Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL.
This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation (~20 % survival). Control groups included a particle control (TiO2), chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 μm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470-715; chrysotile 495-614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 μm were observed in the lungs at the end of exposure and no fibers L > 20 μm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 fibers(L > 20 μm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 fibers(L > 20 μm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 fibers(L > 20 μm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 fibers(L > 20 μm)/lung representing 10-13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations. The exposure and lung burden results provide a sound basis for assessing the potential toxicity of the brake dust in comparison to the TiO2 particle control and the chrysotile, crocidolite and amosite asbestos control groups. The BAL results provide an initial indication of the differential response. Part 2 presents the presentation and discussion of the histopathological and confocal microscopy findings in this study through 90 days post exposure.


Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors.
This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities. The EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed. The EGAPP Working Group found no evidence linking testing for CYP450 to clinical outcomes in adults treated with SSRIs. While some studies of a single SSRI dose in healthy patients report an association between genotypic CYP450 drug metabolizer status and circulating SSRI levels, this association was not supported by studies of patients receiving ongoing SSRI treatment. Further, CYP450 genotypes are not consistently associated with the patient outcomes of interest, including clinical response to SSRI treatment or adverse events as a result of treatment. No evidence was available showing that the results of CYP450 testing influenced SSRI choice or dose and improved patient outcomes, or was useful in medical, personal, or public health decision-making. In the absence of evidence supporting clinical utility, it is not known if potential benefits from CYP450 testing will outweigh potential harms. Potential harms may include increased cost without impact on clinical decision making or improvement in patient outcomes, less effective treatment with SSRI drugs, or inappropriate use of genotype information in the management of other drugs metabolized by CYP450 enzymes.


Short-term results of gastrectomy with Roux-en-Y or Billroth II anastomosis for peptic ulcer. A prospective comparative study.
Since the Roux-en-Y anastomosis prevents the sequela of postoperative enterogastric reflux after gastrectomy, this approach has been advocated as the primary procedure in patients undergoing gastrectomy for peptic ulcer. We have prospectively followed for 2 years 22 patients, in whom gastrectomy was performed with, at random, either Roux-en-Y (n = 11) or Billroth II (n = 11) anastomosis. Two of the 11 patients who had received the Roux-en-Y procedure had anastomotic ulcers, leading to reresection in one of them. These two patients were found to have the highest values for basal and pentagastrin stimulated gastric acid output. After the Billroth II procedure a single patient had a small anastomotic ulcerative lesion. Apart from differences in intragastric bile acids (p less than 0.0001) and the gastritis activity score (p less than 0.01), no significant differences were found between the patients with Roux-en-Y and Billroth II anastomosis with respect to basal and pentagastrin-stimulated gastric acid secretion, basal, postprandial and bombesin-stimulated serum gastrin secretion, serum pepsinogen A and C concentrations, the serum pepsinogen A/C ratio, postprandial glucose, and for a modified Visick grading. From this small series we conclude that, as compared with the Billroth II-anastomosis, the Roux-en-Y procedure effectively prevents enterogastric reflux, and is associated with a higher gastritis activity score, but not with differences in gastric acid, gastrin, pepsinogens, or Visick grading. Furthermore, inadequate reduction of acid secretion in some patients after the Roux-en-Y procedure may lead to recurrent peptic ulcers.


Highly efficient interconnection for use with a multistage optical switching network with orthogonally polarized data and address information.
A novel optical interconnection is introduced for a multistage optical switching network that uses orthogonally polarized data and address information. The network is unique in that the data information is never regenerated and remains in optical form throughout (i.e., it is never converted into electrical information). This has two main consequences: (1) the bandwidth of the data is not restricted by electrical circuit considerations, and (2) the optical interconnections from one stage of the network to the next must be highly efficient. The interconnection meets several goals: high efficiency, preservation of cross polarization of data and address, low cross talk between polarizations, good manufacturability, resistance to misalignment caused by thermal expansion, and absence of significant aberrations. In addition, sychronization of the signals is maintained, as the optical path lengths for all routes through the system are equal.


Exploring the Links between Post-Industrial Landscape History and Ecology through Participatory Methods.
There is increasing recognition of the importance for local biodiversity of post-mining sites, many of which lie near communities that have suffered significant social and economic deprivation as the result of mine closures. However, no studies to date have actively used the knowledge of local communities to relate the history and treatment of post-mining sites to their current ecological status. We report a study of two post-mining sites in the Yorkshire coalfield of the UK in which the local community were involved in developing site histories and assessing plant and invertebrate species composition. Site histories developed using participatory GIS revealed that the sites had a mixture of areas of spontaneous succession and technical reclamation, and identified that both planned management interventions and informal activities influenced habitat heterogeneity and ecological diversity. Two groups of informal activity were identified as being of particular importance. Firstly, there has been active protection by the community of flower-rich habitats of conservation value (e.g. calcareous grassland) and distinctive plant species (e.g. orchids) which has also provided important foraging resources for butterfly and bumblebee species. Secondly, disturbance by activities such as use of motorbikes, informal camping, and cutting of trees and shrubs for fuel, as well as planned management interventions such as spreading of brick rubble, has provided habitat for plant species of open waste ground and locally uncommon invertebrate species which require patches of bare ground. This study demonstrates the importance of informal, and often unrecorded, activities by the local community in providing diverse habitats and increased biodiversity within a post-mining site, and shows that active engagement with the local community and use of local knowledge can enhance ecological interpretation of such sites and provide a stronger basis for successful future management.


Identification of a novel zinc-binding protein, C1orf123, as an interactor with a heavy metal-associated domain.
Heavy metal-associated (HMA) domains bind metal ions at its Cys-x-x-Cys (CxxC) motif and constitute an intracellular network for trafficking of metal ions for utilization and detoxification. We thus expect that novel metalloproteins can be identified by screening proteins interacting with a HMA domain. In this study, we performed yeast two-hybrid screening of the human proteome and found an uncharacterized protein encoded as open reading frame 123 in chromosome 1 (C1orf123) that can interact specifically with the HMA domain of a copper chaperone for superoxide dismutase (CCSdI). Our X-ray structural analysis of C1orf123 further revealed that it binds a Zn2+ ion in a tetrahedral coordination with four thiolate groups from two conserved CxxC motifs. For the interaction between C1orf123 and CCSdI, the CxxC motifs in both C1orf123 and CCSdI were required, implying metal-mediated interaction through the CxxC motifs. Notably, C1orf123 did not interact with several other HMA domains containing CxxC motifs, supporting high specificity in the interaction between C1orf123 and CCSdI. Based upon these results, we further discuss functional and structural significance of the interaction between C1orf123 and CCS.


SMC proteins constitute two subunits of the mammalian recombination complex RC-1.
Recombination protein complex RC-1, purified from calf thymus nuclear extracts, catalyzes cell-free DNA strand transfer and repair of gaps and deletions through DNA recombination. DNA polymerase E, DNA ligase III and a DNA structure-specific endonuclease co-purify with the five polypeptide complex. Here we describe the identification of two hitherto unknown subunits of RC-1. N-terminal amino acid sequences of the 160 and 130 kDa polypeptides display up to 100% identity to proteins of the structural maintenance of chromosomes (SMC) subfamilies 1 and 2. SMC proteins are involved in mitotic chromosome segregation and condensation, as well as in certain DNA repair pathways in fission (rad18 gene) and budding (RHC18 gene) yeast. The assignment was substantiated by immuno-cross-reactivity of the RC-1 subunits with polyclonal antibodies specific for Xenopus laevis SMC proteins. These antibodies, and polyclonal antibodies directed against the bovine 160 and 130 kDa polypeptides, named BSMC1 and BSMC2 (bovine SMC), inhibited RC-1-mediated DNA transfer, indicating that the SMC proteins are necessary components of the reaction. Two independent assays revealed DNA reannealing activity of RC-1, which resides in its BSMC subunits, thereby demonstrating a novel function of these proteins. To our knowledge, this is the first evidence for the association of mammalian SMC proteins with a multiprotein complex harboring, among others, DNA recombination, DNA ligase and DNA polymerase activities.


Feasibility and implementation of a healthy lifestyles program in a community setting in Ontario, Canada: protocol for a pragmatic mixed methods pilot study.
Rates of chronic conditions, such as diabetes, cardiovascular disease and obesity are increasing in Canada and internationally. There are effective lifestyle interventions that are known to improve chronic conditions. However, there is often a gap in 'how to' make lifestyle changes. Mental health and other determinants of health play a role in the development and progression of chronic conditions. Changing habits takes time and requires the use of multiple techniques, including mental health and behavioural change strategies, based on a person's needs. A new, multidisciplinary, person-centred and evidence-based and practice-based programme has been created to address these needs. This proposal aims to evaluate the feasibility and implementation of this programme and to determine changes in participant-directed and clinical outcomes through a pilot study. A pragmatic mixed methods design will be used to study multiple dimensions of the year-long healthy lifestyles programme. The pilot study includes a randomised controlled trial, with 30 participants randomised to either the programme or to a comparator arm, and qualitative components to determine the feasibility of the programme, including recruitment and retention, data missing rates and resources needed to run this programme. Changes in participant-directed and clinical outcomes will be measured. Descriptive statistics, t-tests and repeated measures analysis of variance (ANOVA) for within group comparisons and generalised estimating equations for between group analyses will be used. Qualitative interviews of programme staff and healthcare providers and family focus groups will be used to further enhance the findings and improve the programme. Approval from the Hamilton Integrated Research Ethics Board (HiREB) has been obtained. Informed consent will be obtained prior to enrolling any participant into the study. Participant IDs will be used during data collection and entry. Peer-reviewed publications and presentations will target researchers, health professionals and stakeholders. ClinicalTrials.gov Identifier: NCT03258138.HiREB project number: 3793.


Alzheimer's disease. Age at onset and single-photon emission computed tomographic patterns of regional cerebral blood flow.
We performed this study to determine whether early- and late-onset Alzheimer's disease differ physiologically. Ten patients with a presenile (before 65 years old) onset of the disease and 16 with senile onset of the disease were evaluated clinically and neuropsychologically and studied with single photon emission computed tomography using the blood flow tracer [123I]N-isopropyl-p-iodoamphetamine. Although the presenile subjects had more severe neuropsychological abnormalities in all realms of cognitive function, including language, and showed greater reductions in regional blood flow than the older patients, they were also more severely demented, thus complicating interpretation of the results. Two indexes of cerebral perfusion, a ratio of regional flow compared with occipital flow and a left-right asymmetry index, demonstrated relative left frontal hypoperfusion in presenile- but not senile-onset patients and did not appear to be an artifact of the severity differences. Although no asymmetry of cognitive function was noted, the perfusion asymmetry provides biological evidence for an alteration in left-hemisphere function in patients with the early onset of Alzheimer's disease.


The role of human orbitofrontal cortex in value comparison for incommensurable objects.
The human orbitofrontal cortex is strongly implicated in appetitive valuation. Whether its role extends to support comparative valuation necessary to explain probabilistic choice patterns for incommensurable goods is unknown. Using a binary choice paradigm, we derived the subjective values of different bundles of goods, under conditions of both gain and loss. We demonstrate that orbitofrontal activation reflects the difference in subjective value between available options, an effect evident across valuation for both gains and losses. In contrast, activation in dorsal striatum and supplementary motor areas reflects subjects' choice probabilities. These findings indicate that orbitofrontal cortex plays a pivotal role in valuation for incommensurable goods, a critical component process in human decision making.


Preclinical cognitive decline in late middle-aged asymptomatic apolipoprotein E-e4/4 homozygotes: a replication study.
In a previous cross-sectional study of 100 asymptomatic individuals aged 49-69, we reported age-related decline in immediate and delayed memory that was steeper in apolipoprotein E (apoE)-e4/4 homozygotes than in members of other genetic subgroups. These findings were preliminarily based upon the statistical problem of multiple comparisons. We therefore sought to replicate these findings in a new cohort. From 1998 to 2000, 80 asymptomatic residents of Maricopa County, AZ were recruited through newspaper ads. 20 apoE-e4/4 homozygotes, 20 e3/4 heterozygotes, and 40 e4 noncarriers were matched (1:1:2) by age, gender, and years of education. All had normal neurologic and psychiatric examinations, including Folstein minimental status exam (MMSE) and Hamilton depression scale, and underwent a battery of neuropsychological tests identical to those in our previous study. The groups were well-matched for age (55.9+/-5.9 years), gender (60% women), and education (15.9+/-2.2 years), and were demographically similar to our previous cohort. Complex figure test recall was lower in e3/4 heterozygotes than noncarriers, but there was no significant difference between e4/4 homozygotes and noncarriers. There were no other significant differences in mean test scores between groups, but Wechsler adult intelligence scale-revised (WAIS-R) digit span showed a significant negative correlation with age in the e4/4 homozygote group relative to e4 noncarriers (p=0.008) as we had found in our previous study. In conclusion, we found a significant negative correlation of WAIS-R digit span with age in apoE-e4/4 homozygotes relative to e4 noncarriers in two separate cohorts, possibly reflecting an age-related effect on frontal lobe function in this genetic subgroup.


Urinary tract infections in the critical care unit: A brief review.
The use of indwelling catheters in the Critical Care Units (CCUs) has a major role in determining the incidence and the morbidity as well as mortality from hospital-acquired urinary tract infections (UTIs). Instituting evidence-based protocols can significantly reduce both the prevalence of indwelling catheterization as well as the incidence of hospital-acquired UTIs. The prevalence of catheter-associated urinary tract infections (CAUTIs) in the CCUs is directly linked to the widespread use of indwelling catheters in these settings. CAUTIs result in significant cost escalation for individual hospitals as well as the healthcare system as a whole. A UTI is an inflammatory response to colonization of the urinary tract, most commonly by bacteria or fungi. A UTI should be differentiated from the mere detection of bacteria in the urinary tract. This condition, referred to as asymptomatic bacteriuria, is common and does not require treatment, especially in the patient with an indwelling urinary catheter. A CAUTI occurs when a patient with an indwelling urinary catheter develops 2 or more signs or symptoms of a UTI such as hematuria, fever, suprapubic or flank pain, change in urine character, and altered mental status. CAUTI is classified as a complicated UTI. The current review highlights the important management issues in critical care patients having CAUTI. We performed a MEDLINE search using combinations of keywords such as urinary tract infection, critical care unit and indwelling urinary catheter. We reviewed the relevant publications with regard to CAUTI in patients in CCU.


Fatal trauma injuries in a Brazilian big metropolis: a study of autopsies.
This study aims to review a series of deaths by trauma in a large metropolis. The intention is to identify preventable causes of death. We prospectively studied 500 unselected and consecutive cases of death associated with trauma. The study variables were: mechanism of injury, etiology, site of injury, surgical intervention, medical malpractice, damaged organs and the prevention of mortality. The cases were grouped according to the mechanism of injury in: penetrating trauma, blunt trauma, poisoning, drowning, burns and suffocation. We examined 418 (83.6%) males and 82 (16.4%) females (mean age 39 ± 19.6 years, ranging from three to 91 years). Penetrating trauma accounted for 217 (43%) cases, while blunt trauma accounted for 40% of cases. The most common mechanism of injury in death by penetrating trauma was gunshot, representing 41% of cases. Within the set of blunt trauma, the most common mechanism was traffic accident, which represented 22% of total deaths. There were 71 (14%) cases of preventable deaths: thromboembolism in 35 (7%), infectious complications in 25 (5%), medical malpractice in seven (1%) and treatable lesions in outpatients in five (1%). This study shows that traumatic death in the city of São Paulo is associated with serious and complex injuries. Prevention of these types of death would be related to the control of violence.


Costs of Venous Thromboembolism, Catheter-Associated Urinary Tract Infection, and Pressure Ulcer.
To estimate differences in the length of stay (LOS) and costs for comparable pediatric patients with and without venous thromboembolism (VTE), catheter-associated urinary tract infection (CAUTI), and pressure ulcer (PU). We identified at-risk children 1 to 17 years old with inpatient discharges in the Nationwide Inpatient Sample. We used a high dimensional propensity score matching method to adjust for case-mix at the patient level then estimated differences in the LOS and costs for comparable pediatric patients with and without VTE, CAUTI, and PU. Incidence rates were 32 (VTE), 130 (CAUTI), and 3 (PU) per 10 000 at-risk patient discharges. Patients with VTE had an increased 8.1 inpatient days (95% confidence interval [CI]: 3.9 to 12.3) and excess average costs of $27 686 (95% CI: $11 137 to $44 235) compared with matched controls. Patients with CAUTI had an increased 2.4 inpatient days (95% CI: 1.2 to 3.6) and excess average costs of $7200 (95% CI: $2224 to $12 176). No statistical differences were found between patients with and without PU. The significantly extended LOS highlights the substantial morbidity associated with these potentially preventable events. Hospitals seeking to develop programs targeting VTE and CAUTI should consider the improved turnover of beds made available by each event prevented.


Gender differences in the link between childhood socioeconomic conditions and heart attack risk in adulthood.
A growing body of evidence shows that childhood socioeconomic status (SES) is predictive of disease risk in later life, with those from the most disadvantaged backgrounds more likely to experience poor adult-health outcomes. Most of these studies, however are based on middle-aged male populations and pay insufficient attention to the pathways between childhood risks and specific adult disorders. This article examines gender differences in the link between childhood SES and heart attack risk trajectories and the mechanisms by which early environments affect future disease risk. By using methods that model both latent and path-specific influences, we identify heterogeneity in early life conditions and human, social, and health capital in adulthood that contribute to diverse heart attack risk trajectories between and among men and women as they age into their 60s and 70s. We find that key risk factors for heart attack operate differently for men and women. For men, childhood SES does not differentiate those at low, increasing, and high risk for heart attack. In contrast, women who grew up without a father and/or under adverse economic conditions are the most likely to experience elevated risk for heart attack, even after we adjust for the unequal distribution of working and living conditions, social relationships, access to health care, and adult lifestyle behaviors that influence health outcomes.


Effects of female and male body mass indices on the treatment outcomes and neonatal birth weights associated with in vitro fertilization/intracytoplasmic sperm injection treatment in China.
To investigate the combined effects of Chinese couples' body mass indices (BMIs) on the outcomes of IVF or intracytoplasmic sperm injection (ICSI) and the clinical characteristics of their neonates. Retrospective cohort study. University-affiliated reproductive medicine center. A total of 12,061 first fresh IVF/ICSI cycles with autologous oocytes from September 1, 2009 to December 31, 2014. None. The primary treatment outcome was live birth, and the primary outcome for the neonates was neonatal birth weight (NBW). After adjusting for confounders, our study showed that in IVF cycles, couples with a female BMI ≥25 kg/m(2) had a significantly higher odds of abortion and a significantly lower odds of live birth than couples with both male and female BMIs <25 kg/m(2). Regarding ICSI cycles, no significant relationship was found between the couples' BMIs and the live birth rate. The NBWs of singletons conceived via IVF/ICSI cycles was significantly higher when their parents' BMIs were greater; however, no significant differences were observed in the NBWs of twins conceived via IVF/ICSI cycles. Increased female BMI negatively affected live births conceived via IVF. Regarding ICSI, no significant differences were found in the outcomes in terms of parental BMI. The singleton neonates' NBWs increased with parental BMI conceived via IVF/ICSI. However, parental BMI did not significantly affect the NBWs of twins conceived via IVF/ICSI.


Buddhist-inspired meditation increases the value of calm.
Most studies of meditation have focused on "actual affect" (how people actually feel). We predict that meditation may even more significantly alter "ideal affect" (how people ideally want to feel). As predicted, meditators ideally wanted to feel calm more and excited less than nonmeditators, but the groups did not differ in their actual experience of calm or excited states (Study 1). We ruled out self-selection and nonspecific effects by randomly assigning participants to meditation classes, an improvisational theater class, or a no class control (Study 2). After eight weeks, meditators valued calm more but did not differ in their actual experience of calm compared with the other groups. There were no differences in ideal or actual excitement, suggesting that meditation selectively increases the value placed on calm. These findings were not due to expectancy effects (Study 3). We discuss the implications of these findings for understanding how meditation alters affective life.


Evaluating classification performance of biomarkers in two-phase case-control studies.
Biomarkers are playing an increasingly important role in disease screening, early detection, and risk prediction. The two-phase case-control sampling study design is widely used for the evaluation of candidate biomarkers. The sampling probabilities for cases and controls in the second phase can often depend on other covariates (sampling strata). This biased sampling can lead to invalid inference on a biomarker's classification accuracy if not properly accounted for. In this paper, we adopt the idea of inverse probability weighting and develop inverse probability weighting-based estimators for various measures of a biomarker's classification performance, including the points on the receiver operating characteristics (ROCs) curve, the area under the ROC curve (area under the curve), and the partial area under the curve. In particular, we consider classification accuracy estimators using sampling weights estimated conditionally on sampling strata and further improve their efficiency through the use of estimated weights that additionally take into account the auxiliary variables available from the phase-one cohort. We develop asymptotic properties of the proposed estimators and provide analytical variance for making inference. Extensive simulation studies demonstrate excellent performance of the proposed weighted estimators, while the traditional empirical estimator can be severely biased. We also investigate the advantages in efficiency gain for estimating various classification accuracy estimators through the use of auxiliary variables in addition to sampling strata and apply the proposed method to examples from a renal artery stenosis study and a prostate cancer study.


Functional Significance of Varices in the Muricid Gastropod Ceratostoma foliatum.
Functional significance of varices in the muricid gastropod Ceratostoma foliatum was investigated from the standpoints of (1) frequency of landing in the two upside-down orientations after short vertical falls of less than five body lengths through seawater and energy costs of righting from these upside-down positions, and (2) scaling relationships of varix areas with other body dimensions. Field manipulations showed that C. foliatum occupied habitats that mostly permit short falls of less than five body lengths upon dislodgment, as might occur during predation by fish. After short vertical falls in the laboratory, animals landed 48% of the time on their aperture sides (upright), 15% on their right sides (on right and middle varices), and 37% on their left sides (on left and middle varices). These frequencies differed significantly from the expected frequencies calculated on the basis of the percentage circumference delineated by each varix pair (50%, 31%, and 19%, respectively). Righting from the right-side orientation was slower and four times more energetically costly than from the left-side orientation, underscoring the advantage conferred by animals, if not landing in the upright position after short falls, preferentially landing on their left sides. Removal of individual varices showed that the large, right varix is most influential in producing this "destabilization." Landings are biased to the side from which rightings are easiest due to a combination of the location of center of mass within the left side of the main body whorl and the broad right varix possibly acting as an upward-trailing vane. Morphometric relationships of shell length, live weight, varix areas, aperture dimensions, and labial spine (tooth) length were investigated over a wide range of body sizes in an attempt to infer varix function. Aperture area scaled allometrically with length. Right-, middle-, and left-varix areas also grew relatively larger as the animals increased in length. In contrast, combined varix areas around the aperture increased in direct proportion with aperture area, forming a broad shelf surrounding the aperture. We infer from this that, in addition to their effects on landing orientation from both long and short vertical falls, the varices of C. foliatum may function to protect the aperture, and thus protect the soft body parts that protrude from it during feeding and locomotion.


Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments.
Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1.) in non-activated T lymphocytes to assess the "basal status" of the cascade and 2.) in the process of activation to assess the signal transduction. We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes.


Serum 13C-bicarbonate assay for the diagnosis of gastric Helicobacter pylori infection and response to treatment.
Current serological tests for Helicobacter pylori (HP) infection are not useful in assessing active infection or eradication. The feasibility, sensitivity, and specificity of serum 13C-bicarbonate (13C-HCO3) measurement in determining gastric HP before and after eradication by antibiotics were investigated. Twenty-seven symptomatic patients underwent endoscopy, biopsy, and CLOtest. Patients then consumed a 13C-urea-rich meal; serum was collected before and 1 hour after meal ingestion for quantitative determination of 13C by mass spectrometry. Postprandial fractional elevation of 13C (delta 13C-HCO3) was correlated with endoscopy, histology, and CLOtest at baseline and at 4 and 8 weeks after therapy. delta 13C-HCO3 +/- SEM was 17.02 +/- 2.94 in HP-positive patients and 2.77 +/- 044 in HP-negative patients (P < 0.0001). In HP-positive patients who responded to therapy, the mean change was initially 20.5 +/- 3.1, 3.2 +/- 0.9 1 month after therapy, and 2.8 +/- 0.4 2 months after therapy (P < 0.001). The overall sensitivity of this method was 90.6% (95% confidence interval, 74.9-98.0), and its specificity was 85.7% (95% confidence interval, 42.1%-99.6%). delta 13C-HCO3 correlated positively with the degree of histological gastritis and the number of HP organisms. Serum 13C-HCO3 analysis is a novel, simple, and noninvasive method for diagnosis and assessment of eradication of HP infection.


Stem-cell-based Therapies for Improving Islet Transplantation Outcomes in Type 1 Diabetes.
Beta-cell replacement by human islets or whole pancreas offers a life-saving therapeutic remedy for patients suffering from type 1 diabetes, providing considerable advantages with respect to diminishing total daily insulin dose and lowering frequencies of debilitating hypoglycemic reactions as well as preventing chronic micro- and macrovascular complications. Although remarkable progress has been made in this area, several hurdles remain, hampering its wide-spread applicability. Such hurdles include a limiting supply of islets, the necessity of several donors to achieve enough islet mass for insulin independence, and graft failure because of metabolic pressure, continued autoimmunity, alloimmunity, high concentrations of immunosuppressive drugs as well as oxidative stress caused by hypoxia or inflammation. On the other hand, the islet transplant procedure provides the possibility to undertake multiple practical and beneficial manipulations of the beta cells before engraftment with the intention to reach improved graft survival results. We have focused on the current status of various obstacles in islet transplantation and on the potential of (stem)cell-based treatments able to stimulate islet graft outcome in pre-clinical and clinical transplantation settings in which specific attention is given to the engraftment-enhancing and immunomodulatory potential of various types of stem cells..


Fermat's principle and the formal equivalence of local light-ray rotation and refraction at the interface between homogeneous media with a complex refractive index ratio.
We derive a formal description of local light-ray rotation in terms of complex refractive indices. We show that Fermat's principle holds, and we derive an extended Snell's law. The change in the angle of a light ray with respect to the normal of a refractive index interface is described by the modulus of the refractive index ratio; the rotation around the interface normal is described by the argument of the refractive index ratio.


Guidance for researchers developing and conducting clinical trials in practice-based research networks (PBRNs).
There is increased interest nationally in multicenter clinical trials to answer questions about clinical effectiveness, comparative effectiveness, and safety in real-world community settings. Primary care practice-based research networks (PBRNs), comprising community- and/or academically affiliated practices committed to improving medical care for a range of health problems, offer ideal settings for these trials, especially pragmatic clinical trials. However, many researchers are not familiar with working with PBRNs. Experts in practice-based research identified solutions to challenges that researchers and PBRN personnel experience when collaborating on clinical trials in PBRNs. These were organized as frequently asked questions in a draft document presented at a 2013 Agency for Health care Research and Quality PBRN conference workshop, revised based on participant feedback, then shared with additional experts from the DARTNet Institute, Clinical Translational Science Award PBRN, and North American Primary Care Research Group PBRN workgroups for further input and modification. The "Toolkit for Developing and Conducting Multi-site Clinical Trials in Practice-Based Research Networks" offers guidance in the areas of recruiting and engaging practices, budgeting, project management, and communication, as well as templates and examples of tools important in developing and conducting clinical trials. Ensuring the successful development and conduct of clinical trials in PBRNs requires a highly collaborative approach between academic research and PBRN teams.


Phylogenetic analysis of highly pathogenic avian influenza A(H5N8) virus outbreak strains provides evidence for four separate introductions and one between-poultry farm transmission in the Netherlands, November 2014.
Phylogenetic analysis of highly pathogenic avian influenza A(H5N8) virus strains causing outbreaks in Dutch poultry farms in 2014 provides evidence for separate introduction of the virus in four outbreaks in farms located 16-112 km from each other and for between-farm transmission between the third and fourth outbreak in farms located 550 m from each other. In addition, the analysis showed that all European and two Japanese H5N8 virus strains are very closely related and seem to originate from a calculated common ancestor, which arose between July and September 2014. Our findings suggest that the Dutch outbreak virus strain 'Ter Aar' and the first German outbreak strain from 2014 shared a common ancestor. In addition, the data indicate that the Dutch outbreak viruses descended from an H5N8 virus that circulated around 2009 in Asia, possibly China, and subsequently spread to South Korea and Japan and finally also to Europe. Evolution of the virus seemed to follow a parallel track in Japan and Europe, which supports the hypothesis that H5N8 virus was exchanged between migratory wild waterfowl at their breeding grounds in Siberia and from there was carried by migrating waterfowl to Europe.


Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors.
Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARγ), and constitutive activity of the NFκB and AP1 signaling pathways in GCT. PPARγ presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPARγ is caused by NFκB transrepression in GCT-derived cell lines, KGN and COV434. We showed that abrogation of NFκB signaling in GCT cells enables PPARγ agonists to initiate apoptosis. In addition, we observed overexpression of an NFκB-induced gene, X-linked inhibitor of apoptosis protein (XIAP), in GCT and GCT-derived cells. XIAP is an attractive therapeutic target due to its role in inhibiting the apoptotic pathway. We investigated the antitumor effects of combined XIAP inhibition using Smac-mimetics and PPARγ activation using thiazolidinediones (TZD) in the GCT-derived cells. Transactivation assays revealed that NFκB transrepression of PPARγ can be relieved by NFκB or XIAP inhibition. Combined Smac-mimetic and TZD significantly induced apoptosis, reduced cell viability and proliferation in KGN cells in monolayer and 3D spheroid culture, and in GCT explant models. The Smac-mimetic and TZD cotreatment also delayed cell invasion, upregulated proapoptotic genes, and compromised cell metabolism in KGN cells. This study provides evidence that PPARγ and XIAP cotreatment has antineoplastic effects in GCT. As therapeutics that target these proteins are already in clinical or preclinical use, expedient translation to the clinic is possible.


A Micro-computed Tomographic Assessment of Root Canal Preparation with a Novel Instrument, TRUShape, in Mesial Roots of Mandibular Molars.
A novel S-shaped rotary file was developed to conform to nonround canal cross sections. However, the instrument should also perform well in small curved canals. This study used micro-computed tomographic scans to test the effects of TRUShape (Dentsply Tulsa Dental Specialties, Tulsa, OK) and a conventional rotary on canal geometry. Twenty mandibular molars with independent mesial canals were submitted to preoperative micro-computed tomographic scans (20-μm resolution). Canals were randomly allocated to 2 groups using Vortex (Dentsply Tulsa Dental Specialties) and TRUShape for shaping according to the directions for use. Scans were obtained after size 20/.06 and 30/.06; the following outcome variables were calculated: dentin volume, smallest radicular wall thickness, treated canal surface, canal transportation, and accumulated hard tissue debris. The number of preparation errors was tabulated; data were statistically contrasted using repeated measures and factorial analyses of variance. The initial canal sizes were similar in both groups. Both instruments promoted preparation with no overt procedural errors. Vortex removed significantly more dentin both at size #20 and #30 (P < .02). Significantly (P < .02) more radicular wall dentin remained toward the furcation in the TRUShape group (1.02 ± 0.25 mm vs 0.94 ± 0.22 mm). The untreated surface at size #20 was 28.5 ± 13.9 and 19.4 ± 8.9 (P < .05), and it was 15.1 ± 8.5 and 11.3 ± 4.9 (P > .05) at size #30 for TRUShape and Vortex, respectively. Canal transportation at size #30 varied between 85 ± 57 μm and 179 ± 65 μm; the overall transportation scores were significantly lower for TRUShape (P < .05). TRUShape provided conservation of dentin by limiting dentin removal and in the absence of substantial canal transportation. In the present study, the use of TRUShape in the mesial canals of mandibular molars did not result in decreased amounts of unprepared canal surface.


Introduction to the opioid epidemic: the economic burden on the healthcare system and impact on quality of life.
Opioid analgesics are commonly used to treat acute and chronic pain; in 2016 alone, more than 60 million patients had at least 1 prescription for opioid analgesics filled or refilled. Despite the ubiquitous use of these agents, the effectiveness of long-term use of opioids for chronic noncancer pain management is questionable, yet links among long-term use, addiction, and overdose deaths are well established. Because of overprescribing and misuse, an opioid epidemic has developed in the United States. The health and economic burdens of opioid abuse on individuals, their families, and society are substantial. Part 1 of this supplement will provide a background on the burden of pain and the impact of opioid abuse on individuals, their families, and society; the attempts to remedy this burden through prescription opioid use; and the eventual downward spiral into the current opioid epidemic, including an overview of opioid analgesics and opioid use disorder and the rise in opioid-related deaths.


LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor.
The leukocyte integrin LFA-1 (CD11a/CD18) plays an important role in lymphocyte recirculation and homotypic interactions. Leukocytes from mice lacking CD11a displayed defects in in vitro homotypic aggregation, in proliferation in mixed lymphocyte reactions, and in response to mitogen. Mutant mice mounted normal cytotoxic T cell (CTL) responses against systemic LCMV and VSV infections and showed normal ex vivo CTL function. However, LFA-1-deficient mice did not reject immunogenic tumors grafted into footpads and did not demonstrate priming response against tumor-specific antigen. Thus CD11a deficiency causes a selective defect in induction of peripheral immune responses whereas responses to systemic infection are normal.


Study of Sexual Behaviour of Bar-girls Residing in an Urban Slum Area of Mumbai.
Bar girls are unorganized, difficult to reach high-risk group, and an urban phenomenon. To study the demographic profile and sexual behavior of bar girls. Study setting is an urban slum area situated in the northwest part of Mumbai. Study design is a community-based cross-sectional study. Study duration was from January 2003 to January 2005. Phase I: Identification of key informants was done. Phase II: Mapping of bar girls in the study area was done with the help of key informants. Out of the estimated 800-1200 bar girls, 120 bar girls who were willing to participate in the study were included in the study after obtaining informed consent. Confidentiality of names and locations was assured to both key informants and study subjects. Information was gathered about demographic profile, educational status, and their sexual behavior by conducting one to one interview with the use of predesigned, pre-tested semi-structured questionnaire. Most of the bar girls were in the age group of 21-25 years 52 (43.3%). None of them were educated above secondary level. Most of the subjects belong to West Bengal state 58 (48.4%). Majority of the subjects 88 (73.3%) reported that they have ever practiced commercial sex, and money was the criteria of selection of customers 53 (60.22%). Condom usage was reported less with regular customer as compared with that of nonregular customers (χ(2) = 6.02, P < 0.02). Need to emphasize condom use with each and every sexual act irrespective of type of customers.


The validity of self-rated health as a measure of health status among young military personnel: evidence from a cross-sectional survey.
Single item questions about self ratings of overall health status are widely used in both military and civilian surveys. Limited information is available to date that examines what relationships exist between self-rated health, health status and health related behaviors among relatively young, healthy individuals. The current study uses the population of active duty United States Air Force recruits (N = 31,108). Participants completed surveys that asked about health behaviors and health states and were rated their health on a continuum from poor to excellent. Ratings of health were consistently lower for those who used tobacco (F = 241.7, p < .001), reported binge drinking (F = 69.0, p < .001), reported drinking and driving (F = 19.4, p < .001), reported taking health risks (F = 109.4, p < .001), were depressed (F = 256.1, p < .001) and were overweight (F = 39.5, p < .001). Given the consistent relationship between self-rated overall health and factors important to military health and fitness, self-rated health appears to be a valid measure of health status among young military troops.


Effect of natural full weight-bearing during standing on the rotation of the first metatarsal bone.
To evaluate the rotational change in the first metatarsal bone (1MT) of the foot during natural standing using an upright computed tomography (CT) scanner with 320-detector rows. A total of 52 feet of 28 asymptomatic subjects (aged 23-39 years) were evaluated in the natural standing position with or without weight-bearing. A foot pressure plate was used to determine the non-weight-bearing (NWB) or single leg full-weight-bearing (s-FWB) conditions. CT examinations were performed using a noise index of 15 for a slice thickness of 5 mm, rotation speed of 0.5 sec, and slice thickness of 0.5 mm. The rotation of the 1MT was measured on the coronal CT image, which cut the sesamoids' bellies in the frontal slide of the first metatarsal and sesamoids perpendicular to the longitudinal bisection of the third metatarsal, and compared between the weight-bearing conditions. Intra- and inter-observer reliabilities of the rotation angle were also evaluated. The intra- and inter-observer correlation coefficients were 0.961 and 0.934, respectively. The 1MT pronation angle was significantly greater in the s-FWB condition than in the NWB condition (15.2° ± 5.4° vs. 12.5° ± 5.3°, P < 0.01). No sex difference was found in the magnitude of the 1MT pronation angle as a result of weight-bearing. This study first demonstrated that pronation of 1MT occurs due to natural full-weight-bearing in asymptomatic feet. The 1MT's rotational movement under weight-bearing conditions may relate to the onset and pathogenesis of the hallux valgus. Clin. Anat. 32:715-721, 2019. © 2019 Wiley Periodicals, Inc.


Effect of selenium supplementation on colostral IgG concentration in cows grazing selenium-deficient pastures and on postsuckle serum IgG concentration in their calves.
Effects of selenium (Se) deficiency and supplementation on production of colostral immunoglobulins by beef cows and transfer of antigen-specific and nonspecific immunoglobulins to their calves were examined. Eight beef cows, with marginal to deficient Se status (blood Se concentration, 50 micrograms/L), were allotted by breed and age to 1 of 4 Se treatment groups (n = 20/group): no supplemental Se; parenteral administration of 0.1 mg of Se and 1 mg of vitamin E/kg of body weight; ad libitum consumption of 120 mg of Se/kg of salt-mineral mix (SMM); and parenteral administration of 0.1 mg of Se and 1 mg of vitamin E/kg plus ad libitum consumption of 120 mg of Se/kg of SMM. All cows were inoculated IM with lysozyme. Cows consumed Se-deficient pastures or hay (21 to 62 micrograms/kg) during the study that began at mid-gestation and ended at postpartum hour 24. Although the concentration of specific lysozyme antibodies was not affected, cows given 120 mg of Se/kg of SMM (treatments 3 and 4) had higher colostral IgG concentration (P < 0.002) than did Se-deficient cows (treatments 1 and 2). Calves from cows in treatments 3 and 4 had higher postsuckle serum concentrations of IgG (P < 0.01) than did calves from cows in treatments 1 and 2. Colostral IgM and calf serum IgM concentrations did not differ among treatments.


Possible inhibitory role of endogenous gamma-aminobutyric acid in the nonnicotinic functions of the dog cardiac sympathetic ganglia.
Participation of endogenous gamma-aminobutyric acid (GABA) in the functions of dog cardiac ganglia was investigated. The ganglionic stimulants as well as agents affecting GABA system were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.), unless otherwise mentioned. Inhibition of endogenous GABA degradation by the GABA-transaminase inhibitor, aminooxyacetic acid (AOAA) administered 10 mg/kg i.v. 2 hr before completion of surgical procedures did not alter the positive chronotropic responses to bethanecol (25 and 50 micrograms) and acetylcholine (25, 50 and 100 micrograms) but reduced markedly those to angiotensin II (1 and 2 micrograms). This reduction was antagonized by picrotoxin (5 mg). Diazepam given 10 mg/kg i.v. also inhibited the ganglionic responses to angiotensin II in both untreated and AOAA-pretreated dogs, this inhibition by diazepam being more marked in the AOAA-pretreated than in the untreated dogs. The same dose of diazepam did not affect the responses to acetylcholine but reduced to a certain degree of responses to bethanechol in the AOAA-pretreated dogs. These inhibitions by diazepam were also reversed by picrotoxin. After i.v. treatment with the glutamic acid decarboxylase inhibitors, 3-mercaptopropionic acid (50 mg/kg) or isoniazid (200 mg/kg), the ganglionic responses to angiotensin II were not altered, but inhibitory effects of diazepam on the responses to angiotensin II were eliminated after 3-mercaptopropionic acid but not after isoniazid. These results suggest that endogenous GABA may play an inhibitory role in the nonnicotinic ganglionic pathways and that diazepam probably exerts a ganglionic action through endogenous GABAergic mechanisms.


Association of versican turnover with all-cause mortality in patients on haemodialysis.
Cardiovascular diseases are among the most common causes of mortality in renal failure patients undergoing haemodialysis. A high turnover rate of the proteoglycan versican, represented by the increased presence of its fragmentation products in plasma, has previously been associated with cardiovascular diseases. The objective of the study was to investigate the association of versican turnover assessed in plasma with survival in haemodialysis patients. A specific matrix metalloproteinase-generated neo-epitope fragment of versican (VCANM) was measured in plasma of 364 haemodialysis patients with a 5-years follow-up, using a robust competitive enzyme-linked immunosorbent assays. Association between VCANM plasma concentration and survival was assessed by Kaplan-Meier analysis and adjusted Cox model. Haemodialysis patients with plasma VCANM concentrations in the lowest quartile had increased risk of death (odds ratio, as compared to the highest quartile: 7.1, p<0.001), with a reduced survival of 152 days compared to 1295 days for patients with plasma VCANM in the highest quartile. Multivariate analysis showed that low VCANM (p<0.001) and older age (p<0.001) predicted death in haemodialysis patients. Low concentrations of the versican fragment VCANM in plasma were associated with higher risk of death among haemodialysis patients. A possible protective role for the examined versican fragment is suggested.


Carbon monoxide reverses diabetic gastroparesis in NOD mice.
Diabetic gastroparesis is associated with increased oxidative stress attributable to loss of upregulation of heme oxygenase-1 (HO1), with resultant damage to interstitial cells of Cajal and delayed gastric emptying. These changes can be reversed by induction of HO1. HO1 catalyzes the breakdown of heme into iron, biliverdin and, carbon monoxide (CO). The aim of this study was to determine whether inhalation of CO can mimic the protective effects of HO1. Nonobese diabetic (NOD) mice with delayed gastric emptying were treated with CO inhalation. Serum malondialdehyde was measured as a marker of oxidative stress. Gastric emptying of solids was measured using a [(13)C]octanoic acid breath test. Kit expression levels were determined in immunoblots of protein extracted from the external muscle layers of the gastric body and antrum. The effect of CO on oxidative stress and gastric emptying was also determined in the presence of HO activity inhibitor chromium mesoporphyrin. CO inhalation reduced oxidative stress, restored Kit expression and reversed delayed gastric emptying in diabetic NOD mice with delayed gastric emptying. CO inhalation maintained this effect in the presence of the HO activity inhibitor, chromium mesoporphyrin, also resulting in restoration of the delay in gastric emptying. CO inhalation mimics the protective effect of upregulation of HO1 and decreased oxidative stress, increased Kit expression, and restored delay in gastric emptying. This effect of CO was independent of HO activity, suggesting that its effects were downstream of HO1. CO represents a potential therapeutic option for treatment of diabetic gastroparesis.


Increased Intracranial Pressure in the Setting of Enterovirus and Other Viral Meningitides.
Increased intracranial pressure due to viral meningitis has not been widely discussed in the literature, although associations with Varicella and rarely Enterovirus have been described. Patients with increased intracranial pressure and cerebrospinal fluid analysis suggestive of a viral process are sometimes classified as having atypical idiopathic intracranial hypertension (IIH). However, a diagnosis of IIH requires normal cerebrospinal fluid, and therefore in these cases an infection with secondary intracranial hypertension may be a more likely diagnosis. Here seven patients are presented with elevated intracranial pressure and cerebrospinal fluid suggestive of viral or aseptic meningitis. Of these, 1 had Enterovirus and the remainder were diagnosed with nonspecific viral meningitis. These data suggest that viral meningitis may be associated with elevated intracranial pressure more often than is commonly recognized. Enterovirus has previously been associated with increased intracranial pressure only in rare case reports.


Spatial selectivity and theta phase precession in CA1 interneurons.
Traditionally, most of the information processing of neural networks is thought to be carried out by excitatory cells. Likewise, recent evidence for temporal coding comes from the study of the detailed firing patterns of excitatory neurons. In the CA1 region of the rat hippocampus, pyramidal cells discharge selectively when the animal is in specific locations in its environment, and exhibit a precise relationship with the ongoing rhythmic activity of the network (phase precession). We demonstrate that during a spatial exploratory behavior on a linear track, inhibitory interneurons also show spatial selectivity and phase precession dynamics. We found that the firing rate of interneurons is modulated reliably up and down around an ongoing baseline activity level for specific locations in the environment, producing robust place-specific increases or decreases in discharge. On some sections of the track, the range of theta phases shifts progressively to earlier parts of the theta cycle as the rat advances, so that a negative correlation between phase and position could be demonstrated. Unlike pyramidal cells, phase and rate were not strongly correlated. We discuss the influence of the intrinsic firing properties of interneurons on a model of phase precession, as well as the influence of the detailed shape of the inhibitory oscillation. These results indicate that spatial selectivity and phase precession in CA1 are not properties restricted to pyramidal cells. Rather, they may be a more general expression of a common interaction between the different inputs impinging on both excitatory and inhibitory cells in CA1 and the intrinsic characteristics of those cells. Furthermore, they suggest that the role of interneurons may extend beyond a global damping of the network by participating in a finely-tuned local processing with the pyramidal cells.


Neo-Epitopes--Fragments of Cartilage and Connective Tissue Degradation in Early Rheumatoid Arthritis and Unclassified Arthritis.
Tissue destruction in rheumatoid arthritis (RA) is predominantly mediated by matrix metalloproteinases (MMPs), thereby generating protein fragments. Previous studies have revealed that these fragments include MMP-mediated collagen type I, II, and III degradation, citrullinated and MMP-degraded vimentin and MMP degraded C-reactive protein. We evaluated if biomarkers measuring serum levels of specific sequences of the mentioned fragments would provide further information of diagnostic and/or prognostic processes in early arthritis. Ninety-two early arthritis patients (arthritis duration<1 year, DMARD naïve) were enrolled. Patients either fulfilled the ACR/EULAR2010 criteria for RA (n = 60) or had unclassified arthritis (UA) (n = 32). Patients fulfilling the RA criteria after 2 years follow-up were classified into non-erosive (n = 25), or erosive disease (n = 13). Concentrations of the biomarkers: C1M, C2M, C3M, VICM and CRPM were measured in baseline serum. C1M, C3M and CRPM were able to discriminate between the UA and RA baseline diagnosis in 92 patients with an AUROC of 0.64 (95%CI 0.517 to 0.762), 0.73 (95%CI 0.622 to 0.838) and 0.68 (95%CI 0.570 to 0.795). C2M showed a potential for discrimination between non-erosive and erosive disease in 38 patients with an AUROC of 0.75 (95%CI 0.597 to 0.910). All of the applied biomarkers correlated with one or more of the disease activity parameters: DAS28, ESR, CRP, SJC66, TJC68 and/or HAQ. This is the first study evaluating the applied biomarkers at this early stage of arthritis. C1M, C3M, CRPM might be the best diagnostic marker, whereas high levels of C2M indicated progression of disease at follow-up in early RA patients.


Evolutionary relationships between aquatic anamorphs and teleomorphs: Tricladium and Varicosporium.
Tricladium, with 21 accepted species, is the largest genus of aquatic hyphomycetes. It encompasses species with dematiaceous as well as mucedinaceous colonies. Conidiogenesis is thalloblastic; conidiogenous cells proliferate percurrently or sympodially. Conidia have typically two alternate primary lateral branches. Fontanospora and Variocladium are segregates of Tricladium, differing by conidial branching. Varicosporium comprises nine species, one not well known. Conidiogenesis is blastic or thalloblastic, conidiogenous cells proliferate sympodially or are determinate; conidia regularly produce primary and secondary branches and often fragment into part conidia. Molecular analyses on the 28S rDNA of 86 isolates, including 16 species of Tricladium, five species of Varicosporium, two species of Fontanospora and one species of Variocladium, place these hyphomycetes within Helotiales. Tricladium is polyphyletic and placed in six clades; Varicosporium is polyphyletic and placed in three clades; Fontanospora is polyphyletic within a single clade. Variocladium is placed with poor support as a sister taxon to Varicosporium giganteum, Hymenoscyphus scutula and Torrendiella eucalypti.


Drug administration through feeding tubes; an integrated qualification program.
The literature documents numerous inconveniences of drug administration through feeding tubes. Actions to improve the quality of this practice are of great importance. The objective of this study is to describe the implementation process and results of an Integrated Program to improve drug administration through feeding tubes in a Brazilian general hospital. This is a descriptive study of a clinic quality improvement program which proceeded in four steps: (1) design of a data base with technical characteristics of oral drugs; (2) application of an identification label on non-crushable tablets; (3) evaluation, through focal groups, of nursing technicians' knowledge of drug administration through feeding tubes, and formal training; (4) prescription review of patients prescribed enteral nutrition and subsequent pharmaceutical intervention. A list with 131 oral drugs used within the hospital was compiled with recommendations for their administration through feeding tubes. Seven non-crushable drugs were identified with "do not crush" labels. Formal training regarding drug administration through feeding tubes was elaborated incorporating findings from the focal groups and applied to the nursing team. Over eight months, we analyzed 888 prescriptions written for 185 patients and addressed 263 pharmaceutical interventions to the medical team (which they accepted in 100% of the cases), and 105 interventions to the nursing team. Qualification programs with multiple strategies, as the one described here, may directly improve drug administration through feeding tubes and help to solve and prevent problems related to this practice.


An 8 minute colorimetric paper-based reverse phase vertical flow serum microarray for screening of hyper IgE syndrome.
Reverse phase microarrays are useful tools for affinity-based detection in hundreds of samples simultaneously. However, current methods typically require long assay times and fluorescent detection. Here we describe a paper-based Vertical Flow Microarray (VFM) assay as a rapid 8-minute colorimetric alternative for reverse phase microarray analysis. The VFM platform was optimized for detection of IgE with a detection limit of 1.9 μg mL(-1) in whole serum. Optimized conditions were then used to screen 113 serum samples simultaneously for hyper IgE syndrome (hIgE), a rare primary immunodeficiency characterized by elevated levels of IgE. The same set of samples were then analysed with a conventional planar microarray with fluorescent detection for head-to-head testing. Both assays found elevated levels in three out of four hIgE patient samples, whereas no control samples displayed elevated levels in either method. The comparison experiments showed a good correlation between the two assays, as determined from a linear correlation study (Pearson's r = 0.76). Further, the assay-time reduction and reproducibility (intra assay CV = 12.4 ± 4.11%) demonstrate the applicability of the VFM platform for high throughput reverse phase screening.


[Evaluation of abdominal motor blockade using surface integrated electromyography during bupivacaine spinal anesthesia].
The study was undertaken to investigate abdominal motor blockade and compare sensory-motor differential blockade in bupivacaine spinal anesthesia by surface integrated electromyography (SIEMG). Seventeen physical status I adult male patients underwent lower limb surgery under spinal anesthesia were divided into two groups: hyperbaric bupivacaine (HB) group (n = 8) receiving 3 mL of 0.5% bupivacaine (8% glucose) and isobaric bupivacaine (IB) group (n = 9), 3 mL of 0.5% bupivacaine (glucose-free). Each patient was monitored with a blood pressure cuff, an ECG and a precordial stethoscope. Spinal anesthesia was performed at L3-4 interspace on the lateral position. Immediately following injection of bupivacaine, the patients were turned to the supine position and then simultaneous measurements of sensory blockade using pinprick, abdominal motor blockade at T6, T8, T10, T12 level using SIEMG and lower limb motor blockade using Bromage scale were made for 4 hours. Between two groups, there were no significant differences in terms of age, body weight, height as maximum level and mean times to maximum level of sensory blockade, abdominal motor blockade and lower limb motor blockade. The times of 2-segment regression of sensory blockade were 66.3 +/- 11.1 min in HB group and 115.6 +/- 31.3 min in IB group. The sensory-motor differential blockades were 4.6 +/- 0.5 segments and 4.8 +/- 2.1 segments in HB and IB groups, respectively. According to the linear regression analysis, the correlation between sensory blockade and abdominal motor blockade was better than the lower limb motor blockade and abdominal motor blockade. (Correlation coefficient (r): 0.893 vs 0.580 in HB group; 0.773 vs 0.366 in IB group).(ABSTRACT TRUNCATED AT 250 WORDS)


Rebinding of IgE Fabs at haptenated planar membranes: measurement by total internal reflection with fluorescence photobleaching recovery.
In previous work, a general analytical theory for ligand rebinding at cell surfaces was developed for a reversible bimolecular reaction between ligands in solution and receptors on a membrane surface [Lagerholm, B. C., and Thompson, N. L. (1998) Biophys. J. 74, 1215-1228]. This theory can be used to predict theoretical forms for data obtained by using total internal reflection with fluorescence photobleaching recovery (TIR-FPR) [Thompson, N. L., Burghardt, T. P., and Axelrod, D. (1981) Biophys. J. 33, 435-454]. Thus, one method by which the rebinding theory can be tested is to use TIR-FPR. In the work described herein, the reversible kinetics of mouse monoclonal anti-dinitrophenyl (DNP) IgE Fabs at substrate-supported planar membranes composed of 25 mol % DNP-conjugated phosphatidylethanolamine and 75 mol % dipalmitoylphosphatidylcholine have been examined by using TIR-FPR. Data were obtained as a function of the Fab solution concentration. Higher Fab concentrations reduce rebinding (and increase the fluorescence recovery rate) because different Fab molecules compete for the same surface-binding sites. Data were also obtained for solutions containing different volume fractions of glycerol. In these measurements, higher glycerol concentrations increase rebinding (and decrease the fluorescence recovery rate) because the solution viscosity is increased and the Fab diffusion coefficient in solution is decreased. The TIR-FPR data were quantitatively compared with theoretical predictions which follow from the general theory for rebinding at the membrane surface. The data were consistent with the theoretical predictions and, therefore, provide experimental verification of the previously developed theory.


High-resolution structures of malaria parasite actomyosin and actin filaments.
Malaria is responsible for half a million deaths annually and poses a huge economic burden on the developing world. The mosquito-borne parasites (Plasmodium spp.) that cause the disease depend upon an unconventional actomyosin motor for both gliding motility and host cell invasion. The motor system, often referred to as the glideosome complex, remains to be understood in molecular terms and is an attractive target for new drugs that might block the infection pathway. Here, we present the high-resolution structure of the actomyosin motor complex from Plasmodium falciparum. The complex includes the malaria parasite actin filament (PfAct1) complexed with the class XIV myosin motor (PfMyoA) and its two associated light-chains. The high-resolution core structure reveals the PfAct1:PfMyoA interface in atomic detail, while at lower-resolution, we visualize the PfMyoA light-chain binding region, including the essential light chain (PfELC) and the myosin tail interacting protein (PfMTIP). Finally, we report a bare PfAct1 filament structure at improved resolution.


Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy.
Alzheimer's disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimer's disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimer's disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from -1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).


Combining the fourth-corner and the RLQ methods for assessing trait responses to environmental variation.
Assessing trait responses to environmental gradients requires the simultaneous analysis of the information contained in three tables: L (species distribution across samples), R (environmental characteristics of samples), and Q (species traits). Among the available methods, the so-called fourth-corner and RLQ methods are two appealing alternatives that provide a direct way to test and estimate trait-nvironment relationships. Both methods are based on the analysis of the fourth-corner matrix, which crosses traits and environmental variables weighted by species abundances. However, they differ greatly in their outputs: RLQ is a multivariate technique that provides ordination scores to summarize the joint structure among the three tables, whereas the fourth-corner method mainly tests for individual trait-environment relationships (i.e., one trait and one environmental variable at a time). Here, we illustrate how the complementarity between these two methods can be exploited to promote new ecological knowledge and to improve the study of trait-environment relationships. After a short description of each method, we apply them to real ecological data to present their different outputs and provide hints about the gain resulting from their combined use.


A dual-modal retinal imaging system with adaptive optics.
An adaptive optics scanning laser ophthalmoscope (AO-SLO) is adapted to provide optical coherence tomography (OCT) imaging. The AO-SLO function is unchanged. The system uses the same light source, scanning optics, and adaptive optics in both imaging modes. The result is a dual-modal system that can acquire retinal images in both en face and cross-section planes at the single cell level. A new spectral shaping method is developed to reduce the large sidelobes in the coherence profile of the OCT imaging when a non-ideal source is used with a minimal introduction of noise. The technique uses a combination of two existing digital techniques. The thickness and position of the traditionally named inner segment/outer segment junction are measured from individual photoreceptors. In-vivo images of healthy and diseased human retinas are demonstrated.


Smooth Muscle Cell Genome Browser: Enabling the Identification of Novel Serum Response Factor Target Genes.
Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies.


On the precipice of a "majority-minority" America: perceived status threat from the racial demographic shift affects White Americans' political ideology.
The U.S. Census Bureau projects that racial minority groups will make up a majority of the U.S. national population in 2042, effectively creating a so-called majority-minority nation. In four experiments, we explored how salience of such racial demographic shifts affects White Americans' political-party leanings and expressed political ideology. Study 1 revealed that making California's majority-minority shift salient led politically unaffiliated White Americans to lean more toward the Republican Party and express greater political conservatism. Studies 2, 3a, and 3b revealed that making the changing national racial demographics salient led White Americans (regardless of political affiliation) to endorse conservative policy positions more strongly. Moreover, the results implicate group-status threat as the mechanism underlying these effects. Taken together, this work suggests that the increasing diversity of the nation may engender a widening partisan divide.


Consonant recognition as a function of the number of stimulation channels in the Hybrid short-electrode cochlear implant.
Consonant recognition was measured as a function of the number of stimulation channels for Hybrid short-electrode cochlear implant (CI) users, long-electrode CI users, and normal-hearing (NH) listeners in quiet and background noise. Short-electrode CI subjects were tested with 1-6 channels allocated to a frequency range of 1063-7938 Hz. Long-electrode CI subjects were tested with 1-6, 8, or 22 channels allocated to 188-7938 Hz, or 1-6 or 15 channels from the basal 15 electrodes allocated to 1063-7938 Hz. NH listeners were tested with simulations of each CI group/condition. Despite differences in intracochlear electrode spacing for equivalent channel conditions, all CI subject groups performed similarly at each channel condition and improved up to at least four channels in quiet and noise. All CI subject groups underperformed relative to NH subjects. These preliminary findings suggest that the limited channel benefit seen for CI users may not be due solely to increases in channel interactions as a function of electrode density. Other factors such as pre-operative patient history, location of stimulation in the base versus apex, or a limit on the number of electric channels that can be processed cognitively, may also interact with the effects of electrode contact spacing along the cochlea.


Enantiotopic discrimination in the NMR spectrum of prochiral solutes in chiral liquid crystals.
The splitting of signals in the NMR spectra originating from enantiotopic sites in prochiral molecules when dissolved in chiral solvents is referred to as spectral enantiotopic discrimination. This phenomenon is particularly noticeable in chiral liquid crystals (CLCs) due to the combined effect of the anisotropic magnetic interactions and the ordering of the solute in the mesophase. The enantiorecognition mechanisms are different for rigid and flexible solutes. For the former, discrimination results from symmetry breaking and is restricted to solutes whose point groups belong to one of the following four ("allowed") symmetries, Cs, C2v, D2d and S4. The nature of the symmetry breaking for each one of these groups is discussed and experimental examples, using mainly (2)H 1D/2D-NMR in chiral polypeptide lyotropic mesophases, are presented and analyzed. When flexible optically active solutes undergo fast racemization (on the NMR timescale) their spectrum corresponds to that of an average prochiral molecule and may exhibit enantiotopic sites. In CLCs, such sites will become discriminated, irrespective of their average (improper) symmetry. This enantiodiscrimination results mainly from the different ordering of the interchanging enantiomers. Several examples of such flexible molecules, including solutes with average axial and planar symmetries, are commented. Dynamic processes in solution that are not accompanied by the modulation of magnetic interactions remain "NMR blind". This is sometimes the case for interconversion of enantiomers (racemization) or exchange of enantiotopic sites in isotropic solvents. The limitation can be lifted by using CLCs. In such solvents, non-equivalence between enantiomers or between enantiotopic sites is induced by the chiral environment, thus providing the necessary interactions to be modulated by the dynamic processes. Illustrative examples involving exchange of both, enantiotopic sites and enantiomers are examined. In this comprehensive review, various important aspects of enantiodiscrimination by NMR are presented. Thus the possibility to reveal enantiotopic recognition using residual dipolar couplings or to determine the absolute configuration of enantiotopic NMR signals is discussed. The various kinds of chiral mesophases able to reveal enantiotopic discrimination in guest prochiral molecules are also described and compared with each other. Finally to illustrate the high analytical potentialities of NMR in CLCs, several and various applications involving the enantiodiscrimination phenomenon are described. A strategy for assigning the NMR signals of meso compound in a meso-threo mixture of cyclic molecules is first discussed. This is followed by a description of advantages of the method for the determination of (D/H) natural isotopic fractionation in biocompounds.


The antiinflammatory and analgesic effects of baicalin in carrageenan-evoked thermal hyperalgesia.
We tested baicalin for its antiinflammatory and analgesic effects (and the mechanisms) in a rat model of carrageenan-evoked thermal hyperalgesia. Pre- or posttreatment with baicalin (10, 30, or 100 mg/kg intraperitoneally) caused a significant analgesic effect with a similar effect of dose-matched ibuprofen. Furthermore, baicalin dose-dependently attenuated tumor necrosis factor-alpha (from 3510 +/- 150 pg/mL to 2860 +/- 148 pg/mL to 1480 +/- 210 pg/mL), interleukin (IL)-1beta (from 3210 +/- 210 pg/mL to 2200 +/- 140 pg/mL to 750 +/- 95 pg/mL), and IL-6 (from 58.5 +/- 9.8 pg/mL to 38.5 +/- 9.0 to 21.0 +/- 8.1 ng/mL) formation but enhanced IL-10 (from 18.1 +/- 2.5 pg/mL to 36.1 +/- 5.5 pg/mL to 71.2 +/- 9.5 pg/mL) production in paw exudates at 4 h after carrageenan injection. Prostaglandin E(2) (PGE(2)) and nitrate formation in the carrageenan-injected paws were dose-dependently inhibited by baicalin (10-100 mg/kg intraperitoneally) (PGE(2): from 15.9 +/- 2.1 ng/mL to 12.1 +/- 1.6 ng/mL to 6.2 +/- 1.8 ng/mL; nitrate: from 39.8 +/- 4.8 microM to 27.5 +/- 3.0 microM to 17.2 +/- 1.6 microM) at 4 h but not at 1.5 h after carrageenan injection. Increased myeloperoxidase activity in carrageenan-injected paws was also dose-dependently reduced by baicalin. These findings suggest that the antiinflammatory and analgesic mechanisms of baicalin may be associated with the inhibition of critical inflammatory mediators, including nitric oxide, PGE(2), and proinflammatory cytokines, accompanied by an increase in IL-10 production, as well as neutrophil infiltration at sites of inflammation. Our results showed that baicalin possesses an analgesic effect in carrageenan-evoked thermal hyperalgesia. The possible mechanisms of action of baicalin may be associated with the inhibition of proinflammatory mediator overproduction, including cytokines, nitric oxide, and prostaglandin E(2), as well as neutrophil infiltration. This implies that baicalin may be a potential therapeutic analgesic for inflammatory pain.


Influence of Zingiber officinale Extract on Push-Out Bond Strength of Glass-Fiber Post.
The aim of this study was to evaluate in vitro the influence of 20% glycolic ginger extract on the bond strength of glass-fiber post cemented with etch-and-rinse or self-etching resin cement. Forty-eight bovine roots were standardized (17±0.5 mm) and randomly divided into two groups, according to irrigant used during biomechanical preparation: NaOCl: 1% sodium hypochlorite and GEN: 20% glycolic ginger extract. Root canal was prepared and randomly assigned to one of two subgroups (n=12), according to luting protocol: self-etching (RelyX U200) and etch-and-rinse (RelyX ARC). After 48 h, the roots were sectioned perpendicularly (4 in cervical third and 3 in middle third) and submitted to push-out bond strength test (50 kgf load cell, 1.0 mm/min). Failure mode was analyzed in SEM and stereomicroscopy. Data were analyzed by three-way ANOVA and Tukey tests (p<0.05). ANOVA revealed that there were no significant differences between U200 (2.01±0.17)B and ARC (1.93±0.12)B in GEN group, and at the cervical third for both irrigants, 2.69±0.16A and 2.54±0.17A, respectively. Middle third showed lower bond strength than cervical third, regardless the irrigant. Overall, the cervical third regardless the irrigant employed and the association between NaOCl and ARC, presented better adhesive performance.


Flaxseed alone or in combination with tamoxifen inhibits MCF-7 breast tumor growth in ovariectomized athymic mice with high circulating levels of estrogen.
Flaxseed (FS) is rich in mammalian lignan precursors and alpha-linolenic acid, which have been suggested as having anticancer effects. Previous studies have shown that 10% FS inhibits the growth of human estrogen-dependent breast cancer (MCF-7) in athymic mice, and it enhances the inhibitory effect of tamoxifen (TAM). This study determined whether the effect of FS, alone or in combination with TAM, is dose dependent, and it explored the potential mechanism of action. Ovariectomized athymic mice with estradiol (E2) supplementation (1.7 mg/pellet, 60-day release) and established MCF-7 tumors were treated with basal diet control (0FS), 5% FS (5FS), 10% FS (10FS), and TAM (TAM/ 0FS; 5 mg/pellet, 60-day release), alone or in combination (TAM/ 5FS and TAM/10FS) for 8 weeks. Compared with control, 5FS and 10FS significantly inhibited tumor growth by 26% and 38%, respectively. TAM/0FS had an effect similar to the 10FS. TAM/ 5FS and TAM/10FS, respectively, induced significant 48% and 43% reductions in tumor size compared with 0FS, and 18% and 10% reductions compared with TAM/0FS. The relative uterine weight was significantly lower in all TAM groups compared with the control. The reduction of tumor growth resulted from decreased cell proliferation and increased cell apoptosis. TAM/ 5FS caused a significantly higher expression of estrogen receptor-alpha (ERalpha) compared with 5FS and TAM/0FS, whereas TAM/10FS had a higher ERalpha than 10FS and TAM/0FS. Compared with the control, progesterone receptor (PgR) expression was significantly reduced in all treatment groups, but insulin-like growth factor-1 (IGF-1) expression was reduced only by 10FS, TAM/5FS and TAM/10FS. Tumor cell proliferation was significantly positively associated with expression of PgR and IGF-1 and negatively associated with apoptosis and ERalpha. Apoptosis was only associated with ERalpha. In conclusion, FS inhibited MCF-7 tumor growth in a dose-dependent manner and enhanced the inhibitory effect of TAM due to the modulation of ER and growth factor signal transduction pathways.


Desensitization for solid organ and hematopoietic stem cell transplantation.
Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft.


Intestinal Microbiota Ecological Response to Oral Administrations of Hydrogen-Rich Water and Lactulose in Female Piglets Fed a Fusarium Toxin-Contaminated Diet.
The objective of the current experiment was to explore the intestinal microbiota ecological response to oral administrations of hydrogen-rich water (HRW) and lactulose (LAC) in female piglets fed a Fusarium mycotoxin-contaminated diet. A total of 24 individually-housed female piglets (Landrace × large × white; initial average body weight, 7.25 ± 1.02 kg) were randomly assigned to receive four treatments (six pigs/treatment): uncontaminated basal diet (negative control, NC), mycotoxin-contaminated diet (MC), MC diet + HRW (MC + HRW), and MC diet + LAC (MC + LAC) for 25 days. Hydrogen levels in the mucosa of different intestine segments were measured at the end of the experiment. Fecal scoring and diarrhea rate were recorded every day during the whole period of the experiment. Short-chain fatty acids (SCFAs) profiles in the digesta of the foregut and hindgut samples were assayed. The populations of selected bacteria and denaturing gradient gel electrophoresis (DGGE) profiles of total bacteria and methanogenic Archaea were also evaluated. Results showed that Fusarium mycotoxins not only reduced the hydrogen levels in the caecum but also shifted the SCFAs production, and populations and communities of microbiota. HRW treatment increased the hydrogen levels of the stomach and duodenum. HRW and LAC groups also had higher colon and caecum hydrogen levels than the MC group. Both HRW and LAC protected against the mycotoxin-contaminated diet-induced higher diarrhea rate and lower SCFA production in the digesta of the colon and caecum. In addition, the DGGE profile results indicated that HRW and LAC might shift the pathways of hydrogen-utilization bacteria, and change the diversity of intestine microbiota. Moreover, HRW and LAC administrations reversed the mycotoxin-contaminated diet-induced changing of the populations of Escherichia coli (E. coli) and Bifidobacterium in ileum digesta and hydrogen-utilizing bacteria in colon digesta.


Interventions for waterpipe smoking cessation.
While cigarette smoking has declined globally, waterpipe smoking is rising, especially among youth. The impact of this rise is amplified by mounting evidence of its addictive and harmful nature. Waterpipe smoking is influenced by multiple factors, including appealing flavors, marketing, use in social settings, and misperceptions that waterpipe is less harmful or addictive than cigarettes. People who use waterpipes are interested in quitting, but are often unsuccessful at doing so on their own. Therefore, developing and testing waterpipe cessation interventions to help people quit was identified as a priority for global tobacco control efforts. OBJECTIVES: To evaluate the effectiveness of tobacco cessation interventions for people who smoke waterpipes. We searched the Cochrane Tobacco Addiction Review Group Specialized Register from database inception to 29 July 2022, using variant terms and spellings ('waterpipe' or 'narghile' or 'arghile' or 'shisha' or 'goza' or 'narkeela' or 'hookah' or 'hubble bubble'). We searched for trials, published or unpublished, in any language. We sought randomized controlled trials (RCTs), quasi-RCTs, or cluster-RCTs of any smoking cessation interventions for people who use waterpipes, of any age or gender. In order to be included, studies had to measure waterpipe abstinence at a three-month follow-up or longer. We used standard Cochrane methods. Our primary outcome was abstinence from waterpipe use at least three months after baseline. We also collected data on adverse events. Individual study effects and pooled effects were summarized as risk ratios (RR) and 95% confidence intervals (95% CI), using Mantel-Haenszel random-effects models to combine studies, where appropriate. We assessed statistical heterogeneity with the I2 statistic. We summarized secondary outcomes narratively. We used the five GRADE considerations (risk of bias, inconsistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence for our primary outcome in four categories high, moderate, low, or very low. This review included nine studies, involving 2841 participants. All studies were conducted in adults, and were carried out in Iran, Vietnam, Syria, Lebanon, Egypt, Pakistan, and the USA. Studies were conducted in several settings, including colleges/universities, community healthcare centers, tuberculosis hospitals, and cancer treatment centers, while two studies tested e-health interventions (online web-based educational intervention, text message intervention). Overall, we judged three studies to be at low risk of bias, and six studies at high risk of bias. We pooled data from five studies (1030 participants) that tested intensive face-to-face behavioral interventions compared with brief behavioral intervention (e.g. one behavioral counseling session), usual care (e.g. self-help materials), or no intervention. In our meta-analysis, we included people who used waterpipe exclusively, or with another form of tobacco. Overall, we found low-certainty evidence of a benefit of behavioral support for waterpipe abstinence (RR 3.19 95% CI 2.17 to 4.69; I2 = 41%; 5 studies, N = 1030). We downgraded the evidence because of imprecision and risk of bias. We pooled data from two studies (N = 662 participants) that tested varenicline combined with behavioral intervention compared with placebo combined with behavioral intervention. Although the point estimate favored varenicline, 95% CIs were imprecise, and incorporated the potential for no difference and lower quit rates in the varenicline groups, as well as a benefit as large as that found in cigarette smoking cessation (RR 1.24, 95% CI 0.69 to 2.24; I2 = 0%; 2 studies, N = 662; low-certainty evidence). We downgraded the evidence because of imprecision. We found no clear evidence of a difference in the number of participants experiencing adverse events (RR 0.98, 95% CI 0.67 to 1.44; I2 = 31%; 2 studies, N = 662). The studies did not report serious adverse events. One study tested the efficacy of seven weeks of bupropion therapy combined with behavioral intervention. There was no clear evidence of benefit for waterpipe cessation when compared with behavioral support alone (RR 0.77, 95% CI 0.42 to 1.41; 1 study, N = 121; very low-certainty evidence), or with self-help (RR 1.94, 95% CI 0.94 to 4.00; 1 study, N = 86; very low-certainty evidence). Two studies tested e-health interventions. One study reported higher waterpipe quit rates among participants randomized to either a tailored mobile phone or untailored mobile phone intervention compared with those randomized to no intervention (RR 1.48, 95% CI 1.07 to 2.05; 2 studies, N = 319; very low-certainty evidence). Another study reported higher waterpipe abstinence rates following an intensive online educational intervention compared with a brief online educational intervention (RR 1.86, 95% CI 1.08 to 3.21; 1 study, N = 70; very low-certainty evidence). AUTHORS' CONCLUSIONS: We found low-certainty evidence that behavioral waterpipe cessation interventions can increase waterpipe quit rates among waterpipe smokers. We found insufficient evidence to assess whether varenicline or bupropion increased waterpipe abstinence; available evidence is compatible with effect sizes similar to those seen for cigarette smoking cessation. Given e-health interventions' potential reach and effectiveness for waterpipe cessation, trials with large samples and long follow-up periods are needed. Future studies should use biochemical validation of abstinence to prevent the risk of detection bias. Finally, there has been limited attention given to high-risk groups for waterpipe smoking, such as youth, young adults, pregnant women, and dual or poly tobacco users. These groups would benefit from targeted studies.