Hesperidin attenuated apoptotic-related genes in testicle of a male rat model of varicocoele.
Varicocoele is a swollen bulge of the pampiniform venous plexus inside the scrotum. It is also considered one of the causes of infertility in males. It has been demonstrated that hesperidin has remarkable pharmacological potentials, including antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic effects. The present study aimed to evaluate the protective effect of hesperidin on varicocoele-induced testicular tissue damage and oxidative stress in the testicles of adult male rats. Animals were assigned into the following groups: control group (Ctrl) or sham, varicocoele group (Vcl) which received no treatment, varicocoele group that was daily fed with hesperidin (Vcl+Hsp) at a dose of 50 mg/kg for eight weeks, and hesperidin group (Hsp) which received only hesperidin. At the end of the treatment period, the levels of oxidative stress markers were measured in plasma, and the expression of Bax and Bcl-2 was determined by immunocytochemistry and RT-qPCR methods. The index of apoptosis was assessed by the TUNEL assay. Johnsen's score, the epithelium thickness, and diameter of seminiferous tubules were improved in the Vcl+Hsp group as compared to the Vcl group. Treatment with hesperidin enhanced the serum levels of glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzymes and decreased the heightened concentrations of malondialdehyde (MDA) in testicular tissue (p < 0.001). Moreover, our results demonstrated that hesperidin considerably diminished Bax and increased Bcl-2 expression (gene and protein) levels compared with the Vcl group (p < 0.05). It also markedly reduced the rate of programmed cell death in germ cells (p < 0.05). It seems that the treatment with hesperidin could mitigate testicular tissue damage in rats underwent varicocoele possibly through its antioxidant properties.


Urine patterns, peptide levels and IgA/IgG antibodies to food proteins in children with dyslexia.
There is an association between psychiatric disorders and dyslexia. In some psychiatric disorders abnormal urinary peptide patterns and peptide levels, and elevated levels of IgA antibodies to food proteins have been detected. These abnormalities are probably due to insufficient breakdown of the proteins gluten and casein. The aim of this study was to discover whether such abnormalities could be found in urine samples and serum of children with dyslexia. After screening 291 pupils in the fourth grade, 15 dyslexics and 15 controls were pairwise matched by gender, age, and cognitive level. Word decoding, spelling, and short-term memory tests were carried out, and information on handedness, immune and other disorders was obtained. Analyses of 24-h urine samples and of serum were performed. The reading abilities significantly differentiated the groups, and significant differences were found in frequency of left-handedness, immune disorders and other disorders. Three dyslexic children had elevated IgA antibodies. Two of these had positive endomycium tests, and coeliac disease was confirmed by biopsy. One had antibodies to proteins in milk. Our findings may suggest weak urinary peptide abnormalities in the dyslexic children, and they show significant differences in levels of IgA of antibodies to food proteins.


Cataract induction in lenses cultured with transforming growth factor-beta.
Anterior subcapsular cataracts are characterized by the appearance of opaque plaques of abnormal cells. Distinctive spindle-shaped cells containing alpha-smooth muscle actin are present and are associated with wrinkling of the overlying lens capsule. Accumulations of extracellular matrix, including type I collagen, also are found. The authors previously reported that transforming growth factor-beta (TGF-beta) induces similar aberrant morphologic changes in lens epithelial explants. More recently, they identified alpha-smooth muscle actin in explants cultured with TGF-beta. The aim of this study was to determine whether TGF-beta induces comparable cataractous changes in whole lenses and to examine the effects of this treatment on the transparency of the lens. Whole lenses from 21-day-old rats were cultured in defined serum-free medium with TGF-beta 2 or without added growth factors for 5 days. Lenses were then photographed and prepared for histology and immunolocalization. Lenses cultured with TGF-beta developed distinct anterior opacities just beneath the lens capsule. Histologically, clumps of abnormal cells corresponded with these opacities. Spindle-shaped cells, which contained alpha-smooth muscle actin, were present, and the overlying capsule was often wrinkled. The clumps contained accumulations of type I collagen, laminin, and heparan sulphate proteoglycan. In contrast, lenses cultured without growth factors remained transparent, retained normal lens morphology, and did not accumulate alpha-smooth muscle actin or type I collagen. These results show that TGF-beta induces whole lenses to form opacities that contain morphologic and biochemical markers for subcapsular cataract.


An approach to ear, nose and throat assessment.
An approach is described for assessing ear, nose and throat problems, which may be of assistance to general practitioners in diagnosing common ENT problems. Making an ENT diagnosis requires your well honed skills of history taking and examination. This is aided by a few examination tools.


Intraductal Tissue Sampling Device Designed for the Biliary Tract.
Clinical sampling of tissue that is read by a pathologist is currently the gold standard for making a disease diagnosis, but the few minimally invasive techniques available for small duct biopsies have low sensitivity, increasing the likelihood of false negative diagnoses. We propose a novel biopsy device designed to accurately sample tissue in a biliary stricture under fluoroscopy or endoscopic guidance. The device consists of thin blades organized around the circumference of a cylinder that are deployed into a cutting annulus capable of comprehensively sampling tissue from a stricture. A parametric study of the device performance was done using finite element analysis; this includes the blade deployment under combined axial compression and torsion followed by an axial 'cutting' step. The clinical feasibility of the device is determined by considering maximum deployment forces, the radial expansion achieved and the cutting stiffness. We find practical parameters for the device operation to be an overall length of 10 mm and a diameter of 3.5 mm for a [Formula: see text] blade thickness, which allow the device to be safely deployed with a force of 10N and achieve an expansion over 3x its original diameter. A model device was fabricated with these parameters and a [Formula: see text] thickness out of a NiTi superalloy and tested to validate the performance. The device showed strong agreement with an equivalent numerical model, reaching a peak force within 2% of that predicted numerically and fully recovering after compression to 20% of its length. Clinical and Translational Impact Statement -This pre-clinical research conceptually demonstrates a novel expandable device to biopsy tissue in narrow strictures during an ERCP procedure. It can greatly improve diagnostic tissue yield compared to existing methods.


The Association of Cultural Identification with Obesity among African Americans.
The influence of culture on body mass index (BMI) and obesity within the African American population is an underexplored area in the literature. Therefore, this study explored the extent to which cultural identity was associated with BMI and obesity among African Americans and whether the association of cultural identity with obesity differed between males and females. Participants were African Americans (n = 304) who responded to an online survey. BMI was calculated using self-reported weight and height; a BMI ≥ 30 indicated obesity. Sex assigned at birth was measured by self-report, and identification with African American culture was assessed using scores from six Black Identity Classification Scale (BICS) subscales. Primary analyses were conducted using a series of linear and logistic regression analyses. In almost all cases, BICS was not associated with BMI and obesity among all African Americans, but moderation analyses revealed that stronger identification with certain subscales of BICS, such as Afrocentrism, Black Americanism, and Racial Salience, was associated with an increase in the odds of obesity for males and not for females. Study findings suggest that culture may influence obesity differently among males and females. Uncovering mechanisms linking cultural identification to obesity will provide novel contributions to behavioral interventions designed to reduce obesity within the African American population.


Phylogenetic relationships among East African haplochromine fish as revealed by short interspersed elements (SINEs).
Genomic DNA libraries were prepared from two endemic species of Lake Victoria haplochromine (cichlid) fish and used to isolate and characterize a set of short interspersed elements (SINEs). The distribution and sequences of the SINEs were used to infer phylogenetic relationships among East African haplochromines. The SINE-based classification divides the fish into four groups, which, in order of their divergence from a stem lineage, are the endemic Lake Tanganyika flock (group 1); fish of the nonendemic, monotypic, widely distributed genus Astatoreochromis (group 2); the endemic Lake Malawi flock (group 3); and group 4, which contains fish from widely dispersed East African localities including Lakes Victoria, Edward, George, Albert, and Rukwa, as well as many rivers. The group 4 haplochromines are characterized by a subset of polymorphic SINEs, each of which is present in some individuals and absent in others of the same population at a given locality, the same morphologically defined species, and the same mtDNA-defined haplogroup. SINE-defined group 4 contains six of the seven previously described mtDNA haplogroups. One of the polymorphic SINEs appears to be fixed in the endemic Lake Victoria flock; four others display the presence-or-absence polymorphism within the species of this flock. These findings have implications for the origin of Lake Victoria cichlids and for their founding population sizes.


Cognitive dysfunction in cancer patients: an educational needs area improved by a single intervention.
Chemotherapy-related cognitive dysfunction (CRCD) is increasingly recognized as an important cause of posttreatment morbidity, with significant impact on quality of life. We sought to evaluate the level of need for and awareness of information regarding CRCD among nurses involved with the care of persons receiving chemotherapy. We also hypothesized that educational interventions are useful in this increasingly important area of oncology nursing. Chemotherapy nurse providers were surveyed regarding CRCD beliefs and skills; a subset of individuals attending a CRCD educational session underwent pretesting and posttesting to assess CRCD knowledge. Respondents perceived that CRCD is a serious problem and identified the following needs areas: general CRCD education, diagnostic skills, knowledge regarding behavioral and pharmacologic interventions, and availability of adequate CRCD practice protocols. With a single educational intervention, posttest scoring improved over pretest in most subjects, with a statistically significant overall improvement in mean scores. Our results suggest the need for education in CRCD diagnosis, intervention, and protocol development. A single educational intervention improved knowledge. Our work underscores the importance of CRCD education for the Oncology Education Services and other oncology nurse educational resources.


Disease management programs.
Disease management (DM) activities are described, and their implementation and monitoring in managed care organizations are discussed. DM programs involve systematic evaluation of the relationships between treatment options and the associated resource use and patient outcomes for the purpose of providing a given standard of health care at the lowest possible resource cost. A DM arrangement covers a specified disease or therapy intervention for a patient group that may be defined by diagnosis, drug use, prior resource use, or patient characteristics. Often, the partners in a DM arrangement are a managed care organization and a pharmaceutical industry representative or division. The development and monitoring of disease management arrangements are dependent on access to several types of data, and these data are available in managed care plans. A DM arrangement includes interventions to change prescribing patterns or patient compliance and assessment of the effects of these interventions against target outcomes specified in the contract. The agreement that is developed specifies guidelines for treatment and requirements for data collection, monitoring, and reporting that are consistent with the target outcomes. In many DM arrangements, the partners share cost savings and risk; other arrangements involve case management on a capitated basis. A pharmaceutical company involved in risk sharing must change its focus from market share to optimal use of drugs within the total cost of treatment. If a risk-sharing contract covers an entire therapeutic class of drugs, a pharmaceutical company may share risk for the use of other manufacturers' products as well as its own. Disease management contracts must consider the full impact of each treatment option on the health system; the goal should be not simply to decrease the drug budget, but to decrease overall costs for treatment that achieves desired outcomes for specific diseases.


Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism.
It is generally assumed by practitioners and guideline authors that combined modalities (methods of treatment) are more effective than single modalities in preventing venous thromboembolism (VTE), defined as deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. This is an update of the review first published in 2008. The aim of this review was to assess the efficacy of combined intermittent pneumatic leg compression (IPC) and pharmacological prophylaxis versus single modalities in preventing venous thromboembolism. For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (May 2016). In addition the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 4)). Clinical trials databases were searched for details of ongoing or unpublished studies. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of combined IPC and pharmacological interventions used to prevent VTE. We independently selected trials and extracted data. Disagreements were resolved by discussion. We performed fixed-effect model meta-analyses with odds ratios (ORs) and 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We included a total of 22 trials (9137 participants) of which 15 were randomized trials (7762 participants). The overall risk of bias was mostly unclear or high due to selection and performance bias. We used GRADE to assess the quality of the evidence and this was downgraded from high to moderate or very low due to the risk of bias, imprecision or indirectness.The rate of PE in the studies comparing IPC alone with combined IPC and pharmacological prophylaxis was low, underpowering the analyses. The incidence of symptomatic PE was 0.79% with IPC, but ranged between 0.1 to 1% with combined IPC and pharmacological prophylaxis (OR 0.49, 95% CI 0.18 to 1.34; 12 studies, 3017 participants, moderate quality evidence). The incidence of DVT was 4.10% in the IPC group and 2.19% in the combined group showing a reduced incidence of DVT in favour of the combined group (OR 0.52, 95% CI 0.33 to 0.82; 11 studies, 2934 participants, moderate quality evidence). The addition of an anticoagulant to IPC, however, increased the risk of any bleeding compared to IPC alone; 0.66% (7/1053) in the IPC group and 4.0% (44/1102) in the combined group (OR 5.04, 95% CI 2.36 to 10.77; 7 studies, 2155 participants, moderate quality evidence). Major bleeding followed a similar pattern; 0.1% (1/1053) in the IPC group to 1.5% (17/1102) in the combined group (OR 6.81, 95% CI 1.99 to 23.28; 7 studies, 2155 participants, moderate quality evidence).We detected no difference between the type of surgery subgroups such as orthopedic and non-orthopedic participants for DVT incidence (P = 0.16). Tests for differences between type of surgery subgroups were not possible for PE incidence.Compared with pharmacological prophylaxis alone, the use of combined IPC and pharmacological prophylaxis modalities reduced the incidence of symptomatic PE from 2.92% to 1.20% (OR 0.39, 95% CI 0.23 to 0.64; 10 studies, 3544 participants, moderate quality evidence). The incidence of DVT was 6.2% in the pharmacological prophylaxis group and 2.9% in the combined group showing no difference between the combined and pharmacological prophylaxis groups (OR 0.42, 95% CI 0.18 to 1.03; 11 studies, 2866 participants, moderate quality evidence). Increased bleeding side effects were not observed for IPC when it was added to anticoagulation (bleeding: OR 0.80, 95% CI 0.30 to 2.14, very low quality evidence; major bleeding: OR 1.21, 95% CI 0.35 to 4.18, very low quality evidence, 3 studies, 244 participants).No difference was detected between the type of surgery subgroups for PE incidence (P = 0.68) or for DVT incidence (P = 0.10). Moderate quality evidence suggests that combining IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, decreases the incidence of DVT when compared to compression, and incidence of PE when compared to anticoagulation. Moderate quality evidence suggests that there is no difference between combined and single modalities in the incidence of PE when compared with compression alone and DVT when compared with anticoagulation alone. The quality of evidence for PE or DVT was downgraded to moderate due to imprecision or risk of bias in study methodology, highlighting the need for further research. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method of thromboprophylaxis. The quality of evidence for bleeding was downgraded to moderate due to indirectness or very low due to risk of bias in study methodology, indirectness and imprecision highlighting the need for further research. Nevertheless, the results of the current review agree with current guideline recommendations, which support the use of combined modalities in hospitalised patients (limited to those with trauma or undergoing surgery) at risk of developing VTE. More studies on the role of combined modalities in VTE prevention are needed.


A strong regenerative ability of cardiac stem cells derived from neonatal hearts.
Human cardiac stem cells (CSCs) promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of CSCs in very young patients with nonischemic congenital heart defects has not been explored. We hypothesized that isolated neonatal-derived CSCs may have a higher regenerative ability than adult-derived CSCs and might address the structural deficiencies of congenital heart disease. Human specimens were obtained during routine cardiac surgical procedures from right atrial appendage tissue discarded from 2 age groups: neonates and adults patients. We developed a reproducible isolation method that generated cardiosphere-derived cells (CDCs), regardless of starting tissue weight or age. Neonatal-derived CDCs demonstrated increased number of cardiac progenitor cells expressing c-kit(+), flk-1, and Islet-1 by flow cytometry and immunofluorescence. When transplanted into infarcted myocardium, neonatal-derived CDCs had a significantly higher ability to preserve myocardial function, prevent adverse remodeling, and enhance blood vessel preservation and/or formation when compared with adult-derived CDCs. Last, neonatal-derived CDCs were more cardiomyogenic than adult-derived CDCs when cocultured with neonatal cardiomyocytes and displayed enhanced angiogenic function compared with adult-derived CDCs. Neonatal-derived CDCs have a strong regenerative ability when compared with adult-derived CDCs that may depend on angiogenic cytokines and an increase prevalence of stem cells. This has important implications in the potential use of CDCs in future clinical trials.


Variation in immune defence in relation to age in the green-veined white butterfly (Pieris napi L.).
We investigate how encapsulation ability varies with adult age in overwintering and in direct-developing animals (development without diapause) of the green-veined white butterfly, Pieris napi. Encapsulation is a resource costly trait coupled to the immune system and encapsulation ability is predicted to decrease with age, since the resource pool of important nutrients generally decreases with age in nectar feeding butterflies. The results support this prediction and both sexes showed an age dependent decrease in their encapsulation ability. There were no significant differences between the sexes but direct-developing males tended to have a steeper decrease than females and we hypothesize that this could be the result of low available resources, since this generation is time and nutrient stressed.


Studies on Escherichia coli serotype O157:H7 strains containing a 60-MDa plasmid and on 60-MDa plasmid-cured derivatives.
Seventeen strains of Escherichia coli serotype O157:H7 producing Shiga-like toxin were examined for the presence of plasmids and for the ability to adhere to HEp-2 and Intestine 407 cells. All of the strains possessed a common 60-MDa plasmid. To determine the role of the 60-MDa plasmid, plasmid-cured strains were compared with the parent strains for their ability to produce pili and to adhere to epithelial cells in culture. The total cell lysate protein and outer-membrane protein (OMP) profiles were also compared. Both the parent strains and their plasmid-cured derivatives produced pili. Immunofluorescence assay results indicated that the plasmid-cured and parent strains adhered equally well to HEp-2 and Intestine 407 cells; overall adherence was greater with intestinal cells than HEp-2 cells. SDS-PAGE of polypeptides synthesised in an E. coli system in vitro showed that plasmid DNA encodes c. 35 proteins. SDS-PAGE of OMP preparations demonstrated that the 60-MDa plasmid appears to be involved in the synthesis of a 33-kDa OMP. Two strains cured of the 60-MDa plasmid, one that possessed no plasmids and one that still contained a 2.2-MDa plasmid, produced exopolysaccharide (EPS) when cultured on solid medium at 25 degrees C. Two other strains, which were cured of the 60-MDa plasmid but contained a 4.5-MDa plasmid, did not produce visible amounts of EPS. Gas chromatography analysis showed that the EPS consisted of fucose, glucose and galactose in an approximate molar ratio of 2.0:0.9:1.1 and also had 7% of a uronic acid sugar as part of its structure.


DNA vaccination affords significant protection against feline immunodeficiency virus infection without inducing detectable antiviral antibodies.
To test the potential of a multigene DNA vaccine against lentivirus infection, we generated a defective mutant provirus of feline immunodeficiency virus (FIV) with an in-frame deletion in pol (FIVDeltaRT). In a first experiment, FIVDeltaRT DNA was administered intramuscularly to 10 animals, half of which also received feline gamma interferon (IFN-gamma) DNA. The DNA was administered in four 100-microg doses at 0, 10, and 23 weeks. Immunization with FIVDeltaRT elicited cytotoxic T-cell (CTL) responses to FIV Gag and Env in the absence of a serological response. After challenge with homologous virus at week 26, all 10 of the control animals became seropositive and viremic but 4 of the 10 vaccinates remained seronegative and virus free. Furthermore, quantitative virus isolation and quantitative PCR analysis of viral DNA in peripheral blood mononuclear cells revealed significantly lower virus loads in the FIVDeltaRT vaccinates than in the controls. Immunization with FIVDeltaRT in conjunction with IFN-gamma gave the highest proportion of protected cats, with only two of five vaccinates showing evidence of infection following challenge. In a second experiment involving two groups (FIVDeltaRT plus IFN-gamma and IFN-gamma alone), the immunization schedule was reduced to 0, 4, and 8 weeks. Once again, CTL responses were seen prior to challenge in the absence of detectable antibodies. Two of five cats receiving the proviral DNA vaccine were protected against infection, with an overall reduction in virus load compared to the five infected controls. These findings demonstrate that DNA vaccination can elicit protection against lentivirus infection in the absence of a serological response and suggest the need to reconsider efficacy criteria for lentivirus vaccines.


Reflections on a Physician Assistant Entrance Exam: Does the Profession Need One?
Standardized entrance exams are used in many health professions as one way to objectively measure knowledge and facilitate comparisons across student groups. The physician assistant (PA) profession has historically not employed a profession-specific entrance exam, and the idea was never seriously explored until the Physician Assistant College Admissions Test was developed recently by a commercial assessment publisher, with field testing in some volunteer programs in 2018 and the exam's first administration in May of 2020. The 2020 Physician Assistant Education Association Presidents Commission chose to investigate the issues raised by a consensus-derived, PA-specific entrance exam to stimulate more informed discussion on the efficacy of such an exam. While it may have the potential to enhance efficiency in PA admissions and reduce variability in admissions requirements, a PA entrance exam would also likely introduce new challenges, including increased costs, impact on the diversity of the applicant pool, and incongruence with an increasingly holistic admissions process. The biggest barrier would likely be the lack of current consensus on the knowledge, skills, and attributes that matriculants need to be successful in the program and in clinical practice. Development of a consensus-derived PA entrance exam would be a complex, expensive, and time-consuming endeavor, requiring considerable attention to technical issues of psychometric quality, process transparency, and legal defensibility. Changes being made to health professions admissions practices due to the COVID-19 pandemic, including the dropping of test scores as a requirement by some institutions, may make some of the issues raised in this paper more timely than ever.


Hypothalamic self-stimulation under the chronic morphine treatment in the rat.
The influence of morphine on self-stimulation (SS) under chronic morphine administration (30 injections for 15 days) in increasing doses (from 20 to 20 mg/kg/injection) has been studied. Initial doses had a depressive effect varying in degree in different animals. Subsequent injections activated "reward" behavior. This activation is suggested as one of the neurophysiological mechanisms of morphine abuse and addiction.


Endovascular Rescue Aortic Fenestration After Accidental False Lumen TEVAR in Type B Dissection.
Unintended false-lumen thoracic endovascular aortic repair (TEVAR) is under-reported and often fatal. We present percutaneous endovascular rescue techniques for true-lumen reperfusion with strategies to address the peripheral artery perfusion needs unique to each case. Two patients deteriorated 24 hours after uncomplicated and complicated acute aortic type-B dissection TEVAR treatment at a tertiary community hospital. Reevaluation of index and repeated imaging studies revealed inadvertent false-lumen TEVAR with severe visceral and peripheral ischemia. Stepwise subtraction angiography was used to confirm continuous true-lumen catheterization from femoral puncture into the thoracic aorta. Retrograde fenestration distal to the misplaced TEVAR from the true- into the false-lumen allowed for snorkeling by distal stent-extension across the dissection membrane. In one case, TEVAR stent graft extension resulted in true-lumen re-expansion and in the other case, bare-metal stent-extension for stabilization of the dissection membrane resulted in true-lumen re-expansion in addition to preservation of visceral and peripheral perfusion via the false-lumen. Despite excellent acute hemodynamic results and initial signs of recovery, both patients eventually died (multiorgan failure; cerebral hemorrhagic infarction). Correct indication and prompt recognition of potential inadvertent false-lumen stenting is critical to avoid disastrous sequelae, for example, malperfusion. Endovascular salvage is feasible for restoration of correct perfusion and must be performed in a timely manner. Clinically apparent, complicated type-B dissection necessitates instantaneous treatment. Prerequisite for an endovascular approach is a true-lumen guidewire continuously from access to the ascending aorta. DSA after TEVAR and prompt clinical re-evaluation are to verify effective visceral and peripheral restoration of blood flow. Despite these measures, inadvertent false-lumen TEVAR may occur rarely. Immediate recognition may allow for timely true-lumen re-expansion using percutaneous endovascular salvage techniques e.g. retrograde fenestration from the true- into the false-lumen for distal snorkeling of the misplaced TEVAR across the dissection membrane. However, morbidity and mortality are very high, if erroneous stent graft placement is not identified early.


Fine-tuning of the stability of β-strands by Y181 in perfringolysin O directs the prepore to pore transition.
Perfringolysin O (PFO) is a toxic protein that forms β-barrel transmembrane pores upon binding to cholesterol-containing membranes. The formation of lytic pores requires conformational changes in PFO that lead to the conversion of water-soluble monomers into membrane-bound oligomers. Although the general outline of stepwise pore formation has been established, the underlying mechanistic details await clarification. To extend our understanding of the molecular mechanisms that control the pore formation, we compared the hydrogen-deuterium exchange patterns of PFO with its derivatives bearing mutations in the D3 domain. In the case of two of these mutations F318A, Y181A, known from previous work to lead to a decreased lytic activity, global destabilization of all protein domains was observed in their water-soluble forms. This was accompanied by local changes in D3 β-sheet, including unexpected stabilization of functionally important β1 strand in Y181A. In case of the double mutation (F318A/Y181A) that completely abolished the lytic activity, several local changes were retained, but the global destabilization effects of single mutations were reverted and hydrogen-deuterium exchange (HDX) pattern returned to PFO level. Strong structural perturbations were not observed in case of remaining variants in which other residues of the hydrophobic core of D3 domain were substituted by alanine. Our results indicate the existence in PFO of a well-tuned H-bonding network that maintains the stability of the D3 β-strands at appropriate level at each transformation step. F318 and Y181 moieties participate in this network and their role extends beyond their direct intermolecular interaction during oligomerization that was identified previously.


An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.
New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.


Impact of the integration of proton magnetic resonance imaging spectroscopy to PI-RADS 2 for prediction of high grade and high stage prostate cancer.
To compare the predictions of dominant Gleason pattern ≥ 4 or non-organ confined disease with Prostate Imaging Reporting and Data System (PI-RADS v2) with or without proton magnetic resonance spectroscopic imaging (1H-MRSI). Thirty-nine men underwent 3-tesla endorectal multiparametric MRI including 1H-MRSI and prostatectomy. Two radiologists assigned PI-RADS v2 and 1H-MRSI scores to index lesions. Statistical analyses used logistic regressions, receiver operating characteristic (ROC) curves, and 2x2 tables for diagnostic accuracies. The sensitivity and specificity of 1H-MRSI and PI-RADS v2 for high-grade prostate cancer (PCa) were 85.7% (57.1%) and 92.9% (100%), and 56% (68.0%) and 24.0% (24.0%). The sensitivity and specificity of 1H-MRSI and PI-RADS v2 for extra-prostatic extension (EPE) were 64.0% (40%) and 20.0% (48%), and 50.0% (57.1%) and 71.4% (64.3%). The area under the ROC curves (AUC) for prediction of high-grade prostate cancer were 0.65 and 0.61 for PI-RADS v2 and 0.72 and 0.70 when combined with 1H-MRSI (readers 1 and 2, p = 0.04 and 0.21). For prediction of EPE the AUC were 0.54 and 0.60 for PI-RADS v2 and 0.55 and 0.61 when combined with 1H-MRSI (p > 0.05). 1H-MRSI might improve the discrimination of high-grade prostate cancer when combined to PI-RADS v2, particularly for PI-RADS v2 score 4 lesions, but it does not affect the prediction of EPE.


Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis.
Cl(-) /HCO3- anion exchanger 2 (AE2) participates in intracellular pH homeostasis and secretin-stimulated biliary bicarbonate secretion. AE2/SLC4A2 gene expression is reduced in liver and blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Our previous findings of hepatic and immunological features mimicking PBC in Ae2-deficient mice strongly suggest that decreased AE2 expression might be involved in the pathogenesis of PBC. Here, we tested the potential role of microRNA 506 (miR-506) - predicted as candidate to target AE2 mRNA - for the decreased expression of AE2 in PBC. Real-time quantitative polymerase chain reaction showed that miR-506 expression is increased in PBC livers versus normal liver specimens. In situ hybridization in liver sections confirmed that miR-506 is up-regulated in the intrahepatic bile ducts of PBC livers, compared with normal and primary sclerosing cholangitis livers. Precursor-mediated overexpression of miR-506 in SV40-immortalized normal human cholangiocytes (H69 cells) led to decreased AE2 protein expression and activity, as indicated by immunoblotting and microfluorimetry, respectively. Moreover, miR-506 overexpression in three-dimensional (3D)-cultured H69 cholangiocytes blocked the secretin-stimulated expansion of cystic structures developed under the 3D conditions. Luciferase assays and site-directed mutagenesis demonstrated that miR-506 specifically may bind the 3'untranslated region (3'UTR) of AE2 messenger RNA (mRNA) and prevent protein translation. Finally, cultured PBC cholangiocytes showed decreased AE2 activity, together with miR-506 overexpression, compared to normal human cholangiocytes, and transfection of PBC cholangiocytes with anti-miR-506 was able to improve their AE2 activity. miR-506 is up-regulated in cholangiocytes from PBC patients, binds the 3'UTR region of AE2 mRNA, and prevents protein translation, leading to diminished AE2 activity and impaired biliary secretory functions. In view of the putative pathogenic role of decreased AE2 in PBC, miR-506 may constitute a potential therapeutic target for this disease.


Health care for older populations: society's responsibility.
Current and projected costs of health care for the elderly are fluctuating. Federal policy makers bent on containing Medicare and Medicaid costs have a major effect on this economic health care issue. The challenges of financing and providing both acute and long-term care for older persons are intertwined with society's moral and ethical attitudes toward the elderly in general. New approaches to old services as well as innovative financing options for funding or subsidizing health care costs for the elderly are described and analyzed.


Human hydatid disease: evaluation of an ELISA for diagnosis, population screening and monitoring of control programmes.
The routine use of ELISA and complement fixation tests in the diagnosis of suspected clinical cases of hydatid disease was evaluated. In the ELISA test, dialysed and filtered sheep cyst fluid was used as antigen and two positive cut-off points--+3SD and +2SD of the mean absorbance values of the control sera--were evaluated. The predictive values of ELISA tests were 82% and 90% for positive tests, and 86% and 82% for negative tests, respectively with the two cut-off points. In a population survey of blood donors and veterinary workers in Powys, 4% and 8%, respectively, had ELISA values above the lower cut-off point. However, it would not be appropriate to use the same test for diagnostic population screening in Wales since the predictive value of the test is likely to be very low in this setting. Serological surveys with the ELISA may be of use in monitoring the progress of the South Powys Hydatid Control Programme. The use of cumulative percentages was found to be a useful method of comparing whole distributions of results in different populations.


Comparative epidemiology of tobacco-related cancers.
In a retrospective study, interviews were obtained with 3,716 patients with histologically proven cancer of the lung (Kreyberg types I and II), mouth, larynx, esophagus, or bladder and with over 18,000 controls. For each of these cancers, the relative risk of both male and female present smokers increased with the quantity smoked and the duration of the habit. The strongest increase occurred for cancer of the lung and larynx, and the least increase occurred for cancer of the esophagus and bladder. For exsmokers the risk decreased with years of cessation. The risk for mouth cancer of pipe and cigar smokers who inhaled much less than cigarette smokers was less than that of the latter and increased with the quantity smoked. The risk of mouth, larynx, and esophagus cancer among smokers increased with the quantity of alcohol consumed. Greater smoking habits and lesser cessation rates were noted among lower socioeconomic groups, suggesting that these groups will bear an ever increasing proportion of the burden of tobacco-related cancer.


Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration.
To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.


CLINICAL EXPERIENCE WITH A NEW DIURETIC, TRIAMTERENE, IN CONJESTIVE HEART FAILURE.
Triamterene therapy was evaluated in 35 patients with congestive heart failure over a period of two and one-half years. The parameters used were: clinical assessment; daily 24-hour urine sodium, potassium, chloride, and total volume; bi-weekly serum sodium, potassium, chloride, uric acid, and SGOT; hemogram, and BUN.Triamterene is a moderately potent diuretic and natriuretic, with the added desirable property of potassium conservation. It acts synergistically with spironolactone and not only potentiates the effects of hydrochlorothiazide but greatly minimizes its kaluretic effect.It is particularly useful in patients in whom cardiac arrhythmias are associated with digitalis intoxication or with inadvertently induced hypokalemia. Its main therapeutic value, used either alone or in combination with other diuretics, is in the longterm management of chronic edema, especially in certain patients refractory to the currently used diuretics.No significant undesirable side effects were noted.


Increased School Breakfast Participation from Policy and Program Innovation: The Community Eligibility Provision and Breakfast after the Bell.
School meals provide significant access to food and nutrition for children and adolescents, particularly through universal free meal mechanisms. Alongside added nutritional meal requirements under the Healthy, Hunger-Free Kids Act (2010), schools can utilize meal program and policy mechanisms such as the Community Eligibility Provision (CEP) and Breakfast after the Bell (BATB) to increase participation. This study examines longitudinal statewide school-level CEP and BATB adoption and estimates the impact on increased free and reduced-price (FRP) breakfast participation. We find that FRP breakfast participation increased for schools that utilize both CEP and BATB (14-percentage-point increase) and that CEP-participating schools are more likely to use BATB approaches such as breakfast in the classroom, grab-and-go carts, and second-chance breakfast. Additionally, using a conditional Difference-in-Differences (DiD) approach, we find that BATB adoption accounted for a 1.4-percentage-point increase in FRP school breakfasts served (p < 0.05). Study findings can inform policy and school official decision making around the policy and program mechanisms at their disposal to increase school meal participation and student nutrition.


Effects of excitation light polarization on fluorescence emission in two-photon light-sheet microscopy.
Light-sheet microscopy (LSM) is a powerful imaging technique that uses a planar illumination oriented orthogonally to the detection axis. Two-photon (2P) LSM is a variant of LSM that exploits the 2P absorption effect for sample excitation. The light polarization state plays a significant, and often overlooked, role in 2P absorption processes. The scope of this work is to test whether using different polarization states for excitation light can affect the detected signal levels in 2P LSM imaging of typical biological samples with a spatially unordered dye population. Supported by a theoretical model, we compared the fluorescence signals obtained using different polarization states with various fluorophores (fluorescein, EGFP and GCaMP6s) and different samples (liquid solution and fixed or living zebrafish larvae). In all conditions, in agreement with our theoretical expectations, linear polarization oriented parallel to the detection plane provided the largest signal levels, while perpendicularly-oriented polarization gave low fluorescence signal with the biological samples, but a large signal for the fluorescein solution. Finally, circular polarization generally provided lower signal levels. These results highlight the importance of controlling the light polarization state in 2P LSM of biological samples. Furthermore, this characterization represents a useful guide to choose the best light polarization state when maximization of signal levels is needed, e.g. in high-speed 2P LSM.


Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas.
Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy.


Relations of Early Goal Blockage Response and Gender to Subsequent Tantrum Behavior.
Infants and their mothers participated in a longitudinal study of the sequelae of infant goal blockage responses. Four-month-old infants participated in a standard contingency learning/goal blockage procedure during which anger and sad facial expressions to the blockage were coded. When infants were 12- and 20- months-old, mothers completed a questionnaire about their children's tantrums. Tantrum scores increased with age and boys tended to show more tantrum behavior than girls. Anger expressed to goal blockage at 4 months was unrelated to tantrum behavior. There was a gender by sad expression interaction. Girls who expressed sadness in response to the goal blockage had lower total tantrum scores than boys; otherwise there was no difference. These results suggest that tantrums of infants who display sad, not anger expression, in response to goal blockage, are differentially influenced by children's gender.


Pulmonary disease in HIV-infected adults in the era of antiretroviral therapy.
: HIV in the antiretroviral therapy era is characterized by multimorbidity and the frequent occurrence of HIV-associated non-AIDS chronic health conditions. Respiratory symptoms and chronic pulmonary diseases, including chronic obstructive pulmonary disease, asthma, and cardiopulmonary dysfunction, are among the conditions that may present in persons living with HIV. Tobacco smoking, which is disproportionately high among persons living HIV, strongly contributes to the risk of pulmonary disease. Additionally, features associated with and at times unique to HIV, including persistent inflammation, immune cell activation, oxidative stress, and dysbiosis, may also contribute. This review summarizes the available literature regarding epidemiology of and risk factors for respiratory symptoms and chronic pulmonary disease in the current era.


Predictors of body appearance cognitive distraction during sexual activity in men and women.
Cognitive distraction is a core concept in cognitive models of sexual dysfunction. Body appearance cognitive distraction during sexual activity (BACDSA) has been mainly studied among female college samples. However, the relative contribution of different indicators of body dissatisfaction among men and women from community samples, including the contribution of relationship variables to BACDSA, has yet to be examined. The aim of this study was to examine the extent to which aspects of body dissatisfaction and relationship variables predict BACDSA. A total of 669 cohabitating, heterosexual, Portuguese participants (390 women and 279 men) with no sexual problems completed an anonymous online survey. The survey included a sociodemographic questionnaire and a set of questionnaires assessing body- and relationship-related variables. We used a single item measure of the participant's satisfaction with the opinion that they perceive their partner has about the participant's body (PPO); the Global Body Dissatisfaction Subscale of the Body Attitudes Test (GBD); a version of the Contour Drawing Rating Scale; the Global Measure of Relationship Satisfaction; and the Inclusion of Other in Self Scale. Focus on specific body parts during sexual activity (FBP) and relationship length were assessed with an open-ended question. Hierarchical multiple regression indicated that GBD and FBP were the only body dissatisfaction variables that significantly predicted BACDSA in both men and women. The relationship variables significantly increased the amount of variance explained in BACDSA for both men and women. However, PPO was the only significant relationship variable that predicted BACDSA and only in women. Body and relationship variables are significant factors in body appearance cognitive distraction. They require further research and assessment, particularly for clinical intervention.


Tuneable Phase, Morphology, and Performance of Bismuth Oxyhalide Photocatalysts via Microwave-Assisted Synthesis.
In this study, a facile microwave-assisted synthesis approach was used to produce a series of bismuth oxyhalide photocatalysts, with systematic changes in synthesis pH between 1 and 14 allowing control over a broad range of material properties and characteristics. Detailed structural and morphological investigations with powder X-ray diffraction (PXRD), Rietveld refinements, pair distribution function (PDF) analysis, and scanning electron microscopy (SEM) show that thin particles of BiOCl, BiOBr, Bi24O31Cl10, and Bi24O31Br10 were selectively produced, with progressive changes in morphology, facet dominance, and phase as a function of pH. The impact of these changes on photocatalytic performance was evaluated by studying the aerobic oxidation of benzylamine to N-benzylidenebenzylamine, with all materials exhibiting photocatalytic abilities under UV or blue light. While a combination of material properties and characteristics influenced the photocatalytic performance, certain factors such as surface area, facet dominance, amorphous content, and band gap were found to have a larger impact on the photocatalytic yield. Overall, this study demonstrates the possibilities of phase, morphology, and performance of bismuth oxyhalide photocatalysts over the entire pH range, produced using a fast and facile microwave-assisted synthesis technique as an alternative to the more widely applied hydrothermal synthesis approach. Additionally, the detailed structural and morphological investigations of the materials contribute to a greater understanding of bismuth oxyhalide photocatalysts in general, while also highlighting some of the most desirable properties for improved photocatalytic performance of these materials.


The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery.
Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-specific gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identified a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the final snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the first characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.


Single- and dual-pulse oscillation in a passively Q-switched Nd:YAG microchip laser.
Experimental investigation of single and dual pulses in a passively Q-switched Nd:YAG microchip laser with a Cr4+:YAG saturable absorber has been reported. The dual pulses consist of a main and a satellite pulse with respective spectra, intensities, and durations. It is found that the preponderant oscillating mode gives birth to the main pulse, and the other oscillating mode corresponds to the satellite pulse. Our results demonstrate that the dual-pulse emission results from double-longitudinal-mode oscillation in high pump regime.


Treatment of Cerebellar Ataxia in the Context of Systemic Diseases.
Purpose of review The purpose of this review is to assess the evidence behind treatment regimens for cerebellar ataxias occurring in the context of systemic disease. We will address systemic conditions which are associated with specific involvement of the cerebellum (rather than widespread nervous system involvement) and those conditions for which some degree of evidence of treatment response exists. Recent findings We have divided systemic disorders affecting the cerebellum into systemic immunological disorders, endocrine and metabolic disorders and paraneoplastic. Recent studies have increased understanding of the range of cerebellar disorders associated with a systemic immunological condition. The identification of newer pathogenic antibodies has improved diagnosis in conditions which would have previously been labelled as idiopathic. However, their rarity and phenotypic variability makes defining optimal immunomodulatory treatment regimens challenging. There is some evidence for beneficial effects of immunomodulation, particularly in anti-GAD ataxia and Hashimoto's encephalopathy, although, at this time, specific treatment regimens cannot be defined. Immune-mediated paraneoplastic cerebellar disorders show response to therapy dependent, to some extent, on the underlying pathogenic antibody. Much is still to be understood concerning treatment regimens for the ataxic manifestations of metabolic disorders, notably alcohol-induced cerebellar injury, which are common and which are associated with significant disability. Summary Despite their rarity, cerebellar ataxias occurring in the context of systemic disease cause significant morbidity and better therapies are required to improve outcomes associated with these conditions.


State of the psychometric methods: patient-reported outcome measure development and refinement using item response theory.
This paper is part of a series comparing different psychometric approaches to evaluate patient-reported outcome (PRO) measures using the same items and dataset. We provide an overview and example application to demonstrate 1) using item response theory (IRT) to identify poor and well performing items; 2) testing if items perform differently based on demographic characteristics (differential item functioning, DIF); and 3) balancing IRT and content validity considerations to select items for short forms. Model fit, local dependence, and DIF were examined for 51 items initially considered for the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Depression item bank. Samejima's graded response model was used to examine how well each item measured severity levels of depression and how well it distinguished between individuals with high and low levels of depression. Two short forms were constructed based on psychometric properties and consensus discussions with instrument developers, including psychometricians and content experts. Calibrations presented here are for didactic purposes and are not intended to replace official PROMIS parameters or to be used for research. Of the 51 depression items, 14 exhibited local dependence, 3 exhibited DIF for gender, and 9 exhibited misfit, and these items were removed from consideration for short forms. Short form 1 prioritized content, and thus items were chosen to meet DSM-V criteria rather than being discarded for lower discrimination parameters. Short form 2 prioritized well performing items, and thus fewer DSM-V criteria were satisfied. Short forms 1-2 performed similarly for model fit statistics, but short form 2 provided greater item precision. IRT is a family of flexible models providing item- and scale-level information, making it a powerful tool for scale construction and refinement. Strengths of IRT models include placing respondents and items on the same metric, testing DIF across demographic or clinical subgroups, and facilitating creation of targeted short forms. Limitations include large sample sizes to obtain stable item parameters, and necessary familiarity with measurement methods to interpret results. Combining psychometric data with stakeholder input (including people with lived experiences of the health condition and clinicians) is highly recommended for scale development and evaluation.


The structure of the TsaB/TsaD/TsaE complex reveals an unexpected mechanism for the bacterial t6A tRNA-modification.
The universal N6-threonylcarbamoyladenosine (t6A) modification at position A37 of ANN-decoding tRNAs is essential for translational fidelity. In bacteria the TsaC enzyme first synthesizes an l-threonylcarbamoyladenylate (TC-AMP) intermediate. In cooperation with TsaB and TsaE, TsaD then transfers the l-threonylcarbamoyl-moiety from TC-AMP onto tRNA. We determined the crystal structure of the TsaB-TsaE-TsaD (TsaBDE) complex of Thermotoga maritima in presence of a non-hydrolysable AMPCPP. TsaE is positioned at the entrance of the active site pocket of TsaD, contacting both the TsaB and TsaD subunits and prohibiting simultaneous tRNA binding. AMPCPP occupies the ATP binding site of TsaE and is sandwiched between TsaE and TsaD. Unexpectedly, the binding of TsaE partially denatures the active site of TsaD causing loss of its essential metal binding sites. TsaE interferes in a pre- or post-catalytic step and its binding to TsaBD is regulated by ATP hydrolysis. This novel binding mode and activation mechanism of TsaE offers good opportunities for antimicrobial drug development.


Short communication: Detection and monitoring of metritis in dairy cows using an automated grooming device.
Metritis, a prevalent disease on dairy farms, is negatively associated with reproduction, milk production, and the welfare of cows. The objective of this study was to evaluate the efficacy of monitoring low-resilience activities (i.e., behaviors that typically decrease when energy resources are limited or when the cost involved in the activity increases; e.g., brush usage) in the early detection of metritis. Data on daily brush usage (i.e., proportion of cows using the brush and the duration of usage) were collected from 28 metritic and 60 control cows 28 d postpartum using an automated monitoring system developed for the purpose of this study. During the first week following partum (before clinical diagnosis), we found no differences in brush usage between sick and control cows. However, 8 to 21 d postpartum (the week of clinical diagnosis and the first week of medical treatment), a lower proportion of metritic cows used the brush compared with control cows (0.49 compared with 0.64, respectively, at brushes installed away from the feed bunk). In addition, the daily duration of brush usage was 50% lower among cows diagnosed with metritis compared with control cows 8 to 28 d postpartum (44 s/d compared with 88 s/d, respectively). The results of this study suggest that on-farm monitoring of low-resilience behaviors, combined with existing systems that monitor core behaviors (e.g., activity and rumination), may serve as an improved method for detecting events that compromise the welfare of animals. The slow recovery of low-resilience behaviors following medical treatment (wk 4) might serve as a particularly useful indicator of progress of recovery from disease.


Mechanism Dictates Mechanics: A Molecular Substituent Effect in the Macroscopic Fracture of a Covalent Polymer Network.
The fracture of rubbery polymer networks involves a series of molecular events, beginning with conformational changes along the polymer backbone and culminating with a chain scission reaction. Here, we report covalent polymer gels in which the macroscopic fracture "reaction" is controlled by mechanophores embedded within mechanically active network strands. We synthesized poly(ethylene glycol) (PEG) gels through the end-linking of azide-terminated tetra-arm PEG (Mn = 5 kDa) with bis-alkyne linkers. Networks were formed under identical conditions, except that the bis-alkyne was varied to include either a cis-diaryl (1) or cis-dialkyl (2) linked cyclobutane mechanophore that acts as a mechanochemical "weak link" through a force-coupled cycloreversion. A control network featuring a bis-alkyne without cyclobutane (3) was also synthesized. The networks show the same linear elasticity (G' = 23-24 kPa, 0.1-100 Hz) and equilibrium mass swelling ratios (Q = 10-11 in tetrahydrofuran), but they exhibit tearing energies that span a factor of 8 (3.4 J, 10.6, and 27.1 J·m-2 for networks with 1, 2, and 3, respectively). The difference in fracture energy is well-aligned with the force-coupled scission kinetics of the mechanophores observed in single-molecule force spectroscopy experiments, implicating local resonance stabilization of a diradical transition state in the cycloreversion of 1 as a key determinant of the relative ease with which its network is torn. The connection between macroscopic fracture and a small-molecule reaction mechanism suggests opportunities for molecular understanding and optimization of polymer network behavior.


Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report.
Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple cafè-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease.


Neonatal chest wall afferents and regulation of respiration.
We have studied two groups of eight preterm infants, relating chest wall afferent information to respiratory timing. Rib cage and abdominal motion were monitored by magnetometers and flow and tidal volume via a face mask. In the first group, studies were done in REM sleep when spontaneously occurring distortion of the rib cage occurred and a significant linear relationship between the rate of distortion of the chest wall and shortening of the inspiratory time (Ti) was found in all infants. Reduction in this distortion by the use of continuous positive airway pressure (CPAP) or continuous negative pressure at the body surface (CNeg) was associated with a significant (P less than 0.01) lengthening of Ti. Absence of changes in Ti when pressure was applied in quiet sleep suggested that lung volume or chemical changes were not involved. In the second group of infants we artificially generated the afferent inflow by using vibratory stimuli applied in one intercostal interspace and produced a significant (P less than 0.05) shortening in Ti. We suggest that the distortion of the rib cage in REM sleep generates afferent information from intercostal muscle spindles that is related to the rate of distortion and this, via a supraspinal reflex, inhibits phrenic motoneuron discharge. It may then be of importance in the etiology of apneic episodes in these infants. Applied pressure may be of benefit because it reduces an inhibitory afferent inflow.


Intranasal nicotine increases postoperative nausea and is ineffective in reducing pain following laparoscopic bariatric surgery in tobacco-Naïve females: a randomized, double blind trial.
Nicotine is a known analgesic. Our primary aim was to test the hypothesis that intranasal nicotine administered intraoperatively reduces the need for postoperative opioids. The secondary outcomes included evaluation of both postoperative pain and nausea and vomiting (PONV). Nonsmoking female patients undergoing laparoscopic bariatric operations were randomized to receive either 3 mg intranasal nicotine (N = 42) or placebo spray (N = 47) at the conclusion of surgery. Postoperative opioid use converted to intravenous morphine equivalents (iv MEQ) and PONV rates were recorded during both the recovery room postanesthesia care unit (PACU) stay and the first 24 postoperative hours. All patients received multimodal antiemetic prophylaxis. Total iv MEQ were not significantly reduced during the PACU stay in patients receiving nicotine (median [interquartile range (IQR)], 5.3 [0, 10.0] mg for nicotine vs. 5.2 [0, 12.7] mg for placebo, one-tailed P = 0.414) or for the first 24 h following PACU discharge (39.6 [20.0, 52.5] mg for nicotine vs. 32.7 [20.3, 51.3] mg for placebo, one-tailed P = 0.752). For the combined period (PACU + 24-h post-PACU discharge), iv MEQ were 45.8 [27.0, 58.6] mg for nicotine and 39.4 [23.5, 60.0] mg for placebo, one-tailed P = 0.801. Compared to placebo, a higher percentage of patients administered nicotine received antiemetics in the PACU (57.1 vs. 25.5 %, P = 0.002). Intraoperative intranasal nicotine did not exhibit opioid-sparing effect in nonsmoking bariatric female patients. Despite antiemetic prophylaxis, the use of nicotine was associated with the higher frequency of the use of rescue antiemetics in PACU.


Gamma irradiations induced morphological and biochemical variations in in vitro regenerated ginger (Zingiber officinale rosc.)- an invaluable medicinal spice.
To evaluate the effect of gamma irradiations on morphological and biochemical variations of in vitro shoots, regenerated plants and rhizomes of ginger (Zingiber officinale Rosc.) var. Himgiri. In vitro established shoot cultures were treated with different doses of gamma irradiations (10-100 Gy). Nonirradiated shoots were used as controls. Radio sensitivity of shoots and in vitro growth parameters were recorded. Surviving shoots along with controls were multiplied, rooted and hardened. Irradiation effect on chromosomes was evaluated by comparing with controls. Various morphological and biochemical observations were recorded in regenerated plants and rhizomes and compared to controls. Irradiated shoots showed decline in survival percentage (95% in 10 Gy to 12.33% in 100 Gy) with increase in dose rate after 4 weeks of irradiation. Shoot survival significantly decreased with irradiation dose rate above 20 Gy. Shoot multiplication rate showed an increase from 1:2 in 1st subculture to 1:9 after 5th subculture, in 10 Gy irradiated cultures with 4.5 cm average length of shoots and 8.19 number of leaves after 5th subculture. Average rooting showed an increase from 15.55% after 2nd subculture to 100% after 5th subculture, in 10 Gy irradiated shoots; however, no multiplication and rooting was observed in higher doses. In vitro rooted shoots were subjected to hardening with 100 percent survival in a mixture comprised of soil, cocopeat and FYM. One-year-old hardened plants when observed for morphological variations showed nonsignificant variations in comparison to controls. Rhizomes obtained from 10 Gy irradiated plants showed enhanced concentration of 6-gingerol and reduced crude fiber content when compared with controls. Gamma irradiation doses up to 10 Gy resulted in nonsignificant phenotypic variations but can positively affect biochemical composition of rhizomes leading to development of biochemically improved mutant lines of ginger with increased 6-gingerol and lowered crude fiber content. Therefore, suggesting the lower doses of gamma irradiations for improvement of biochemical constituents in vegetatively propagated plants.


The gene encoding IIAB(Man)L in Streptococcus salivarius is part of a tetracistronic operon encoding a phosphoenolpyruvate: mannose/glucose phosphotransferase system.
Glucose and mannose are transported in streptococci by the mannose-PTS (phosphoenolpyruvate:mannose phosphotransferase system), which consists of a cytoplasmic IIAB protein, called IIAB(Man), and an uncharacterized membrane permease. This paper reports the characterization of the man operon encoding the specific components of the mannose-PTS of Streptococcus salivarius. The man operon was composed of four genes, manL, manM, manN and manO. These genes were transcribed from a canonical promoter (Pman) into a 3.6 kb polycistronic mRNA that contained a 5'-UTR (untranslated region). The predicted manL gene product encoded a 35.5 kDa protein and contained the amino acid sequences of the IIA and IIB phosphorylation sites already determined from purified S. salivarius IIAB(Man)L. Expression of manL in Escherichia coli generated a 35 kDa protein that reacted with anti-IIAB(Man)L antibodies. The predicted ManM protein had an estimated size of 27.2 kDa. ManM had similarity with IIC domains of the mannose-EII family, but did not possess the signature proposed for mannose-IIC proteins from Gram-negative bacteria. From multiple alignment analyses of sequences available in current databases, the following modified IIC(Man) signature is proposed: GX3G[DNH]X3G[LIVM]2XG2[STL][LT][EQ]. The deduced product of manN was a hydrophobic protein with a predicted molecular mass of 33.4 kDa. The ManN protein contained an amino acid sequence similar to the signature sequence of the IID domains of the mannose-EII family. manO encoded a 13.7 kDa protein. This gene was also transcribed as a monocistronic mRNA from a promoter located in the manN-manO intergenic region. A search of current databases revealed the presence of IIAB(Man)L, ManM, ManN and ManO orthologues in Streptococcus mutans, Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis. This work has elucidated the molecular structure of the mannose PTS in streptococci and enterococci, and demonstrated the presence of a putative regulatory protein (ManO) within the man operon.


Treatment of syphilis in pregnancy.
Only penicillin has been adequately studied in treating syphilis during pregnancy. It is safe for the fetus and highly effective in doses currently recommended by the USPHS. Since these schedules appear to represent a minimal effective dose, smaller amounts should never be used. Whether higher doses would produce higher cure rates is not known. Penicillin is the drug of choice and the standard against which all others must be measured. Tetracyclines in any dose or form should not be used because of toxicity to both mother and child. Erythromycin (except the estolate) and cephalosporins are promising because of low toxicity, but their efficacy has not been established.


[Ciguatera fish poisoning in New Caledonia. Clinical and epidemiological aspects (author's transl)].
The author studies the incidence of ciguatera fish poisoning on the public health in New Caledonia. He gives the results of a large scaled inquiry on the clinical and epidemiological aspects of the disease. The geographical distribution and the toxic species are discussed. It does appear that, though being not an acute medical problem, ciguatera is an important cause of morbidity in some tribus of the Pines and Loyalty Islands primarily, where the reef fish is the chief animal proteic resource.


Smart, Biomimetic Periosteum Created from the Cerium(III, IV) Oxide-Mineralized Eggshell Membrane.
The periosteum orchestrates the microenvironment of bone regeneration, including facilitating local neuro-vascularization and regulating immune responses. To mimic the role of natural periosteum for bone repair enhancement, we adopted the principle of biomimetic mineralization to delicately inlay amorphous cerium oxide within eggshell membranes (ESMs) for the first time. Cerium from cerium oxide possesses unique ability to switch its oxidation state from cerium III to cerium IV and vice versa, which provides itself promising potential for biomedical applications. ESMs are mineralized with cerium(III, IV) oxide and examined for their biocompatibility. Apart from serving as physical barriers, periosteum-like cerium(III, IV) oxide-mineralized ESMs are biocompatible and can actively regulate immune responses and facilitate local neuro-vascularization along with early-stage bone regeneration in a murine cranial defect model. During the healing process, cerium-inlayed biomimetic periosteum can boost early osteoclastic differentiation of macrophage lineage cells, which may be the dominant mediator of the local repair microenvironment. The present work provides novel insights into expanding the definition and function of a biomimetic periosteum to boost early-stage bone repair and optimize long-term repair with robust neuro-vascularization. This new treatment strategy which employs multifunctional bone-and-periosteum-mimicking systems creates a highly concerted microenvironment to expedite bone regeneration.


The relationship between conidial germination and esterase activities in Neurospora crassa.
Esterase activity in rapidly germinating Neurospora conidia was several times higher than the esterase activity in conidia which germinate slowly. Starch gel electrophoresis experiments demonstrated the existence of esterase isoenzymes which are specific to the conidia. These isoenzymes completely disappeared during 20 h of conidial germination at 30 degrees C. Electron microscopy showed the successive breakdown of electron-dense compounds in storage bodies during conidial germination. These observations, taken together, indicate that the electron-dense compounds may be hydrolysed by specific esterases to serve as an endogenous energy and material source for germ tube formation. The levels of esterase activity, however, were not always proportional to the time required for conidial germination, indicating the possibility that additional enzyme systems might also be involved in the initial stages of germination.


[Characteristics of the biological properties of a Kemerovo group arbovirus isolated in Transcarpathia].
A strain of an arbovirus named Mircha was isolated from Ixodes ricinus L. ticks (30 incompletely engorged females) collected in May, 1972 from cows pastured in a forest near the village of Mircha of the Velikobereznyansky district of the Zakarpathye region of the Ukrainian SSR. The strain was found to be pathogenic for newborn white mice and rats by the intracerebral and intraperitoneal routes and for chick embryos inoculated into the yolk sac, to replicate in chick embryo fibroblast culture producing a marked cytopathic effect to be relatively stable to ethyl ether and sodium deoxylate. On the basis of the results of serological identification (CFT) it was classified into arboviruses of the Kemerovo group, the antigenic subgroup Kemeroxo-Tribec. The factors of natural focality are described briefly, and the results of the study of virus persistence in adult white mice, rats, and guinea pigs and of its immunodepressive effect are presented.


Pharmacometric modeling to explore 4F-PCC dosing strategies for VKA reversal in patients with INR below 2.
The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR. FX and FII levels over time were simulated for mean baseline INR levels of the clinical trial participants plus baseline INRs 3.1, 1.9, and 1.6. For each INR, 200 virtual male patients were simulated to evaluate 4F-PCC doses of 35, 25, 20, 15, 12.5, and 10 IU/kg. Given an elevated bleeding risk with VKA therapy in Japanese vs Western populations, results were stratified by Japanese and non-Japanese patients. Target levels of FX and FII were ≥50% activity at 30 minutes after dosing in ≥80% of patients. FX- and FII-time models were developed with 1088 FX observations from 193 patients and 1074 FII observations from 192 patients. Model-based simulations indicated that at baseline INR 3.1, ≥80% of patients achieved ≥50% FX and FII activity with 25 IU/kg and 20 IU/kg 4F-PCC, respectively; at baseline INR 1.9, corresponding doses were 20 IU/kg and 15 IU/kg 4F-PCC, and at baseline INR 1.6, corresponding doses were 15 IU/kg, and 10 IU/kg 4F-PCC. Trends in Japanese and non-Japanese patients were similar. In conclusion, low 4F-PCC doses (15-20 IU/kg) may be sufficient to achieve hemostatic levels of FX and FII in Japanese and non-Japanese patients with baseline INR <2.


The Establishment of a Noninvasive Bioluminescence-Specific Viral Encephalitis Model by Pseudorabies Virus-Infected NF-κBp-Luciferase Mice.
Encephalitis is a rare brain inflammation that is most commonly caused by a viral infection. In this study, we first use an in vivo imaging system (IVIS) to determine whether NF-κBp-luciferase expression could be detected in the brain of pseudorabies virus (PRV)-infected NF-κBp-luciferase mice and to evaluate proinflammatory mediators in a well-described mouse model of PRV encephalitis. In in vitro studies, we used murine microglia (BV-2) cells to demonstrate the PRV-induced encephalitis model entailing the activation of microglia cells. The results indicate that PRV-induced neuroinflammation responses through the induction of IL-6, TNF-α, COX-2, and iNOS expression occurred via the regulation of NF-κB expression in BV-2 cells. In in vivo studies, compared with MOCK controls, the mice infected with neurovirulent PRV exhibited significantly elevated NF-κB transcription factor activity and luciferase protein expression only in the brain by IVIS. Mild focal necrosis was also observed in the brain. Further examination revealed biomarkers of inflammation, including inducible cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF)-α and interleukin (IL)-6, both of which constituted proinflammatory cytokines. PRV infection stimulated inflammation and COX-2 and iNOS expression of IL-6 and TNF-α. The presented results herein suggest that PRV induces iNOS and COX-2 expression in the brain of NF-κBp-luciferase mice via NF-κB activation. In conclusion, we used NF-κBp-luciferase mice to establish a specific virus-induced encephalitis model via PRV intranasal infection. In the future, this in vivo model will provide potential targets for the development of new therapeutic strategies focusing on NF-κB inflammatory biomarkers and the development of drugs for viral inflammatory diseases.


MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure.
Assessment of prognosis in fulminant hepatic failure (FHF) is essential for the need and appropriate timing of orthotopic liver transplantation (OLT). In this study we investigated the prognostic efficacy of King's College criteria, Clichy's criteria, Model for End-Stage Liver Disease (MELD), and Pediatric End-Stage Liver Disease (PELD) in 120 consecutive patients with FHF. Survival with medical therapy (18%), death without OLT (15%), and receipt of a liver transplant were similar in adults (n = 64) and children (n = 56). MELD scores were significantly higher in patients who died compared to those who survived without OLT, both in adults (38 +/- 7 vs. 26 +/- 7, P = 0.0003) and children (39 +/- 7 vs. 23 +/- 6, P = 0.0004). Using logistic regression analysis in this cohort of patients, concordance statistics were significantly higher for MELD (0.95) and PELD (0.99) when compared to King's College (0.74) and Clichy's criteria (0.68). When data was analyzed in a Cox model including patients receiving transplants and censoring the time from admission, the concordance statistic for MELD (0.77) and PELD (0.79) remained significantly higher than that of King's College criteria but not higher than that of Clichy's criteria. In conclusion, this study is the first to show that MELD and PELD are superior to King's College and Clichy's criteria to assess prognosis in FHF. However, because data was generated from a single center and included a rather low number of patients who survived or died without OLT, further confirmation of our findings is required.


Encapsulation of soybean meal with fats enriched in palmitic and stearic acids: effects on rumen-undegraded protein and in vitro intestinal digestibility.
Fat coating of soybean meal (SBM) can reduce its protein degradability in the rumen, but the encapsulation of SBM with palmitic (PA) and stearic acids (SA) has not yet been investigated, despite both fatty acids are common energy sources in dairy cow diets. This study aimed to evaluate the effects of applying a novel method, using either 400 or 500 g fat/kg (treatments FL40 and FL50, respectively), which was enriched in PA and SA at different ratios (100:0, 75:25, 50:50, 25:75 and 0:100), on physical and chemical characteristics, ruminal degradability, solubility and in vitro intestinal protein digestibility (IVIPD) of the obtained products. Encapsulation of SBM in fat resulted in greater mean particle size and lower bulk density and protein solubility than unprotected SBM (USBM). Treatment FL50 resulted in increased (p < 0.01) rumen-undegraded protein (RUP) compared to USBM. There were no differences in RUP of SBM when different PA: SA ratios were used. The mean RUP content of treatments FL40 and FL50 (306 and 349 g/kg, respectively) was greater compared to USBM (262 g/kg, p < 0.05), but lower than that for a standard heat-treated SBM (431 g/kg). Values of IVIPD did not differ among SBM, heat-treated SBM and FL40 and FL50 samples, all being greater than 97.8%. In conclusion, encapsulation of SBM with fats enriched in PA and SA proved to be effective in reducing protein solubility and increasing RUP without depressing protein digestibility in the intestine. For validation of the method, in vivo research to investigate the effects of these products on the production of dairy cows is warranted.


The transition of closely opposed lesions to double-strand breaks during long-patch base excision repair is prevented by the coordinated action of DNA polymerase delta and Rad27/Fen1.
DNA double-strand breaks can result from closely opposed breaks induced directly in complementary strands. Alternatively, double-strand breaks could be generated during repair of clustered damage, where the repair of closely opposed lesions has to be well coordinated. Using single and multiple mutants of Saccharomyces cerevisiae (budding yeast) that impede the interaction of DNA polymerase delta and the 5'-flap endonuclease Rad27/Fen1 with the PCNA sliding clamp, we show that the lack of coordination between these components during long-patch base excision repair of alkylation damage can result in many double-strand breaks within the chromosomes of nondividing haploid cells. This contrasts with the efficient repair of nonclustered methyl methanesulfonate-induced lesions, as measured by quantitative PCR and S1 nuclease cleavage of single-strand break sites. We conclude that closely opposed single-strand lesions are a unique threat to the genome and that repair of closely opposed strand damage requires greater spatial and temporal coordination between the participating proteins than does widely spaced damage in order to prevent the development of double-strand breaks.


Circulating microRNAs: macro-utility as markers of prostate cancer?
The realization that microRNAs (miRNAs) are frequently deregulated in malignancy has had a major impact on cancer research. In particular, the recent finding that highly stable forms of miRNAs can be accurately measured in body fluids, including blood, has generated considerable excitement. Here, we discuss the potential of blood-based circulating miRNAs as diagnostic, prognostic, and predictive biomarkers of prostate cancer. We also describe practical considerations that may influence identification and/or measurement of miRNA biomarkers in the circulation. Finally, evidence is prevented for the emerging concept that circulating miRNAs are actively released by their cells of origin and can modulate gene expression at distal sites. These mobile miRNAs, which we term 'hormomirs' because of their hormone-like characteristics, could act as local or long-range signals to maintain normal homeostasis or influence the development and progression of diseases such as cancer.


Early cognitive impairment in a subset of patients with presumed low-grade glioma.
We investigated the presence of cognitive impairment, in adults with presumed low-grade glioma at early stage of disease prior to major treatments, in relation to neurological symptoms and radiological characteristics of the tumour. Sixteen patients were evaluated. A subset of patients was identified with clearly impaired cognition. Patients with cognitive impairment often had large tumours in the left frontal lobe, were relatively young, and most of them were males. We conclude that cognitive dysfunction may be present already at early stage of disease, and that early identification of patients at risk is warranted.


A nonparametric method to generate synthetic populations to adjust for complex sampling design features.
Outside of the survey sampling literature, samples are often assumed to be generated by a simple random sampling process that produces independent and identically distributed (IID) samples. Many statistical methods are developed largely in this IID world. Application of these methods to data from complex sample surveys without making allowance for the survey design features can lead to erroneous inferences. Hence, much time and effort have been devoted to develop the statistical methods to analyze complex survey data and account for the sample design. This issue is particularly important when generating synthetic populations using finite population Bayesian inference, as is often done in missing data or disclosure risk settings, or when combining data from multiple surveys. By extending previous work in finite population Bayesian bootstrap literature, we propose a method to generate synthetic populations from a posterior predictive distribution in a fashion inverts the complex sampling design features and generates simple random samples from a superpopulation point of view, making adjustment on the complex data so that they can be analyzed as simple random samples. We consider a simulation study with a stratified, clustered unequal-probability of selection sample design, and use the proposed nonparametric method to generate synthetic populations for the 2006 National Health Interview Survey (NHIS), and the Medical Expenditure Panel Survey (MEPS), which are stratified, clustered unequal-probability of selection sample designs.


Bridge Damage Detection Approach Using a Roving Camera Technique.
Increasing extreme climate events, intensifying traffic patterns and long-term underinvestment have led to the escalated deterioration of bridges within our road and rail transport networks. Structural Health Monitoring (SHM) systems provide a means of objectively capturing and quantifying deterioration under operational conditions. Computer vision technology has gained considerable attention in the field of SHM due to its ability to obtain displacement data using non-contact methods at long distances. Additionally, it provides a low cost, rapid instrumentation solution with low interference to the normal operation of structures. However, even in the case of a medium span bridge, the need for many cameras to capture the global response can be cost-prohibitive. This research proposes a roving camera technique to capture a complete derivation of the response of a laboratory model bridge under live loading, in order to identify bridge damage. Displacement is identified as a suitable damage indicator, and two methods are used to assess the magnitude of the change in global displacement under changing boundary conditions in the laboratory bridge model. From this study, it is established that either approach could detect damage in the simulation model, providing an SHM solution that negates the requirement for complex sensor installations.


First Report of Rust Disease Caused by Uromyces galegae on Galega officinalis in Turkey.
Galega officinalis L. is an obnoxious invasive weed in the United States and a potential target for biological control efforts. The plant, a member of the legume family, is native to western Asia and southern Europe. During September 2001, uredinial pustules were observed on leaves of G. officinalis L. in Kizilcahamam, Ankara. Specimens were examined microscopically and compared with published descriptions (2) and herbarium specimens in the U.S. National Fungus Collections, Beltsville, MD. The fungus was subsequently identified as Uromyces galegae (Opiz) Sacc. on the basis of morphological characteristics of the uredinia, urediniospores, and teliospores. The following description is from the Turkish material: uredinia subcircular to oblong, hypophyllous, rarely epiphyllous at petiole, and 0.5 to 1 mm in diameter; urediniospores subovoid to subglobose, 17.5 to 20.0 × 19.5 to 22.5 μm (average = 18.0 × 20.0 μm), wall 1 to 2 μm thick, finely echinulate, cinnamon brown, and with 3 to 5 usually equatorial germ pores; telia similar to uredinia; teliospores irregular in shape ranging from globose to ovoid to triangular, apex papillate, wall 2 to 3 μm thick, thicker at the apex, chestnut brown, strongly verrucose to tuberculate, 17.5 to 22.5 × 22.5 to 27.5 μm (average = 20.3 × 24.5 μm), pedicel hyaline, and easily broken. Voucher specimens are deposited in the U.S. National Fungus Collections (BPI 863535); a nucleotide sequence spanning the ITS2 and 28S rDNA genes of this isolate was obtained and deposited in Gen-Bank (Accession No. DQ250133). U. galegae has been reported on G. officinalis from Bulgaria, Greece, and Italy (1). To our knowledge, this is the first report of U. galegae in Turkey and marks the eastern-most record for its distribution. References: (1) D. F. Farr et al. Fungal Databases. Systematic Botany and Mycology Laboratory, On-line publication, USDA-ARS, 2005. (2) M. Pantidou and D. M. Henderson. Notes R. Bot. Gard. Edinb. 29:277, 1969.


Chemosense for luminal environment in the large intestine.
Gut lumen is continually exposed to many agents, including noxious compounds. The intestinal epithelia form a barrier between the internal and luminal (external) environments. Chemical receptors that detect the luminal environment are thought to play an important role as sensors and as modulators of epithelial cell functions. The Molecular analysis of various epithelial cell membrane receptor proteins has elucidated the sensory role of these cells in the gut chemosensing system. Nutrient sensing systems by these receptors in the small intestinal epithelia are thought to influence nutrient metabolism and local physiological function. Much less is known, however, about the physiological roles of chemosensing in the large intestine. We have investigated the contractile and secretory effects of short-chain fatty acids (SCFAs), the primary products of commensal bacteria, and the expression of SCFA receptors in the large intestine. The findings indicate that the epithelia in the large intestine also detect and respond to luminal contents, particularly bacterial metabolites, for host defense. We recently reported that luminal bitter tastants and odorants affect transepithelial ion transport in human and rat colon, and that putative receptors are expressed in colonic mucosa. In this review, we describe the secretory effects of chemical stimuli on lumen associated with the expression pattern of sensory receptors, focusing on the large intestine.


Ghrelin antagonist overrides the mRNA expression of NPY in hypothalamus in feed restricted ewes.
A negative energy balance (NEB) is detrimental to reproduction in animals. A suggested link between NEB and reproductive failure is the gastrointestinal hormone ghrelin, because of the association between ghrelin and the hypothalamo-pituitary-gonadal axis. The [D-Lys3]-Growth Hormone Releasing Peptide-6 ([D-Lys3]-GHRP-6) is a ghrelin antagonist that acts on ghrelin receptors (GHS-R1). The objective of this study was to evaluate the effect of [D-Lys3]-GHRP-6 on reproduction variables in feed restricted ewes. Two experiments were conducted. Experiment I was conducted for 30 days; and Experiment II for 13 days. In both experiments the ewes (n = 18) were randomly assigned to: Control (CO): fed to meet maintenance requirements; Feed restriction (FR): 80% of maintenance restriction; or Ghrelin antagonist (GA): feed restricted and daily subcutaneous of 7.5μg/kg of [D-Lys3]-GHRP-6. Plasma was collected to measure hormones and metabolite concentration. In Experiment II, the hypothalamus and ovaries were collected on day 13. In both Experiments, sheep allocated to the FR and GA treatments decreased their body weight compared with sheep in the CO group (P < 0.06); progesterone however, did not differ between treatments (P > 0.10). Experiment I: Plasma ghrelin concentration was greater (P < 0.01) in FR and GA compared with CO ewes. Plasma non-esterified fatty acids concentration was greater (P < 0.01) in GA and FR than CO. Experiment II: Kisspeptin1-Receptor (Kiss1-R) mRNA expression was greater in FR (P < 0.01) and tended to be greater in GA (P = 0.10) compared with CO ewes. The neuro peptide-Y (NPY) mRNA expression was greater (P = 0.03) in FR than CO; and tended to be greater (P = 0.06) compared with GA ewes. Growth hormone releasing hormone (GhRH) mRNA expression was greater in GA (P = 0.04) and tended to be greater in FR (P = 0.07) compared with CO ewes. Feed restriction increased GhRH, NPY, and Kiss-R mRNA expression in hypothalamus without affecting reproductive variables.Ghrelin antagonist may prevent an increase inNPY expression in ewes.