Association of healthy sleep pattern with risk of recurrent cardiovascular events among patients with coronary heart disease.
To examine the association of a healthy sleep pattern with the risk of recurrent cardiovascular events among patients with coronary heart disease (CHD). This prospective cohort study included 21 193 individuals with CHD from the UK Biobank. A healthy sleep score was generated based on a combination of chronotype, sleep duration, insomnia, and excessive daytime sleepiness. Cox proportional hazards regression models were applied to estimate the associations between healthy sleep score and recurrent cardiovascular events. During a median of 11.1 years of follow up, we documented 3771 recurrent cardiovascular events, including 1634 heart failure cases and 704 stroke cases. After multivariable adjustment, including lifestyle factors, medical history, and CHD duration, sleep 7-8 h/day, never/rarely insomnia, and no frequent daytime sleepiness were each significantly associated with a 12-22% lower risk of heart failure. In addition, compared with participants who had a healthy sleep score of 0-1, the multivariable-adjusted HR (95% CI) for participants with a healthy sleep score of 4 was 0.86 (0.75, 0.99) for recurrent cardiovascular events, 0.71 (0.57, 0.89) for heart failure, and 0.72 (0.51, 1.03) for stroke. Adherence to a healthy sleep pattern was significantly associated with a lower risk of recurrent cardiovascular events among patients with CHD, especially for heart failure. These findings indicate that healthy sleep behaviours could be beneficial in the prevention of cardiovascular event recurrence.


Grape juice concentrate alleviates epididymis and sperm damage in cadmium-intoxicated rats.
The possibility of long-term grape juice concentrate (GJC) consumption conferring a protective effect against cadmium (Cd)-induced damage to the epididymis, completely preserving sperm profile, was evaluated here for the first time in the scientific literature. Male Wistar rats (n = 6/per group) received an intraperitoneal Cd injection (1.2 mg/Kg) at age 80 days and GJC (2 g/Kg) by gavage from 50 days until 136 days old. Groups receiving either Cd or GJC were added. An intraperitoneal injection of saline (0.9%) and water by gavage was administered in the absence of treatment with Cd or GJC. Animals were anaesthetized and exsanguinated at 136 days; the vas deferens, left testis and epididymis were removed; and perfusion continued with fixative. The right epididymis was collected for morphological analysis. Cd had a devastating effect demonstrated by reduced sperm count in testes and epididymis, sperm production and normal sperm count, besides increased epididymis sperm transit time and completely disorganized morphology. These alterations were attributed to higher Cd levels in the testes and a lipid peroxidation (LP) process. Consumption of GJC plus Cd intoxication was effective, reducing metal accumulation and LP. Consequently, we could identify a preserved sperm profile, with improvement in testis and epididymis sperm count, normal sperm structure and sperm transit time. Moreover, GJC extends its protective effect to the epididymis, allowing complete re-establishment of its morphology, ensuring successful sperm maturation process. In conclusion, our study indicates long-term GJC as a promising therapy against reproductive chemical intoxication injury damage, preserving sperm prior to ejaculation.


Effect of esomeprazole, a proton pump inhibitor on the pharmacokinetics of sonidegib in healthy volunteers.
This study aimed to evaluate the impact of esomeprazole on the pharmacokinetics of sonidegib. This Phase I study evaluated the impact of the proton pump inhibitor (PPI) esomeprazole on the oral absorption and pharmacokinetics (PKs) of a single dose of sonidegib under fasted conditions. A total of 42 healthy subjects were enrolled to receive either sonidegib alone (200 mg single dose) or sonidegib in combination with esomeprazole (40 mg pre-treatment 5 days and combination were given on day 6). Primary PK parameters assessed in the study were area under the concentration-time curve (AUC) from 0-14 days and 0-7 days and maximum observed plasma concentration (Cmax ). The plasma exposure (AUC0-14d, AUC0-7d and Cmax ) of a single 200 mg oral dose of sonidegib was decreased by 32-38% when sonidegib was co-administered with esomeprazole compared with sonidegib alone, with no apparent change in elimination slope and tmax . Baseline gastric pH was similar between the two arms. These results suggest a modest reduction in the extent of sonidegib absorption by esomeprazole. There was no obvious metabolic drug-drug interaction between the two agents. Both sonidegib and esomeprazole were well tolerated in the study population.


Bilateral Anterolateral Thigh Myocutaneous Flaps for Giant Complex Chest Wall Reconstruction.
Extensive reconstruction of complex full-thickness chest wall oncological defects is challenging. Bilateral free anterolateral thigh (ALT) myocutaneous flap transfer for the complex reconstruction of a large area of the chest wall is discussed. We reported a single unit's experience in 1-staged multilayered reconstruction of large full-thickness chest wall defects in 22 patients (16 primary chest wall tumor cases, 5 locally advanced breast cancer cases, and 1 osteoradionecrosis case) treated between 2011 and 2018. Bilateral ALT myocutaneous flaps together with traditional cement implant or unmovable/movable joint conformable titanium struts were used for chest wall reconstruction. The anatomical characteristics of pedicle origin and pattern of the venae comitantes of the ALT myocutaneous flap, recipient vessels, and anastomosis patterns were described. Bilateral ALT myocutaneous flaps were used for soft tissue reconstruction in 22 cases. Different methods of flap harvesting and vascular anastomosis were selected as needed. No vein grafts or arteriovenous loops were required. We observed 3 vascular patterns of the flap pedicle, including 1 oblique branch and descending branch (59.1%, n = 26), 2 single descending branch (9.1%, n = 4), and 3 double branches of the descending branch (31.8%, n = 14). The flap was harvested pedicled with solely the oblique branch in 7 (15.9%) cases, solely the descending branch in 28 (63.6%) cases to minimize the donor site morbidity, and pedicled with the oblique and descending branch in 9 (20.5%) cases to achieve multiple vascular anastomosis choices. Stable skeletal reconstructions were achieved using traditional cement implant (13.6%, n = 3) or conformable titanium struts (86.4%, n = 19), with good fixation strength. Complication risk was low. An algorithmic approach to management is presented and recommended. Various forms of bilateral ALT myocutaneous flap transfer with different skeletal reconstruction presents as a reliable treatment for patients with large full-thickness chest wall defects. Anatomical variations in the pedicle and pattern of venae comitantes of the ALT myocutaneous flap are reported. In some challenging cases, finding the vessels in the recipient area is difficult. The clinical significance of each vascular pattern is delineated, and surgical technical considerations are discussed on the basis of the recipient area requirements and types of a flap's vascular anatomy.


Modulation of xenobiotic receptors by steroids.
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in regulating nuclear receptors; in addition to being ligands of steroid receptors, steroids (and their metabolites) also regulate other NRs, such as the pregnane X receptor and constitutive androstane receptor (termed xenobiotic receptors), which participate in steroid metabolism. Xenobiotic receptors have promiscuous ligand-binding properties, and their structurally diverse ligands include steroids and their metabolites. Therefore, steroids, their metabolism and metabolites, xenobiotic receptors, steroid receptors, and the respective signaling pathways they regulate have functional interactions. This review discusses these functional interactions and their implications for activities mediated by steroid receptors and xenobiotic receptors, focusing on steroids that modulate pathways involving the pregnane X receptor and constitutive androstane receptor. The emphasis of the review is on structure-function studies of xenobiotic receptors bound to steroid ligands.


EAU guidelines on vesicoureteral reflux in children.
Primary vesicoureteral reflux (VUR) is a common congenital urinary tract abnormality in children. There is considerable controversy regarding its management. Preservation of kidney function is the main goal of treatment, which necessitates identification of patients requiring early intervention. To present a management approach for VUR based on early risk assessment. A literature search was performed and the data reviewed. From selected papers, data were extracted and analyzed with a focus on risk stratification. The authors recognize that there are limited high-level data on which to base unequivocal recommendations, necessitating a revisiting of this topic in the years to come. There is no consensus on the optimal management of VUR or on its diagnostic procedures, treatment options, or most effective timing of treatment. By defining risk factors (family history, gender, laterality, age at presentation, presenting symptoms, VUR grade, duplication, and other voiding dysfunctions), early stratification should allow identification of patients at high potential risk of renal scarring and urinary tract infections (UTIs). Imaging is the basis for diagnosis and further management. Standard imaging tests comprise renal and bladder ultrasonography, voiding cystourethrography, and nuclear renal scanning. There is a well-documented link with lower urinary tract dysfunction (LUTD); patients with LUTD and febrile UTI are likely to present with VUR. Diagnosis can be confirmed through a video urodynamic study combined with a urodynamic investigation. Early screening of the siblings and offspring of reflux patients seems indicated. Conservative therapy includes watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in patients with LUTD. The goal of the conservative approach is prevention of febrile UTI, since VUR will not damage the kidney when it is free of infection. Interventional therapies include injection of bulking agents and ureteral reimplantation. Reimplantation can be performed using a number of different surgical approaches, with a recent focus on minimally invasive techniques. While it is important to avoid overtreatment, finding a balance between cases with clinically insignificant VUR and cases that require immediate intervention should be the guiding principle in the management of children presenting with VUR.


Retrieval effort or intention: Which is more important for participants' classification of involuntary and voluntary memories?
Theories of autobiographical memory distinguish between involuntary and voluntary memories. While involuntary memories are retrieved with no conscious intention and are therefore unexpected, voluntary memories are both intended and expected. Recent research has shown that participants sometimes classify their memories as either involuntary or voluntary based on retrieval effort instead of intention. These findings question whether intention really is the defining difference between these two types of retrieval or whether retrieval effort is also an important determinant. In two experimental studies, we investigated the extent to which participants rely on retrieval effort while classifying their memories as involuntary or voluntary. We created experimental conditions that maximize the probability of one type of retrieval while minimizing the probability of another type. Participants reported autobiographical memories in each condition while the programme registered their retrieval time. They then classified their memories as either voluntary or involuntary and rated all memories on perceived retrieval effort. This gave us four categories of memories: experimentally defined voluntary and involuntary memories with an objective measure of effort (retrieval time) and subjectively classified involuntary and voluntary memories with a subjective measure of effort. This allowed us to investigate the relative contribution of intention and effort to involuntary and voluntary memories. We replicated and extended previous findings by showing that the majority of memories were classified as involuntary independently of whether they were retrieved in the experimentally defined voluntary or involuntary condition. This could indicate that subjective effort is more important than intention for the involuntary-voluntary distinction in contrast with existing theories. We discuss theoretical and methodological implications of this finding.


Accessibility of Medicines for Children: A Systematic Review.
Background: Accessibility of medicines for children is a matter of global concern. Medicines prescribed for children are often off-label. To formulate appropriate policies and undertake necessary interventions to improve access to medicines for children, it is necessary to evaluate the accessibility of medicines for children. However, there is no systematic review of the medicine accessibility for children. Methods: Relevant studies were identified through searching Pubmed, Embase, CNKI, Wanfang, VIP, World Health Organization website, and Health Action International website. Besides, the references of included studies as a supplementary search were read. We extracted the basic information of articles (the first author, published year, the name of journal, research institution, etc.), the basic study characteristics (survey area, survey time, survey method, survey medicine lists, the number of medicine outlets surveyed, etc.), and the study results (the current situation of the accessibility of medicines for children, including the availability, price, and affordability of medicines for children, etc.). Two reviewers independently selected studies and extracted the data. Descriptive analysis methods to analyze the current situation of the accessibility of children's medicines were used. Results: A total of 18 multicenter cross-sectional studies were included in this systematic review, which were from low-income and middle-income countries. Seventeen studies (17/18, 94.4%) used the WHO/Health Action International (HAI) medicine price methodology to investigate the accessibility of medicines for children. Fifteen studies (15/18, 83.3%) were selected to investigate medicines based on the WHO Model List of Essential Medicines for Children (WHO EMLc). In the public sectors, the availability of originator brands (OBs) ranged from 0 to 52.0%, with a median of 24.2%, and the availability of lowest-priced generics (LPGs) ranged from 17.0 to 72.6%, with a median of 38.1%. In the private sectors, the availability of OBs ranged from 8.9 to 80%, with a median of 21.2%. The availability of LPGs ranged from 20.6 to 72.2%, with a median of 35.9%. In most regions, the availability of OBs in the private sectors was higher than in the public sectors. Collectively, in the price of medicines for children, the median price ratio (MPR) of the OBs in the public sectors and private sectors were much higher than that of the LPGs. And the affordability of the LPGs in the public sectors and private sectors was higher than that of originator brands (OBs). Conclusion: The availability of medicines for children is low in both the public sectors and private sectors in low-income and middle-income countries. The MPR of originator brands (OBs) is higher than that of lowest-priced generics (LPGs), and the most lowest-priced generics (LPGs) have better affordability.


Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study.
The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes. To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations. This retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis. A total of 408 IBD-related admissions were included. With implementation of specialized IBD inpatient care, we observed increased frequency of use of high-dose biologic therapy for induction (26% versus 9%, odds ratio 5.50, 95% confidence interval 1.30-23.17) and higher proportion of patients in remission at 90 days after discharge (multivariate odds ratio 1.60, 95% confidence interval 0.99-2.69). Although there was no difference in surgery by 90 days, among those who underwent surgery, early surgery defined as in-hospital or within 30 days of discharge, was more common in the study period (71%) compared with the control period (46%, multivariate odds ratio 2.73, 95% confidence interval 1.22-6.12). There was no difference in length of stay between the 2 years. Implementation of specialized inpatient IBD care beneficially impacted remission and facilitated early surgical treatment.


Purification and amino acid composition of monomeric and polymeric collagens.
The preparations and amino acid compositions of highly purified tropocollagen and insoluble polymerized collagen are described. These collagens appear to be very suitable for comparative studies in an investigation of the cross-linkages that are introduced into tropocollagen during the formation of polymerized collagen.


Tuberculosis and interleukin blocking monoclonal antibodies: Is there risk?
Several new monoclonal antibodies that interfere with interleukin (IL) cascades have come to market in recent years. They follow a generation of drugs that block tumor necrosis factor (TNF). It has been well established that TNF is important in the containment of Mycobacterium tuberculosis (Mtb) and that blocking this cytokine increases the risk of tuberculosis (TB) infection. Thus, judicious screening for Mtb of patients taking TNF blocking drugs has been the standard of care. It remains unclear if the newer monoclonal, interleukin blocking drugs, which affect IL-12, IL-23, and IL-17 pathways are associated with risk of Mtb reactivation. Herein we discuss what is known about the immunologic response to Mtb and discuss the data that is currently available for the new interleukin monoclonal antibody blocking medications regarding the risk of latent TB reactivation or active TB infection.


Implantable cardioverter defibrillator does not cure the heart.
A man with non-ischemic cardiomyopathy, EF 22%, permanent AF and ICD was admitted for elective device replacement. The need for the optimization of the ventricular rate and avoidance of right ventricular pacing made it necessary to up-grade the existing pacing system using direct His bundle pacing and dual chamber ICD. This enabled the regularization of ventricular rate, avoiding the RV pacing and optimize the beta-blocker dose. The one month follow-up already showed reduction in left ventricle diameter, improvement in ejection fraction, NYHA class decrease to II. The His bundle pacing enabled the optimal treatment of the patient resulting in excellent clinical improvement.


An analysis of the substrate specificity of insulin-stimulated protein kinase-1, a mammalian homologue of S6 kinase-II.
The specificity determinants for insulin-stimulated protein kinase-I (ISPK-1) have been investigated with synthetic peptides based on naturally-occurring protein phosphoacceptor sequences. Peptides (Arg-Arg-Xaa-Ser-Xaa) that fulfill the consensus sequence for cyclic-AMP-dependent protein kinase (PK-A) are also phosphorylated readily by ISPK-1. The phosphorylation efficiency is improved by increasing the number of N-terminal arginine residues and by moving the arginyl cluster one residue further away from the serine, the nonapeptide (Arg)4-Ala-Ala-Ser-Val-Ala being the best substrate among all the short peptides tested (Km = 15 microM). Conversely, the substitution of either Thr for Ser or Lys for Arg is detrimental. Likewise, two flanking Pro residues and an Arg immediately N-terminal to the Ser act as negative specificity determinants. While the specificity of ISPK-1 shows several similarities to that of PK-A, including an absolute requirement for basic residues on the N-terminal side of the target Ser, it differs in several other respects including (1), the detrimental effect of a Lys for Arg substitution which is still compatible with some phosphorylation by ISPK-1, but not PK-A; (2), the presence of C-terminal acidic residues which are tolerated very well by ISPK-1, but are detrimental to PK-A; (3), the effect of substituting Phe for Val in the peptide Arg-Arg-Ala-Ser-Val-Ala, which improves the efficiency of phosphorylation by PK-A (lowering the Km 4-fold), but has no effect on phosphorylation by ISPK-1. These differences in peptide substrate specificity may account in part for the different rates of phosphorylation of physiological substrates for ISPK-1 and PK-A, such as the G subunit of protein phosphatase-1.


LncRNA FOXD2-AS1 stimulates glioma progression through inhibiting P53.
The aim of this study was to elucidate whether FOXD2-AS1 stimulated glioma progression by inhibiting the P53 level. FOXD2-AS1 expression in glioma tissues and cell lines was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Meanwhile, FOXD2-AS1 expression in glioma patients with different tumor tissues and tumor staging was examined as well. The subcellular distribution of FOXD2-AS1 was analyzed. RNA Binding Protein Immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assay were applied to explore the interaction between FOXD2-AS1 and P53. Furthermore, the influences of FOXD2-AS1 and P53 on the viability and colony formation abilities of LN229 and U87 cells were assessed. FOXD2-AS1 was significantly upregulated in glioma tissues and cells. The expression level of FOXD2-AS1 was positively correlated with tumor size and staging of glioma. FOXD2-AS1 was mainly distributed in the nucleus, which could attenuate recruitment ability to P53 by bounding to EZH2. The silence of FOXD2-AS1 significantly decreased the viability and colony formation abilities of glioma cells. However, the attenuated proliferative ability was partially reversed by P53 knockdown. FOXD2-AS1 stimulated the proliferation of glioma by inhibiting P53, thus aggravating the progression of glioma.


A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production.
Anti-TNF-alpha Ab therapy has been shown to be of benefit in the treatment of active Crohn's disease, but the tissue-injuring processes in the gut mediated by TNF-alpha that might be inhibited by neutralizing Ab are unknown. In this work, we have used a p55 TNF receptor-human IgG fusion protein (TNFR-IgG) to prevent the severe mucosal injury that ensues when lamina propria T cells in explant cultures of human fetal small intestine are directly activated with the lectin PWM. Following T cell activation and associated with mucosal injury, there is a marked elevation of soluble TNF-alpha in organ culture supernatants and a large increase in TNF-alpha mRNA transcripts. The addition of TNFR-IgG at the onset of cultures greatly reduced PWM-induced tissue injury, without inhibiting the increase in TNF-alpha and IFN-gamma transcripts seen following T cell activation. Mucosal injury in this model is mediated by endogenously-produced matrix metalloproteinases (MMPs). When TNFR-IgG was added to PWM-stimulated explants, there was a reduction in MMPs in the explant culture supernatants, especially stromelysin-1. Recombinant TNF-alpha and IL-1beta added directly to mucosal mesenchymal cell lines also caused an increase in MMP production, but only the former was inhibited by the TNFR-IgG. These results suggest that one of the ways in which TNF-alpha causes tissue injury in the gut is by stimulating mucosal mesenchymal cell to secrete matrix-degrading metalloproteinases. Neutralization of this activity should help maintain tissue integrity.


Increased Contractile Function of Human Saphenous Vein Grafts Harvested by "No-Touch" Technique.
Saphenous vein grafts are the most common conduits used for coronary artery bypass grafting (CABG); however, no more than 60% of vein grafts remain open after 10 years and graft failure is associated with poor clinical outcome. The "no-touch" harvesting technique-where a sheet of perivascular tissue is retained around the vein-improves graft patency to over 80% after 16 years of follow-up, but the mechanism for the improved patency rate is unclear. In this study, we investigated acute functional differences between vein grafts harvested conventionally and by "no-touch" technique and explored the importance of perivascular tissue for reducing surgical trauma, minimizing excessive distension, and releasing vasoactive paracrine factors. Segments of human saphenous veins were obtained from CABG surgery and their functional properties investigated by isometric and isobaric myography. We found a broad diameter-tension relationship for human saphenous veins, with peak capacity for active tension development at diameters corresponding to transmural pressures around 60 mmHg. Across the investigated transmural pressure range between 10 and 120 mmHg, maximal tension development was higher for "no-touch" compared to conventionally harvested saphenous veins. Contractile responses to serotonin, noradrenaline, and depolarization induced with elevated extracellular [K+] were significantly larger for saphenous veins harvested by "no-touch" compared to conventional technique. Conventional vein grafts are routinely pressurized manually in order to test for leaks; however, avoiding this distension procedure did not change the acute contractile function of the conventionally excised saphenous veins. In contrast, even though surgical removal of perivascular tissue during conventional harvesting was associated with a substantial decrease in force development, removal of perivascular tissue by careful dissection under a stereomicroscope only marginally affected contractile responses of veins harvested by "no-touch" technique. In conclusion, we show that saphenous veins harvested by "no-touch" technique have greater contractile capacity than veins harvested by conventional technique. The different capacity for smooth muscle contraction is not due to vasoactive substances released by the perivascular tissue. Instead, we propose that the larger tension development of saphenous veins harvested by "no-touch" technique reflects reduced surgical damage, which may have long-term consequences that contribute to the superior graft patency.


Mapping of human autoantibody epitopes on aromatic L-amino acid decarboxylase.
Aromatic l-amino acid decarboxylase (AADC) is target of autoantibodies in autoimmune polyendocrine syndrome I (APS I), especially in patients with autoimmune hepatitis. Little information is currently available on AADC autoantibody epitopes and on the interrelation between autoantibody-mediated inhibition of enzymatic activity and epitope specificity. We tested the immunoreactivity of full-length porcine AADC and of eight fragments of the enzyme with human serum from 18 patients with APS I, 199 with non-APS I autoimmune Addison's disease, 124 with type 1 diabetes mellitus, 36 with Graves' disease, and 141 healthy control subjects, and we evaluated the autoantibody-mediated enzymatic inhibition. AADC antibodies (Ab) were detected in 12 of 18 (67%) APS I patients and in six of 199 (3%) autoimmune Addison's disease patients. Four patients with autoimmune hepatitis were all positive for AADCAb. None of the 141 healthy control subjects, 82 patients with nonautoimmune adrenal insufficiency, 124 with type 1 diabetes mellitus, and 36 with Graves' disease were found positive. Two epitope regions, corresponding to amino acids 274-299 (E1) and 380-471 (E2) were identified. Localization of E1 was confirmed by displacement studies with synthetic peptides corresponding to peptides of porcine AADC. All 12 AADCAb-positive APS I sera reacted with E1, and seven of 12 (58%) reacted also with E2. E2-specific, but not E1-specific, autoantibodies were associated with a significant inhibition of in vitro AADC enzymatic activity. We mapped the human AADCAb epitopes to the middle and COOH-terminal regions of the enzyme. Autoantibodies to the COOH-terminal region induce a significant inhibition of enzymatic activity.


Cervical cancer in Khon Khaen University Hospital, Thailand 1985-1990.
From 1985 to 1990, 3040 patients with carcinoma of the uterine cervix were diagnosed and treated at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand. The epidemiological aspects including ages and geographical distributions, histology, stages, treatment and outcome were presented and compared with those of the previous report.


Chromium isotope fractionation during reduction of Cr(VI) under saturated flow conditions.
Chromium isotopes are potentially useful indicators of Cr(VI) reduction reactions in groundwater flow systems; however, the influence of transport on Cr isotope fractionation has not been fully examined. Laboratory batch and column experiments were conducted to evaluate isotopic fractionation of Cr during Cr(VI) reduction under both static and controlled flow conditions. Organic carbon was used to reduce Cr(VI) in simulated groundwater containing 20 mg L(-1) Cr(VI) in both batch and column experiments. Isotope measurements were performed on dissolved Cr on samples from the batch experiments, and on effluent and profile samples from the column experiment. Analysis of the residual solid-phase materials by scanning electron microscopy (SEM) and by X-ray absorption near edge structure (XANES) spectroscopy confirmed association of Cr(III) with organic carbon in the column solids. Decreases in dissolved Cr(VI) concentrations were coupled with increases in δ(53)Cr, indicating that Cr isotope enrichment occurred during reduction of Cr(VI). The δ(53)Cr data from the column experiment was fit by linear regression yielding a fractionation factor (α) of 0.9979, whereas the batch experiments exhibited Rayleigh-type isotope fractionation (α = 0.9965). The linear characteristic of the column δ(53)Cr data may reflect the contribution of transport on Cr isotope fractionation.


Concurrent Monte Carlo transport and fluence optimization with fluence adjusting scalable transport Monte Carlo.
The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and "4π" delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship within a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of "concurrent" Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7-8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead.


Unidirectional multiple comparisons of Poisson rates.
This paper presents an exact significance test procedure for unidirectional multiple comparisons of Poisson variables. It is sufficiently general for application to situations where the 'denominator', which might be the amount of follow-up time in cohort studies or the expected number of events in studies that use standardized rates, differs from one group to the other, and where a group-specific alternative hypothesis is of interest. We use unidirectional Z statistics, of the form proposed by Dunnett, along with the conditional distribution needed in computing the exact attained significance levels, to address three distinct unidirectional hypotheses. In one case, we compare one exposed with several reference groups, while in the other two cases, we compare several exposed groups with one reference group. We also provide a multiple stage testing approach. Data from studies in cancer and trauma epidemiology illustrate the procedures.


Abrolhos bank reef health evaluated by means of water quality, microbial diversity, benthic cover, and fish biomass data.
The health of the coral reefs of the Abrolhos Bank (Southwestern Atlantic) was characterized with a holistic approach using measurements of four ecosystem components: (i) inorganic and organic nutrient concentrations, [1] fish biomass, [1] macroalgal and coral cover and (iv) microbial community composition and abundance. The possible benefits of protection from fishing were particularly evaluated by comparing sites with varying levels of protection. Two reefs within the well-enforced no-take area of the National Marine Park of Abrolhos (Parcel dos Abrolhos and California) were compared with two unprotected coastal reefs (Sebastião Gomes and Pedra de Leste) and one legally protected but poorly enforced coastal reef (the "paper park" of Timbebas Reef). The fish biomass was lower and the fleshy macroalgal cover was higher in the unprotected reefs compared with the protected areas. The unprotected and protected reefs had similar seawater chemistry. Lower vibrio CFU counts were observed in the fully protected area of California Reef. Metagenome analysis showed that the unprotected reefs had a higher abundance of archaeal and viral sequences and more bacterial pathogens, while the protected reefs had a higher abundance of genes related to photosynthesis. Similar to other reef systems in the world, there was evidence that reductions in the biomass of herbivorous fishes and the consequent increase in macroalgal cover in the Abrolhos Bank may be affecting microbial diversity and abundance. Through the integration of different types of ecological data, the present study showed that protection from fishing may lead to greater reef health. The data presented herein suggest that protected coral reefs have higher microbial diversity, with the most degraded reef (Sebastião Gomes) showing a marked reduction in microbial species richness. It is concluded that ecological conditions in unprotected reefs may promote the growth and rapid evolution of opportunistic microbial pathogens.


Fetal and neonatal cardiopulmonary response to histamine.
Effects of intravenous histamine and its H1 receptor blocker (Benadryl) were investigated in near-term fetal and in newborn lambs. Fetuses were studied before and after closure of the ductus arteriosus. Newborn lambs were chronically instrumented and the same animal was tested periodically from 3 to 70 days old. The results show that a) in the fetus whose pulmonary vascular resistance is already high, histamine produces a profound pulmonary vasodilation; b) in contrast, in the neonate with reduced pulmonary vascular resistance, histamine produces pulmonary vasoconstriction similar to that of the adult; c) both responses can be attenuated by Benadryl indicating that they are mediated by the same receptor; d) in the fetus, histamine produces marked constriction of the ductus arteriosus which could be partly attributed to the pulmonary vasocilatation; and e) when neonatal pulmonary vascular resistance was raised by hypoxia, histamine elicited a biphasic response, part of which was blocked by Benadryl. These findings are discussed in terms of their possible role in cardiovascular and pulmonary changes that occur after birth.


Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate.
Neutral ceramidase (NCDase) and sphingosine kinases (SphKs) are key enzymes regulating cellular sphingosine-1-phosphate (S1P) levels. In this study we found that stress factor-induced apoptosis of rat renal mesangial cells was significantly reduced by dexamethasone treatment. Concomitantly, dexamethasone increased cellular S1P levels, suggesting an activation of sphingolipid-metabolizing enzymes. The cell-protective effect of glucocorticoids was reversed by a SphK inhibitor, was completely absent in SphK1-deficient cells, and was associated with upregulated mRNA and protein expression of NCDase and SphK1. Additionally, in vivo experiments in mice showed that dexamethasone also upregulated SphK1 mRNA and activity, and NCDase protein expression in the kidney. Fragments (2285, 1724, and 1126 bp) of the rat NCDase promoter linked to a luciferase reporter were transfected into rat kidney fibroblasts and mesangial cells. There was enhanced NCDase promoter activity upon glucocorticoids treatment that was abolished by the glucocorticoid receptor antagonist RU-486. Single and double mutations of the two putative glucocorticoid response element sites within the promoter reduced the dexamethasone effect, suggesting that both glucocorticoid response elements are functionally active and required for induction. Our study shows that glucocorticoids exert a protective effect on stress-induced mesangial cell apoptosis in vitro and in vivo by upregulating NCDase and SphK1 expression and activity, resulting in enhanced levels of the protective lipid second messenger S1P.


Improved Pre-attentive Processing With Occipital rTMS Treatment in Major Depressive Disorder Patients Revealed by MMN.
To investigate the improvement effect of occipital repetitive transcranial magnetic stimulation (rTMS) combined with escitalopram oxalate tablets on pre-attentive processing in patients with first-episode, medication-naive depression. Patients who were hospitalized between January and December 2019 were selected. They were randomly allocated to real occipital rTMS stimulation group with 27 cases receiving intermittent theta-burst (iTBS) and sham stimulation group with 24 cases over 20 days. The rTMS treatment target is located at the Oz point of the occipital region. Both groups took escitalopram oxalate tablets, and the average daily drug dose was 15.294 ± 5.041 mg. Hamilton Depression Rating Scale (HAMD) was used to assess the symptoms of depression before and after treatment, and mismatch negativity (MMN) was used to assess the improvement of pre-attentive processing before and after treatment. After 20 days of treatment, the total score of HAMD (13.495 ± 3.700) in both groups was significantly lower than that before treatment [21.910 ± 3.841, F(1, 49) = 46, 3.690, p < 0.001]. After treatment, the latency of MMN in the real stimulation group (182.204 ± 31.878 ms) was significantly lower than that in the sham stimulation group (219.896 ± 42.634 ms, p < 0.001), and the amplitude of MMN in the real stimulation group (-7.107 ± 3.374 ms) was significantly higher than that in the sham stimulation group (-2.773 ± 3.7 32 ms, p < 0.001). Occipital rTMS treatment can enhance the early therapeutic effect and effectively improve the pre-attentive processing of patients with depression and provide a scientific basis for the new target of rTMS therapy in clinical patients with depression.


[Unusual appearance of axillary lipoblastoma of infancy].
Lipoblastoma is an uncommon benign soft tissue tumor of infancy and early childhood with a predilection for the extremities. CT and MRI can confirm the presence of fat components in the tumor. In addition, MRI better shows the anatomical extent. By showing lipoblastoma proliferation, histology confirms the diagnosis. Gross total excision is the treatment of choice. The authors report a case of unusual lipoblastoma of the axillary region, composed of fatty components with multiple cystic areas presenting at birth, with recurrence 9 months after excision.


Diagnostic value of combined magnetic resonance imaging techniques in the evaluation of Parkinson disease.
The incidence of Parkinson disease (PD) has been increasing each year. The development of new magnetic resonance imaging (MRI) technology can help understand its pathogenesis and identify more effective imaging-based biological indicators. The clinical and MRI imaging data of 40 patients with PD and 40 healthy controls were analyzed. All participants underwent susceptibility-weighted imaging (SWI), neuromelanin-sensitive magnetic resonance imaging (NM-MRI), and T2*mapping sequence examination. The diagnostic value of single and combined multiparameter indicators was analyzed using the receiver operating characteristic curve. Compared with the healthy control group, the PD group showed significant differences in the disappearance of bilateral "swallow tail sign", the distribution volume of melanocytes in the substantia nigra and the smaller volume in the bilateral substantia nigra, the maximum signal of the locus coeruleus and the smaller and average volume in the bilateral substantia nigra, and the values of T2* and R2* in the bilateral substantia nigra (P<0.01). The maximum and smaller value and the average value of the bilateral locus coeruleus signal were negatively correlated with the disease course duration (P<0.05), and the smaller distribution volume of the melanin neurons in the bilateral substantia nigra was negatively correlated with Hoehn and Yahr (H-Y) grade (P<0.05). In the joint diagnosis with multiple indicators, some composite parameters were found to be negatively correlated with H-Y grading (P<0.05), while others were negatively correlated with disease course duration (P<0.05). Joint use of multiple parameter indicators greatly improved diagnostic efficacy [area under the curve (AUC) =0.958]. The distribution volume of melanin in substantia nigra and the maximum value of locus coeruleus signal may be the biological imaging indicators for the early diagnosis, severity, and follow-up evaluation of PD. Compared with a single indicator, composite indicators used in combination with multiple techniques have a significantly better diagnostic efficacy for PD.


Resolving Ultrafast Photoinduced Deactivations in Water-Solvated Pyrimidine Nucleosides.
For the first time, ultrafast deactivations of photoexcited water-solvated pyrimidine nucleosides are mapped employing hybrid QM(CASPT2)/MM(AMBER) optimizations that account for explicit solvation, sugar effects, and dynamically correlated potential energy surfaces. Low-energy S1/S0 ring-puckering and ring-opening conical intersections (CIs) are suggested to drive the ballistic coherent subpicosecond (<200 fs) decays observed in each pyrimidine, the energetics controlling this processes correlating with the lifetimes observed. A second bright 1π2π* state, promoting excited-state population branching and leading toward a third CI with the ground state, is proposed to be involved in the slower ultrafast decay component observed in Thd/Cyd. The transient spectroscopic signals of the competitive deactivation channels are computed for the first time. A general unified scheme for ultrafast deactivations, spanning the sub- to few-picosecond time domain, is eventually delivered, with computed data that matches the experiments and elucidates the intrinsic photoprotection mechanism in solvated pyrimidine nucleosides.


Intracluster correlation coefficient in multicenter childhood trauma studies.
To calculate the intracluster correlation coefficient (ICC) for emergency department (ED) shock rate, early trauma death (ie, death during the first 24 h after arrival at hospital), and in-hospital trauma death rate for multicenter childhood injuries. The National Trauma Data Bank (5th revision), the largest multicenter trauma registry in the US, was used. Data from 80 trauma centers were used to calculate the ICC for in-hospital trauma death rate. Thirty three states provided data for calculation of the ICC for ED shock and early trauma death rate. From 2000 to 2004, 13% of the 952 242 patients in the National Trauma Data Bank were <15 years old. Approximately 17 000 of these children had injuries with an injury severity score >15, of whom 84% (14 095 subjects) were hospitalized at 80 level I or II trauma centers in 33 states. The ICCs for ED shock rate, early trauma death rate, and in-hospital death rate were 0.005 (95% CI 0.000 to 0.010), 0.014 (95% CI 0.004 to 0.024), and 0.023 (95% CI 0.013 to 0.033), respectively. These ICCs were calculated for boys and girls and also for blunt and penetrating injuries. Clustered childhood trauma studies that aim to compare different aspects of pre-hospital and hospital trauma care should incorporate these ICCs for sample calculation. When cluster randomized clinical trials are mounted, if sample sizes are calculated without adjustment for ICC, then the planned trial is likely to be seriously underpowered.


Immediate effects of mammary artery revascularization versus saphenous vein on global and regional myocardial function: an intraoperative echocardiographic assessment.
The immediate effect of coronary artery bypass surgery on global and regional myocardial function using the internal mammary artery (IMA) versus saphenous vein (SV) was studied intraoperatively using transesophageal echocardiography (TEE). Thirty-two patients received an IMA and 10 patients only SV. Transesophageal echocardiography was recorded before thoracotomy, 5 minutes after the end of cardiopulmonary bypass (CPB) and after chest closure. Global and regional left ventricular function were expressed as a percent of the short axis area change (%SAAC) and a percent of the fractional area change (%FAC), respectively. Segments were classified according to their baseline function as normal, %FAC greater than 40%, or dysfunctional, %FAC less than 40%. Only normal segments were considered in this study. No significant change in %SAAC in either group was observed in this study. Internal mammary artery revascularized segments showed a significant decrease in %FAC from 57 +/- 1 before thoractomy to 53 +/- 2 5 minutes after CPB, whereas SV segments showed a significant improvement in %FAC from 56 +/- 1 to 61 +/- 1. Applying strict criteria derived from intraobserver and cycle-to-cycle variability, 17% of IMA segments had deteriorated by more than 36% whereas only 4% of SV segments showed such deterioration. Conversely, 17% of SV segments showed an increase in %FAC by more than 36% and only 3% of IMA segments improved similarily. The observed changes were of short duration and had largely resolved by chest closure.(ABSTRACT TRUNCATED AT 250 WORDS)


Upper limb morbidity as a direct consequence of intravenous drug abuse.
To quantify and qualify the types of upper limb injuries admitted to hospital as a direct result of illicit intravenous drug use (IVDU). A retrospective case series identified all inpatient admissions for upper limb injuries as a direct result of IVDU over a two-year period. The type of injury, procedures, complications, co-morbidities, relevant investigations and other notable events during admission and follow-up were identified. Thirty-six people were admitted with upper limb injuries. Infective presentations (abscess, cellulitis, osteomyelitis, and septic arthritis) were most common. Other injuries were due to accidental intra-arterial injection, soft-tissue necrosis and compartment syndrome. Microbiological analysis from abscesses showed a high frequency of multiple organisms, and most commonly identified Streptococci, Staphylococcus aureus, and anaerobes. These patients had high rates of hepatitis C, malnutrition, psychiatric and behavioural co-morbidities; 77% were lost to follow-up. The most common injuries from IVDU are infections, and ischaemia. High rates of concurrent medical and psychosocial co-morbidities add further challenges to effective patient care.


Brief Report: Virologic Monitoring Can Be a Cost-Effective Strategy to Diagnose Treatment Failure on First-Line ART.
CD4 count testing is perceived to be an affordable strategy to diagnose treatment failure on first-line antiretroviral therapy. We hypothesize that the superior accuracy of viral load (VL) testing will result in less patients being incorrectly switched to more expensive and toxic second-line regimens. Using data from a drug resistance cohort, we show that CD4 testing is approximately double the cost to make 1 correct regimen switch under certain diagnostic thresholds (CD4 = US $499 vs. VL = US $186 or CD4 = US $3031 vs. VL = US $1828). In line with World Health Organization guidelines, our findings show that VL testing can be both an accurate and cost-effective treatment monitoring strategy.


[Urinary incontinence in the elderly: a proposal for nursing behavior].
The authors make it evident the Urinary Incontinence in elderly people showing up the prevalence, their motives and types. It is subsidize the evaluation of the historical, the physical exam, registry of the incontinence and also the exercises for the training of the bladder, the musculature, hygiene habits and also the manipulation of the catheters and the aspects of the environment looking for the restoration of the continence and/or to treat and to live with in the urinary incontinence. They distinguish that the nursing conduct is done interrelated with the medical team with homely cares and elderly investing in the self care for to improve the urinary incontinence and favouring the continence.


Osteoporosis detection using intraoral densitometry.
To determine the diagnostic accuracy of mandibular and maxillary bone density in detecting osteoporosis using receiver operating characteristic (ROC) analysis. 671 women between 45 years and 70 years of age underwent dual energy X-ray absorptiometry (DXA) of the hip and lumbar spine. This was the gold standard for diagnosing osteoporosis. Intraoral radiography of the upper and lower right premolar region was performed, using an aluminium wedge as a densitometric reference. Jaw bone density was determined using dedicated software. Observer differences and ROC curves were analysed. For detecting osteoporosis using jaw bone density, the area under the ROC curve (A(z)) was 0.705. For separate analysis of mandibular and maxillary films, sensitivity varied from 33.9% to 38.7% and specificity from 83.5% to 85.3% when using a threshold of 4.3 mm Al equivalent. Density of the premolar region reaches a fair diagnostic accuracy, which might improve when including additional factors in the analysis and refining the densitometric tool.


Specific IgG antibody responses in Oestrus ovis L. (Diptera: Oestridae) infected sheep: associations with intensity of infection and larval development.
Larvae of Oestrus ovis (Diptera: Oestridae) are ubiquitous parasites of nasal and sinusal cavities of sheep and goats. According to the chronobiology of O. ovis infections in Sardinia and the seasonal pattern of the IgG response, the optimal period to investigate the relationships between O. ovis larval populations and intensity of local and systemic IgG antibody responses was mid-July in the summer season. Sarda x Lacaune ewes (n=186), divided into three ram-families were used in the study. Systemic and local IgG responses were measured by ELISA tests using second stage larval crude extracts (L2CE) and L2 (L2SGC) and L3 (L3SGC) salivary gland contents as coating antigens. The number of larval instars, larval length of L1, L2 and L3 larvae, and larval weight of L2 and L3 larvae were individually recorded after ewe necropsy. Negative correlations among larval establishment and/or larval development on the one hand and intensity of local or systemic IgG responses on the other hand were found in two out of three studied ram-families.


Childbirth self-efficacy and fear of childbirth and their predictors in adolescent and adult pregnant women referring to health centres of Urmia-Iran: a cross-sectional study.
Adolescent pregnancy as a growing phenomenon in the world has been investigated from different aspects. However, the examination of childbirth fear and self-efficacy has received less attention. Therefore, this study was conducted to compare the self-efficacy and fear of childbirth and to determine their predictors in adolescent and adult pregnant women. In this comparative cross-sectional study, participants were selected through two-stage cluster sampling method. Data were collected using the Childbirth Self-Efficacy Inventory and Wijma Delivery Expectancy/Experience Questionnaire. The Pearson correlation test, independent t-test, and general linear model were used for data analysis. Urmia health centres, Iran in 2020. Three hundred and sixty adults and adolescent pregnant women. The mean (SD) of fear of childbirth was 114.7 (14.1) and 108.1 (23.1) in adolescent and adult pregnant women, respectively. The mean (SD) of childbirth self-efficacy in the active phase and the second stage of labour respectively were also obtained 208.8 (28.6) and 203.5 (32.1) for adolescent pregnant women and 213.8 (25.7) and 212.0 (26.5) for adult ones. There was a significant difference between adolescent and adult pregnant women in fear of childbirth (p=0.001), self-efficacy expectancy (p=0.003) and total childbirth self-efficacy (p=0.008) in the second stage of labour. After adjusting the sociodemographic characteristics, the mean score of fear of childbirth was significantly higher in adolescent pregnant women than in adult ones whereas the mean total self-efficacy score in the second stage of labour was significantly lower in adolescent pregnant women than in adult ones. This study showed that adolescent pregnant women had more fear of childbirth and low self-efficacy than adult mothers, and there was also a relationship between fear of childbirth and self-efficacy. Paying more attention to fear and self-efficacy in childbirth and their predictors by health providers can improve pregnancy and childbirth outcomes.


Erectile dysfunction, endothelium dysfunction, and microvascular damage in patients with systemic sclerosis.
Erectile dysfunction (ED) prevalence in men with systemic sclerosis (SSc) is high and can be considered a manifestation of endothelium damage. This study aims to correlate ED with endothelial dysfunction and digital vascular damage in SSc patients. The main outcome measures were erectile function, Doppler indices of cavernous arteries, flow-mediated dilation (FMD), capillaroscopic damage, skin perfusion, and digital pulsatility. In 23 SSc patients, erectile function was investigated using the International Index of Erectile Function-5 (IIEF-5). Doppler indices of cavernous arteries, peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were measured at the penoscrotal junction before and after pharmacostimulation with 20 mg prostaglandin E1. FMD and nailfold videocapillaroscopy (NVC) were used to evaluate endothelial dysfunction and capillaroscopic damage. Skin perfusion and digital sphygmic waves were measured by laser Doppler perfusion imaging (LDPI) and digital photoplethysmography (PPG), respectively. IIEF-5 score was reduced in 83% of patients. PSV was reduced in 96%, while EDV was increased in 48% of patients. A positive correlation was observed between IIEF-5 score and FMD (r = 0.71, P < 0.0001) and between the former and PSV (r = 0.76, P < 0.0001). A negative correlation was observed between EDV and FMD (r = -0.509, P < 0.01). FMD and Doppler indices were reduced with capillaroscopic damage progression. A positive correlation exists between LDPI perfusion and IIEF-5 score (r = 0.743, P < 0.0001) and between the former and PSV (r = 0.714, P < 0.0001), while a negative correlation is observed between LDPI perfusion and EDV (r = -0.677, P < 0.0001). A positive correlation exists between PPG pulsatility and IIEF-5 score (r = 0.752, P < 0.0001) and between the former and PSV (r = 0.747, P < 0.0001), while negative correlation is observed between PPG pulsatility and EDV (r = -0.689, P < 0.0001). In SSc patients, ED correlates with endothelial dysfunction and digital microvascular damage.


Monte Carlo simulations of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB): Pressure and temperature effects for the solid phase and vapor-liquid phase equilibria.
The transferable potentials for phase equilibria (TraPPE) force field was extended to nitro and amino substituents for aromatic rings via parametrization to the vapor-liquid coexistence curves of nitrobenzene and aniline, respectively. These groups were then transferred to model 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). Without any further parametrization to solid state data, the TraPPE force field is able to predict TATB's unit cell lengths and angles at 295 K with mean unsigned percentage errors of 0.3% and 1.8% and the specific density within 0.5%. These predictions are comparable in accuracy to the GRBF model [Gee et al., J. Chem. Phys. 120, 7059 (2004)] that was parametrized directly to TATB's solid state properties. Both force fields are able to reproduce the pressure dependence of TATB's unit cell volume, but they underestimate its thermal expansion. Due to its energetic nature and unusually large cohesive energy, TATB is not chemically stable at temperature in its liquid range. Gibbs ensemble simulations allow one to determine TATB's vapor-liquid coexistence curve at elevated temperatures and the predicted critical temperature and density for the TraPPE and GRBF model are 937+/-8 and 1034+/-8 K, and 0.52+/-0.02 and 0.50+/-0.02 gcm(3), respectively.


Terbutaline sulfoconjugate: characterization and urinary excretion monitored by LC/ESI-MS/MS.
Terbutaline is a fast-acting beta(2)-adrenergic agonist used in the treatment of obstructive pulmonary diseases. Doping control for beta(2)-agonists, which are forbidden in sports by the World Anti-doping Agency (WADA), is performed in screening by liquid chromatography/mass spectrometry after hydrolysis of phase-II metabolites. In this study, the mono-sulfoconjugated phase-II metabolite of terbutaline was synthesized and the chemical structure was characterized by (1)H-nuclear magnetic resonance spectrometry and high resolution/high accuracy Orbitrap mass spectrometry. The metabolite was designated as the phenolic esterified compound, which has been mentioned in most literature reports but has not been verified so far. The benzylic esterified compound was also synthesized and characterized by high-resolution/high accuracy Orbitrap mass spectrometry but was not detectable in urine samples from an excretion study performed after a single application of one terbutaline capsule (7.5 mg terbutaline sulfate salt). The phenolic sulfate of terbutaline was detected for two to four days after administration, whereas the unchanged terbutaline was detected for four to five days. A glucuronidated, disulfated or trisulfated phase-II metabolite of terbutaline was not found. The measurement of phase-II metabolites is planned to be incorporated into existing screening procedures to allow a faster sample preparation.


Endovascular repair of blunt extremity arterial injury: case report.
Surgical revascularization is the standard treatment of complex blunt traumatic extremity vascular injuries. Limb salvage may be improved with minimally invasive endovascular therapies because of the ability to perform diagnostic and therapeutic intervention simultaneously. Two cases of acute limb-threatening arterial injuries successfully treated with percutaneous endovascular therapy are reported. A skier suffered hemodynamic instability after shoulder reduction. An axillary arterial injury was suspected and confirmed with angiography. A covered stent successfully controlled the hemorrhage. A morbidly obese female sustained anterior dislocation of her left knee 7 years previously requiring repair. She developed recurrent knee dislocation with acute leg ischemia. Emergent fixation was performed followed by percutaneous angiography. Short segment thrombosis of the popliteal was noted. Wire recanalization of the thrombosed artery and stent placement restored 3-vessel runoff. Endovascular therapy can offer faster, easier access to the extremity vascular injury facilitating revascularization and avoiding long incisions and dissections.


Macular and Optic Nerve Microvascular Alteration in Relation to Axial Length, by Optical Coherence Tomography Angiography (OCTA).
To study the effect of axial length (AL) on quantitative characterization of macular and optic nerve microvasculature using optical coherence tomography angiography (OCTA) in healthy individuals. A cross-sectional study where participants were divided into 3 groups according to AL; A: ≤22.5 mm, B: 22.6-24.5 mm, C: >24.5 mm. Superficial vascular density (SVD), deep vascular density (DVD), foveal avascular zone (FAZ), and radial peripapillary capillary density (RPCD) were calculated using OCTA. Pearson correlation was run to identify the relation between AL and study parameters. One hundred and twelve eyes of 56 participants (20 males, 36 females) were included. Mean FAZ was 0.33 ± 0.15 mm2, 0.27 ± 0.1 mm2 and 0.28 ± 0.2 mm2 in Groups A, B, and C, respectively (p value 0.073). No significant difference was found between 3 groups, as regards superficial foveal density and vessel density inside the disc. Deep foveal density was significantly lower in Group A in comparison to Groups B and C (p value 0.021 and 0.005, respectively). As for other parameters of SVD, DVD and RPCD, no significant difference was observed between Groups A and B; however, the same parameters were significantly lower in Group C when compared to Group A and B. AL was found to be negatively correlated to FAZ (r -0.191, p value 0.043) and most of parameters of SVD, DVD, and RPCD (p value < 0.0001). Most of optic nerve and macular microvascular parameters were significantly lower in eyes with longer axial lengths when compared to those with shorter axial lengths. Moreover, most of these parameters were negatively correlated with AL.


Multiple configurations and fluctuating trophic control in the Barents Sea food-web.
The Barents Sea is a subarctic shelf sea which has experienced major changes during the past decades. From ecological time-series, three different food-web configurations, reflecting successive shifts of dominance of pelagic fish, demersal fish, and zooplankton, as well as varying trophic control have been identified in the last decades. This covers a relatively short time-period as available ecological time-series are often relatively short. As we lack information for prior time-periods, we use a chance and necessity model to investigate if there are other possible configurations of the Barents Sea food-web than those observed in the ecological time-series, and if this food-web is characterized by a persistent trophic control. We perform food-web simulations using the Non-Deterministic Network Dynamic model (NDND) for the Barents Sea, identify food-web configurations and compare those to historical reconstructions of food-web dynamics. Biomass configurations fall into four major types and three trophic pathways. Reconstructed data match one of the major biomass configurations but is characterized by a different trophic pathway than most of the simulated configurations. The simulated biomass displays fluctuations between bottom-up and top-down trophic control over time rather than persistent trophic control. Our results show that the configurations we have reconstructed are strongly overlapping with our simulated configurations, though they represent only a subset of the possible configurations of the Barents Sea food-web.


[Primary management of fresh injuries of the thoracic and lumbar vertebrae].
Results of conservative treatment of vertebral body fractures and of repositioning and internal fixation, are compared with those obtained by dorsoventral repositioning and fusion. The results achieved with patients treated by dorsoventral fusion were statistically significantly better than those obtained with the other two treatment methods. Consequently, we modified the treatment concept of thoracic and lumbar vertebral body fractures. Every vertebral disk showing irreversible damage is now resected and the mobility segment involved is fused. The fracture is treated conservatively only in case MR does not reveal any lesion of the vertebral disk, or it is stabilised only from the dorsal approach.


[Is the governmental vocational rehabilitation program too ambitious?].
The Norwegian government has stressed the importance of supporting vocational training for clients with health problems in order to secure their active participation in the labour force. On average, 35,000-40,000 people were referred from the National Insurance Scheme to the Directorate of Labour to take part in vocational rehabilitation projects in 1995. The majority of the vocationally handicapped are young. Three out of four have a poor educational background, and close to 70% have health problems, mainly in the form of chronic musculoskeletal pain or psychiatric illness, usually depression and anxiety-states. So far, the success of the rehabilitation seems to be rather limited, since approximately 40% of the clients were referred back to the Insurance Scheme. They were considered unfit for training because of impaired health. Another 40% of the cases were considered fully or partly successful. Clients with psychiatric illness seem to be particularly difficult to rehabilitate to vocational activity.


Bending Modulated Ultralarge Magnetoresistance in Flexible La0.67Ba0.33MnO3 Thin Film Based Device.
Magnetoresistance based information devices have attracted much attention due to the ability to utilize spins as information carriers. To promote the magnetoresistance-based devices, ultrahigh magnetoresistance ratios are highly desirable for magnetic sensing, memory, and artificial intelligent devices, etc. However, today the magnetoresistance devices are facing the challenge of limited magnetoresistance ratio, low work temperature, or high magnetic field, which calls for proper theories and mechanisms. To address it, we first introduce the flexible bending-controlled magnetoresistance device based on the La0.67Ba0.33MnO3 film. Due to the anisotropic resistance of the La0.67Ba0.33MnO3 film and the nonlinear amplification effect of the Zener diode, the device has exhibited strong magnetoresistive performance (∼8725% at 1 T, 300 K). Combining the assist from mechanical bending and diode, high magnetic field sensitivity with large magnetoresistance ratio (∼1.7 × 104% at 1 T, 300 K) and low work current (∼0.15 mA) is simultaneously achieved at room temperature, which is over 104 times larger than that of the planar La0.67Ba0.33MnO3 film. Based on the above results, we propose one but not the only possible application as tunable multistage switch. Our findings may pave a strategy to develop flexible diode-enhanced magnetoresistance device with ultrahigh magnetoresistance ratios and bending tunable performances.


T2*-sensitized high-resolution magnetic resonance venography using 3D-PRESTO technique.
We evaluated the ability of the PRESTO (principles of echo shifting with a train of observations) technique to reveal small veins and microbleeds in the human brain. In an experimental study, we calculated contrast-to-noise ratio (CNR) between a cerebral parenchymal phantom and human venous blood using 3 sequences of 3-dimensional (3D)-PRESTO, 3D-gradient recalled echo (GRE), and 3D-GRE echo-planar imaging (EPI). Then, we examined 7 healthy volunteers and 5 patients with venous angiomas or traumatic brain injuries using the 3D-PRESTO technique. In volunteer studies, MR venographies were reconstructed from 10-mm, 15-mm, and 20-mm thickness data using the minimum-intensity-projection (MinIP) technique. Three radiologists identified deep brain venous anatomy and counted the visible left medullary veins. In clinical studies, we evaluated the lesion conspicuity of small venous diseases and microbleeds. In the phantom study, 3D-PRESTO showed the highest CNR. In all volunteer studies, the deep brain venous anatomy was readily identified in the MinIP images at each thickness. The mean numbers of counted left medullary veins were 5.1 for 10 mm, 5.9 for 15 mm, and 6.7 for 20 mm in the MinIP images. The difference was significant between 10-mm and 20-mm MinIP images (P=0.02). In patient studies, abnormal small veins and microbleeds were clearly revealed. High-resolution MR venography using 3D-PRESTO technique can clearly depict small veins and microbleeds in the human brain.


Biologics in the treatment of pustular psoriasis.
Pustular psoriasis is a group of skin diseases characterized by neutrophil infiltration in the epidermis and formation of sterile pustules. Conventional treatments, such as retinoids and immunosuppressive drugs, have improved the clinical manifestations; however, many patients suffer from drug-related toxicity or are resistant to therapy. In this review, the authors focus on the efficacy and safety of these biologics, including anti-IL-1β (gevokizumab and canakinumab), anti-IL-1 R (anakinra), anti-IL-36 R (BI 655130), anti-tumor necrosis factor-α (etanercept, infliximab, and adalimumab), anti-IL-12/23 (ustekinumab), anti-IL-17A (secukinumab and ixekizumab), anti-IL-17RA (brodalumab), anti-IL-2 R (basiliximab), anti-IL-6 R (tocilizumab), and anti-IL-23 (risankizumab and guselkumab), for treating pustular psoriasis. Patients with pustular psoriasis treated with biologics demonstrated positive responses. Anti-TNF-α is the most available biologics for the treatment of pustular psoriasis, and anti-IL-12/23 and anti-IL-17A might be considered as the first- or second-line therapy for moderate-to-severe and refractory pustular psoriasis. Anti-IL-17A can be used in the pustular psoriasis patients who failed to respond to anti-TNF agents and anti-IL-12/23. Therapeutic efficacy of biologics in pustular psoriasis might have no association with IL-36 RN mutation status.


The effect of Macleaya cordata extract on in vitro ruminal fermentation and methanogenesis.
Methane production is the main gas energy loss in ruminants and generates a powerful greenhouse gas that contributes to climate changes. Macleaya cordata is a plant commonly utilized additive in livestock diet as it contains various chemical compounds with beneficial health effects. This study aimed to explore the influence of M. cordata extract on in vitro methanogenesis and rumen fermentation. Three cannulated Jingjiang cattle were used as rumen fluid donors. The mixture of rumen fluid and a buffer (60 ml, 1:2 volume ratio) was treated with 6 different concentrations of M. cordata extract (0.01%, 0.11%, 0.21%, 0.31%, 0.41%, and 0.51%) and incubated for 12 and 24 hr. The control sample, with no addition of plant extract, was also analyzed. At each time point, pH, total gas, methane, dry matter (DM) digestibility, neutral detergent fiber (NDF), acid detergent fiber (ADF), ammonia nitrogen (NH3-N), microbial protein (MCP), and volatile fatty acids (VFA) concentrations were determined. Total gas production decreased with increasing the amount of M. cordata extract at all time points. Methane production also decreased dose-dependently with M. cordata extract after 3, 6, 9, and 12 hr of incubation, but increased after 24 hr. M. cordata extract decreased the concentration of NH3-N and VFA, and the amount of acetic, propionic, and butyric acid. M. cordata extract decreased the MCP concentration after 12 hr, but its level returned to the initial value after 24 hr. Supplementation with 0.01, 0.11, and 0.21% of M. cordata extract did not affect the DM digestibility. However, supplementation with 0.31, 0.41, and 0.51% of M. cordata extract significantly decreased the DM digestibility. Supplementation with 0.11% of M. cordata extract effectively reduced methane production without affecting the DM digestion in vitro. However, its effect on in vivo methane production, rumen fermentation, and ruminant production requires further investigation.


Coadministration of Dexamethasone and Melissa officinalis Has Neuroprotective Effects in Rat Animal Model with Spinal Cord Injury.
Spinal cord injury (SCI) causes inflammation, deformity and cell loss. It has been shown that Melissa officinalis (MO), as herbal medicine, and dexamethasone (DEX) are useful in the prevention of various neurological diseases. The present study evaluated combinational effects of DEX and MO on spinal cord injury. Thirty six adult male Wistar rats were used in this experimental study. The weight-drop contusion method was employed to induce spinal cord injury in rats. DEX and MO were administrated alone and together in different treatment groups. Intra-muscular injection of DEX (1 mg/kg) was started three hours after injury and continued once a day for seven days after injury. Intra-peritoneal (I.P) injection of MO (150 mg/ kg) was started one day after injury and continued once a day for 14 days. Our results showed motor and sensory functions were improved significantly in the group received a combination of DEX and MO, compared to spinal cord injury group. Mean cavity area was decreased and loss of lower motor neurons and astrogliosis in the ventral horn of spinal cord was significantly prevented in the group received combination of DEX and Melissa officinalis, compared to spinal cord injury group. Furthermore, the findings showed a significant augmentation of electromyography (EMG) recruitment index, increase of myelin diameter, and up-regulation of myelin basic protein in the treated group with combination of DEX and MO. Results showed that combination of DEX and MO could be considered as a neuroprotective agent in spinal cord injury.


Investigation of internal electric fields in graphene/6H-SiC under illumination by the Pockels effect.
In this paper, we introduce a method for mapping profiles of internal electric fields in birefringent crystals based on the electro-optic Pockels effect and measuring phase differences of low-intensity polarized light. In the case of the studied 6H-SiC crystal with graphene electrodes, the experiment is significantly affected by birefringence at zero bias voltage applied to the crystal and a strong thermo-optical effect. We dealt with these phenomena by adding a Soleil-Babinet compensator and using considerations based on measurements of crystal heating under laser illumination. The method can be generalized and adapted to any Pockels crystal that can withstand sufficiently high voltages. We demonstrate the significant formation of space charge in semi-insulating 6H-SiC under illumination by above-bandgap light.


Translational evaluation of gait behavior in rodent models of arthritic disorders with the CatWalk device - a narrative review.
Arthritic disorders have become one of the main contributors to the global burden of disease. Today, they are one of the leading causes of chronic pain and disability worldwide. Current therapies are incapable of treating pain sufficiently and preventing disease progression. The lack of understanding basic mechanisms underlying the initiation, maintenance and progression of arthritic disorders and related symptoms represent the major obstacle in the search for adequate treatments. For a long time, histological evaluation of joint pathology was the predominant outcome parameter in preclinical arthritis models. Nevertheless, quantification of pain and functional limitations analogs to arthritis related symptoms in humans is essential to enable bench to bedside translation and to evaluate the effectiveness of new treatment strategies. As the experience of pain and functional deficits are often associated with altered gait behavior, in the last decades, automated gait analysis has become a well-established tool for the quantitative evaluation of the sequalae of arthritic disorders in animal models. The purpose of this review is to provide a detailed overview on the current literature on the use of the CatWalk gait analysis system in rodent models of arthritic disorders, e.g., Osteoarthritis, Monoarthritis and Rheumatoid Arthritis. Special focus is put on the assessment and monitoring of pain-related behavior during the course of the disease. The capability of evaluating the effect of distinct treatment strategies and the future potential for the application of the CatWalk in rodent models of arthritic disorders is also addressed in this review. Finally, we discuss important consideration and provide recommendations on the use of the CatWalk in preclinical models of arthritic diseases.


Microbial transglutaminase-mediated synthesis of hapten-protein conjugates for immunoassays.
Hapten-protein conjugates are essential in many immunochemical assays, in particular, in assays employing titration or competitive assay formats. By exploitation of the catalytic properties of the microbial transglutaminase from Streptoverticillium mobarense sp. (MTGase), i.e., acyl transfer between gamma-carboxamide groups and various primary amines, new techniques for the synthesis of hapten-protein conjugates were developed. This is demonstrated by two examples. The feasibility of MTGase for hapten-protein conjugate synthesis was studied by coupling the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) to casein. Different procedures for the synthesis and the immobilization of these 2,4-D-casein conjugates were evaluated, comprising (i) a batch procedure, (ii) coupling of 2,4-D to an already immobilized layer of casein, and (iii) a method for simultaneous immobilization and conjugation. Kinetic studies revealed that conjugate formation in the batch procedure was almost complete after approx 2 h. By employing the conjugates in a competitive ELISA, detection limits as low as 0.05 microgram/L 2,4-D were reached. Using the approach with simultaneous immobilization and conjugation, the time for the whole assay could be reduced to only 2 h. Finally, to demonstrate the versatility of the enzymatic synthesis of hapten-protein conjugates, an ELISA for 2,4,6-trinitrotoluene (TNT) determination based on transglutaminase-synthesized conjugates was developed. In this assay, a detection limit as low as 0.04 microgram/l TNT was obtained.


Radiation damage of biosystems mediated by secondary electrons: resonant precursors for uracil molecules.
Calculations are presented for the energy locations and spatial structures of low-energy resonant states describing transient negative ions (TNIs) of the uracil molecule in the gas phase. The resonant states are modeled using scattering calculations of low energy electrons interacting with isolated molecules in their equilibrium geometry. The interaction forces used in this model are described in detail. Examination of the spatial densities of the excess resonant electrons for the various TNIs found by the calculations allows one to associate the metastable anions with specific features of the experimentally observed fragmentation patterns.


Quorum sensing signaling molecules involved in the production of violacein by Pseudoalteromonas.
The production of violacein by Pseudoalteromonas sp. 520P1 has many features of quorum sensing. Signaling molecules were extracted from bacterial culture and subsequently identified as N-(3-oxooctanoyl)-homoserine lactone and N-tetradecanoyl-homoserine lactone. The former but not the latter induced the production of violacein in strain 520P1. We conclude that N-(3-oxooctanoyl)-homoserine lactone is a signaling molecule involved in the production of violacein.


A call for health justice: Striving toward health equity at a community health center.
Community health centers play a key role in promoting health justice and equity. Health justice, which is the attainment of health equity, or the fair, unambiguous, and non-arbitrary distribution of all health resources necessary for optimal health of the individual, family, and community, is necessary to optimize their wellbeing and to build healthy communities. Community-based health centers are well-positioned to lead in these efforts, as they connect with, seek to understand, and innovatively serve communities that experience complex health-related needs and are differentially impacted by structural vulnerabilities (i.e., racism). The purpose of this article is to present a nurse-led model of culturally responsive health care that is rooted in partnerships designed to address medical and health-related social needs. Current health inequities in the United States across constructs of race and socioeconomic status warrant comprehensive healthcare models that explicitly incorporate health justice, trauma-informed, and antiracist approaches into practice, especially when serving high/complex-need and under-resourced communities. Foundationally, it is imperative that these models of care strive toward equity regarding access to compassionate, affordable, culturally relevant health care; center community members' voices and guidance; promote growth and development of staff in understanding structural barriers and act to dismantle them; and create learning opportunities for students and staff to understand and address social determinants of health to provide high-quality care, with an ultimate goal to improve community health.


Surgical treatment of gastric gastrointestinal stromal tumors: analysis of 92 operated patients.
To review and evaluate the clinicopathological factors predictive of recurrence after surgical resection for gastrointestinal stromal tumor (GIST) of the stomach. The clinicopathological records of 92 gastric GIST patients who were operated upon at a single institute from 1996 to 2005 were retrospectively reviewed and assessed for recurrence-free survival. The patients included 43 men and 49 women. Their ages ranged from 25 to 91 years. The size of the tumors varied from 0.8 to 47.7 cm (median 5.8; 95% CI 6.4-9.2 cm). All but one operative margin were clear. The follow-up period ranged from 11 to 112 months (median 31, 95% CI 33.7-43.5 months). Fifteen patients (16%) developed disease recurrence, of which liver metastasis was the most common. Only 1 of the patients with tumors <4 cm developed recurrence. The 3-year recurrence-free survival rates for patients with tumors smaller or larger than 4 cm were 93 and 56.0%, respectively (p < 0.01). Multivariate analysis showed that the tumor size was the independent factor that was inversely associated with recurrence-free survival. The tumor size is an important prognostic factor for recurrence after surgery. Early excision is recommended for gastric GISTs even of small size.


Association of Fisher scale and changes of language in patients with aneurysmal subarachnoid hemorrhage.
Cognitive deficits caused by subarachnoid hemorrhage (SAH) after rupture of cerebral aneurysms are common, as approximately half of patients have severe, or at least striking, declines in one or more functions of the cognitive domain. The Fisher Scale is associated with the development of vasospasm and thus with the final performance of the patient after SAH. The association of this scale with language disorders in the period preceding the treatment has not been reported yet in the literature. Associate the presence of language deficits with varying degrees of the Fisher Scale in patients with SAH in the period preceding the treatment of aneurysm, as well as compare the various degrees of this scale, identifying the Fisher Scale degrees more associated with the decline of language. The database of 185 preoperative evaluations of language was studied, through the Montreal Toulouse Protocol Alpha version and verbal fluency through CERAD battery, of patients of Hospital da Restauração with aneurysmal SAH. The data relating to the Fisher Scale, the location of the aneurysm, the age and the gender of patients were obtained through review of medical records. Patients were divided according to the Fisher Scale (Fisher I, II, III or IV) and compared with a control group of individuals considered normal. Disorders in language and verbal fluency in patients with SAH in the preoperative period were evidenced. The classification of the patients according to the Fisher Scale allowed to identify differences between the sub-groups and to conclude that patients with bulkier bleeding (Fisher III and IV) have larger declines in the analyzed functions.


Sexual expression of mentally retarded people: educational and legal implications.
Issues of legal consent and competency, in addition to the relevant psychological literature, were reviewed in relation to institutional policy for sexual management of mentally retarded individuals. The significance of comprehensive sex education was also discussed. Finally, suggestions were provided that minimize prejudicial treatment of mentally retarded people, without eliminating their opportunities for sexual expression.


Spirituality and health outcomes within the context of social determinants of health.
Spirituality has a significant impact on patients' overall quality of life, however, it is often overlooked in the context of social determinants of health (SDOH). Nurses are well positioned to lead the expansion of SDOH models to include spirituality; however, routine nursing care does not emphasize spiritual assessment knowledge and skills. This article discusses spirituality and how it fits into the SDOH model, nursing education, and interdisciplinary healthcare. Spiritual care training may improve the confidence of nurses to integrate routine mental and spiritual assessments in clinical practice and serve as leaders in promoting spiritual care within interdisciplinary healthcare teams.


Small regulatory RNAs in Vibrio cholerae.
Vibrio cholerae is a major human pathogen causing the diarrheal disease, cholera. Regulation of virulence in V. cholerae is a multifaceted process involving gene expression changes at the transcriptional and post-transcriptional level. Whereas various transcription factors have been reported to modulate virulence in V. cholerae, small regulatory RNAs (sRNAs) have now been established to also participate in virulence control and the regulation of virulence-associated processes, such as biofilm formation, quorum sensing, stress response, and metabolism. In most cases, these sRNAs act by base-pairing with multiple target transcripts and this process typically requires the aid of an RNA-binding protein, such as the widely conserved Hfq protein. This review article summarizes the functional roles of sRNAs in V. cholerae, their underlying mechanisms of gene expression control, and how sRNAs partner with transcription factors to modulate complex regulatory programs. In addition, we will discuss regulatory principles discovered in V. cholerae that not only apply to other Vibrio species, but further extend into the large field of RNA-mediated gene expression control in bacteria.


Guidelines on the Use of Methotrexate in Psoriasis.
Psoriasis, a chronic multifactorial inflammatory disease that develops in genetically predisposed individuals, affects approximately 1.5% of the Spanish population. This disease has a negative impact on patients' quality of life, and long-term therapy is often required to control the symptoms. In addition to the classical systemic treatments (methotrexate, acitretin, cyclosporine, and ultraviolet light), the group of drugs known as biologics (etanercept, infliximab, adalimumab, and ustekinumab) provides the dermatologist with an expanded therapeutic armamentarium, thereby improving the likelihood of controlling psoriasis in patients with severe and/or extensive disease. Methotrexate, a classic antipsoriatic drug, is still very useful either as single-drug therapy or in combination with other systemic drugs, particularly as a rescue therapy or combined with biologics. This article aims to establish the role of methotrexate in the treatment of psoriasis. We considered it of interest to develop guidelines for using methotrexate in the management of psoriasis with a view to ensuring the safe and proper use of this drug in the management of psoriasis. This document was developed by consensus among members of the Psoriasis Group of the Spanish Academy of Dermatology and Venereology.


A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease.
Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.


Parathyroid carcinoma and hungry bone syndrome.
We hereby report two patients with parathyroid carcinoma presenting extremely high calcium and PTH levels, severe bone disease, and palpable neck mass at diagnosis. They both underwent parathyroidectomy, and one of them evolved to lung metastasis. Important hypocalcemia was observed after surgery in both: after parathyroidectomy in one patient, and only after surgical removal of the metastasis in the other. Both required intravenous calcium replacement, thus revealing hungry bone syndrome (HBS). HBS usually reflects rapid mineralization after correction of hyperparathyroidism. The more severe the bone disease before surgery, the more prone the patient is to HBS after surgery. Despite being an unfavorable outcome, HBS state suggests that surgical removal of hypersecretory parathyroid tissue was accomplished. In this study, HBS was observed in both patients, who presented severe bone disease prior to surgery. HBS would be expected post-operatively in successful parathyroid carcinoma removal.


Survey for secondary dapsone and rifampicin resistance in Cuba.
A total of 1211 Cuban multibacillary leprosy patients treated for at least 5 years were clinically and bacteriologically examined. They were being treated according to a 2-phase monotherapy regimen with RMP first and DADDS afterwards. On skin-smear examination 50 patients were found positive, of which 9 showed a BI of 3+ or higher at any site. With regard to the clinical status the only cases found with clinical signs of relapse were 5 out of 7 long-standing patients with BI of 4+ and 5+. A 6th patient of this high BI group who showed a good clinical condition, except for a heavy infiltration of both earlobes, was receiving a second RMP course when examined and biopsied for this research. These 9 patients were biopsied and susceptibility tests to RMP and DDS performed. The results showed that in 1 case the Mycobacterium leprae were resistant to both drugs; the organisms from 2 other patients were susceptible to RMP but low-grade resistant to DDS. Those from another patient were susceptible to RMP and fully resistant to DDS. In 3 other cases the bacilli did not multiply in any of the mice but 1 of these strains was from the patient taking a second RMP course, therefore this strain might also be susceptible to RMP and resistant to DDS. In the last 2 cases multiplication was only observed in 2 of the controls and in 1 of the 0.0001% DDS treated mice; therefore, these experiments were not conclusive, and the AFB recovered were inoculated into fresh mice to repeat the tests but these failed to multiply.


ADP-Glucose Pyrophosphorylase: A Regulatory Enzyme for Plant Starch Synthesis.
In plants, the synthesis of starch occurs by utilizing ADP-glucose as the glucosyl donor for the elongation of alpha-1,4-glucosidic chains. In photosynthetic bacteria the synthesis of glycogen follows a similar pathway. The first committed step in these pathways is the synthesis of ADP-glucose in a reaction catalyzed by ADP-glucose pyrophosphorylase (ADPGlc PPase). Generally, this enzyme is allosterically regulated by intermediates of the major carbon assimilatory pathway in the respective organism. In oxygenic photosynthesizers, ADPGlc PPase is mainly regulated by 3-phosphoglycerate (activator) and inorganic orthophosphate (inhibitor), interacting in four different patterns. Recent reports have shown that in higher plants, some of the enzymes could also be redox regulated. In eukaryotes, the enzyme is a heterotetramer comprised of two distinct subunits, a catalytic and a modulatory subunit. The latter has been proposed as related to variations in regulation of the enzyme in different plant tissues. Random and site-directed mutagenesis experiments of conserved amino acids revealed important residues for catalysis and regulation. Prediction of the ADPGlc PPase secondary structure suggests that it shares a common folding pattern to other sugar-nucleotide pyrophosphorylases, and they evolved from a common ancestor.


Metformin: effects on cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus.
Non-insulin-dependent diabetes mellitus (NIDDM) affects approximately 12 million people in the United States. NIDDM is frequently found to coexist with other conditions, such as obesity, dyslipidemia, atherosclerotic vascular disease, and hypertension, which contribute to morbidity and mortality. Although the major clinical objective in the management of NIDDM is to control hyperglycemia, the long-term objective is to prevent microvascular and macrovascular complications. Cardiovascular disease is the major cause of death in NIDDM patients. Although hyperglycemia may be adequately controlled, risk factors for coronary heart disease may remain unchanged. Treatment with metformin controls hyperglycemia and may have positive effects on cardiovascular risk factors. When used alone or in combination with sulfonylureas, metformin tends to stabilize or decrease weight, maintains or reduces insulin levels, has beneficial effects on plasma lipid profiles, and may also have beneficial effects on blood pressure and the fibrinolytic system.


On-off affinity binding modulation on thermoresponsive polymer-grafted surfaces for capture and release of proteins and cells.
This review describes new types of thermoresponsive surfaces modified with biologically active ligands to thermally modulate on-off affinity binding between ligands and receptors. To achieve the thermal regulation of affinity binding, molecules of thermoresponsive polymer poly(N-isopropylacrylamide) (PIPAAm) are typically used to tune the degree of steric hindrance in response to temperature. The coil-to-globule transition of surface-grafted PIPAAm chains induces dynamic changes in the degree of steric hindrance in the vicinity of the immobilized ligand, resulting in the thermoresponsive modulation of on-off affinity interactions with receptors, and the subsequent on-off switching of the capture and release of proteins and cells on the surface. Thermoresponsive biomaterial surfaces to modulate on-off affinity binding between ligands and receptors has potential to realize the creation of functional cell sheet-based tissues, as well as novel separation system of specific proteins and cells without any labeling. These materials will thus be beneficial for clinical use in cell-based therapies, including tissue engineering and regenerative medicine.


"To B or not to B?" B-cells and graft rejection.
There is increasing evidence that various maturational stages of B-cells infiltrate various solid organ transplants undergoing acute rejection. The presence of immature CD20 and mature CD138 plasma cells associate with more aggressive and steroid-recalcitrant graft rejection and portend poor graft outcomes. Though associative, the causal role of B-cells in graft rejection remains to be better understood. This review discusses the possible roles of B-cells in graft rejection, whether involved as antigen presenting, as indirect effector, or antibody producing cells.