic disease.


TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.
A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations.


[Swallowing disorders, pneumonia and respiratory tract infectious disease in the elderly].
Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patient's oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures).


Interactions of C-reactive protein with the complement system. III. Complement-dependent passive hemolysis initiated by CRP.
Interactions of CRP with various substrates in the presence of human serum have been shown to result in efficient activation of C components C1-C5. We now report the ability of CRP to initiate C-dependent hemolysis. For this purpose CRP was isolated by affinity chromatography using pneumococcal CPS and gel filtration; its purity was established by several criteria. Erythrocytes were coated with CPS (E-CPS) and passively sensitized with CRP. C-dependent lysis of these cells was observed upon the addition of suitably absorbed human serum, and the efficiency of hemolysis compared favorably with that initiated by rabbit IgG anti-CPS antibody. CRP also sensitized E-CPS for lysis by guinea pig C; partial lysis was seen when C4-deficient guinea pig serum was used, suggesting that CRP also shares with antibody the ability of CRP to fully activate the C system and provide further evidence for a role for CRP similar to that of antibody in the initiation and modulation of inflammatory reactions via the complete system.


Clinical laboratory assessments for Mycoplasma genitalium in a high-prevalence sexually-transmitted infection community reveal epidemiologic dichotomies with Trichomonas vaginalis.
Mycoplasma genitalium is an emerging agent of sexually-transmitted infection and is responsible for clinically-significant genital tract disease in both females and males. Similar to scenarios recently experienced with the urogenital flagellate Trichomonas vaginalis, an evolving molecular diagnostic reference standard based on transcription-mediated amplification allows for accurate detection of the organism, plus additional insight into disease epidemiology. Areas covered. The basis for this article includes primary peer-reviewed literature plus compilations of data derived from routine clinical laboratory screening of females and males for agents of sexually-transmitted infection. Introductory laboratory and epidemiologic data related to T. vaginalis provides not only a foreshadowing to the dichotomies inherent to M. genitalium prevalence but also advocacy of a common non-invasive specimen source that could be used to screen females for both agents. This review also documents increased prevalence rates of M. genitalium in both females and males by way of transcription-mediated amplification. Expert commentary. Molecular detection of M. genitalium should be a consideration in the development of comprehensive sexually-transmitted infection screening programs for both females and males. Transcription-mediated amplification has additionally identified novel facets of M. genitalium and T. vaginalis epidemiology that warrant further investigation.


Traditional risk factors and ischemic stroke in young adults: the Baltimore-Washington Cooperative Young Stroke Study.
To determine the association of hypertension, diabetes, and cigarette smoking with incidence of ischemic stroke in young adults. Case-control study. Population-based sample of cases and controls. The study included 296 cases of incident ischemic stroke among black and white adults aged 18 to 44 years in central Maryland counties from the Baltimore-Washington Cooperative Young Stroke Study and 1220 black and white adults aged 18 to 44 years from the Maryland Behavioral Risk Factor Survey, a telephone survey of a random sample of the same region, to serve as controls. Logistic regression models were developed to determine the age-adjusted odds ratios for each risk factor. Population-attributable risk percent were computed based on the odds ratios and prevalence of each risk factor. The age-adjusted odds ratios (95% confidence intervals) for white men (WM), white women (WW), black men (BM), and black women (BW) were as follows: current cigarette smoking: WM, 2.0 (1.1-3.8), WW, 2.1 (1.1-4.3), BM, 3.3 (1.6-6.6), and BW, 2.2 (1.3-3.9); history of diabetes mellitus: WM, 22.9 (5.8-89.6), WW, 6.2 (1.9-20.2), BM, 4.2 (0.8-21.9), and BW, 3.3 (1.4-7.7); and history of hypertension: WM, 1.6 (0.7-3.2), WW, 2.5 (1.1-5.9), BM, 3.8 (1.8-7.9), and BW, 4.2 (2.4-7.5). The population-attributable risk percent (95% confidence intervals) were as follows: current cigarette smoking: WM, 22.6 (3.1-38.2), WW, 17.2 (4.0-34.0), BM, 40.5 (23.1-54.0), and BW, 29.1 (13.5-41.9); history of diabetes mellitus: WM, 19.0 (8.2-28.5), WW, 15.8 (3.8-26.3), BM, 13.2 (5.3-20.4), and BW, 22.1 (12.5-30.7); and history of hypertension: WM, 21.7 (6.2-34.6), WW, 21.3 (5.4-34.5), BM, 53.5 (39.0-64.4), and BW, 50.5 (37.1-61.1). Hypertension, diabetes mellitus, and current cigarette smoking are important risk factors in a biracial young adult population. Cigarette smoking and hypertension, the 2 most modifiable risk factors, were particularly important risk factors in young blacks.


The yeast histone chaperone hif1p functions with RNA in nucleosome assembly.
Hif1p is an H3/H4-specific histone chaperone that associates with the nuclear form of the Hat1p/Hat2p complex (NuB4 complex) in the yeast Saccharomyces cerevisiae. While not capable of depositing histones onto DNA on its own, Hif1p can act in conjunction with a yeast cytosolic extract to assemble nucleosomes onto a relaxed circular plasmid. To identify the factor(s) that function with Hif1p to carry out chromatin assembly, multiple steps of column chromatography were carried out to fractionate the yeast cytosolic extract. Analysis of partially purified fractions indicated that Hif1p-dependent chromatin assembly activity resided in RNA rather than protein. Fractionation of isolated RNA indicated that the chromatin assembly activity did not simply purify with bulk RNA. In addition, the RNA-mediated chromatin assembly activity was blocked by mutations in the human homolog of Hif1p, sNASP, that prevent the association of this histone chaperone with histone H3 and H4 without altering its electrostatic properties. These results suggest that specific RNA species may function in concert with histone chaperones to assemble chromatin.


Phase unwrapping in three dimensions with application to InSAR time series.
The problem of phase unwrapping in two dimensions has been studied extensively in the past two decades, but the three-dimensional (3D) problem has so far received relatively little attention. We develop here a theoretical framework for 3D phase unwrapping and also describe two algorithms for implementation, both of which can be applied to synthetic aperture radar interferometry (InSAR) time series. We test the algorithms on simulated data and find both give more accurate results than a two-dimensional algorithm. When applied to actual InSAR time series, we find good agreement both between the algorithms and with ground truth.


Debt and depression.
We examine the effect of household financial indebtedness on psychological well-being using a large household survey of families with children in Britain. Existing studies that find a link between debt and depression tend to utilise small and highly selective samples of people and only self-reported measures of financial stress, responses to which are likely to correlate with subjective measures of health. From additional household data, we can construct a variety of 'objective' quantitative measures of financial stress in order to validate self-reported measures. We show that, although there is a positive association between subjective measures of financial well-being and psychological well-being, individuals differ in their psychological response to objective household financial situations. We also examine how the potential simultaneity of financial and psychological health might be handled.


Recent trends in cutaneous melanoma incidence among whites in the United States.
It is not yet clear whether increasing melanoma incidence is real or whether recent incidence trends mainly reflect improved diagnosis. To address this question, we examined the most recent melanoma incidence patterns among the white population stratified by sex, age, tumor stage, and tumor thickness by use of data from the Surveillance, Epidemiology, and End Results Program. We examined log-transformed age-specific rates for melanoma by 5-year age groups and time periods by year of diagnosis and birth cohort. Melanoma trends were further examined among broader age groups (<40 years, 40-59 years, and > or =60 years) by tumor stage and tumor thickness. Rates were age-adjusted to the 1970 U.S. standard population, and trends were tested by use of a two-sided Student's t test. Melanoma incidence increased in females born since the 1960s. From 1974-1975 through 1988-1989, upward trends for the incidence of localized tumors and downward trends for the incidence of distant-stage tumors occurred in the age group under 40 years. In the more recent time period, 1990-1991 through 1996-1997, age specific rates among females compared with males generally remained stable or declined more for distant-stage tumors and increased less for local-stage tumors. Thin tumors (<1 mm) increased statistically significantly in all age groups (P<.05 for all), except in men under age 40 years. In contrast, rates for thick tumors (> or =4 mm) increased statistically significantly (P =.0003) only in males aged 60 years and older. Melanoma incidence may well continue to rise in the United States, at least until the majority of the current population in the middle-age groups becomes the oldest population. The recent trends may reflect increased sunlight exposure.


Association of leukocyte telomere length in peripheral blood leukocytes with endometrial cancer risk in Caucasian Americans.
Telomeres are the protective structure at the ends of each chromosome and play an important role in maintaining genomic integrity. Interindividual variation of telomere length in peripheral blood leukocytes has been associated with the risks of developing many human diseases including several cancers. The association between leukocyte telomere length (LTL) and endometrial cancer risk is still inconsistent. Using a case-control study of endometrial cancer patients (n = 139) and control subjects (n = 139) in a Caucasian population, we assessed the association of relative LTL with the risk of endometrial cancer. We calculated odds ratios and 95% confidence intervals using multivariate logistic regression. We also determined the joint effects of LTL with established risk factors of endometrial cancer. The normalized LTL was significantly longer in endometrial cancer cases (median, 0.93; range, 0.19-1.62) than in controls (median, 0.70; range, 0.03-2.14) (P < 0.001). When individuals were dichotomized into long and short groups based on the median LTL value in the controls, individuals with long LTL had a significantly increased risk of endometrial cancer (adjusted OR, 3.84; 95%CI, 2.16-6.85; P < 0.001) compared to those with short LTL. When individuals were categorized into three groups or four groups according to tertile or quartile LTL value in the controls, there was a significant dose-response association between LTL and the risk of endometrial cancer (P < 0.001). Joint effects between LTL and smoking status, body mass index and a history of hypertension or diabetes in elevating endometrial cancer risk were observed. Long telomere length in peripheral blood leukocytes is associated with a significantly increased risk of endometrial cancer.


The roles of GATA-4, -5 and -6 in vertebrate heart development.
The transcription factors GATA-4, -5 and -6 are expressed very early in heart tissue. Essential GATA sites have been detected in several cardiac genes and the cardiac GATA factors interact with a wide variety of cofactors which synergistically increase gene expression. These multi-protein transcriptional complexes confer promoter-specificity on the GATA factors and also on the more broadly expressed cofactors. Here we summarise the data on these interactions and represent the conclusions as a GATA factor-based genetic regulatory network for the heart. Of the three cardiac GATAs, GATA-4 is by far the most extensively studied, however, loss-of-function data question its presumed dominance during heart development as opposed to hypertrophy.


Lower anti-echovirus antibody responses in children presenting to hospital with asthma exacerbations.
Rhinoviruses from the Enterovirus genus cause frequent infections and induce remarkably high titres of anticapsid antigen antibodies in asthmatics, while the prevalence of neutralising antibodies to the gut-trophic echoviruses from the same genus is diminished. To assess the absolute and specific antibody titres to VP1 antigens of the gut-trophic enteroviruses, echovirus 30 and Sabin 1 poliovirus, in asthmatic and non-asthmatic children. Recombinant polypeptides representing the VP1 capsid antigens of echovirus 30 and Sabin poliovirus 1 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n = 45) and non-asthmatic (n = 29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls (P < 0.05) and inversely correlated with total IgE levels for the whole study population (r = -0.262; P < 0.05). There was no difference in the prevalence and titre between groups to the VP1 antigen of Sabin poliovirus. Anti-tetanus toxoid titres measured for comparison did not correlate with anti-echovirus or poliovirus, but correlated with anti-rhinovirus titres in controls but not asthmatics, where the titres were higher for the asthmatic group. The associations of lower antibody titres of asthmatic children to echovirus reported here and those of our previous findings of a heightened response to rhinovirus suggest a dichotomy where respiratory enterovirus infection/immunity increases the probability of developing asthma and enteric infections lower the risk. This provides further support for the concept of intestinal infection playing a key role in the development of allergic respiratory disease.


Deleterious reproductive effects of nilotinib in mouse model.
Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) that is widely used to treat patients with Philadelphia chromosome-positive chronic myeloid leukaemia (CML). TKIs provided a significant improvement in terms of survival rates and disease-free period in CML; however, there is insufficient knowledge about their side effects, including reproductive toxicity. Since nearly half of the CML patients are in their reproductive age, and newly announced indications cover the treatment of the paediatric age groups, concerns arise about the effects of these drugs on the reproductive system, as there are no controlled preclinical studies. We investigated acute and long-term gonadotoxic and teratogenic effects of nilotinib, utilising a mouse model that simulates various clinical scenarios. We observed significant testicular damage in mice receiving nilotinib according to Johnsen's score analysis. Alterations were observed in female mice's number of follicles, as the primordial follicle numbers significantly decreased. Proliferating cell number in both genders' gonads decreased and apoptosis rate increased significantly. The nilotinib-received female and male mice's pregnancy rates were low compared to controls. A significant decrease in the thickness of the spongiotrophoblast and decidual layers of the placenta was detected in pregnancies consisting of male and/or female mice treated with nilotinib. The results of this study establish a critical point of view for clinical translation and indicate the importance of consulting patients for directing them to fertility preservation and contraception options for both genders before nilotinib treatment.


IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation.
Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients. In CF patients with an S1251N mutation (N = 16; age 9-35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10-24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor. At baseline, median FGF19 was lower (52% and 53%, P < .001) and median C4 higher (350% and 364%, P < .001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function. We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs.


Multisensory top-down sets: Evidence for contingent crossmodal capture.
Numerous studies that have investigated visual selective attention have demonstrated that a salient but task-irrelevant stimulus can involuntarily capture a participant's attention. Over the years, a lively debate has erupted concerning the impact of contingent top-down control settings on such stimulus-driven attentional capture. In the research reported here, we investigated whether top-down sets would also affect participants' performance in a multisensory task setting. A nonspatial compatibility task was used, in which the target and the distractor were always presented sequentially from the same spatial location. We manipulated target-distractor similarity by varying the visual and tactile features of the stimuli. Participants always responded to the visual target features (color); the tactile features were incorporated into the participants' top-down set only when the experimental context allowed for the tactile feature to be used in order to discriminate the target from the distractor. Larger compatibility effects after bimodal distractors were observed only when the participants were searching for a bimodal target and when tactile information was useful. Taken together, these results provide the first demonstration of nonspatial contingent crossmodal capture.


Design, synthesis, and imaging of an activatable photoacoustic probe.
Photoacoustic tomography is a rapidly growing imaging modality that can provide images of high spatial resolution and high contrast at depths up to 5 cm. We report here the design, synthesis, and evaluation of an activatable probe that shows great promise for enabling detection of the cleaved probe in the presence of high levels of nonactivated, uncleaved probe, a difficult task to attain in absorbance-based modality. Before the cleavage by its target, proteolytic enzyme MMP-2, the probe, an activatable cell-penetrating peptide, Ceeee[Ahx]PLGLAGrrrrrK, labeled with two chromophores, BHQ3 and Alexa750, shows photoacoustic signals of similar intensity at the two wavelengths corresponding to the absorption maxima of the chromophores, 675 and 750 nm. Subtraction of the images taken at these two wavelengths makes the probe effectively photoacoustically silent, as the signals at these two wavelengths essentially cancel out. After the cleavage, the dye associated with the cell-penetrating part of the probe, BHQ3, accumulates in the cells, while the other dye diffuses away, resulting in photoacoustic signal seen at only one of the wavelengths, 675 nm. Subtraction of the photoacoustic images at two wavelengths reveals the location of the cleaved (activated) probe. In the search for the chromophores that are best suited for photoacoustic imaging, we have investigated the photoacoustic signals of five chromophores absorbing in the near-infrared region. We have found that the photoacoustic signal did not correlate with the absorbance and fluorescence of the molecules, as the highest photoacoustic signal arose from the least absorbing quenchers, BHQ3 and QXL 680.


Tropical mid-tropospheric CO2 variability driven by the Madden-Julian oscillation.
Carbon dioxide (CO(2)) is the most important anthropogenic greenhouse gas in the present-day climate. Most of the community focuses on its long-term (decadal to centennial) behaviors that are relevant to climate change, but there are relatively few discussions of its higher-frequency forms of variability, and none regarding its subseasonal distribution. In this work, we report a large-scale intraseasonal variation in the Atmospheric Infrared Sounder CO(2) data in the global tropical region associated with the Madden-Julian oscillation (MJO). The peak-to-peak amplitude of the composite MJO modulation is ∼1 ppmv, with a standard error of the composite mean < 0.1 ppmv. The correlation structure between CO(2) and rainfall and vertical velocity indicate positive (negative) anomalies in CO(2) arise due to upward (downward) large-scale vertical motions in the lower troposphere associated with the MJO. These findings can help elucidate how faster processes can organize, transport, and mix CO(2) and provide a robustness test for coupled carbon-climate models.


Controlled synthesis of Au-Fe heterodimer nanoparticles and their conversion into Au-Fe3O4 heterostructured nanoparticles.
We report a facile synthesis of Au-Fe heterodimer nanoparticles (NPs) with tunable Au/Fe sizes and their sequential oxidations to Au-Fe3O4 heterostructured NPs with controllable morphologies. The size of Au in Au-Fe heterodimer NPs was tuned to be 4, 7 and 10 nm, while the Fe crystal structure was maintained as single-crystal bcc. Further oxidation of the as-synthesized Au-Fe NPs led to the formation of Au-hollow Fe3O4 yolk-shell, Au-hollow Fe3O4 heterodimer NPs and Au-porous hollow Fe3O4 yolk-shell NPs, depending on the size of the Au-Fe NPs and the oxidation conditions used. Our study has provided not only a variety of bifunctional NPs with tunable surface plasmon absorption and magnetic properties, but also a new general approach to design and synthesize multicomponent NPs with multiple heterostructures.


Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy.
The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein-coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.


Reduced superoxide dismutase activity in Palaemonetes argentinus (Decapoda, Palemonidae) infected by Probopyrus ringueleti (Isopoda, Bopyridae).
Cellular oxidative stress may promote damage or death in biological systems and may be caused by production of pro-oxidant molecules known as reactive oxygen species (ROS). The aim of this work was to analyze the activity of antioxidant enzymes (catalase [CAT], superoxide dismutase [SOD] and glutathione peroxidase [GPx]) in the shrimp Palaemonetes argentinus Nobili, 1901 infected by Probopyrus ringueleti (Verdi & Schuldt, 1987), a gill chamber parasite known for its capacity to cause host metabolic changes, including changes in oxygen consumption rates. Infested and non-infested shrimp were collected in the Patos Lagoon estuary (southern Brasil), where the prevalence of the parasite may be as high as 70%. No significant differences were observed for either CAT or GPx activities. However, SOD activity was significantly reduced in infected shrimp, suggesting that bopyrid isopod respiratory impairment resulted in reduced SOD enzyme activity.


Toxoplasma gondii isolates from free-range chickens from the northeast region of Brazil.
The prevalence of Toxoplasma gondii in free-ranging chickens is a good indicator of the prevalence of T. gondii oocysts in the soil because chickens feed from the ground. The prevalence of T. gondii in 152 free-range chickens (Gallus domesticus) from 22 municipalities in 7 northeastern states (Pernambuco, Rio Grande do Norte, Maranhão, Bahia, Ceará, Sergipe, and Alagoas) of Brazil was determined. Antibodies to T. gondii were assayed by the modified agglutination test (MAT); 81 (53.3 %) chickens had titers of 1:5 in 26, 1:10 in 9, 1:20 in 4, 1:40 in 1, 1:80 in 6, 1:160 in 6, 1:320 in 13, 1:640 in 6, 1:1,280 in 3, 1:2,560 in 6, and 1:5,120 or higher in 1. Hearts and brains of 81 seropositive chickens were bioassayed individually in mice. Toxoplasma gondii was isolated from 23 chickens with MAT titers of 1:5 or higher; the isolates were designated TgCKBr165-187. Five isolates killed all infected mice. Results indicate widespread contamination of rural environment in Brazil with T. gondii oocysts.


Complication rates on weekends and weekdays in US hospitals.
Recent studies and anecdotal evidence suggest that patient safety may be compromised on weekends. Our objective was to determine whether rates of complications in hospitals are higher on weekends than on weekdays. We examined records from 4,967,114 admissions to acute care hospitals in 3 states and analyzed complication rates using the Patient Safety Indicators. We selected 8 indicators that could be assigned to a single day: complications of anesthesia, retained foreign bodies, postoperative hemorrhage, accidental cuts and lacerations during procedures, birth trauma, obstetric trauma during vaginal deliveries with and without instrumentation, and obstetric trauma during cesarean delivery. Odds ratios (ORs) comparing weekends versus weekdays were adjusted for demographics, type of admission, and admission route. In a subgroup analysis of surgical complications, we restricted the population to patients who underwent cardiac or vascular procedures. Four of the 8 complications occurred more frequently on weekends: postoperative hemorrhage (OR 1.07, 95% confidence interval [CI], 1.01-1.14), newborn trauma (OR 1.06, 95% CI, 1.03-1.10), vaginal deliveries without instrumentation (OR 1.03, 95% CI, 1.02-1.04), and obstetric trauma during cesarean sections (OR 1.36, 95% CI, 1.29-1.44). Complications related to anesthesia occurred less frequently on weekends (OR 0.86). Among patients undergoing vascular procedures, surgical complications occurred more frequently on weekends (OR 1.46, 95% CI, 1.16-1.85). Rates of complications are marginally higher on weekends than on weekdays for some surgical and newborn complications, but more significantly for obstetric trauma and for surgical complications involving patients undergoing vascular procedures. Hospitals should work toward increasing the robustness of safeguards on weekends.


Salivary antimicrobial protein responses during multistage ultramarathon competition conducted in hot environmental conditions.
Prolonged strenuous exercise is commonly reported to depress oral-respiratory immune status and increase the incidence of upper respiratory symptoms. This novel investigation aimed to determine the salivary antimicrobial responses and hydration status of ultraendurance runners (n = 23) during a 230-km multistage ultramarathon conducted in hot ambient conditions (32-40 °C). Body mass was measured and unstimulated saliva and venous blood samples were taken before and after each stage of the ultramarathon. Ad libitum fluid intake was permitted throughout each race day. Upper respiratory symptoms were monitored during and until 4 weeks after race completion. Samples were analyzed for salivary immunoglobulin A (IgA), lysozyme, α-amylase, and cortisol, as well as for plasma and saliva osmolality. Mean exercise-induced body mass loss over the 5 stages ranged from 1.3% to 2.4%. Overall mean pre- and post-stage plasma osmolality measurements in the ultraendurance runners were 279 ± 14 mOsmol·kg(-1) and 293 ± 15 mOsmol·kg(-1), respectively. Decreases in saliva flow rate (overall change 22%) and post-stage increases in saliva osmolality (36%) were observed in the ultraendurance runners during the ultramarathon. Reduced salivary IgA (32%) (p < 0.001 vs. pre-stage salivary IgA), enhanced salivary α-amylase (187%) (p < 0.001 vs. pre-stage salivary α-amylase), and no change in salivary lysozyme secretion rates were observed in the ultraendurance runners throughout the ultramarathon. Only 1 ultraendurance runner reported upper respiratory symptoms during and 1 month after competition. Observed depressions in salivary IgA secretion rates were offset by favourable increases in salivary α-amylase and unchanged lysozyme responses in the majority of runners during the competition. Ensuring euhydration throughout a multistage ultramarathon competition in the heat may play a role in protecting the upper respiratory tract.


Diagnostic accuracy of panoramic radiography and MRI for detecting signs of TMJ degenerative joint disease.
The objective of this study was to determine the diagnostic accuracy of panoramic radiography and magnetic resonance imaging (MRI) for detection of signs of temporomandibular joint (TMJ) degenerative joint disease (DJD). Panoramic radiography and bilateral MRI and computed tomography (CT) of the TMJs were performed for 705 subjects. Three calibrated board-certified radiologists who were blinded to the clinical findings interpreted all images. The diagnoses of DJD established using the panoramic radiographs and MRIs were compared to the reference standard diagnoses derived from the CTs. DJD was defined as the presence of at least 1 of the following 4 signs: a subcortical cyst, surface erosion, osteophyte formation, or generalized sclerosis. The target values for sensitivity and specificity were 70% or greater and 95% or greater, respectively. Compared to the reference standard CTs, the panoramic radiographs had the following sensitivity and specificity values: subcortical cysts, 14% and 100%, respectively; erosion, 20% and 100%, respectively; osteophytes, 12% and 100%, respectively; and sclerosis, 33% and 100%, respectively. The MRIs achieved the following sensitivity and specificity values: subcortical cysts, 32% and 100% respectively; erosion, 35% and 99% respectively; osteophytes, 71% and 98%, respectively; and sclerosis, 50% and 100%, respectively. The radiologists' interexaminer reliability was slight (κ = 0.16) when using panoramic radiographs, moderate (κ = 0.47) when using MRIs, and substantial when using CTs (κ = 0.71) for diagnosis of signs of DJD. Panoramic radiographs and MRIs had below-target sensitivity but above-target specificity in detecting all CT-depicted signs of DJD with the exception of osteophytes, for which MRIs demonstrated adequate diagnostic accuracy. Use of CT for diagnosis of TMJ DJD is recommended to avoid the false-negative findings that can occur if panoramic radiographs and MRIs are used.


Antenatal management and outcomes of gastroschisis in the U.K.
The birth prevalence of gastroschisis is increasing worldwide, yet little evidence exists concerning the optimal monitoring strategies after diagnosis. The aim of this study was to describe the U.K. prevalence, antenatal management and outcomes of affected pregnancies. Cases were identified throughout the U.K. between October 2006 and September 2007, using three different sources. The overall birth prevalence of gastroschisis was 4.2 cases per 10, 000 total births (95% CI 3.6-4.8). Infants were variably monitored with growth scans (90%), umbilical artery Doppler ultrasound (85%), cardiotocography (65%) and biophysical profile (27%). Bowel measurements were undertaken for only 113 infants (52%). Eighty-nine women (43%) were induced and 63 (31%) laboured spontaneously. Eleven women (5%) had an elective caesarean delivery where the sole indication was fetal gastroschisis. The variability in management and paucity of evidence on antenatal monitoring approaches suggests there may be a place for randomised trials of fetal surveillance strategies in order to develop the evidence to improve outcomes for the at-risk fetus with gastroschisis. This study suggests that case ascertainment by regional congenital anomaly registers is high; extension of the coverage of these registers to the entire cohort of U.K. births would facilitate ongoing surveillance and research.


Multi-crease Self-folding by Global Heating.
This study demonstrates a new approach to autonomous folding for the body of a 3D robot from a 2D sheet, using heat. We approach this challenge by folding a 0.27-mm sheetlike material into a structure. We utilize the thermal deformation of a contractive sheet sandwiched by rigid structural layers. During this baking process, the heat applied on the entire sheet induces contraction of the contracting layer and thus forms an instructed bend in the sheet. To attain the targeted folding angles, the V-fold spans method is used. The targeted angle θout can be kinematically encoded into crease geometry. The realization of this angle in the folded structure can be approximately controlled by a contraction angle θin. The process is non-reversible, is reliable, and is relatively fast. Our method can be applied simultaneously to all the folds in multi-crease origami structures. We demonstrate the use of this method to create a lightweight mobile robot.


Two-stage vs single-stage management for concomitant gallstones and common bile duct stones.
To evaluate the safety and effectiveness of two-stage vs single-stage management for concomitant gallstones and common bile duct stones. Four databases, including PubMed, Embase, the Cochrane Central Register of Controlled Trials and the Science Citation Index up to September 2011, were searched to identify all randomized controlled trials (RCTs). Data were extracted from the studies by two independent reviewers. The primary outcomes were stone clearance from the common bile duct, postoperative morbidity and mortality. The secondary outcomes were conversion to other procedures, number of procedures per patient, length of hospital stay, total operative time, hospitalization charges, patient acceptance and quality of life scores. Seven eligible RCTs [five trials (n = 621) comparing preoperative endoscopic retrograde cholangiopancreatography (ERCP)/endoscopic sphincterotomy (EST) + laparoscopic cholecystectomy (LC) with LC + laparoscopic common bile duct exploration (LCBDE); two trials (n = 166) comparing postoperative ERCP/EST + LC with LC + LCBDE], composed of 787 patients in total, were included in the final analysis. The meta-analysis detected no statistically significant difference between the two groups in stone clearance from the common bile duct [risk ratios (RR) = -0.10, 95% confidence intervals (CI): -0.24 to 0.04, P = 0.17], postoperative morbidity (RR = 0.79, 95% CI: 0.58 to 1.10, P = 0.16), mortality (RR = 2.19, 95% CI: 0.33 to 14.67, P = 0.42), conversion to other procedures (RR = 1.21, 95% CI: 0.54 to 2.70, P = 0.39), length of hospital stay (MD = 0.99, 95% CI: -1.59 to 3.57, P = 0.45), total operative time (MD = 12.14, 95% CI: -1.83 to 26.10, P = 0.09). Two-stage (LC + ERCP/EST) management clearly required more procedures per patient than single-stage (LC + LCBDE) management. Single-stage management is equivalent to two-stage management but requires fewer procedures. However, patient's condition, operator's expertise and local resources should be taken into account in making treatment decisions.


Supercharged reverse-flow sural flap: a new modification increasing the reliability of the flap.
The management of soft-tissue defects in the lower third of the leg and foot presents a considerable problem because of composite tissue defects, inadequate and tight local tissue for reconstruction, and poor circulation. Although the reverse sural flap is frequently preferred and is fairly reliable, some complications arising from the circulation may be encountered in large flaps or in diabetic patients. In the present study, we developed a new modification by supercharging the sural flap to reduce venous congestion and edema and to increase the reliability of the flap. We treated 3 patients (2 men and 1 woman) by utilizing a supercharged reverse sural flap. All flaps survived and healed uneventfully. We also suggest a new and more distinctive classification for supercharging and turbocharging, which defines the vessel type to be anastomosed and the relationship of the vessel to be anastomosed with the main vessel to the flap.


An exploratory study of environmental and medical factors potentially related to childhood cancer.
To determine whether a general-purpose epidemiologic questionnaire can be used in childhood cancer hospitals to identify associations between environmental factors and the major types of childhood cancer, we report the results of the analysis of the data obtained from such a questionnaire. On admission to St. Jude Children's Research Hospital in Memphis, Tennessee, between 1979 and 1986 a questionnaire was administered to 1,270 mothers of patients diagnosed with childhood cancer. Approximately one-half of the children had acute leukemias (n = 629); the remainder had lymphomas (n = 237) or solid tumors (n = 404). Responses to questions regarding the patients' and parents' environmental and medical histories were compared across nine diagnostic categories. Only 5 of 232 variables remained nominally statistically significant (P less than 0.05) after adjusting for confounding by patient or maternal age, year of birth or diagnosis, patient's race, and social class. The variables identified were length of time the patient was breast-fed (chi 2 = 16.1, P = 0.04); having a garden with fertilizers, herbicides, and pesticides (chi 2 = 17.2, P = 0.03); maternal use of sex hormones during the year before the patient's birth (chi 2 = 18.2, P = 0.02); maternal cigarette consumption (chi 2 = 18.0, P = 0.02); and patient contact with persons with cancer (chi 2 = 20.7, P = 0.01). Despite the large number of patients studied, we identified fewer significant variables than would be expected, on the average, under the null hypothesis. We conclude that the data obtained from a general-purpose epidemiologic questionnaire do not provide a useful overview of the association between exposure to environmental factors and several types of childhood cancer.


Monitoring the long-term molecular epidemiology of the pneumococcus and detection of potential 'vaccine escape' strains.
While the pneumococcal protein conjugate vaccines reduce the incidence in invasive pneumococcal disease (IPD), serotype replacement remains a major concern. Thus, serotype-independent protection with vaccines targeting virulence genes, such as PspA, have been pursued. PspA is comprised of diverse clades that arose through recombination. Therefore, multi-locus sequence typing (MLST)-defined clones could conceivably include strains from multiple PspA clades. As a result, a method is needed which can both monitor the long-term epidemiology of the pneumococcus among a large number of isolates, and analyze vaccine-candidate genes, such as pspA, for mutations and recombination events that could result in 'vaccine escape' strains. We developed a resequencing array consisting of five conserved and six variable genes to characterize 72 pneumococcal strains. The phylogenetic analysis of the 11 concatenated genes was performed with the MrBayes program, the single nucleotide polymorphism (SNP) analysis with the DNA Sequence Polymorphism program (DnaSP), and the recombination event analysis with the recombination detection package (RDP). The phylogenetic analysis correlated with MLST, and identified clonal strains with unique PspA clades. The DnaSP analysis correlated with the serotype-specific diversity detected using MLST. Serotypes associated with more than one ST complex had a larger degree of sequence polymorphism than a serotype associated with one ST complex. The RDP analysis confirmed the high frequency of recombination events in the pspA gene. The phylogenetic tree correlated with MLST, and detected multiple PspA clades among clonal strains. The genetic diversity of the strains and the frequency of recombination events in the mosaic gene, pspA were accurately assessed using the DnaSP and RDP programs, respectively. These data provide proof-of-concept that resequencing arrays could play an important role within research and clinical laboratories in both monitoring the molecular epidemiology of the pneumococcus and detecting 'vaccine escape' strains among vaccine-candidate genes.


Factors influencing long-term home care utilization by the older population: implications for targeting.
This research was designed to explore factors that affect the choice of long-term care modalities in the older population and to discuss the appropriate target population of home health care services within the entire long-term care system. The study subjects' activities of daily living limitations, cognitive status, and sociodemograhic data at the time of admission were obtained from retrospective chart reviews. The sample included 134 older subjects who were receiving long-term care from a Long-Term Home Health Care Program or a nursing home in New York City. The results indicated that Long-Term Home Health Care Program use by older persons was characterized by a higher rate of being admitted from private homes, less cognitive impairments, less limitations in activities of daily living, and younger age than older patients who were nursing home residents. Consequently, in the choice of different care modalities, health-related factors of the older population were found to be more important predictors than sociodemographic characteristics or support system. The implication to both nurses and researchers is the development of eligibility criteria that captures the unique characteristics of disabled older persons in each of the different long-term care programs to serve them better in a cost-effective manner.


Predictions of the Contribution of HCN Half-Maximal Activation Potential Heterogeneity to Variability in Intrinsic Adaptation of Spiral Ganglion Neurons.
Spiral ganglion neurons (SGNs) exhibit a wide range in their strength of intrinsic adaptation on a timescale of 10s to 100s of milliseconds in response to electrical stimulation from a cochlear implant (CI). The purpose of this study was to determine how much of that variability could be caused by the heterogeneity in half-maximal activation potentials of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, which are known to produce intrinsic adaptation. In this study, a computational membrane model of cat type I SGN was developed based on the Hodgkin-Huxley model plus HCN and low-threshold potassium (KLT) conductances in which the half-maximal activation potential of the HCN channel was varied and the response of the SGN to pulse train and paired-pulse stimulation was simulated. Physiologically plausible variation of HCN half-maximal activation potentials could indeed determine the range of adaptation on the timescale of 10s to 100s of milliseconds and recovery from adaptation seen in the physiological data while maintaining refractoriness within physiological bounds. This computational model demonstrates that HCN channels may play an important role in regulating the degree of adaptation in response to pulse train stimulation and therefore contribute to variable constraints on acoustic information coding by CIs. This finding has broad implications for CI stimulation paradigms in that cell-to-cell variation of HCN channel properties are likely to significantly alter SGN excitability and therefore auditory perception.


Live-cell photoactivated localization microscopy of nanoscale adhesion dynamics.
We demonstrate live-cell super-resolution imaging using photoactivated localization microscopy (PALM). The use of photon-tolerant cell lines in combination with the high resolution and molecular sensitivity of PALM permitted us to investigate the nanoscale dynamics within individual adhesion complexes (ACs) in living cells under physiological conditions for as long as 25 min, with half of the time spent collecting the PALM images at spatial resolutions down to approximately 60 nm and frame rates as short as 25 s. We visualized the formation of ACs and measured the fractional gain and loss of individual paxillin molecules as each AC evolved. By allowing observation of a wide variety of nanoscale dynamics, live-cell PALM provides insights into molecular assembly during the initiation, maturation and dissolution of cellular processes.


Asymmetrical distribution of non-conserved regulatory sequences at PHOX2B is reflected at the ENCODE loci and illuminates a possible genome-wide trend.
Transcriptional regulatory elements are central to development and interspecific phenotypic variation. Current regulatory element prediction tools rely heavily upon conservation for prediction of putative elements. Recent in vitro observations from the ENCODE project combined with in vivo analyses at the zebrafish phox2b locus suggests that a significant fraction of regulatory elements may fall below commonly applied metrics of conservation. We propose to explore these observations in vivo at the human PHOX2B locus, and also evaluate the potential evidence for genome-wide applicability of these observations through a novel analysis of extant data. Transposon-based transgenic analysis utilizing a tiling path proximal to human PHOX2B in zebrafish recapitulates the observations at the zebrafish phox2b locus of both conserved and non-conserved regulatory elements. Analysis of human sequences conserved with previously identified zebrafish phox2b regulatory elements demonstrates that the orthologous sequences exhibit overlapping regulatory control. Additionally, analysis of non-conserved sequences scattered over 135 kb 5' to PHOX2B, provides evidence of non-conserved regulatory elements positively biased with close proximity to the gene. Furthermore, we provide a novel analysis of data from the ENCODE project, finding a non-uniform distribution of regulatory elements consistent with our in vivo observations at PHOX2B. These observations remain largely unchanged when one accounts for the sequence repeat content of the assayed intervals, when the intervals are sub-classified by biological role (developmental versus non-developmental), or by gene density (gene desert versus non-gene desert). While regulatory elements frequently display evidence of evolutionary conservation, a fraction appears to be undetected by current metrics of conservation. In vivo observations at the PHOX2B locus, supported by our analyses of in vitro data from the ENCODE project, suggest that the risk of excluding non-conserved sequences in a search for regulatory elements may decrease as distance from the gene increases. Our data combined with the ENCODE data suggests that this may represent a genome wide trend.


Habits predict physical activity on days when intentions are weak.
Physical activity is regulated by controlled processes, such as intentions, and automatic processes, such as habits. Intentions relate to physical activity more strongly for people with weak habits than for people with strong habits, but people's intentions vary day by day. Physical activity may be regulated by habits unless daily physical activity intentions are strong. University students (N = 128) self-reported their physical activity habit strength and subsequently self-reported daily physical activity intentions and wore an accelerometer for 14 days. On days when people had intentions that were weaker than typical for them, habit strength was positively related to physical activity, but on days when people had typical or stronger intentions than was typical for them, habit strength was unrelated to daily physical activity. Efforts to promote physical activity may need to account for habits and the dynamics of intentions.


Carotid artery stenting with distal protection using the carotid wallstent and filterwire neuroprotection: single-center experience of 380 cases with midterm outcomes.
Emerging data have supported the clinical efficacy of carotid artery stenting (CAS) in stroke prevention in high-risk surgical patients. This study was performed to evaluate the midterm clinical outcome of CAS using the Carotid Wallstent and FilterWire distal protection (both Boston Scientific, Natick, MA) at an academic institution. Risk factors for in-stent restenosis (ISR) were also analyzed. Clinical variables and treatment outcome of high-risk patients who underwent Carotid Wallstent placement with FilterWire EX/EZ neuroprotection were analyzed during a recent 54-month period. Three hundred eighty CAS procedures were performed in 354 patients. Technical success was achieved in 372 cases (98%), and symptomatic lesions existed in 85 (24%) patients. No patient experienced periprocedural mortality or neuroprotective device-related complication. The 30-day stroke and death rate was 2.7%, and the overall complication rate was 6.9%. The overall major or fatal stroke rates in symptomatic and asymptomatic patients were 4.6% and 1.3%, respectively (not significant). The overall stroke and death rates between the symptomatic and asymptomatic groups were 5.8% and 2.4%, respectively (not significant). The median follow-up period was 29 months (range 1-53 months). With Kaplan-Meier analysis, the rates of freedom from 60% or greater ISR after CAS procedures at 12, 24, 36, and 48 months were 97%, 94%, 92%, and 90%, respectively. The rates of freedom from all fatal and nonfatal strokes at 12, 24, 36, and 48 months were 97%, 91%, 89%, and 85%, respectively. Multivariable analysis of significant univariate predictors identified that postendarterectomy stenosis (odds ratio [OR] 3.98, p = .02) and multiple stent placement (OR 3.68, p = .03) were independent predictors of ISR. Our study yielded favorable short-term and midterm clinical results using Carotid Wallstent with FilterWire neuroprotection. Late follow-up results showed low rates of fatal and nonfatal stroke and favorable ISR rates compared with other carotid stent trials. Postendarterectomy and multiple stent placement were associated with subsequent ISR.


Endoscopic management of familial adenomatous polyposis in patients refusing colectomy.
Colectomy protects against colorectal cancer in familial adenomatous polyposis (FAP); however, some patients with FAP refuse surgery. The aim of this study was to evaluate the feasibility and safety of endoscopic management of these patients. A retrospective review of medical records was performed to identify adult patients with FAP who refused colectomy and were managed by repeated colonoscopies to remove numerous polyps between 2001 and 2012. Polyps were removed by hot snare polypectomy or endoscopic mucosal resection. Polyps of < 10 mm in size and without endoscopic features suggesting cancer were discarded without histological examination; the remaining polyps were examined histologically. Of the 95 eligible patients, five (5.3 %) were excluded. The remaining 90 patients (median age at first visit 29 years [range 16 - 68 years]; 46 males) were followed for a median of 5.1 years (interquartile range [IQR] 3.3 - 7.3 years). During this period, a total of 55 701 polyps were resected without adverse events such as bleeding or perforation. The median numbers of endoscopic treatment sessions and polyps removed per patient were 8 (IQR 6 - 11) and 475 (IQR 211 - 945), respectively. Five patients had noninvasive carcinoma (Category 4.2 according to the revised Vienna classification), detected within 10 months from the start of the follow-up period. All of these patients were treated endoscopically, without signs of recurrence during a median follow-up of 4.3 years (IQR 2.0 - 7.1 years). No invasive colorectal cancer was recorded during the study period. Two patients (2.2 %) underwent colectomy because the polyposis phenotype had changed to dense polyposis. Endoscopic management of FAP is feasible and safe in the medium term.


Is the Treatment of Constipation Can Relieve the Migraine Symptoms? A Randomized Clinical Trial Study.
Many patients presenting with migraine also complain of constipation. The relationship between these two symptoms has not been explored yet in detail. This study, therefore, was carried out to investigate the effect of treatment of constipation with lactulose on the improvement of migraine headache in patients who referred to neurology clinics in Arak. A total of 50 patients with migraine were selected based on the Headache International Society (HIS) index and the Rome Foundation is an independent not for profit 501(c) 3 organization that provides support for activities designed to create scientific data and educational information to assist in the diagnosis and treatment of functional gastrointestinal disorders (FGIDs) (ROME III) scale so as to diagnose their migraine and constipation. The patients were randomly divided into an experimental group and a control group. A 15 cc daily of lactulose syrup was prescribed to the experimental group with the antimigraine drugs (10-mg nortriptyline and 10-mg propranonol daily). In contrast, only the standard treatment for migraine was prescribed for the control group. The severity of disability was assessed based on the severity of migraine-induced disability (MIDAS) questionnaire. Having collected the data, the data analysis was carried out using Statistical Package for the Social Sciences (SPSS) (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) statistical t-tests, and repeated measures test. The results of the independent sample t-test showed no significant difference between the control and intervention group's main variables of the research before the intervention (P < 0.05). On the contrary, the results of the repeated measures test indicated that the mean scores ‑of the severity of disability and the severity of migraine pain between the measurement times were significantly different for the intervention and control groups, in a way that after one and/or two months of using lactulose syrup, the severity of disability and pain in the intervention group was lower than those of the control group (P < 0.001). Short-term follow-up of this study showed that lactulose syrup could remove the constipation with no significant side effects--can be used as an adjunct for the treatment of patients with migraine. However, future studies suggested for long-term consequences of constipation control.


Amniotic fluid-derived mesenchymal stem cells lead to bone differentiation when cocultured with dental pulp stem cells.
Mesenchymal stem cells are present in many tissues of the human body, including amniotic fluid (AF) and dental pulp (DP). Stem cells of both AF and DP give rise to a variety of differentiated cells. In our experience, DP stem cells (DPSCs) display a high capacity to produce bone. Therefore, our aim was to investigate if AF-derived stem cells (AFSCs) were able to undergo bone differentiation in the presence of DPSCs. AFSCs were seeded under three different conditions: (i) cocultured with DPSCs previously differentiated into osteoblasts; (ii) cultured in the conditioned medium of osteoblast-differentiated DPSCs; (iii) cultured in the osteogenic medium supplemented with vascular endothelial growth factor and bone morphogenetic protein-2 (BMP-2). Results showed that AFSCs were positive for mesenchymal markers, and expressed high levels of Tra1-60, Tra1-80, BMPR1, BMPR2, and BMP-2. In contrast, AFSCs were negative for epithelial and hematopoietic/endothelial markers. When AFSCs were cocultured with DPSCs-derived osteoblasts, they differentiated into osteoblasts. A similar effect was observed when AFSCs were cultured in the presence of a conditioned medium originated from DPSCs. We found that osteoblasts derived from DPSCs released large amounts of BMP-2 and vascular endothelial growth factor into the culture medium and that those morphogens significantly upregulate RUNX-2 gene, stimulating osteogenesis. This study highlights the mechanisms of osteogenesis and strongly suggests that the combination of AFSCs with DPSCs may provide a rich source of soluble proteins useful for bone engineering purposes.


Albiglutide: a unique GLP-1 receptor agonist.
Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.


Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective.
Tamoxifen has been the gold standard adjuvant therapy for the treatment of postmenopausal women with hormone-receptor-positive (HR+) early breast cancer for many years. Tamoxifen treatment is limited to 5 years because of the development of de novo and acquired resistance, and an ongoing risk of adverse events, including endometrial cancer, thromboembolic events, and gynecological symptoms with long-term use. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole, and exemestane, are displacing tamoxifen as the first-choice therapy for HR+ early breast cancer, and are now recommended as the preferred therapy by national and international guidelines. Recent randomized trials have demonstrated that the AIs are more effective than tamoxifen in preventing disease recurrence when used in substitution and sequential strategies in the early adjuvant setting, and letrozole has been shown to be more effective than placebo in the extended adjuvant setting (after 5 years of tamoxifen therapy). Trial safety data show that the overall tolerability of AIs is similar to that of tamoxifen, with adverse events being predictably characteristic of estrogen deprivation; however, some important differences in adverse event profiles between tamoxifen and the AIs have been demonstrated. In addition to antiestrogenic effects, tamoxifen acts as an estrogen agonist in some tissues, which can lead to serious side effects not associated with the AIs, which prevent estrogen biosynthesis. A lower incidence of gynecological and thromboembolic events is observed in patients taking AIs, and fewer cases of endometrial cancer are seen compared with tamoxifen. Adverse events that are more frequent with adjuvant AI therapy compared with tamoxifen include arthralgia and myalgia, bone loss, and effects on the cardiovascular system and blood lipids. The effects of AIs on bone are predictable and may be easily managed, where necessary, with bisphosphonates. Studies examining the effects of AIs on the cardiovascular system and lipid profiles, including in the extended adjuvant setting, suggest that these adverse events may be due to the absence of a protective effect of tamoxifen rather than true AI toxicity. Further studies are required to determine the long-term safety of AI therapy in postmenopausal women with HR+ early breast cancer.


Coinfection with HIV and hepatitis C virus in 229 children and young adults living in Europe.
To characterize children, adolescents and young adults infected with HIV/hepatitis C virus (HCV) vertically or before age of 18 years and living in Europe regarding mode of acquisition, HCV genotype, clinical status and treatment. Retrospective, cross-sectional study using pooled data from 11 European paediatric HIV cohorts. Patients aged more than 18 months and less than 25 years, with HIV/HCV acquired vertically or in childhood, were included. Anonymized individual patient data were collected using a standard protocol and modified HIV Cohorts Data Exchange Protocol. Of 229 patients included, 142 (62%) had vertically acquired infection. Median age at last follow-up was 16.2 years. Most children had HCV genotype 1 (101/184, 55%) or 3 (57/184, 31%). One-fifth (46/214) had a previous AIDS diagnosis (data missing on prior AIDS diagnoses for 15). At their last clinic visit, 70% (145/208) had no/mild immunosuppression (Centers for Disease Control and Prevention stage 1), and 131 of 179 on antiretroviral therapy had undetectable HIV RNA (assay thresholds varied from <20 to <150 copies/ml). Overall, 42% (86/204) had hepatomegaly in the previous year, and 55% (116/213) had alanine aminotransferase more than 40 IU/l at their last test. Of 97 patients with transient elastography, 12 had results more than 9 kPa; this was associated with duration of HCV infection (P = 0.033), but not with CD4 cell count, antiretroviral therapy use or sex in univariable analysis. Of 17 patients with liver biopsies, six had bridging fibrosis and one had cirrhosis. Twenty-five (11%) had been treated successfully for HCV. The high proportion of patients with progressive liver disease underscores the need for close monitoring and earlier and more effective HCV treatment.


Around-the-World Relativistic Sagnac Experiment.
In 1971 Hafele and Keating carried portable atomic clocks east and then west around the world and verified the Sagnac effect, a special relativity effect attributable to the earth's rotation. In the study reported here observations of the effect were made by using electromagnetic signals instead of portable clocks to make clock comparisons. Global Positioning System satellites transmit signals that can be viewed simultaneously from remote stations on the earth; thus an around-the-world Sagnac experiment can be performed with electromagnetic signals. The effect is larger than that occurring when portable clocks are used. The average error over a 3-month experiment was only 5 nanoseconds.


A prospective, randomized trial of an emergency department observation unit for acute onset atrial fibrillation.
An emergency department (ED) observation unit protocol for the management of acute onset atrial fibrillation is compared with routine hospital admission and management. Adult patients presenting to the ED with atrial fibrillation of less than 48 hours' duration without hemodynamic instability or other comorbid conditions requiring hospitalization were enrolled. Participants were randomized to either ED observation unit care or routine inpatient care. The ED observation unit protocol included pulse rate control, cardiac monitoring, reassessment, and electrical cardioversion if atrial fibrillation persisted. Patients who reverted to sinus rhythm were discharged with a cardiology follow-up within 3 days, whereas those still in atrial fibrillation were admitted. All cases were followed up for 6 months and adverse events recorded. Of the 153 patients, 75 were randomized to the ED observation unit and 78 to routine inhospital care. Eighty-five percent of ED observation unit patients converted to sinus rhythm versus 73% in the routine care group (difference 12%; 95% confidence interval [CI] -1% to 25%]; P=.06). The median length of stay was 10.1 versus 25.2 hours (difference 15.1 hours; 95% CI 11.2 to 19.6; P<.001) for ED observation unit and inhospital care respectively. Nine ED observation unit patients required inpatient admission. Eleven percent of the ED observation unit group had recurrence of atrial fibrillation during follow-up versus 10% of the routine inpatient care group (difference 1%; 95% CI -9% to 11%; P=.93). There was no significant difference between the groups in the frequency of hospitalization or the number of tests, and the number of adverse events during follow-up was similar in the 2 groups. An ED observation unit protocol that includes electrical cardioversion is a feasible alternative to routine hospital admission for acute onset of atrial fibrillation and results in a shorter initial length of stay.


Drosophila immunity: a large-scale in vivo RNAi screen identifies five serine proteases required for Toll activation.
Unlike mammalian Toll-like Receptors, the Drosophila Toll receptor does not interact directly with microbial determinants but is rather activated upon binding a cleaved form of the cytokine-like molecule Spatzle (Spz). During the immune response, Spz is thought to be processed by secreted serine proteases (SPs) present in the hemolymph that are activated by the recognition of gram-positive bacteria or fungi . In the present study, we have used an in vivo RNAi strategy to inactivate 75 distinct Drosophila SP genes. We then screened this collection for SPs regulating the activation of the Toll pathway by gram-positive bacteria. Here, we report the identification of five novel SPs that function in an extracellular pathway linking the recognition proteins GNBP1 and PGRP-SA to Spz. Interestingly, four of these genes are also required for Toll activation by fungi, while one is specifically associated with signaling in response to gram-positive bacterial infections. These results demonstrate the existence of a common cascade of SPs upstream of Spz, integrating signals sent by various secreted recognition molecules via more specialized SPs.


An association between ethnic diversity and HIV prevalence in sub-Saharan Africa.
This paper investigates whether ethnic diversity at the Demographic and Health Surveys (DHS) cluster level predicts HIV serostatus in three sub-Saharan African countries (Kenya, Malawi and Zambia), using DHS household survey and HIV biomarker data for men and women aged 15–59 collected since 2006. The analysis relates a binary dependent variable (HIV positive serostatus) and a weighted aggregate predictor variable representing the number of different ethnic groups within a DHS Statistical Enumeration Area (SEA) or cluster, which roughly corresponds to a neighbourhood. Multilevel logistic regression is used to predict HIV prevalence within each SEA, controlling for known demographic, social and behavioural predictors of HIV serostatus. The key finding was that the cluster-level ethnic diversity measure was a significant predictor of HIV serostatus in Malawi and Zambia but not in Kenya. Additional results reflected the heterogeneity of the epidemics: male gender, marriage (Kenya), number of extramarital partners in the past year (Kenya and Malawi, but probably confounded with younger age) and Muslim religion (Zambia) were associated with lower odds of positive HIV serostatus. Condom use at last intercourse (a spurious result probably reflecting endogeneity), STD in the past year, number of lifetime sexual partners, age (Malawi and Zambia), education (Zambia), urban residence (Malawi and Zambia) and employment (Kenya and Malawi) were associated with higher odds of positive serostatus. Future studies might continue to employ multilevel models and incorporate additional, more robust, controls for individual behavioural risk factors and for higher-level social and economic factors, in order to verify and further clarify the association between neighbourhood ethnic diversity and HIV serostatus.


The role of serotonin in the canine secretory response to cholera toxin in vivo.
This study was initiated to evaluate the role of serotonin in cholera toxin-induced jejunal secretion of water and electrolytes. Chronic Thiry-Vella loops, constructed in six dogs, were perfused with an isosmotic neutral perfusate containing [14C]polyethylene glycol as the recovery marker. Fluxes of water, sodium, chloride and potassium were calculated and immunoreactive serotonin levels were measured in blood and effluent perfusates. Intraluminal application of 20 micrograms of cholera toxin induced secretion; fluxes of water (basal, 32.3 +/- 11.1; 6 hr, -541 +/- 35 microliter/min), sodium (basal, 9.0 +/- 2.8; 6 hr, -78.3 +/- 5.6 microEq/min), chloride (basal, 3.8 +/- 1.5; 6 hr, -65.7 +/- 4.0 muEq/min) and potassium (basal, 0.10 +/- 0.08; 6 hr, -2.80 +/- 0.18 muEq/min) were all significantly different from basal. Serum electrolytes remained normal, except that potassium fell from 4.9 +/- 0.5 to 3.9 +/- 0.2 mEq/l. Although circulating serotonin levels did not change from base line (180.9 +/- 29.3 ng/ml), effluent concentrations increased significantly from 68.2 +/- 4.6 to 81.1 +/- 5.0 ng/ml (at 3 hr) and jejunal outputs increased from 136.6 +/- 10.2 to 205.1 +/- 10.1 ng/min (at 6 hr). In a separate set of experiments, verapamil was infused i.v. (12.5 micrograms/kg/min) during the 4th hr in four dogs exposed to cholera toxin. The lower dose of toxin (5 micrograms) induced secretion which was unaffected by the calcium channel blocker. In another series of studies, ketanserin (a 5-HT2 receptor blocker) was infused i.v. at 33 micrograms/kg/min during the 4th hr in four additional dogs exposed to the lower dose of cholera toxin. This potent serotonin antagonist failed to inhibit cholera toxin-induced jejunal secretion.(ABSTRACT TRUNCATED AT 250 WORDS)


Bucky ball organizes germ plasm assembly in zebrafish.
In many animals, gamete formation during embryogenesis is specified by maternal cytoplasmic determinants termed germ plasm. During oogenesis, germ plasm forms a distinct cellular structure such as pole plasm in Drosophila or the Balbiani body, an aggregate of organelles also found in mammals. However, in vertebrates, the key regulators of germ plasm assembly are largely unknown. Here, we show that, at the beginning of zebrafish oogenesis, the germ plasm defect in bucky ball (buc) mutants precedes the loss of polarity, indicating that Buc primarily controls Balbiani body formation. Moreover, we molecularly identify the buc gene, which is exclusively expressed in the ovary with a novel, dynamic mRNA localization pattern first detectable within the Balbiani body. We find that a Buc-GFP fusion localizes to the Balbiani body during oogenesis and with the germ plasm during early embryogenesis, consistent with a role in germ plasm formation. Interestingly, overexpression of buc seems to generate ectopic germ cells in the zebrafish embryo. Because we discovered buc homologs in many vertebrate genomes, including mammals, these results identify buc as the first gene necessary and sufficient for germ plasm organization in vertebrates.


Cryptosporidium infections in inbred strains of mice.
Cryptosporidium, a protozoan parasite of man and animals, is an important etiological agent of diarrhea throughout the world, particularly in children and immunocompromised individuals such as AIDS patients. Unfortunately, because of the lack of both in vivo laboratory models and reliable in vitro parasite culture systems, virtually nothing is known about the immunological events occurring during disease. In order to identify reliable animal models for infection, we studied C. parvum infections in 19 different strains of mice representing 12 H-2 haplotypes: A/J, AKR/J, B10.D2/J, B10.M/J, C3H/HeJ, C57BL/65, C57BL/6J-bgJ, CBA/NJ, DBA/1J, DBA/2J, HRS/J, HTG/J, NZB/B1NJ, NZW/J, P/J, RIII/J, SJL/J, SWR/J, and WB/ReJ, and in one gerbil: Meriones unguiculatus. Fecal samples and histological sections of the intestine taken on day 7 post-Cryptosporidium inoculation indicated that only the beige mouse (C57BL/6J-bgJ) harbored significant numbers of parasites compared to the other strains. The numbers of parasites harbored in these NK cell-deficient beige mice were, however, considerably lower than those seen in neonatal mice. Adult inbred mouse strains susceptible to Cryptosporidium infections are discussed.


Comparison of anterior cingulate vs. insular cortex as targets for real-time fMRI regulation during pain stimulation.
Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback allows learning voluntary control over specific brain areas by means of operant conditioning and has been shown to decrease pain perception. To further increase the effect of rt-fMRI neurofeedback on pain, we directly compared two different target regions of the pain network, notably the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC). Participants for this prospective study were randomly assigned to two age-matched groups of 14 participants each (7 females per group) for AIC and ACC feedback. First, a functional localizer using block-design heat pain stimulation was performed to define the pain-sensitive target region within the AIC or ACC. Second, subjects were asked to down-regulate the BOLD activation in four neurofeedback runs during identical pain stimulation. Data analysis included task-related and functional connectivity analysis. At the behavioral level, pain ratings significantly decreased during feedback vs. localizer runs, but there was no difference between AIC and ACC groups. Concerning neuroimaging, ACC and AIC showed consistent involvement of the caudate nucleus for subjects that learned down-regulation (17/28) in both task-related and functional connectivity analysis. The functional connectivity toward the caudate nucleus is stronger for the ACC while the AIC is more heavily connected to the ventrolateral prefrontal cortex. Consequently, the ACC and AIC are suitable targets for real-time fMRI neurofeedback during pain perception as they both affect the caudate nucleus, although functional connectivity indicates that the direct connection seems to be stronger with the ACC. Additionally, the caudate, an important area involved in pain perception and suppression, could be a good rt-fMRI target itself. Future studies are needed to identify parameters characterizing successful regulators and to assess the effect of repeated rt-fMRI neurofeedback on pain perception.


Iron and zinc status in multiple sclerosis patients with pressure sores.
Measurements of weighted dietary intakes and plasma determinations of albumin, iron, zinc, ascorbic acid and TIBC were carried out on twenty female multiple sclerosis patients in a long-stay hospital for disabled people. The group included ten patients with a recent history of pressure sores, closely matched with ten patients without pressure sores. Mean daily intake of carbohydrate was found to be higher in the non-pressure sore group whilst intake of zinc was lower in this group. Intakes of all other nutrients were comparable between the two groups. For both groups, intakes of energy, folate, vitamin D, iron and zinc were less than recommended values. Mean plasma levels of albumin and iron were towards the lower limit of the normal range, whilst that for zinc was considerably less than the normal range. Plasma TIBC was slightly above the normal range. Levels of plasma iron and zinc were significantly lower in the pressure sore group. The data indicate that severely disabled hospitalized patients with multiple sclerosis may be at risk of poor nutritional status. The results suggest that in the presence of pressure sores, there are increased requirements for specific nutrients, notably zinc and iron. Consideration is given to the possible value of supplementation of these individuals.


Comparative efficacy and safety of intravenous or subcutaneous belimumab in combination with standard therapy in patients with active systemic lupus erythematosus: a Bayesian network meta-analysis of randomized controlled trials.
Objective In this study, we aimed to assess the relative efficacy and safety of intravenous (IV) or subcutaneous (SC) belimumab compared with those of placebo in patients with active systemic lupus erythematosus (SLE). Methods We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of belimumab 1 mg/kg and 10 mg/kg IV administration, and belimumab 200 mg SC injection, and placebo in patients with active SLE despite having received standard therapy. Results Five RCTs (3460 patients) met the inclusion criteria. The SLE Responder Index (SRI) response rate at week 52 was significantly higher in the belimumab 10 mg/kg group than in the placebo group (OR 2.63, 95% CrI 2.14-3.23). Similarly, the SRI response rates were significantly higher in the belimumab 1 mg/kg, and belimumab 200 mg SC groups than in the placebo group (OR 2.42, 95% CrI 1.90-3.09; OR 1.71, 95% CrI 1.27-2.29). Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that belimumab 10 mg/kg had the highest probability of being the best treatment for achieving the SRI response (SUCRA = 0.9174), followed by belimumab 1 mg/kg (SUCRA = 0.7338), belimumab 200 mg SC (SUCRA = 0.3487), and placebo (SUCRA = 0.0000). However, a sensitivity test by omitting one outlier study showing low SRI response rate compared with the other three studies (11% vs. 33%, 40%, 48%) showed that belimumab 200 mg SC and belimumab 10 mg/kg had the highest probability of being the best treatment for achieving the SRI response (SUCRA = 0.7903, SUCRA = 0.7456), followed by belimumab 1 mg/kg, and placebo. The number of serious adverse events (SAEs) did not differ significantly among the four treatment options. Conclusions Belimumab at 1 and 10 mg/kg IV and belimumab 200 mg SC in combination with standard therapy was an efficacious intervention for active SLE, and was not associated with a significant risk of SAEs.


Group size, survival and surprisingly short lifespan in socially foraging bats.
The relationships between group size, survival, and longevity vary greatly among social species. Depending on demographic and ecological circumstances, there are both positive and negative effects of group size variation on individual survival and longevity. For socially foraging species in particular there may be an optimal group size that predicts maximum individual survival that is directly related to the potential for information transfer, social coordination, and costs of conspecific interference. Our aim was to investigate this central aspect of evolutionary ecology by focusing on a socially foraging bat, Molossus molossus. This species optimizes foraging success by eavesdropping on the echolocation calls of group members to locate ephemeral food patches. We expected to find the highest survival and longest lifespans in small groups as a consequence of a trade-off between benefits of information transfer on ephemeral resources and costs of conspecific interference. In a mark-recapture study of 14 mixed-sex M. molossus social groups in Gamboa, Panama, spanning several years we found the expected relatively small and intermediate, but stable groups, with a mean size of 9.6 ± 6.7 adults and juveniles. We estimated survival proxies using Cox proportional hazard models and multistate-mark recapture models generated with recapture data as well as automated monitoring of roost entrances in a subset of the groups. Median survival of females was very short with 1.8 years and a maximum estimated longevity of 5.6 years. Contrary to our expectations, we found no relationship between variation in group size and survival, a result similar to few other studies. Strong selection towards small group size may result from psychoacoustic and cognitive constraints related to acoustic interference in social foraging and the complexity of coordinated flight. The short lifespans were unexpected and may result from life at the energetic edge due to a highly specialized diet. The absence of a relationship between group size and survival may reflect a similar but optimized survival within the selected range of group sizes. We expect the pattern of small group sizes will be consistent in future research on species dependent on social information transfer about ephemeral resources.


Ingestion of broccoli sprouts does not improve endothelial function in humans with hypertension.
Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension. 40 hypertensive individuals without diabetes and with normal levels of cholesterol were examined. The participants were randomized either to ingest 10 g dried broccoli sprouts, a natural donor of glucosinolates with high in vitro antioxidative potential, for a 4 week period or to continue their ordinary diet and act as controls. Blood pressure, endothelial function measured by flow mediated dilation (FMD) and blood samples were obtained from the participants every other week and the content of glucosinolates was measured before and after the study. Measurements were blinded to treatment allocation. In the interventional group overall FMD increased from 4% to 5.8% in the interventional group whereas in the control group FMD was stable (4% at baseline and 3.9% at the end of the study). The change in FMD in the interventional group was mainly due to a marked change in FMD in two participants while the other participants did not have marked changes in FMD. The observed differences were not statistically significant. Likewise significant changes in blood pressure or blood samples were not detected between or within groups. Diastolic blood pressure stayed essentially unchanged in both groups, while the systolic blood pressure showed a small non significant decrease (9 mm Hg) in the interventional group from a value of 153 mm Hg at start. Daily ingestion of 10 g dried broccoli sprouts does not improve endothelial function in the presence of hypertension in humans. Clinicaltrials.gov NCT00252018.


Periparturient Behavior and Physiology: Further Insight Into the Farrowing Process for Primiparous and Multiparous Sows.
Giving birth is a critical time for many species and is often the most painful event ever experienced by females. In domestic species, like the pig, pain associated with parturition represents a potential welfare concern, and the consequences of pain can cause economic losses (e.g., by indirectly contributing to piglet mortality as pain could slow post-farrowing recovery, reduce food and water intake, reducing milk let-down). This study investigated pain assessment and its management in primiparous (gilts) and multiparous (sows) breeding pigs, including the provision of a non-steroidal anti-inflammatory drug (NSAID) post-parturition. Individuals were randomly allocated to receive the NSAID ketoprofen (3 mg/kg bodyweight) (n = 11 gilts, 16 sows) or the equivalent volume of saline (n = 13 gilts, 16 sows) by intramuscular injection 1.5 h after the birth of the last piglet. Data collected included putative behavioral indicators of pain (back leg forward, tremble, back arch), salivary cortisol concentrations pre-farrowing and up to 7 days post-injection. In addition, post-partum biomarkers of inflammation, including the acute phase protein C-reactive protein (CRP) and 3 porcine cytokines [interleukin-1 β (IL1 β), interleukin-6 (IL6), and tumor necrosis factor α (TNF α)] were measured in plasma collected 6 h following the injection. Behaviors were analyzed using generalized linear mixed models, and physiological variables with linear mixed models. No difference in putative pain behaviors, salivary cortisol, CRP, or cytokines were found between individuals treated with ketoprofen or those administered the saline control. However, there were some differences between gilts and sows, as sows exhibited more putative pain behavior than gilts, had higher salivary cortisol on the day of farrowing and had higher plasma TNF α. Conversely, gilts had higher salivary cortisol than sows on day 3 post-farrowing and had higher CRP. This indicates that, like human females, multiparous sows experience more pain from uterine activity following birth than primiparas. This study provides useful information for developing management practices relating to post-farrowing care for breeding pigs.


Pharmaco-EEG: A Study of Individualized Medicine in Clinical Practice.
Pharmaco-electroencephalography (Pharmaco-EEG) studies using clinical EEG and quantitative EEG (qEEG) technologies have existed for more than 4 decades. This is a promising area that could improve psychotropic intervention using neurological data. One of the objectives in our clinical practice has been to collect EEG and quantitative EEG (qEEG) data. In the past 5 years, we have identified a subset of refractory cases (n = 386) found to contain commonalities of a small number of electrophysiological features in the following diagnostic categories: mood, anxiety, autistic spectrum, and attention deficit disorders, Four abnormalities were noted in the majority of medication failure cases and these abnormalities did not appear to significantly align with their diagnoses. Those were the following: encephalopathy, focal slowing, beta spindles, and transient discharges. To analyze the relationship noted, they were tested for association with the assigned diagnoses. Fisher's exact test and binary logistics regression found very little (6%) association between particular EEG/qEEG abnormalities and diagnoses. Findings from studies of this type suggest that EEG/qEEG provides individualized understanding of pharmacotherapy failures and has the potential to improve medication selection.


Mechanism of interferon action: phosphorylation of protein synthesis initiation factor eIF-2 in interferon-treated human cells by a ribosome-associated kinase processing site specificity similar to hemin-regulated rabbit reticulocyte kinase.
The phosphorylation of purified protein synthesis factors catalyzed by protein kinase preparations isolated from interferon-treated human amnion cells was examined. Ribosomal salt-wash fractions prepared from interferon-treated human cells contained a protein kinase that catalyzed the [gamma-(32)P]ATP-mediated phosphorylation of the 38,000-dalton subunit of eukaryotic initiation factor 2 (eIF-2alpha); this kinase activity was significantly enhanced in interferon-treated as compared to untreated cells. The tryptic [(32)P]phosphopeptide pattern obtained for eIF-2alpha phosphorylated by the interferon-mediated human kinase was indistinguishable from the pattern obtained for eIF-2alpha phosphorylated by the hemin-regulated rabbit reticulocyte kinase when analyzed by thin-layer chromatography with three different solvent systems and by high-voltage electrophoresis. O-[(32)P]Phosphoserine was liberated by partial acid hydrolysis from eIF-2alpha phosphorylated by either the human or the rabbit kinase. In addition to the phosphorylation of eIF-2alpha, interferon treatment of human cells enhanced the phosphorylation of two additional ribosome-associated proteins designated P(1) and P(f). The major phosphoester linkage observed for the human, as well as murine, phosphoprotein P(1) was O-phosphoserine. The interferon-mediated phosphorylation of both eIF-2alpha and protein P(1) was dependent upon the presence of RNA with double-stranded character; P(f) phosphorylation was not affected by double-stranded RNA. These results suggest that the interferon-mediated ribosome-associated human protein kinase catalyzes the phosphorylation of eIF-2alpha in a site-specific manner that is apparently identical with the reaction catalyzed by the hemin-regulated rabbit reticulocyte kinase; hence, the phosphorylation of eIF-2 may play a role in regulating the initiation of translation in interferon-treated cells.


Risk Indicators of Papillary Recession in the Anterior Maxilla.
The interdental papilla is the portion of the gingiva that occupies the space between two adjacent teeth. When papillary recession occurs, an array of problems arises ranging from phonetics to food impaction and esthetic concerns. The aim of this study was to identify risk indicators for visible papillary recession in the anterior maxilla among a Caucasian population utilizing an advanced analytical approach. A dataset of 211 adult dentate Caucasian patients that had undergone intraoral assessment of midline papillary recession and extra-oral assessment of visible papillary recession during maximum ("Duchenne") smile was utilized. An enhanced analytical approach was employed to identify risk indicators for papillary recession. Approximately one-third of the participants (38%) demonstrated papillary recession during maximum smile ("visible papillary recession"). An association between sex (male preference) and visible papillary recession was found in this sample population, while age was found to be a risk indicator for papillary recession in individuals over 65 years of age. Visible midline papillary recession in the maxilla is a highly prevalent clinical entity in Caucasian individuals, thus the development of efficacious treatment modalities for papillary regeneration is necessary. Findings of the present study on risk indicators for visible papillary absence, namely sex and age, may facilitate clinicians in treating patient with compromised interdental aesthetics as well as identifying patients that are in high risk for loss of interdental tissues. Findings of the present study on risk indicators for visible papillary absence, namely sex and age, indicate the need for careful assessment and meticulous treatment planning with respect to preservation of the interdental tissues. The consideration of these risk indicators can help dentists to identify patients at risk for papillary recession.


Flow cytometric analysis of cell division by dilution of CFSE and related dyes.
The technique described in this unit uses the intracellular fluorescent label carboxyfluorescein diacetate succinimidyl ester (CFSE) to track proliferating cells. Covalently bound CFSE is divided equally between daughter cells, allowing discrimination of successive rounds of cell division. The technique is applicable to in vitro cell division, as well as to in vivo division of adoptively transferred cells and can resolve eight or more successive generations. CFSE is long lived, permitting analysis for several months after cell transfer, and has the same spectral characteristics as fluorescein, so monoclonal antibodies conjugated to phycoerythrin or other compatible fluorochromes may be used to immunophenotype the dividing cells. In addition, information is given on a second-generation dye, Cell Trace Violet (CTV), excited by 405-nm blue laser light. CTV is chemically related to CFSE, but allows the 488-nm line of the Argon laser to be used for other probes.