Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates.
Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4(+) or CD8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4(+) or CD8(+) T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4(+) and CD8(+) lymphocyte depletions were followed by a largely lineage-specific CD4(+) and CD8(+) T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4(+) T cells than RMs. In addition, in both species CD8(+) T-cell repopulation was faster than that of CD4(+) T cells, with CD8(+) T cells reconstituting a normal pool within 60 days and CD4(+) T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4(+) T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4(+) T-cell destruction is chronic.


Fine-scale oceanographic drivers of reef manta ray (Mobula alfredi) visitation patterns at a feeding aggregation site.
Globally, reef manta rays (Mobula alfredi) are in decline and are particularly vulnerable to exploitation and disturbance at aggregation sites. Here, passive acoustic telemetry and a suite of advanced oceanographic technologies were used for the first time to investigate the fine-scale (5-min) influence of oceanographic drivers on the visitation patterns of 19 tagged M. alfredi to a feeding aggregation site at Egmont Atoll in the Chagos Archipelago. Boosted regression trees indicate that tag detection probability increased with the intrusion of cold-water bores propagating up the atoll slope through the narrow lagoon inlet during flood tide, potentially transporting zooplankton from the thermocline. Tag detection probability also increased with warmer near-surface temperature close to low tide, with near-surface currents flowing offshore, and with high levels of backscatter (a proxy of zooplankton biomass). These combinations of processes support the proposition that zooplankton carried from the thermocline into the lagoon during the flood may be pumped back out through the narrow inlet during an ebb tide. These conditions provide temporally limited feeding opportunities for M. alfredi, which are tied on the tides. Results also provide some evidence of the presence of Langmuir Circulation, which transports and concentrates zooplankton, and may partly explain why M. alfredi occasionally remained at the feeding location for longer than that two hours. Identification of these correlations provides unique insight into the dynamic synthesis of fine-scale oceanographic processes which are likely to influence the foraging ecology of M. alfredi at Egmont Atoll, and elsewhere throughout their range.


Sexual Desire among Veterans Receiving Prolonged Exposure Therapy for PTSD: Does Successful PTSD Treatment Also Yield Improvements in Sexual Desire?
Objective: People with posttraumatic stress disorder (PTSD) commonly report difficulties with sexual desire and other aspects of sexual functioning, but it is currently unknown if people who respond to psychotherapy for PTSD also report improvements in sexual desire. Method: One hundred and eighty-seven veterans with PTSD received prolonged exposure (PE) therapy at two outpatient PTSD specialty clinics and completed measures of PTSD symptoms (the PTSD Checklist - Military Version) and sexual desire (item 21 of the Beck Depression Inventory - Second Edition) repeatedly throughout the course of treatment. Results: The results of a conditional generalized mixed ordinal regression model showed a significant interaction between weeks in treatment and PTSD treatment response in predicting change in sexual desire across the course of treatment. Specifically, PTSD treatment responders reported improvement in sexual desire over the course of treatment, whereas nonresponders did not show changes in sexual desire over time. However, the effect of PTSD treatment response was no longer significant when accounting for severity of depression at the start of treatment. Participants reporting more severe depression at the start of treatment reported less improvement in sexual desire, regardless of PTSD symptom response. Conclusions: People with PTSD who respond to PE also report improvements in sexual desire over time, indicating that response to PE is associated with improved sexual desire, but the effect is complicated by the presence of co-occurring depression symptomatology.


Successive Dimensional Transition in (TMTTF)_{2}PF_{6} Revealed by Synchrotron X-ray Diffraction.
A quasi-one-dimensional organic charge-transfer salt (TMTTF)_{2}PF_{6} undergoes a multistep phase transition as the temperature decreases. One of these transitions is called a "structureless transition," and these detailed structures were unknown for many years. With synchrotron x-ray diffraction, we observed a slight structural difference owing to the effect of charge-order transition between two TMTTF molecules in a dimer, which corresponds to the charge transfer δ_{CO}=0.20e. The two-dimensional Wigner crystallization was determined from an electron density analysis using core differential Fourier synthesis. Furthermore, we found that the ground state due to tetramerization, called the spin Peierls phase, is a three-dimensional transition with interchain correlation.


Thermodynamics and kinetics of vapor bubbles nucleation in one-component liquids.
The multivariable theory of nucleation (J. Chem. Phys. 2006, 124, 124512) is applied to the problem of vapor bubbles formation in pure liquids. The presented self-consistent macroscopic theory of this process employs thermodynamics (classical, statistical, and linear nonequilibrium), hydrodynamics, and interfacial kinetics. As a result of thermodynamic study of the problem, the work of formation of a bubble is obtained and parameters of the critical bubble are determined. The variables V (the bubble volume), ρ (the vapor density), and T (the vapor temperature) are shown to be natural for the given task. An equation for the dependence of surface tension on bubble state parameters is obtained. An algorithm of writing the equations of motion of a bubble in the space {V, ρ, T}--equations for V, ρ, and T--is offered. This algorithm ensures symmetry of the matrix of kinetic coefficients. The equation for T written on the basis of this algorithm is shown to represent the first law of thermodynamics for a bubble. The negative eigenvalue of the motion equations which alongside with the work of the critical bubble formation determines the stationary nucleation rate of bubbles is obtained. Various kinetic limits are considered. One of the kinetic constraints leads to the fact that the nucleation cannot occur in the whole metastable region; it occurs only in some subregion of the latter. Zeldovich's theory of cavitation is shown to be a limiting case of the theory presented. The limiting effects of various kinetic processes on the nucleation rate of bubbles are shown analytically. These are the inertial motion of a liquid as well as the processes of particles exchange and heat exchange between a bubble and surrounding liquid. The nucleation rate is shown to be determined by the slowest kinetic process at positive and moderately negative pressures in a liquid. The limiting effects of the processes of evaporation-condensation and heat exchange vanish at high negative pressures.


The "Complex Restrictive" Pulmonary Function Pattern: Clinical and Radiologic Analysis of a Common but Previously Undescribed Restrictive Pattern.
Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV1 are reduced to a similar degree. This pattern is called "simple restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (pp) is disproportionately reduced relative to TLCpp. This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features. This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCpp-FVCpp ≤ 10%, and CR was stratified into four classes based on TLCpp-FVCpp discrepancy: Class 1 CR, TLCpp-FVCpp > 10% and ≤ 15%; Class 2 CR, TLCpp-FVCpp > 15% and ≤20%; Class 3 CR, TLCpp-FVCpp > 20% and ≤ 25%; and Class 4 CR, TLCpp-FVCpp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed. Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m2 or < 18.5 kg/m2, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001). CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.


Risk factors for the first episode of Klebsiella pneumoniae resistant to carbapenems infection in critically ill patients: a prospective study.
To identify risk factors for the first episode of Klebsiella Pneumonia resistant to carbapenems (KPRC) infection in critically ill patients. This prospective cohort study was conducted in a 12-bed general Intensive Care Unit (ICU) in a University Hospital on ICU patients who required mechanical ventilation (MV) for >48 hours during a 12-month period. Clinical and microbiologic data were studied. Characteristics of KPRC patients were compared with those of critically ill patients who presented nonmultidrug resistant (MDR) bacterial infections or no documented infection at all. Twenty-five patients presented KPRC infection, 18 presented non-MDR bacterial infection, and 39 patients presented no infection. Compared to patients without documented infection or infected by non MDR bacteria, patients with KPRC infection had received more frequently or for longer duration antibiotics against Gram-negative bacteria (carbapenems, colistin P < 0.05). Duration of colistin administration prior to KPRC isolation was independently associated with increased frequency of KPRC infection (odds ratio, 1.156 per day; 95% confidence interval, 1.010 to 1.312; P = 0.025). KPRC patients stayed longer in the ICU and received mechanical ventilation and sedation for longer periods and presented increased mortality (P < 0.05). KPRC infection is an emerging problem which might be more common in patients with previous use of antibiotics and especially colistin.


Increasing the Room-Temperature Electric Double Layer Retention Time in Two-Dimensional Crystal FETs.
Poly(vinyl alcohol) (PVA) and LiClO4, a solid polymer electrolyte with a glass transition temperature (Tg) of 80 °C, is used to electrostatically gate graphene field-effect transistors. The ions in PVA:LiClO4 are drifted into place by field-effect at T > Tg, providing n- or p-type doping, and when the device is cooled to room temperature, the polymer mobility and, hence ion mobility are arrested and the electric double layer (EDL) is "locked" into place in the absence of a gate bias. Unlike other electrolytes used to gate two-dimensional devices for which the Tg, and therefore the "locking" temperature, is well below room temperature, the electrolyte demonstrated in this work provides a route to achieve room-temperature EDL stability. Specifically, a 6 orders of magnitude increase in the room temperature EDL retention time is demonstrated over the commonly used electrolyte, poly(ethylene oxide) (PEO) and LiClO4. Hall measurements confirm that large sheet carrier densities can be achieved with PVA:LiClO4 at top gate programming voltages of ±2 V (-6.3 ± 0.03 × 1013 cm-2 for electrons and 1.6 ± 0.3 × 1014 cm-2 for holes). Transient drain current measurements show that at least 75% of the EDL is retained after more than 4 h at room temperature. Unlike PEO-based electrolytes, PVA:LiClO4 is compatible with the chemicals used in standard photolithographic processes enabling the direct deposition of patterned, metal contacts on the surface of the electrolyte. A thermal instability in the electrolyte is detected by both I-V measurements and differential scanning calorimetry, and FTIR measurements suggest that thermally catalyzed cross-linking may be driving phase separation between the polymer and the salt. Nevertheless, this work highlights how the relationship between polymer and ion mobility can be exploited to tune the state retention time and the charge carrier density of a 2D crystal transistor.


Assessing the Role of Selection Bias in the Protective Relationship Between Caregiving and Mortality.
Caregivers have lower mortality rates than noncaregivers in population-based studies, which contradicts the caregiver-stress model and raises speculation about selection bias influencing these findings. We examined possible selection bias due to 1) sampling decisions and 2) selective participation among women (baseline mean age = 79 years) in the Caregiver-Study of Osteoporotic Fractures (Caregiver-SOF) (1999-2009), an ancillary study to the Study of Osteoporotic Fractures (SOF). Caregiver-SOF includes 1,069 SOF participants (35% caregivers) from 4 US geographical areas (Baltimore, Maryland; Minneapolis, Minnesota; the Monongahela Valley, Pennsylvania; and Portland, Oregon). Participants were identified by screening all SOF participants for caregiver status (1997-1999; n = 4,036; 23% caregivers) and rescreening a subset of caregivers and noncaregivers matched on sociodemographic factors 1-2 years later. Adjusted hazard ratios related caregiving to 10-year mortality in all women initially screened, subsamples representing key points in constructing Caregiver-SOF, and Caregiver-SOF. Caregivers had better functioning than noncaregivers at each screening. The association between caregiving and mortality among women invited to participate in Caregiver-SOF (41% died; adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI): 0.61, 0.88) was slightly more protective than that in all initially screened women (37% died; aHR = 0.83, 95% CI: 0.73, 0.95), indicating little evidence of selection bias due to sampling decisions, and was similar to that in Caregiver-SOF (39% died; aHR = 0.71, 95% CI: 0.57, 0.89), indicating no participation bias. These results add to a body of evidence that informal caregiving may impart health benefits.


Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression.
The effect of interferon-gamma (IFN-gamma) on endothelial cell (EC) and fibroblast (FB) class II major histocompatibility complex (MHC) gene product expression and antigen presenting ability was examined. Control FB did not express class II MHC gene products, whereas a small (less than 1%) population of passaged EC expressed class II gene products. IFN-gamma induced a comparable density of HLA-DR expression on nearly all EC and FB. IFN-gamma-treated EC and FB also expressed HLA-DP but at a lower density, whereas HLA-DQ expression was barely detectable on either cell type. Control FB were not able to stimulate allogeneic T4 cell DNA synthesis or function as antigen-presenting cells (APC). Control EC were also unable to stimulate allogeneic T4 cell DNA synthesis unless large numbers of stimulator cells were used. Small numbers of IFN-gamma-treated EC were able to stimulate allogeneic T4 cell DNA synthesis, whereas larger numbers were markedly more effective than control EC. In contrast, IFN-gamma-treated FB were ineffective stimulators of allogeneic T4 cell DNA synthesis. IFN-gamma-treated FB were able to present the exogenous antigen SKSD to autologous but not allogeneic T4 cells, but they were extremely inefficient APC. The inability of IFN-gamma-treated FB to function as APC could not be explained by FB-mediated immunosuppression, Ia density, or HLA-DQ expression. This limited capacity of IFN-gamma-treated FB to participate in Ia-restricted functional interactions with T4 cells correlated with a similar diminished capacity to support nonspecific mitogen-induced proliferation of T4 cells before IFN-gamma-induced Ia expression. This accessory cell function was not enhanced by IFN-gamma treatment. Monocytes syngeneic to the responding T4 cells but not interleukin 1 (IL 1) permitted IFN-gamma-treated FB but not control FB to stimulate allogeneic T4 cell DNA synthesis, but they remained markedly less effective stimulators than monocytes. Moreover, IFN-gamma-treated FB were effective stimulators of alloprimed T4 cells, in contrast to their inability to stimulate fresh T4 cells. Furthermore, monocytes and IFN-gamma-treated FB were comparably effective stimulators of alloreactive T cell lines. These data suggest that accessory cells perform functions unrelated to Ia and IL 1 that are necessary for mitogen-, alloantigen-, and antigen-induced proliferation of freshly isolated T cells. Monocytes and EC effectively perform this function, but FB do not. This accessory cell function does not seem to be as important for the activation of primed T cells.


Periodontal disease and hypertriglyceridemia in Japanese subjects: potential association with enhanced lipolysis.
Although periodontal disease may be associated with increased risk for atherosclerosis, the mechanism by which the disease causes atherosclerosis is still unknown. The candidates contributing to atherosclerosis in periodontal disease include low-grade inflammation such as C-reactive protein (CRP) and insulin resistance. A previous study demonstrated that periodontal therapy leads to an improvement in CRP as well as insulin resistance, indicating the relationship between periodontal disease and low-grade inflammation or insulin resistance. On the other hand, we previously demonstrated that serum triglyceride (TG) per se is independently associated with CRP or insulin resistance in Japanese populations with a body mass index (BMI) of 21.5 to 27.0 (midrange BMI). To the best of our knowledge, however, the relationship between periodontal disease and serum TG is not fully clarified. The first aim of the present study is to investigate whether periodontal disease is associated with serum TG in Japanese subjects with midrange BMI. If so, another aim of the study is to determine which mechanism is responsible for the association between periodontal disease and serum TG in these subjects. We have performed a periodontal examination in the Ogaki metabolic syndrome medical examination. One hundred sixty-two participants from 40 to 74 years old (56 men and 106 women; mean age, 66.43 ± 6.25 years) were enrolled in the study. Besides medical examination, oral panoramic radiograph was taken for all participants. Average bone score was also calculated. Periodontal bone destruction increased according to the age of the participants (r = 0.227, P < .004, Spearman correlation coefficient). Periodontal bone destruction was also associated with serum TG levels (r = 0.299, P = .000). This association was more evident in subjects with midrange BMI (r = 0.332, P < .001). In subjects with midrange BMI, TG was not correlated with BMI or waste circumstances. Furthermore, TG was not associated with age itself in the midrange BMI group. We then investigated the lipolytic activity of endotoxin in cocultures of adipocytes and macrophages. Low-dose lipopolysaccharide dose-dependently increased lipolytic activity in cocultures, and this activity was neutralized by anti-tumor necrosis factor α neutralizing antibodies. These results suggest that periodontal infection, especially bacterial endotoxinemia, is associated with enhanced lipolysis and subsequent up-regulation of circulating TG in Japanese with midrange BMI.


Two-dimensional phase unwrapping with use of statistical models for cost functions in nonlinear optimization.
Interferometric radar techniques often necessitate two-dimensional (2-D) phase unwrapping, defined here as the estimation of unambiguous phase data from a 2-D array known only modulo 2pi rad. We develop a maximum a posteriori probability (MAP) estimation approach for this problem, and we derive an algorithm that approximately maximizes the conditional probability of its phase-unwrapped solution given observable quantities such as wrapped phase, image intensity, and interferogram coherence. Examining topographic and differential interferometry separately, we derive simple, working models for the joint statistics of the estimated and the observed signals. We use generalized, nonlinear cost functions to reflect these probability relationships, and we employ nonlinear network-flow techniques to approximate MAP solutions. We apply our algorithm both to a topographic interferogram exhibiting rough terrain and layover and to a differential interferogram measuring the deformation from a large earthquake. The MAP solutions are complete and are more accurate than those of other tested algorithms.


Structural analysis of the carbohydrate chains of beta-N-acetylhexosaminidases from bovine brain.
The oligosaccharide structures of bovine brain beta-N-acetylhexosaminidases A and B (EC 220.127.116.11) were studied at the glycopeptide level by employing 500 MHz 1H-n.m.r. spectroscopy and methylation analysis involving g.l.c.-m.s. More than 90% of the chains were found to be of the oligomannoside type, containing, on average, five to six mannose residues. Biantennary N-acetyl-lactosamine-type chains terminated in N-acetylneuraminic acid were found to comprise the remaining 5-10% of the total carbohydrate. The isoenzyme forms A and B do not differ from each other in the structure of their carbohydrate moiety, but do deviate in carbohydrate content and, in consequence, in the number of carbohydrate chains per molecule.


Role of transesophageal echocardiography in the clinical management of a patients with a giant coronary artery aneurysm.
Transthoracic echocardiography (TTE) has substantial limitations for the study of abnormalities of the coronary tree. Transesophageal echocardiography (TEE) allows a more complete examination of the coronary arteries, particularly the proximal segments. This report describes the use of TEE after cardiac catheterization in the clinical management of a patient with unstable angina. While angiography first showed the giant aneurysm of the left circumflex coronary artery. TEE, by revealing an active thrombus of the lumen, prompted an immediate surgical resolution.


[Laparoscopy and hysteroscopy in Müllerian duct malformations: usefulness and reproductive results].
Determine the type and the possibility of corrective surgery, reproductive results of infertility patients with Müllerian malformations. The clinic and the laparoscopic and hysteroscopic evaluation were performed to 40 patients with Müllerian anomalies and infertility history analyzing the reproductive results. The uterine septum was present in 23/40 patients (57.5%), bicornual uterus in 6/40 (15%), didelfus uterus 5/40 (12.5%), arcuate uterus 4/40 (10%), unicorn uterus 2/40 (5%). After septum resection we had 13 pregnancies (56.5%). 2 abortions, 4 already delivered and 7 continue normal evolution with on twin case. Strassman metroplasty by laparotomy was performed in 4 cases of bicornual uterus achieving pregnancy in two cases. In one didelfus uterus, a salpingoclasy of the smaller horn was done as an alternative. Of the arcuated uterus, the small septum was removed. Of the unicorn uterus, one pregnancy was lost in the first trimester and the other one reach the term date. Our data show that the endoscopic procedures can perform the correct diagnosis of the Müllerian anomalies and of course the best surgical treatment improving the fertility rates.


CE: Reducing Bias Against People with Substance Use Disorders.
Addiction is a highly misunderstood and stigmatized chronic illness frequently encountered by health care providers during routine medical care. People with substance use disorders, in particular, face extraordinary stigma and bias when interacting with health care providers, including nurses. Stigma associated with addiction contributes to health inequities and is recognized as a significant barrier to people seeking and receiving necessary health care. Since patients often spend the most time with nurses in the clinical setting, nurses are ideally positioned to address addiction stigma. However, many nurses lack knowledge about addiction, stigma, and the impact of the words they use, whether in conversation or in clinical documentation. This article reviews the consequences of addiction stigma (labeling, stereotyping, or discrimination) and the steps nurses can take to reduce biases related to substance use. A case scenario based on our experience will be used to guide a discussion of opportunities for nurses to intervene and improve care.


Lenalidomide for the treatment of B-cell malignancies.
Lenalidomide is a novel anticancer agent that has made a major impact in the treatment of patients with B-cell malignancies. A more potent analog of thalidomide, lenalidomide was developed to enhance immunomodulatory properties with improved safety profile. Its antitumor activity seems mediated through modulation of both the cytokine and cellular tumor cell microenvironment. Preclinical as well as clinical observations demonstrate that lenalidomide downregulates production of various critical prosurvival cytokines in the tumor microenvironment while concurrently promoting activation of T- and natural killer (NK) cell-mediated antitumor response. Early clinical investigations noted its efficacy in relapsed and/or refractory multiple myeloma patients. Subsequently, larger randomized studies confirmed the clinical benefit of lenalidomide when added to dexamethasone compared with dexamethasone alone in previously treated myeloma patients resulting in its recent approval by the US Food and Drug Administration. Consequently, the role of lenalidomide in other B-cell malignancies has been investigated, with impressive results in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. This review summarizes the data from various clinical investigations and highlights the impact of lenalidomide in the management of patients with B-cell malignancies.


Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita.
Dyskeratosis congenita (DKC) is a rare and fatal congenital syndrome characterized by the triad of reticular skin pigmentation, nail dystrophy and mucosal leukoplakia, and the predisposition to bone marrow failure and malignancies. Mutations in DKC1 gene encoding dyskerin are responsible for the X-linked dyskeratosis congenita. Here we report mutation analysis of two Chinese pedigrees with dyskeratosis congenita. The 15 coding exons of DKC1 and their flanking regions were amplified from genomic DNA by PCR. DNA sequencing and restriction endonuclease digestion were used for mutation detection. Transition mutation of 1226C-->T (P409L) found in the first pedigree is a novel mutation. In the second pedigree, the proband's mother phenotypically normal carried a de novo transition mutation of 1058C-->T (A353 V) in one allele, and transmitted the mutant allele to her two sons who had typical manifestations of dyskeratosis congenita.


Challenges with Percent Predicted Maximal V˙O2 in Patients with Heart Failure.
This study aimed to describe the influence of different equations to predict maximal oxygen uptake (MV˙O2) on the percent predicted MV˙O2 (ppMV˙O2) and the resultant categorization of patients with heart failure with reduced ejection fraction into high or low risk. In this retrospective cohort study, ppMV˙O2 was calculated using six different equations to predict MV˙O2 among 1168 patients with heart failure with reduced ejection fraction (33% women). Repeated-measures ANOVA was used to compare within-subject differences in mean ppMV˙O2 between the prediction equations. Cochrane's Q test was used to compare the within-subject difference in the proportion of patients with ppMV˙O2 of <50% (high risk) and ≥75% (low risk) between the prediction equations. The ppMV˙O2 varied significantly (P < 0.001) between the MV˙O2 prediction equations, with mean (10th, 90th percentile) ppMV˙O2 ranging from 39% (25%, 54%) to 60% (39%, 83%) in men and 37% (24%, 49%) to 70% (47%, 94%) in women. Significant variation (P < 0.001) was also observed between prediction equations for the proportion of patients with ppMV˙O2 of <50% and ≥75% in men and women. Statistically significant and clinically meaningful variations in the ppMV˙O2 are observed on the basis of the reference equation used to predict MV˙O2. Future writing committees should specify the preferred reference equation when identifying a ppMV˙O2 criterion in guideline statements.


[Carney triad: Report of one case].
Carney described a disorder characterized by the presence of several uncommon tumors which were pulmonary chondromas, gastric sarcomas and extra-adrenal paragangliomas. We report a 14 year-old girl in whom multiple gastric tumors were discovered during a study of an iron deficiency anemia and was subjected to a partial gastrectomy. At 25 years of age, she developed several pulmonary chondromas and at 33 years, a mediastinal tumor with features of an extra-adrenal paraganglioma was found. At 35 years of age, a total gastrectomy was performed to remove a gastrointestinal stromal tumor with excision of peritoneal and lymph node metastasis. One year later, the patient died due to liver failure secondary to liver metastases.


Environmental factors associated with disordered weight-control behaviours among youth: a systematic review.
Environmental factors may be very important in the development of disordered weight-control behaviours (DWCB) among youth, yet no study to date has conducted a review that synthesizes these findings. The purpose of the present study was to systematically review existing literature on environmental influences on DWCB among youth and to identify conceptual and methodological gaps in the literature. Systematic review. Studies were identified through a systematic search using PubMed, PsycINFO, Google Scholar and secondary references. Inclusion criteria included observational studies published in peer-reviewed journals from 1994 to 2012 that examined environmental exposure(s) associated with DWCB among youth. Ninety-three studies, the majority of which utilized a cross-sectional design (75 %; n 70), were identified. Longitudinal studies' follow-up time ranged from 8 months to 10 years. Parental, peer and media influences have been extensively studied as factors associated with DWCB among youth. Fewer studies have examined behavioural settings (i.e. homes, schools, neighbourhoods) or sectors of influence other than the media on DWCB. No studies utilized multilevel methods to parse out environmental influences on DWCB. Most studies (69 %, n 64) did not explicitly utilize a theory or model to guide the research. Findings indicate that exploring a wider range of environmental influences on DWCB, specifically behavioural settings and sectors of influence, using diverse study samples and multilevel methodology is needed to advance the field and to inform the design of comprehensive prevention programmes that target DWCB and other weight-related behaviours.


The anti-carbamylated protein antibody response is of overall low avidity despite extensive isotype switching.
To better understand the contribution of autoantibodies in RA and the biology of their responses, we evaluated the avidity of the anti-carbamylated protein (anti-CarP) antibody response. The avidity of anti-CarP antibody, ACPA and anti-tetanus toxoid IgG were determined using elution assays. Anti-CarP IgG avidity was measured in sera of 107 RA patients, 15 paired SF and serum samples and 8 serially sampled sera before and after disease onset. The avidity of anti-CarP IgG is low compared with the avidity of anti-tetanus toxoid IgG present in the same sera. Likewise, although less pronounced, anti-CarP also displayed a lower avidity as compared with the avidity of ACPA IgG. No difference in anti-CarP IgG avidity is observed between ACPA positive or ACPA negative patients. Anti-CarP IgG avidity is higher in anti-CarP IgM-negative compared with IgM-positive individuals. Furthermore, the anti-CarP avidity in serum is higher than in SF. Using samples of individuals that over time developed RA we observed no anti-CarP avidity maturation in the years before disease onset. In contrast to ACPA avidity, the anti-CarP avidity is not associated with severity of joint destruction. The anti-CarP response is of overall low avidity, even lower than the ACPA IgG avidity, and does not show apparent avidity maturation before or around disease onset. Overall, isotype switch and avidity maturation seem to be uncoupled as isotype switch occurs without avidity maturation, pointing towards a commonality in the regulation of both autoantibody responses as opposed to the pathways governing recall responses.


Association Between Poor Cognitive Functioning and Risk of Incident Parkinsonism: The Rotterdam Study.
Cognitive dysfunction is a common feature among patients with parkinsonism, including Parkinson disease (PD). However, there is a scarcity of data on cognitive functioning before parkinsonism diagnosis, a stage at which patients may still respond to putative disease-modifying interventions. To assess whether poor cognitive functioning is associated with an increased risk of parkinsonism. Between January 8, 2002, and December 14, 2008, baseline cognitive function was assessed in 7386 participants of the Rotterdam Study who were free of parkinsonism and dementia. Four tests were administered (Stroop color word test, letter-digit substitution, verbal fluency, and word learning) and a global cognition score was derived from principal component analysis. Subsequently, participants were followed up until January 1, 2015, for the onset of parkinsonism through serial in-person examinations and complete access to medical records. Parkinsonism was defined as the (1) presence of hypokinesia or bradykinesia plus at least 1 other cardinal sign and/or (2) clinical diagnosis by a neurologist or geriatrician. Patients with dementia diagnosis before parkinsonism diagnosis were considered to have probable PD. Hazard ratios (HRs) for incident parkinsonism per SD decrease in global cognition, adjusted for age, sex, and study subcohort. A total of 7386 patients were included in the analysis; of these, 4236 (57.4%) were women and mean (SD) age was 65.3 (10.2) years. During follow-up (median, 8.3 years; range, 0-15 years), 79 (1.1%) individuals received a diagnosis of incident parkinsonism; of these, 57 (72.2%) received a diagnosis of probable PD. Among patients with incident parkinsonism, 24 (30.4%) also developed dementia (10 before and 14 after parkinsonism onset). Poor global cognition at baseline was associated with a higher hazard of incident parkinsonism (hazard ratio [HR], 1.79; 95% CI, 1.37-2.33). The association remained robust beyond the first 8 years (HR, 1.59; 95% CI, 1.01-2.59) and after removing individuals with dementia onset before parkinsonism (HR, 1.72; 95% CI, 1.28-2.27). Poor global cognition at baseline was also associated with incident probable PD (HR, 1.52; 95% CI, 1.11-2.08). Letter-digit substitution (HR, 1.59; 95% CI, 1.22-2.04), verbal fluency (HR, 1.61; 95% CI, 1.23-2.08), and inverted interference task Stroop color word test (HR, 1.56; 95% CI, 1.25-1.96) scores were each associated with incident parkinsonism, whereas the association with word learning delayed-task scores was weaker (HR, 1.18; 95% CI, 0.92-1.52). Poor cognitive functioning is associated with an increased risk of incident parkinsonism, including probable PD. Cognition indicates the probability of parkinsonism over long intervals and extends beyond patients with onset of parkinsonism after dementia. The findings suggest that cognitive dysfunction can be considered a sign of prodromal PD.


Glucoreceptors controlling feeding and blood glucose: location in the hindbrain.
Microinfusion of 5-thioglucose into either the lateral or fourth cerebral ventricle caused increased feeding and hyperglycemia in rats when the cerebral aqueduct was unobstructed. If the aqueduct was obstructed and 5-thioglucose was infused into the fourth ventricle, increased feeding and hyperglycemia persisted, whereas feeding and hyperglycemia in response to lateral ventricle infusion were abolished. Drinking in response to infusion of angiotensin II into the lateral ventricle was not diminished by aqueduct obstruction. These results indicate that glucoreceptors that mediate feeding and hyperglycemia in response to cerebral glucoprivation are located in the caudal hindbrain and not in the hypothalamus where they have previously been sought.


Microfluidics and cancer: are we there yet?
More than two decades ago, microfluidics began to show its impact in biological research. Since then, the field of microfluidics has evolving rapidly. Cancer is one of the leading causes of death worldwide. Microfluidics holds great promise in cancer diagnosis and also serves as an emerging tool for understanding cancer biology. Microfluidics can be valuable for cancer investigation due to its high sensitivity, high throughput, less material-consumption, low cost, and enhanced spatio-temporal control. The physical laws on microscale offer an advantage enabling the control of physics, biology, chemistry and physiology at cellular level. Furthermore, microfluidic based platforms are portable and can be easily designed for point-of-care diagnostics. Developing and applying the state of the art microfluidic technologies to address the unmet challenges in cancer can expand the horizons of not only fundamental biology but also the management of disease and patient care. Despite the various microfluidic technologies available in the field, few have been tested clinically, which can be attributed to the various challenges existing in bridging the gap between the emerging technology and real world applications. We present a review of role of microfluidics in cancer research, including the history, recent advances and future directions to explore where the field stand currently in addressing complex clinical challenges and future of it. This review identifies four critical areas in cancer research, in which microfluidics can change the current paradigm. These include cancer cell isolation, molecular diagnostics, tumor biology and high-throughput screening for therapeutics. In addition, some of our lab's current research is presented in the corresponding sections.


Imaging in patients with cardiovascular implantable electronic devices - Part 1: Imaging before and during device implantation.
More than 500,000 cardiovascular implantable electronic devices (CIED) are implanted in the European Society of Cardiology countries each year. The role of cardiovascular imaging in patients being considered for CIED is distinctly different from imaging in CIED recipients. In the former group, imaging can help identify specific or potentially reversible causes of heart block, the underlying tissue characteristics associated with malignant arrhythmias, the mechanical consequences of conduction delays and can also aid challenging lead placements. On the other hand, cardiovascular imaging is required in CIED recipients both for standard indications, and to assess the response to device implantation, to diagnose immediate and delayed complications after implantation, and to guide device optimization. The present clinical consensus statement (Part 1) from the European Association of Cardiovascular Imaging, in collaboration with the European Heart Rhythm Association, provides comprehensive, up-to-date and evidence-based guidance to cardiologists, cardiac imagers and pacing specialists regarding the use of imaging in patients undergoing implantation of conventional pacemakers, cardioverter defibrillators and resynchronization therapy devices. The document summarizes the existing evidence regarding the use of imaging in patient selection and during the implantation procedure and also underlines gaps in evidence in the field. The role of imaging after CIED implantation is discussed in the second document (Part 2).


Functional Transcranial Doppler (fTCD) investigation of brain lateralization following visual stimuli.
This preliminary investigation of the local cerebral perfusion evaluated by Transcranial Doppler (TCD) monitoring of the Posterior Cerebral Arteries shows that selective stimulation of visual hemifields evokes significantly different vascular responses. TCD can therefore allow for functional evaluation of lateralized enhancements in cerebral metabolism.Clinical Relevance-The cerebral lateralization evaluated with the functional TCD can be a useful and low-cost approach to evaluate the effectiveness of the rehabilitation therapy in post stroke subjects experiencing hemianopia or to assess cerebral reorganization after cerebrovascular accidents.


Essential Tremor as a "Waste Basket" Diagnosis: Diagnosing Essential Tremor Remains a Challenge.
Introduction: The diagnosis of essential tremor (ET) remains a clinical one, and diagnostic errors are common. We aimed to (1) determine precisely how frequently ET diagnoses are misapplied (i.e., what percentage of patients who have been assigned an "ET" diagnosis actually have another movement disorder), (2) determine which other movement disorders are most often misclassified as "ET," and (3) examine the clinical features that were most associated with diagnostic errors. Methods: One hundred four consecutive patients were included who met the following criteria: (1) initial outpatient evaluation by one of the authors (EDL) between January 2015 and December 2019 and (2) pre-evaluation diagnosis of ET. Data on an extensive number of clinical features were extracted from the electronic medical record. Results: Forty-seven (45.2%) patients received a post-evaluation diagnosis of ET, 29 (27.9%) of dystonia, and 28 (26.9%) of other diagnoses including Parkinson's disease (PD) [6 (5.8%)]. Factors associated with an alternative post-evaluation diagnosis other than ET were pre-evaluation diagnosis made by a non-neurologist, shorter tremor duration, irregular tremor, abnormal limb postures, among others. Discussion: Diagnosing ET remains a challenge, with the diagnosis being over-applied and being used as a "waste basket." More than one-half of the patients who were referred to our clinic with an intake diagnosis of ET were given an alternative post-evaluation diagnosis. While PD was reported to be the most frequently missed diagnosis in a past study, dystonia was most commonly missed in our study. Several clinical features can help to differentiate ET from other tremor disorders.


Effects of Supervised Multimodal Exercise Interventions on Cancer-Related Fatigue: Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Cancer-related fatigue (CRF) is the most common and devastating problem in cancer patients even after successful treatment. This study aimed to determine the effects of supervised multimodal exercise interventions on cancer-related fatigue through a systematic review and meta-analysis. A systematic review was conducted to determine the effectiveness of multimodal exercise interventions on CRF. Databases of PubMed, CENTRAL, EMBASE, and OVID were searched between January and March 2014 to retrieve randomized controlled trials. Risk of bias was evaluated using the PEDro scale. Nine studies (n = 772) were included in both systematic review and meta-analysis. Multimodal interventions including aerobic exercise, resistance training, and stretching improved CRF symptoms (SMD = -0.23; 95% CI: -0.37 to -0.09; P = 0.001). These effects were also significant in patients undergoing chemotherapy (P < 0.0001). Nonsignificant differences were found for resistance training interventions (P = 0.30). Slight evidence of publication bias was observed (P = 0.04). The studies had a low risk of bias (PEDro scale mean score of 6.4 (standard deviation (SD) ± 1.0)). Supervised multimodal exercise interventions including aerobic, resistance, and stretching exercises are effective in controlling CRF. These findings suggest that these exercise protocols should be included as a crucial part of the rehabilitation programs for cancer survivors and patients during anticancer treatments.


2020 Chitranjan S. Ranawat Award: Perioperative essential amino acid supplementation suppresses rectus femoris muscle atrophy and accelerates early functional recovery following total knee arthroplasty.
The aim of this study was to assess the effectiveness of perioperative essential amino acid (EAA) supplementation to prevent rectus femoris muscle atrophy and facilitate early recovery of function after total knee arthroplasty (TKA). The study involved 60 patients who underwent unilateral TKA for primary knee osteo-arthritis (OA). This was a double-blind, placebo-controlled, randomized control trial with patients randomly allocated to two groups, 30 patients each: the essential amino acid supplementation (9 g daily) and placebo (lactose powder, 9 g daily) groups. Supplementation and placebo were provided from one week before to two weeks after surgery. The area of the rectus femoris muscle were measured by ultrasound imaging one month before surgery and one, two, three, and four weeks postoperatively. The serum albumin level, a visual analogue knee pain score, and mobility were also measured at each time point. The time to recovery of activities of daily living (ADLs) was recorded. Postoperative nutrition and physiotherapy were identical in both groups. The mean relative change from baseline was as follows for the amino acid group: 116% in rectus femoris muscle area (71% to 206%); 95% in serum albumin (80% to 115%) and 39% in VAS pain (0% to 100%) at four weeks after surgery. These values in the placebo group were: 97% in muscle area (68 to 155); 89% in serum albumin (71% to 100%) and 56% in VAS pain four weeks after surgery (0% to 100%). All changes were statistically significant (p < 0.05). The mean time to recovery of ADLs was shorter in the amino acid group compared with the placebo group (p = 0.005). Perioperative essential amino acid supplementation prevents rectus femoris muscle atrophy and accelerates early functional recovery after TKA. Cite this article: Bone Joint J 2020;102-B(6 Supple A):10-18.


Routine developmental and autism screening in an epilepsy care setting.
Developmental delay (delay) and co-morbidities like autism are common in children with epilepsy. We assessed the yield of routine screening for delay and autism in a hospital-based program. Parents completed developmental and autism screeners for 65 children (average age=2.5y; 38(58%) boys). Forty-nine (75%) were established epilepsy patients, and 16 (25%) were new patients. For development, 47 (72%) children screened positive and 8 (12%) had borderline results. Twenty-four (37%) scored positive for autism, all of whom also screened positive for developmental delay. Delays and neurologic deficits accounted for the positive autism results in 20 of the 24. Developmental findings were confirmatory (already receiving services) in 32/55 (58%) children and actionable in 17 (31%) (requiring further evaluation). Referrals for further evaluations were made for most with actionable findings. The yield of routine screening of children in a tertiary center is sufficiently high to support its use and to consider screening of all children seen with epilepsy.


Stress and dentistry: better practice through control.
It's impossible to give a single definition to stress. That's because people experience it in different ways. It is possible, however, to get it and keep it under control. In fact stress control is necessary to every successful dental practice.


Intestinal ischemic manifestations of SARS-CoV-2: Results from the ABDOCOVID multicentre study.
Intestinal ischemia has been described in case reports of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (coronavirus disease 19, COVID-19). To define the clinical and histological, characteristics, as well as the outcome of ischemic gastrointestinal manifestations of SARS-CoV-2 infection. A structured retrospective collection was promoted among three tertiary referral centres during the first wave of the pandemic in northern Italy. Clinical, radiological, endoscopic and histological data of patients hospitalized for COVID-19 between March 1st and May 30th were reviewed. The diagnosis was established by consecutive analysis of all abdominal computed tomography (CT) scans performed. Among 2929 patients, 21 (0.7%) showed gastrointestinal ischemic manifestations either as presenting symptom or during hospitalization. Abdominal CT showed bowel distention in 6 patients while signs of colitis/enteritis in 12. Three patients presented thrombosis of main abdominal veins. Endoscopy, when feasible, confirmed the diagnosis (6 patients). Surgical resection was necessary in 4/21 patients. Histological tissue examination showed distinctive features of endothelial inflammation in the small bowel and colon. Median hospital stay was 9 d with a mortality rate of 39%. Gastrointestinal ischemia represents a rare manifestation of COVID-19. A high index of suspicion should lead to investigate this complication by CT scan, in the attempt to reduce its high mortality rate. Histology shows atypical feature of ischemia with important endotheliitis, probably linked to thrombotic microangiopathies.


Efficient de novo production of bioactive cordycepin by Aspergillus oryzae using a food-grade expression platform.
Cordycepin (3'-deoxyadenosine) is an important bioactive compound in medical and healthcare markets. The drawbacks of commercial cordycepin production using Cordyceps spp. include long cultivation periods and low cordycepin yields. To overcome these limitations and meet the increasing market demand, the efficient production of cordycepin by the GRAS-status Aspergillus oryzae strain using a synthetic biology approach was developed in this study. An engineered strain of A. oryzae capable of cordycepin production was successfully constructed by overexpressing two metabolic genes (cns1 and cns2) involved in cordycepin biosynthesis under the control of constitutive promoters. Investigation of the flexibility of carbon utilization for cordycepin production by the engineered A. oryzae strain revealed that it was able to utilize C6-, C5-, and C12-sugars as carbon sources, with glucose being the best carbon source for cordycepin production. High cordycepin productivity (564.64 ± 9.59 mg/L/d) was acquired by optimizing the submerged fermentation conditions. This study demonstrates a powerful production platform for bioactive cordycepin production by A. oryzae using a synthetic biology approach. An efficient and cost-effective fermentation process for cordycepin production using an engineered strain was established, offering a powerful alternative source for further upscaling.


A novel BRAF::PTPRN2 fusion in meningioma: a case report.
Gene fusion events have been linked to oncogenesis in many cancers. However, gene fusions in meningioma are understudied compared to somatic mutations, chromosomal gains/losses, and epigenetic changes. Fusions involving B-raf proto-oncogene, serine/threonine kinase (BRAF) are subtypes of oncogenic BRAF genetic abnormalities that have been reported in certain cases of brain tumors, such as pilocytic astrocytomas. However, BRAF fusions have not been recognized in meningioma. We present the case of an adult female presenting with episodic partial seizures characterized by déjà vu, confusion, and cognitive changes. Brain imaging revealed a cavernous sinus and sphenoid wing mass and she underwent resection. Histopathology revealed a World Health Organization (WHO) grade 1 meningioma. Genetic profiling with next generation sequencing and microarray analysis revealed an in-frame BRAF::PTPRN2 fusion affecting the BRAF kinase domain as well as chromothripsis of chromosome 7q resulting in multiple segmental gains and losses including amplifications of cyclin dependent kinase 6 (CDK6), tyrosine protein-kinase Met (MET), and smoothened (SMO). Elevated pERK staining in tumor cells provided evidence of activated mitogen-activated protein kinase (MAPK) signaling. This report raises the possibility that gene fusion events may be involved in meningioma pathogenesis and warrant further investigation.


A picture tells 1000 words: learning teamwork in primary care.
Teamwork and patient centredness are frequently articulated concepts in medical education, but are not always explicit in the curriculum. In Ireland, recent government policy emphasises the importance of a primary care team approach to health care. We report on an appraisal of a newly introduced community-based student attachment, which focused on teamwork. To review students' experience of teamwork following a community clinical placement by examining student assignments: essays, poetry, music and art. Year-2 graduate-entry students (n = 45) spent 2 weeks with a primary care team. Attachments comprised placements with members of the primary care team, emphasising team dynamics, at the end of which students submitted a representative piece of work, which captured their learning. Essays (n = 22) were analysed using a thematic content analysis. Artwork consisted of painting, collage, photography, poetry and original music (n = 23). These were analysed using Gardner's entry points. Three core themes emerged in both written and visual work: patient centredness; communication; and an improved appreciation of the skills of other health care professionals. Students identified optimal team communication occurring when patient outcomes were prioritised. Metaphors relating to puzzles, hands and inter-connectedness feature strongly. The poems and artwork had a high impact when they were presented to tutors. Primary care team placements focus student attention on teamwork and patient centredness. Student artwork shows potential as a tool to evaluate student learning in medical education.


Upper limit on the inner radiation belt MeV electron intensity.
No instruments in the inner radiation belt are immune from the unforgiving penetration of the highly energetic protons (tens of MeV to GeV). The inner belt proton flux level, however, is relatively stable; thus, for any given instrument, the proton contamination often leads to a certain background noise. Measurements from the Relativistic Electron and Proton Telescope integrated little experiment on board Colorado Student Space Weather Experiment CubeSat, in a low Earth orbit, clearly demonstrate that there exist sub-MeV electrons in the inner belt because their flux level is orders of magnitude higher than the background, while higher-energy electron (>1.6 MeV) measurements cannot be distinguished from the background. Detailed analysis of high-quality measurements from the Relativistic Electron and Proton Telescope on board Van Allen Probes, in a geo-transfer-like orbit, provides, for the first time, quantified upper limits on MeV electron fluxes in various energy ranges in the inner belt. These upper limits are rather different from flux levels in the AE8 and AE9 models, which were developed based on older data sources. For 1.7, 2.5, and 3.3 MeV electrons, the upper limits are about 1 order of magnitude lower than predicted model fluxes. The implication of this difference is profound in that unless there are extreme solar wind conditions, which have not happened yet since the launch of Van Allen Probes, significant enhancements of MeV electrons do not occur in the inner belt even though such enhancements are commonly seen in the outer belt. Quantified upper limit of MeV electrons in the inner beltActual MeV electron intensity likely much lower than the upper limitMore detailed understanding of relativistic electrons in the magnetosphere.


Incidence of deep vein thrombosis and pulmonary embolus following periacetabular osteotomy.
Venous thromboembolism, a known complication of orthopaedic procedures, is thought to be more prevalent following hip surgery. Venous thromboembolism risk assessment and appropriate prophylaxis according to the American College of Chest Physicians guidelines has become the standard of care. However, it is accepted that venous thromboembolism prophylaxis is associated with potential adverse sequelae including hematoma, wound drainage, and infection. Little is known regarding the incidence of venous thromboembolism following periacetabular osteotomy and the necessity for and method of routine prophylaxis. A total of 1067 periacetabular osteotomies performed at six North American centers utilizing different methods of prophylaxis against venous thromboembolism were analyzed for type of prophylaxis and incidence of clinically symptomatic venous thromboembolism. There were four cases of pulmonary embolus and seven cases of deep vein thrombosis. There were no reported deaths. The crude incidence of clinically symptomatic venous thromboembolism was 9.4 per 1000 procedures. The risk from chemoprophylaxis and the development of hematoma may be greater than the risk of clinically important venous thromboembolism in patients undergoing periacetabular osteotomy.


Synthesis of [3-N-(11) C-methyl]temozolomide via in situ activation of 3-N-hydroxymethyl temozolomide and alkylation with [(11) C]methyl iodide.
Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3-N-(11) C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [(11) C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-(11) C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [(11) C]methyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 ± 0.38 GBq (n = 5), the specific activity was 88 ± 25 GBq/µmol and the radiochemical purity was 98.5 ± 1.9%. (13) C-NMR spectroscopy confirmed the labelled position after colabelling with (11) C and (13) C.


Carotid artery stenting: first consensus document of the ICCS-SPREAD Joint Committee.
The prevention of stroke and the correct treatment of carotid artery stenosis represent today a major debate in cardiovascular medicine. Beside carotid endarterectomy, carotid angioplasty and stenting is becoming more widely performed for the treatment of severe carotid obstructive disease, and is now accepted as a less invasive technique that may provide an alternative for selected patients, particularly those with significant comorbidities. An Italian multidisciplinary task force, in which converged the most representative scientific societies involved in carotid treatment, was created to provide neurologists, radiologist, cardiologists, vascular surgeons, and all those involved in prevention and treatment of carotid disease with a simple, clear and updated evidence-based consensus document. This First Consensus Document of the ICCS (Italian Consensus Carotid Stenting)/SPREAD group addressed the main issues related to methodology, definition of symptomatic and asymptomatic carotid stenosis, indication and procedures for carotid artery stenting, including the use of devices for preventing procedural embolic complications. Special attention was paid to credentials and competency for physicians qualifications to perform vascular angioplasty and stent placement, including training, acceptable complication rates and certification. As any guideline or consensus statement, also this document is valid as long as the evidence on which it is based remains up-to-date. In such a fast-evolving field of medicine as the management of carotid stenosis, it is mandatory to stimulate a continuous and fruitful discussion among all the professionals involved in this very evolutionary field.


African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations.
Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the genomes of 92 individuals from 44 indigenous African populations. Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120-100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54-16 kya. Eastern and western CRHG lineages diverged by ~ 50-31 kya, and the western CRHG lineages diverged by ~ 18-12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations. We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans.


HIV infection of the male genital tract--consequences for sexual transmission and reproduction.
Despite semen being the main vector of human immunodeficiency virus (HIV) dissemination worldwide, the origin of the virus in this bodily fluid remains unclear. It was recently shown that several organs of the male genital tract (MGT) are infected by HIV/simian immunodeficiency virus (SIV) and likely to contribute to semen viral load during the primary and chronic stages of the infection. These findings are important in helping answer the following questions: (i) does the MGT constitute a viral reservoir responsible for the persistence of virus release into the semen of a subset of HIV-infected men under antiretroviral therapy, who otherwise show an undetectable blood viral load? (ii) What is the aetiology of the semen abnormalities observed in asymptomatic HIV-infected men? (iii) What is the exact nature of the interactions between the spermatozoa, their testicular progenitors and HIV, an important issue in the context of assisted reproductive techniques proposed for HIV-seropositive (HIV+) men? Answers to these questions are crucial for the design of new therapeutic strategies aimed at eradicating the virus from the genital tract of HIV+ men--thus reducing its sexual transmission--and for improving the care of serodiscordant couples wishing to have children. This review summarizes the most recent literature on HIV infection of the male genital tract, discusses the above issues in light of the latest findings and highlights future directions of research.


Effects of delta 9-tetrahydrocannabinol, cannabinol and cannabidiol on the immune system in mice. I. In vivo investigation of the primary and secondary immune response.
The effects of the cannabinoids delta 9-tetrahydrocannabinol (THC), cannabinol and cannabidiol on the primary humoral immune response, the secondary humoral immune response and the memory aspect of humoral immunity in response to sheep red blood cell (SRBC) immunization was investigated. Mice treated with THC (10 and 15 mg/kg) during the primary immunization period exhibited a suppression of the primary humoral immune response. Mice treated with THC during the secondary immunization period showed no measurable suppression of the secondary humoral immune response to the immunizing antigen. The memory aspect of humoral immunity was assessed when treatment with cannabinoids was carried out during the primary immunization period and the ability of mice to undergo a secondary immune response was evaluated; suppression of the secondary humoral immune response was evident with THC treatment (10 and 15 mg/kg). Cannabinol and cannabidiol (10 and 25 mg/kg) treated mice showed no impairment in the ability to undergo primary or secondary immune responses with any treatment protocol. In vivo investigations of the effects of cannabinoids on the thymus were also carried out. Thymus weight and thymus cell number were depressed in mice undergoing a primary humoral immune response when treated with THC (10 and 15 mg/kg) during this period. THC treatment, however, did not alter these parameters in mice not challenged with antigen. In both challenged and unchallenged animals, cannabinol and cannabidiol did not measurably alter the thymus.


Morphogenetic restructuring and formation of basement membranes by Sertoli cells and testis peritubular cells in co-culture: inhibition of the morphogenetic cascade by cyclic AMP derivatives and by blocking direct cell contact.
Addition of dibutyryl cyclic AMP (dbcAMP), methylisobutylxanthine (MIX), or cytochalasin D to co-cultures of Sertoli cells and testicular peritubular myoid cells blocks a series of morphogenetic changes which otherwise occur during culture. When Sertoli cells are plated directly onto preexisting layers of peritubular cells maintained under basal conditions, structures form which display many of the characteristics of germ cell-depleted seminiferous tubules. The presence of dbcAMP, MIX, or cytochalasin D, added at varying times after plating Sertoli cells, results in the inhibition of each successive stage of in vitro remodeling: the inhibition of migration of Sertoli cells, the inhibition of initial ridge formation, the blockage of subsequent formation of mounds and nodules of compacted Sertoli cell aggregates, the prevention of the formation of basal lamina and associated layers of extracellular matrix between Sertoli cell aggregates and surrounding peritubular cells, and the inhibition of tubule formation. The presence of dbcAMP also inhibits the migration of peritubular cells, contractions by these cells, and compaction of Sertoli cell aggregates. When intimate cell apposition is prevented by plating the two cell types on either side of a membrane filter, the morphogenetic cascade is blocked, and no formation of a germ cell-depleted seminiferous tubule-like structure occurs. Other effects of dbcAMP on cell shape, cell movement, and cell association patterns during co-culture are described. Possible mechanisms by which dbcAMP, MIX, or cytochalasin D blocks restructuring are discussed. Since each elicits perturbations of the cytoskeleton, we offer the interpretation that cytoskeletal changes may be correlated with the prevention of closely apposing cell compact and the inhibition of basement membrane formation. Interactions observed between Sertoli cells and peritubular cells during co-culture are postulated to be analogous to those occurring in other types of mesenchymal cell-epithelial cell interactions during organogenesis and during tubulogenesis in the fetal testis. Speculatively, the blockage by dbcAMP of the morphogenetic cascade in the co-cultured system may be related to the inhibition by dbcAMP of testis cord formation in organ cultures of fetal gonads reported by others.


A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family.
Argininemia is a rare autosomal recessive metabolic disorder caused by a deficiency in the arginase enzyme, which is the final enzyme in the urea cycle and responsible for the hydrolysis of arginine to urea and ornithine. The disease becomes symptomatic during childhood and is characterized by progressive spastic quadriplegia, progressive mental impairment, growth retardation, and periodic episodes of hyperammonemia. At least 19 distinct mutations in the ARG1 gene have been identified indicating the molecular heterogeneity of this condition. We report a homozygous novel mutation (c.93 delG) in the ARG1 gene from 3 affected children of a Pakistani family living in the United Arab Emirates. The mutation is expected to lead to a frame shift after the thirtieth residue and a stop codon at residue 44 (p.T30fsX14). Therefore, this mutation is expected to result in complete loss-of-function of the arginase enzyme and therefore is the mostly likely cause of argininemia in this family.


The Internet as a source for current patient information.
The purpose of this study was to assess the quality of information a lay person could obtain from Internet (Net) sources regarding the treatment of childhood diarrhea. It also afforded an opportunity to evaluate the awareness and compliance of the general medical community with the American Academy of Pediatrics (AAP) guidelines on the management of acute diarrhea. This was a prospective, open, observational, literature review performed with a computer workstation and medical library. The AAP practice parameter on the management of acute gastroenteritis in young children was selected as the current standard by which to judge all other documents. The Net was searched, and all documents retrievable from the first 300 references were evaluated for compliance with current recommendations on the management of diarrhea in children. Of 60 articles published by traditional medical sources, only 12 (20%) conformed to current AAP recommendations for treatment of children. The source of the information, even if from a major academic medical center, did not improve the likelihood of compliance. As demonstrated by information supplied on World Wide Web sites by traditional medical sources, recommendations for the treatment of acute diarrhea show a low percentage of concurrence with the AAP guidelines. Major medical institutions, schools, and hospitals need to devise ways to carefully monitor and establish quality control of what is being distributed from their home pages. Patients must be warned about the voluminous misinformation available on medical subjects on the Net.


Reporting of Factorial Randomized Trials: Extension of the CONSORT 2010 Statement.
Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal. To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials. Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist. This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported. This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.


k-Space tutorial: an MRI educational tool for a better understanding of k-space.
A main difference between Magnetic Resonance (MR) imaging and other medical imaging modalities is the control over the data acquisition and how it can be managed to finally show the adequate reconstructed image. With some basic programming adjustments, the user can modify the spatial resolution, field of view (FOV), image contrast, acquisition velocity, artifacts and so many other parameters that will contribute to form the final image. The main character and agent of all this control is called k-space, which represents the matrix where the MR data will be stored previously to a Fourier transformation to obtain the desired image.This work introduces 'k-Space tutorial', a MATLAB-based educational environment to learn how the image and the k-space are related, and how the image can be affected through k-space modifications. This MR imaging educational environment has learning facilities on the basic acceleration strategies that can be encountered in almost all MR scanners: scan percentage, rectangular FOV and partial Fourier imaging. It also permits one to apply low- and high-pass filtering to the k-space, and to observe how the contrast or the details are selected in the reconstructed image. It also allows one to modify the signal-to-noise ratio of the acquisition and create some artifacts on the image as a simulated movement of the patient - with variable intensity level - and some electromagnetic spikes on k-space occurring during data acquisition.


Association of μ-Calpain and Calpastatin Polymorphisms with Meat Tenderness in a Brahman-Angus Population.
Autogenous proteolytic enzymes of the calpain family are implicated in myofibrillar protein degradation. As a result, the μ-calpain gene and its specific inhibitor, calpastatin, have been repeatedly investigated for their association with meat quality traits in cattle; however, no functional mutation has been identified for these two genes. The objectives of this study were: (1) to assess breed composition effect on tenderness; (2) to perform a linkage disequilibrium (LD) analysis in μ-calpain and calpastatin genes as well as an association analyses with tenderness; and (3) to analyze putative functional SNPs inside the significant LD block for an effect on tenderness. Tenderness measurements and genotypes for 16 SNPs in μ-calpain gene and 28 SNPs in calpastatin gene from 673 steers were analyzed. A bioinformatic analysis identified "putative functional SNPs" inside the associated LD block - polymorphisms able to produce a physical and/or chemical change in the DNA, mRNA, or translated protein in silico. Breed composition had a significant (P < 0.0001) effect on tenderness where animals with more than 80% Angus composition had the most tender meat. One 11-kb LD-block and three LD-blocks of 37, 17, and 14 kb in length were identified in the μ-calpain and calpastatin genes, respectively. Out of these, the LD-block 3 in calpastatin, tagged by SNPs located at 7-98566391 and 7-98581038, had a significant effect on tenderness with the TG-CG diplotype being approximately 1 kg more tender than the toughest diplotype, TG-CG. A total of 768 SNPs in the LD-block 3 of calpastatin were included in the bioinformatic analysis, and 28 markers were selected as putative functional SNPs inside the LD-block 3 of calpastatin; however, none of them were polymorphic in this population. Out of 15 initial polymorphisms segregating inside the LD-block 3 of calpastatin in this population, markers ARSUSMARC116, Cast5, rs730723459, and rs210861835 were found to be significantly associated with tenderness.


Intermittent short courses of cyclosporin (Neoral(R)) for psoriasis unresponsive to topical therapy: a 1-year multicentre, randomized study. The PISCES Study Group.
We performed a 1-year study to determine whether intermittent short courses of the microemulsion formulation of cyclosporin (Neoral) could effectively control plaque psoriasis and whether tapering or abrupt cessation of cyclosporin therapy would influence time to relapse. Four hundred patients with plaque psoriasis were included in this open, multicentre, randomized study. All patients commenced cyclosporin at a dose of 2.5 mg/kg daily. Cyclosporin dosage could be increased to a maximum of 5 mg/kg daily. Treatment was continued until clearance of psoriasis or for a maximum of 12 weeks. Patients were then randomly assigned either to stop cyclosporin abruptly or to have the dose reduced by 1 mg/kg daily each week until cessation. On relapse, patients were given another course of cyclosporin. Patients were followed for at least 1 year, during which they could receive as many treatment courses as necessary. The number of patients who required one, two, three and four treatment courses was 400, 259, 117 and 26, respectively. The median time to relapse after the end of the first treatment period was 109 days in the group of patients randomized to stop cyclosporin abruptly and 113 days in patients randomized to taper off cyclosporin (P = 0.038). More than 30% of patients had not relapsed 6 months after having stopped treatment. After each treatment course, the Kaplan-Meier probability of achieving 75% or more reduction in disease area by day 84 of treatment was 83%, 76%, 73% and 66%, respectively. Mean serum creatinine concentration and blood pressure did not show any clinically significant changes over time. Our results show that intermittent short-course therapy with Neoral, when used in conjunction with topical therapy, is well tolerated and provides effective control of plaque psoriasis for 1 year. Tapering off cyclosporin on treatment cessation induces a slight delay in psoriasis relapse.


Clinician safety: assessing and managing the violent patient.
Many clinicians deny the possibility of violence occurring in their practices, and this denial has its roots in fear of violence or overconfidence in safety. To appropriately address the issue of violence, clinicians must engage in proactive behaviors and attitudes that will ensure their safety.


Patients with medical risk factors for chronic kidney disease are at increased risk of renal impairment despite the use of nephron-sparing surgery.
To determine whether patients with normal preoperative renal function, but who possess medical risk factors for chronic kidney disease (CKD), experience poorer renal function after partial nephrectomy (PN) for renal cell carcinoma (RCC) compared with those without risk factors. The effects of age, hypertension (HTN) and diabetes mellitus (DM) on estimated glomerular filtration rate (eGFR) were investigated in 488 consecutive operations for RCC performed during 2005-2012 at six Australian tertiary referral centres; 156 patients underwent PN and 332 patients underwent radical nephrectomy (RN). We used chi-squared test and binary logistic regression to analyse new-onset CKD, and multiple linear regression to investigate determinants of postoperative eGFR. The development of new-onset eGFR of <60 mL/min was related to undergoing RN rather than PN (risk ratio [RR] 2.7, P < 0.001), older age (RR 1.6, P < 0.001) and the presence of HTN (RR 1.6, P = 0.001) and DM (RR 1.5, P = 0.003). Patients undergoing PN were still at risk of new-onset CKD if medical risk factors were present. Whereas 7% of patients undergoing PN without CKD risk factors developed new-onset eGFR <60 mL/min, this figure increased to 24%, 30% and 42% for older age, HTN and DM, respectively. Patients with eGFR of 45-59 mL/min were more likely to progress to more severe forms of CKD and end-stage renal failure than those with eGFR of ≥60 mL/min. On multivariate analysis, RN, rather than PN, age and the presence of DM (but not HTN), predicted both the development of new-onset eGFR of <60 mL/min (R(2) = 0.37) and new-onset eGFR <45 mL/min (R(2) = 0.42). Patients with medical risk factors for CKD are at increased risk of progressive renal impairment despite the use of PN. Where feasible, nephron-sparing surgery should be considered for these patients.


Ventriculoatrial versus ventriculoperitoneal shunt complications in idiopathic normal pressure hydrocephalus.
Idiopathic normal pressure hydrocephalus (iNPH) is a devastating condition that affects the elderly population. Although ventriculoatrial (VA) shunts can be used to manage iNPH, concerns for associated cardiopulmonary and renal complications have decreased their use. However, the rate of these complications is not well understood within this population of patients. A retrospective review of the electronic medical records of patients diagnosed with iNPH by the senior author between 1993 and 2015 was performed. Demographic information and baseline symptoms were assessed. Complications including infection, shunt obstruction, overdrainage, cardiopulmonary events, renal dysfunction, and shunt revision were recorded. Complication rates were compared between VA and VP shunted patients. Statistical analysis using Chi-square test, Fisher's exact test, logistic regression, Wald t-test, Poisson regression, ANOVA, and ANCOVA was performed. 496 Patients, including 150 receiving VA shunts and 346 receiving VP shunts, were included in the study. The median age was 74 and 73 for VA and VP shunted patients, respectively, with slight male predominance in both (58.0% and 58.4% for VA and VP groups, respectively). A total of 36.0% of VA shunted patients and 42.5% of VP shunted patients experienced at least one post-operative complication. Overdrainage was the most commonly experienced complication in both VA (27.4%) and VP patients (19.9%). Infection occurred in only 2.0% of patients, and renal complications occurred in 1.3%. No patients had cardiopulmonary complications. VA shunted patients were significantly less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients (p=0.008 and <0.001, respectively). Only dizziness and gait disturbance at baseline were correlated with a shorter time to revision in VA shunted patients (p=0.002 for both). Although cardiopulmonary and renal complications are serious concerns associated with VA shunt placement, they were uncommon in patients with iNPH. VA shunted patients were less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients. Therefore, VA shunts should be considered as an alternative primary treatment option in the iNPH population.


'First, do no harm': managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer.
Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long-term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival-prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.


Decreased prefrontal lobe interhemispheric functional connectivity in adolescents with internet gaming disorder: a primary study using resting-state FMRI.
Recent neuroimaging studies have shown that people with Internet gaming disorder (IGD) have structural and functional abnormalities in specific brain areas and connections. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (rsFC) in participants with IGD. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric rsFC of the whole brain in participants with IGD. We compared interhemispheric rsFC between 17 participants with IGD and 24 healthy controls, group-matched on age, gender, and education status. All participants were provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired for all participants. The rsFC between bilateral homotopic voxels was calculated. Regions showing abnormal VMHC in IGD participants were adopted as regions of interest for correlation analyses. Compared to healthy controls, IGD participants showed decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part), middle frontal gyrus and superior frontal gyrus. Further analyses showed Chen Internet Addiction Scale (CIAS)-related VMHC in superior frontal gyrus (orbital part) and CIAS (r = -0.55, p = 0.02, uncorrected). Our findings implicate the important role of altered interhemispheric rsFC in the bilateral prefrontal lobe in the neuropathological mechanism of IGD, and provide further supportive evidence for the reclassification of IGD as a behavioral addiction.


Willingness to Participate in Health Research Among Community-Dwelling Middle-Aged and Older Adults: Does Race/Ethnicity Matter?
Older adults, including racial and ethnic minorities, are underrepresented in research. As the US population ages, the number of older racial and ethnic minority individuals will increase. Including these individuals in research is an important step towards reducing health disparities. We used data from HealthStreet, a University of Florida community engagement program which uses community health workers to assess the health of the community, to assess willingness to participate in different types of health research by race/ethnicity. Descriptive statistics and logistic regression models were used to assess willingness to participate among adults aged 50 and older, by race/ethnicity (n = 4694). Our sample was 42.0% non-Hispanic White, 52.8% non-Hispanic Black, and 5.2% Hispanic. Non-Hispanic White participants reported more past research participation than non-Hispanic Black and Hispanic participants (28.7% vs. 19.0% and 19.2%, respectively). Compared with non-Hispanic White participants, non-Hispanic Black participants were less willing to participate in most types of studies, while Hispanic participants were less willing to participate in studies that might be seen as invasive (required blood sample, genetic sample, or participants to take medicine, or use of medical equipment). Our study provides investigators with a general profile of research preferences by race/ethnicity; compared with non-Hispanic White individuals, non-Hispanic Black individuals are less willing to participate in most studies, while Hispanic individuals are less willing to participate in studies that may be seen as invasive or demanding. It is imperative to include diverse older adults in health research. By tailoring research based on preferences we can improve recruitment in underrepresented populations.


Recent advances in analysis of trace elements in environmental samples by X-ray based techniques (IUPAC Technical Report).
Trace elements analysis is a fundamental challenge in environmental sciences. Scientists measure trace elements in environmental media in order to assess the quality and safety of ecosystems and to quantify the burden of anthropogenic pollution. Among the available analytical techniques, X-ray based methods are particularly powerful, as they can quantify trace elements in situ. Chemical extraction is not required, as is the case for many other analytical techniques. In the last few years, the potential for X-ray techniques to be applied in the environmental sciences has dramatically increased due to developments in laboratory instruments and synchrotron radiation facilities with improved sensitivity and spatial resolution. In this report, we summarize the principles of the X-ray based analytical techniques most frequently employed to study trace elements in environmental samples. We report on the most recent developments in laboratory and synchrotron techniques, as well as advances in instrumentation, with a special attention on X-ray sources, detectors, and optics. Lastly, we inform readers on recent applications of X-ray based analysis to different environmental matrices, such as soil, sediments, waters, wastes, living organisms, geological samples, and atmospheric particulate, and we report examples of sample preparation.


Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine.
The C2 domain acts as a membrane-targeting module in a diverse group of proteins including classical protein kinase Cs (PKCs), where it plays an essential role in activation via calcium-dependent interactions with phosphatidylserine. The three-dimensional structures of the Ca(2+)-bound forms of the PKCalpha-C2 domain both in the absence and presence of 1, 2-dicaproyl-sn-phosphatidyl-L-serine have now been determined by X-ray crystallography at 2.4 and 2.6 A resolution, respectively. In the structure of the C2 ternary complex, the glycerophosphoserine moiety of the phospholipid adopts a quasi-cyclic conformation, with the phosphoryl group directly coordinated to one of the Ca(2+) ions. Specific recognition of the phosphatidylserine is reinforced by additional hydrogen bonds and hydrophobic interactions with protein residues in the vicinity of the Ca(2+) binding region. The central feature of the PKCalpha-C2 domain structure is an eight-stranded, anti-parallel beta-barrel with a molecular topology and organization of the Ca(2+) binding region closely related to that found in PKCbeta-C2, although only two Ca(2+) ions have been located bound to the PKCalpha-C2 domain. The structural information provided by these results suggests a membrane binding mechanism of the PKCalpha-C2 domain in which calcium ions directly mediate the phosphatidylserine recognition while the calcium binding region 3 might penetrate into the phospholipid bilayer.


Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway.
While oxygen free radicals are important mediators of brain injury, questions remain regarding which cell types and enzyme pathways trigger this radical generation. Microglial cells have been hypothesized to be an important source of radical generation; however, the magnitude, kinetics, and mechanism of this process are unknown. Oxygen radical generation by stimulated primary microglia was directly measured and characterized by electron paramagnetic resonance spin trapping. Microglia, when stimulated by phorbol ester or opsonified zymosan, gave rise to EPR spectra characteristic of superoxide. Experiments performed in the presence of superoxide dismutase, catalase, deferoxamine, and dimethyl sulfoxide excluded generation of hydroxyl radicals in significant amounts. Microglial superoxide generation was blocked by the NADPH oxidase inhibitor diphenylene iodonium in a manner similar to that seen in neutrophils, suggesting that a neutrophil like NADPH oxidase was the source of superoxide production. However, microglia produced 20 to 40 times less superoxide compared to a similar number of neutrophils during the first 30 min following stimulation, indicating a marked difference in the regulation of NADPH oxidase activation. Western blots of microglia lysates demonstrated that both large (gp91-phox) and small (p22-phox) NADPH oxidase subunits are expressed in both unstimulated and stimulated microglia. Indirect immunofluorescence demonstrated localization at the membrane surfaces of activated cells. Thus, microglial cells generate superoxide via a neutrophil-like NADPH oxidase but exhibit distinctly different time course and magnitude of activation than that seen in neutrophils.


A minimum entropy approach to adaptive image polygonization.
This paper introduces a novel adaptive image segmentation algorithm which represents images by polygonal segments. The algorithm is based on an intuitive generative model for pixel intensities and its associated cost function which can be effectively optimized by a hierarchical triangulation algorithm. A triangular mesh is iteratively refined and reorganized to extract a compact description of the essential image structure. After analyzing fundamental convexity properties of our cost function, we adapt an information-theoretic bound to assess the statistical significance of a given triangulation step. The bound effectively defines a stopping criterion to limit the number of triangles in the mesh, thereby avoiding undesirable overfitting phenomena. It also facilitates the development of a multiscale variant of the triangulation algorithm, which substantially improves its computational demands. The algorithm has various applications in contextual classification, remote sensing, and visual object recognition. It is particularly suitable for the segmentation of noisy imagery.


Structure-based prediction of protein- peptide binding regions using Random Forest.
Protein-peptide interactions are one of the most important biological interactions and play crucial role in many diseases including cancer. Therefore, knowledge of these interactions provides invaluable insights into all cellular processes, functional mechanisms, and drug discovery. Protein-peptide interactions can be analyzed by studying the structures of protein-peptide complexes. However, only a small portion has known complex structures and experimental determination of protein-peptide interaction is costly and inefficient. Thus, predicting peptide-binding sites computationally will be useful to improve efficiency and cost effectiveness of experimental studies. Here, we established a machine learning method called SPRINT-Str (Structure-based prediction of protein-Peptide Residue-level Interaction) to use structural information for predicting protein-peptide binding residues. These predicted binding residues are then employed to infer the peptide-binding site by a clustering algorithm. SPRINT-Str achieves robust and consistent results for prediction of protein-peptide binding regions in terms of residues and sites. Matthews' Correlation Coefficient (MCC) for 10-fold cross validation and independent test set are 0.27 and 0.293, respectively, as well as 0.775 and 0.782, respectively for area under the curve. The prediction outperforms other state-of-the-art methods, including our previously developed sequence-based method. A further spatial neighbor clustering of predicted binding residues leads to prediction of binding sites at 20-116% higher coverage than the next best method at all precision levels in the test set. The application of SPRINT-Str to protein binding with DNA, RNA and carbohydrate confirms the method's capability of separating peptide-binding sites from other functional sites. More importantly, similar performance in prediction of binding residues and sites is obtained when experimentally determined structures are replaced by unbound structures or quality model structures built from homologs, indicating its wide applicability. http://sparks-lab.org/server/SPRINT-Str. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Does concurrent posterior repair for an asymptomatic rectocele reduce the risk of surgical failure in patients undergoing sacrocolpopexy?
To determine if a concurrent posterior repair for an asymptomatic rectocele at the time of sacrocolpopexy reduces the incidence of surgical failure. This is a retrospective chart review with a cross-sectional follow-up survey of all patients who underwent sacrocolpopexy from 2004 to 2014. Demographic and operative data were collected from the medical record. For the cross-sectional portion, patients were contacted to obtain information on symptoms and retreatment after surgery. In this study, we included patients with an asymptomatic rectocele on examination, defined as Ap or Bp ≥ -1 on POP-Q without defecatory dysfunction, which was defined as constipation based on the Rome III criteria, dyschezia, excessive straining and/or splinting to have a bowel movement. The primary outcome was a composite score of subjective bulge symptoms or retreatment for prolapse. Three hundred forty-four patients met the inclusion criteria: 185 (53.8%) had a sacrocolpopexy only (SCP) and 159 (46.2%) had a concurrent posterior repair (SCP + PR). The composite failure rate was 10.2% (95% CI = 7.4-13.8%), with a 13.5% (25) failure rate in the SCP group compared with 6.3% (10) in the SCP + PR group (p = 0.03). On multivariable logistic regression, the adjusted odds of failure was 2.79 in the SCP compared with the SCP + PR group (CI 1.25-6.23; P = 0.01). The rates of de novo defecatory dysfunction following surgery were low (SCP = 5.6% vs. SCP + PR = 7.5%, p = 0.55). For patients with asymptomatic rectoceles, a concurrent posterior repair at the time of sacrocolpopexy reduces the odds of composite patient-centered failure without an increased rate of dyspareunia or de novo defecatory dysfunction.