Insulin-like growth factors stimulate chemotaxis in human melanoma cells.
Insulin and insulin-like growth factors stimulate motility in the highly metastatic human melanoma cell line, A2058. Insulin-like growth factor-I (IGF-I) is the most potent with a maximal response at a concentration of 10 nM compared to the activities of insulin and insulin-like growth factor-II (IGF-II) which peak at 300-400 nM. Using checkerboard analysis, the responses to IGF-I and insulin are predominantly chemotactic, although insulin had a significant chemokinetic component. Pertussis toxin does not inhibit the response to any of these polypeptides. However, in previous studies, it was shown that the motile response to autocrine motility factor from these same A2058 cells was markedly inhibited by pertussis toxin. 125I-labelled IGF-I binds saturably and specifically to the A2058 cells. Scatchard analysis indicates a high binding affinity (Kd approximately 3 x 10(-10) M) and an estimated 5000 receptors/cell. These studies indicate that in addition to their mitogenic properties, certain growth factors may profoundly enhance metastasis of tumor cells by their ability to induce motility.


Paper spray-atmospheric pressure photoionization-high resolution mass spectrometry for the direct analysis of neutral fluorinated compounds in waterproof impregnation sprays.
In this work, paper spray (PS) is combined with atmospheric pressure photoionization-mass spectrometry (PS-APPI-MS) for the determination of non-polar and low polar compounds, such as the neutral per- and polyfluorinated alkyl substances (PFAS). The proposed PS-APPI-MS method has been developed for the analysis of fluorotelomer alcohols (FTOHs), fluoroctanesulfonamides (FOSAs) and fluorooctane sulfonamido-ethanols (FOSEs), using both negative ion mode and high-resolution mass spectrometry (HRMS). The most critical working parameters (i.e., UV-krypton lamp position, sample drying time, spray dopant solvent and spray voltage) have been evaluated to study both the ionization behaviour and ionization efficiency. The best results were achieved using dopant-assisted PS-APPI-HRMS with toluene as dopant solvent. The most intense ions observed in the mass spectra, [M‒H]‒ for FOSAs and [M+O2]‒• for FTOHs and FOSEs, were selected and proposed for fast screening and quantitative analysis of target compounds in waterproof impregnation sprays samples using internal standard calibration method and being able to detect down to μg L-1 levels. The satisfactory values of the method quality parameters (detection capability, repeatability, trueness and linearity) demonstrated the good performance of the PS-APPI-HRMS method and allowed the identification and quantitation of some FTOHs (6:2 FTOH, 7-Me-6:2 FTOH, 8:2 FTOH, 10:2 FTOH) and N-MeFOSE at mg L-1 in some of the waterproof impregnation spray products analyzed. This low-cost PS-APPI-HRMS method allows a fast screening, with minimum sample preparation, of non-polar and low polar compounds simultaneously, which can significantly improve the throughput on routine laboratories.


[Patient care pathway and securing immunoglobulin supplies in primary immunodeficiency: Results of a pilot study].
Securing the supply of immunoglobulins is essential in indications without therapeutic alternatives, such as primary immunodeficiencies (PIDs). The objective was to obtain an inventory of patients with PID, and to quantify their immunoglobulin needs. The retrospective study was conducted using data from January to June 2018, in Bordeaux, Lyon and Paris (Saint-Louis). Patients with PID were included based on the pharmaceutical traceability of the 3 centres. The concordance between the patients included and the patients in the CEREDIH register was analysed. For the 361 patients included (sex ratio: M/F 0.8; mean age: 45±20years, mean weight: 62±19kg), 2082 dispensations were performed for a total volume of 57kg of immunoglobulins. Of the 108 specialty changes identified, 68% were due to supply tensions. In total, the analysis of CEREDIH data made it possible to identify 727 patients with PID and followed up once in the study centres, 161 of whom were recorded in the 2 data follow-ups (patients included and CEREDIH). A complete overview of immunoglobulin needs in PIDs is difficult to obtain. Supply tensions have been observed although PIDs are a priority indication. Measures must be proposed to ensure an adequate supply regardless of the location of patients in the territory.


Unwillingness to participate in colorectal cancer screening: examining fears, attitudes, and medical mistrust in an ethnically diverse sample of adults 50 years and older.
Identify the influence of medical mistrust, fears, attitudes, and sociodemographic characteristics on unwillingness to participate in colorectal cancer (CRC) screening. Cross-sectional, disproportionally allocated, stratified, random-digit-dial telephone questionnaire of noninstitutionalized households. New York City, New York; Baltimore, Maryland; San Juan, Puerto Rico. Ethnically diverse sample of 454 adults ≥50 years of age. Health status, cancer screening effectiveness, psychosocial factors (e.g., perceptions of pain, fear, trust), and CRC screening intentions using the Cancer Screening Questionnaire, which addresses a range of issues related to willingness of minorities to participate in cancer screening. Multivariate logistic regression was used to model the probability of reporting unwillingness to participate in CRC screening. Fear of embarrassment during screening (odds ratio [OR] = 10.72; 95% confidence interval [CI], 2.15-53.39), fear of getting AIDS (OR = 8.75; 95% CI, 2.48-30.86), fear that exam might be painful (OR = 3.43; 95% CI, 1.03-11.35), and older age (OR = 1.10; 95% CI, 1.04-1.17) were positively associated with unwillingness to participate in CRC screening. Fear of developing cancer (OR = .12; 95% CI, .03-.57) and medical mistrust (OR = .19; 95% CI, .06-.60) were negatively associated with unwillingness to screen. Findings suggest that CRC health initiatives should focus on increasing knowledge, addressing fears and mistrust, and normalizing CRC screening as a beneficial preventive practice, and should increase focus on older adults.


Pyramiding Fusarium head blight resistance QTL from T. aestivum, T. dicoccum and T. dicoccoides in durum wheat.
FHB resistance of durum wheat was improved by introgression of Fhb1 and resistance genes from emmer wheat and by selection against adverse alleles of elite durum wheat. Durum wheat is particularly susceptible to Fusarium head blight (FHB) and breeding for resistance is impeded by the low genetic variation within the elite gene pool. To extend the genetic basis for FHB resistance in durum wheat, we analyzed 603 durum wheat lines from crosses of elite durum wheat with resistance donors carrying resistance alleles derived from Triticum aestivum, T. dicoccum and T. dicoccoides. The lines were phenotyped for FHB resistance, anthesis date, and plant height in artificially inoculated disease nurseries over 5 years. A broad variation was found for all traits, while anthesis date and plant height strongly influenced FHB severities. To correct for spurious associations, we adjusted FHB scorings for temperature fluctuations during the anthesis period and included plant height as a covariate in the analysis. This resulted in the detection of seven quantitative trait loci (QTL) affecting FHB severities. The hexaploid wheat-derived Fhb1 QTL was most significant on reducing FHB severities, highlighting its successful introgression into several durum wheat backgrounds. For two QTL on chromosomes 1B and 2B, the resistance alleles originated from the T. dicoccum line Td161 and T. dicoccoides accessions Mt. Hermon#22 and Mt. Gerizim#36, respectively. The other four QTL featured unfavorable alleles derived from elite durum wheat that increased FHB severities, with a particularly negative effect on chromosome 6A that simultaneously affected plant height and anthesis date. Therefore, in addition to pyramiding resistance genes, selecting against adverse alleles present in elite durum wheat could be a promising avenue in breeding FHB-resistant durum wheat.


Immune system paralysis by anthrax lethal toxin: the roles of innate and adaptive immunity.
Since the deliberate use of anthrax as a bioweapon in the USA in 2001, an enormous amount of attention has been focused on the biology of Bacillus anthracis, the causative bacterium of anthrax. Fatal systemic anthrax involves massive bacteraemia and toxaemia with non-descript early symptoms until the onset of shock and sudden death. The outbreak of fatal symptoms after the incubation period of B anthracis suggests an impairment of the host immune system against this pathogen. Thus, it is likely that B anthracis will possess certain strategies to escape from the host immune system. However, the mechanisms of such immune-evasion strategies are not fully characterised yet. Given the critical role of B anthracis toxins in anthrax pathogenesis, much effort has been made to understand the pathological nature of the toxins. Recent studies have shown the pleiotropic actions of anthrax lethal toxin on host innate immune cells, and that several effects of anthrax lethal toxin may directly account for the mechanism of immune intervention by B anthracis.


The COVID-19 Sentinel Schools Network of Catalonia (CSSNC) project: Associated factors to prevalence and incidence of SARS-CoV-2 infection in educational settings during the 2020-2021 academic year.
The Sentinel Schools project was designed to monitor and evaluate the epidemiology of COVID-19 in Catalonia, gathering evidence for health and education policies to inform the development of health protocols and public health interventions to control of SARS-CoV-2 infection in schools. The aim of this study was to estimate the prevalence and incidence of SARS-CoV-2 infections and to identify their determinants among students and staff during February to June in the academic year 2020-2021. We performed two complementary studies, a cross-sectional and a longitudinal component, using a questionnaire to collect nominal data and testing for SARS-CoV-2 detection. We describe the results and perform a univariate and multivariate analysis. The initial crude seroprevalence was 14.8% (95% CI: 13.1-16.5) and 22% (95% CI: 18.3-25.8) for students and staff respectively, and the active infection prevalence was 0.7% (95% CI: 0.3-1) and 1.1% (95% CI: 0.1-2). The overall incidence for persons at risk was 2.73 per 100 person-month and 2.89 and 2.34 per 100 person-month for students and staff, respectively. Socioeconomic, self-reported knowledge, risk perceptions and contact pattern variables were positively associated with the outcome while sanitary measure compliance was negatively associated, the same significance trend was observed in multivariate analysis. In the longitudinal component, epidemiological close contact with SARS-CoV-2 infection was a risk factor for SARS-CoV-2 infection while the highest socioeconomic status level was protective as was compliance with sanitary measures. The small number of active cases detected in these schools suggests a low transmission among children in school and the efficacy of public health measures implemented, at least in the epidemiological scenario of the study period. The major contribution of this study was to provide results and evidence that help analyze the transmission dynamic of SARS-CoV-2 and evaluate the associations between sanitary protocols implemented, and measures to avoid SARS-CoV-2 spread in schools.


808 nm wavelength light induces a dose-dependent alteration in microglial polarization and resultant microglial induced neurite growth.
Despite the success of using photobiomodulation (PBM), also known as low level light therapy, in promoting recovery after central nervous system (CNS) injury, the effect of PBM on microglia, the primary mediators of immune and inflammatory response in the CNS, remains unclear. Microglia exhibit a spectrum of responses to injury, with partial or full polarization into pro- and anti-inflammatory phenotypes. Pro-inflammatory (M1 or classically activated) microglia contribute to chronic inflammation and neuronal toxicity, while anti-inflammatory (M2 or alternatively activated) microglia play a role in wound healing and tissue repair; microglia can fall anywhere along this spectrum in response to stimulation. The effect of PBM on microglial polarization therefore was investigated using colorimetric assays, immunocytochemistry, proteomic profiling and RT-PCR in vitro after exposure of primary microglia or BV2 microglial cell line to PBM of differing energy densities (0.2, 4, 10, and 30 J/cm(2) , 808 nm wavelength, 50 mW output power). PBM has a dose-dependent effect on the spectrum of microglial M1 and M2 polarization. Specifically, PBM with energy densities between 4 and 30 J/cm(2) induced expression of M1 markers in microglia. Markers of the M2 phenotype, including CD206 and TIMP1, were observed at lower energy densities of 0.2-10 J/cm(2) . In addition, co-culture of PBM or control-treated microglia with primary neuronal cultures demonstrated a dose-dependent effect of PBM on microglial-induced neuronal growth and neurite extension. These data suggest that the Arndt-Schulz law as applied to PBM for a specific bioassay does not hold true in cells with a spectrum of responses, and that PBM can alter microglial phenotype across this spectrum in a dose-dependent manner. These data are therefore of important relevance to not only therapies in the CNS but also to understanding of PBM effects and mechanisms.


Effect of acid concentration and pulp properties on hydrolysis reactions of mercerized sisal.
The influence of sulfuric acid concentration (H2SO4 5-25%, 100°C), crystallinity and fibers size on the hydrolysis reaction of sisal pulps were investigated, with the goal of evaluating both the liquor composition, as an important step in the production of bioethanol, and the residual non-hydrolyzed pulp, to determine its potential application as materials. Aliquots were withdrawn from the reaction media, and the liquor composition was analyzed by HPLC. The residual non-hydrolyzed pulps were characterized by SEM, their average molar mass and crystallinity index, and their size distribution was determined using a fiber analyzer. Sulfuric acid 25% led to the highest glucose content (approximately 10gL(-1)), and this acid concentration was chosen to evaluate the influence of both the fiber size and crystallinity of the starting pulp on hydrolysis. The results showed that fibers with higher length and lower crystallinity favored glucose production in approximately 12%, with respect to the highly crystalline shorter fibers.


The 9th European Conference on Marine Natural Products.
The 9th European Conference on Marine Natural Products (ECMNP) in Glasgow follows its predecessors in La Toja (2013), Tjärnö (2011), Porto (2009), Ischia (2007), Paris (2005), Elmau (2002), Santiago de Compostela (1999), and Athens (1997). [...].


Immunolocalization of lipid peroxidation/advanced glycation end products in amyloid A amyloidosis.
Chronic inflammation, superimposed by amyloid fibril deposition, is believed to trigger the cascade of oxidative stress response in the affected organs and tissues. We examined immunohistochemically the distribution of 4-hydroxy-2-nonenal (HNE) and N(epsilon)-(carboxymethyl)lysine (CML), markers of lipid peroxidation and advance glycation end products (AGE), respectively, in spleen sections and peritoneal macrophages (MPhi) from mice before and during AA amyloidosis. With time, both HNE and CML immunoreactivities increased significantly in MPhi and splenic reticuloendothelial cells, known to be associated with the clearance of serum amyloid A, the precursor of AA fibrils. HNE and CML were localized to the plasma membrane and the cytoplasmic compartment of MPhi and HNE only at the nuclear membrane. These markers were also colocalized bound to AA fibrils infiltrating the splenic sinus walls. Our results reinforce the notion that oxidative stress is an integral component of amyloidotic tissues. Both lipid peroxidation and AGE have been implicated in protein modification and amyloid fibril formation. The significance of HNE and CML associated with the monocytoid cells and implicated in SAA clearance and AA fibril formation, is discussed with the pathogenesis of AA fibrils.


Associations among negative life events, changes in cortico-limbic connectivity, and psychopathology in the ABCD Study.
Adversity exposure is a risk factor for psychopathology, which most frequently onsets during adolescence, and prior research has demonstrated that alterations in cortico-limbic connectivity may account in part for this association. In a sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study (N = 4006), we tested a longitudinal structural equation model to examine the indirect effect of adversity exposure (negative life events) on later psychopathology via changes in cortico-limbic resting-state functional connectivity (rsFC). We also examined the potential protective effects of parental acceptance. Generally, cortico-limbic connectivity became more strongly negative between baseline and year 2 follow-up, suggesting that stronger negative correlations within these cortico-limbic networks may reflect a more mature phenotype. Exposure to a greater number of negative life events was associated with stronger negative cortico-limbic rsFC which, in turn, was associated with lower internalizing (but not externalizing) symptoms. The indirect effect of negative life events on internalizing symptoms via cortico-limbic rsFC was significant. Parental acceptance did not moderate the association between negative life events and rsFC. Our findings highlight how stressful childhood experiences may accelerate neurobiological maturation in specific cortico-limbic connections, potentially reflecting an adaptive process that protects against internalizing problems in the context of adversity.


Morphometric analysis of the gonadal veins in human foetuses.
Professional literature data demonstrates morphometric features of the gonadal veins in adults. The length of the gonadal veins and their outlet angles in 130 human foetuses (71 males, 59 females), between the 4th and 6th month of prenatal life, were studied by means of anatomical, digital and statistical methods. In all specimens the left gonadal veins entered the left renal artery, and the right gonadal veins terminated in the inferior vena cava. In all age ranges the left gonadal veins were longer than the right ones (P < or = 0.01), and the outlet angles of the left gonadal veins were larger than these angles on the right side (P < or = 0.01). The correlation coefficient between the length of the left and right testicular veins was r1 = 0.975 (P < or = 0.01). The correlation coefficients between the length of the testicular veins and foetal age were r2 = 0.591 for the right testicular vein and r3 = 0.578 for the left testicular vein (P < or = 0.01). A low correlation between the outlet angles of the testicular veins and foetal age was observed, for the right side r4 = 0.187, and for the left side r5 = 0.177 (P < or = 0.05). The correlation coefficient between the length of the left and right ovarian veins in foetuses aged 4-6 months was r6 = 0.855 (P < or = 0.01). The correlation coefficients between the length of the ovarian veins and foetal age were r7 = 0.578 for the right ovarian vein and r8 = 0.566 for the left ovarian vein (P < or = 0.01). No correlation between the outlet angles of the ovarian veins and foetal age was observed (P > 0.05).


The immunosuppressive potency of various steroids on peripheral blood lymphocytes, T cells, NK and K cells.
The immunosuppressive effect of natural and synthetic steroids was tested in vitro on phytohemagglutinin (PHA) stimulated T lymphocytes and peripheral blood lymphocytes (PBL), as well as on NK and K cell activity. Three groups of steroids, significantly different in their immunosuppressive activity, were identified. Fluorohydrocortisone, and methylprednisolone were highly potent in suppressing PHA stimulation of T lymphocytes and PBL. Hydrocortisone was of intermediate potency, whereas cortisone, dihydrocortisol, and tetrahydrocortisol were of low potency. T lymphocytes were more sensitive to the suppressive effect of fluorohydrocortisone and methylprednisolone than were PBL cultures. NK and K cell activity was suppressed only by the high potency synthetic steroids and even then the suppression of K cell activity was not significant except at high in vitro steroid concentrations. The present findings support the conception that different lymphocyte subpopulations have different susceptibility to the effect of highly potent steroids. Thus, lymphocyte heterogeneity must be taken into account when the immunosuppressive potencies of different glucocorticoids are studied. Furthermore, the findings in different lymphocyte populations ranked the relative in vitro immunosuppressive potency of glucocorticoids different from the relative anti-inflammatory potencies reported in the literature.


Testing the impact of renewable energy and oil price on carbon emission intensity in China's transportation sector.
As the largest carbon emitter in the world, with its transportation sector contributing the largest shares of its emission, the need for a low-carbon transition economy has become a policy agenda for China because in order to reach carbon neutrality by 2050, lowering the intensity of carbon emissions in the transportation sector will be crucial. In this regard, we used the "bootstrap autoregressive distributed lag model" to explore the impact of clean energy and oil prices on the intensity of carbon emissions in China's transportation sector. The study found that an increase in oil prices decreases the intensity of carbon emissions in the short and long run. Similarly, an increase in the level of renewable energy and economic complexity declines the intensity of carbon emissions in the transportation sector. On the contrary, the research demonstrates that non-renewable energy contributes positively to carbon emission intensity. Therefore, the authorities must promote green technology to neutralize the transportation system's detrimental effects on China's environmental quality. The implications for successfully promoting carbon emission intensity mitigation in the transportation sector are examined in the conclusion.


Prevalence and phenomenology of neonaticide in Switzerland 1980-2010: a retrospective study.
For a child, the likelihood of being murdered is highest during the first year of life, and many such cases are neonaticides. Although several recent studies have examined neonaticide in different countries and cultures, there has been no in-depth analysis of Swiss cases, even though this country has special neonaticide legislation and four "baby hatches" have been opened to prevent such killings. The primary objective of this retrospective study was to analyze the prevalence and phenomenon of neonaticide in Switzerland. Using data from judicial files, 11 cases were identified in 15 German-speaking cantons between 1980 and 2010. The sample included two uncommon cases of nonmaternal neonaticide. The discussion addresses possible prevention strategies.


A meta-analysis: to compare the clinical results between gastric bypass and sleeve gastrectomy for the obese patients.
We attempted to compare the effects of two kinds of surgery for obesity: laparoscopic gastric bypass (LGB) and laparoscopic sleeve gastrectomy (LSG). We performed an electronic literature search of published articles relating to obesity surgery since inception to July 2012, in which LGB was compared with LSG for patients with a body mass index (BMI) >30, and eight studies were finally selected. We recorded a benefit of LGB on the change of BMI (OR = 1.84, 95 % CI = 0.50-3.18). Besides, we found that the homeostasis model assessment was lower after LGB than LSG (OR = -0.83, 95 % CI = -1.43 to -0.22), the total cholesterol was also lower (OR = -17.43, 95 % CI = -34.72 to -0.14), and the high-density lipoprotein cholesterol was higher in the LGB group (OR = 3.27, 95 % CI = 0.48-6.06). Based on these findings, LGB could have a better effect compared with LSG.


Characteristics of families of soldiers who return prematurely from overseas deployments: an assessment from Operation Restore Hope (Somalia).
Nearly 500 wives, married to enlisted soldiers who deployed to Somalia for Operation Restore Hope, participated in a postdeployment study in the summer of 1993. About 10% of their husbands had returned early from Somalia for family reasons. Analysis of their wives' reports suggests that early returns were associated most often with childbirth or problematic pregnancies rather than other factors such as inexperience with deployments, negative attitudes towards the military, a lack of support services, or lower coping abilities. However, in hindsight, our results probably reflect compliance with military policy at that time for that deployment, under which pregnancy-related concerns were one of the most legitimate reasons for permitting an early return. The results support sociological theories that highlight the importance of macrosocial factors in influencing the lives of individual families somewhat independently of the microsocial environment of the families.


The role of family meals in the treatment of eating disorders: a scoping review of the literature and implications.
Family meal research is a fast growing field that has significant implications for the prevention and treatment of eating disorders (ED). Using a scoping review procedure, this article overviewed major historical and clinical trends that have guided the use of family meals or lunch sessions in adolescent ED family therapy over the past 40 years, and synthesized essential findings from current therapeutic family meal research. The relevant body of literature is reported within the framework of three models of family therapy (Maudsley model, family-based treatment, multi-family therapy), with a focus on their specific use of family lunch sessions and related empirical evidence. Although promising, current evidence remains contradictory, tentative and colored by therapists' convictions, resistance and fears. Future research priorities are discussed, including the need for a more direct examination of the impact of the family meal practice on therapeutic change, as well as a better understanding of its active ingredients and of the characteristics of patients/families that may benefit most from it. This review of the literature may help clinicians and family therapists (1) adhere more reliably and confidently to ED-focused treatment protocols that include a strong family meal component, and (2) make more informed decisions regarding the inclusion or exclusion of family meals in their practice. When feasibility or acceptability issues preclude their use, alternatives to family meals are also discussed, including family meal role-plays and drawings, coaching of home-based family meals and manual/DVD-based guidance.


Disparities in Latino substance use, service use, and treatment: implications for culturally and evidence-based interventions under health care reform.
The goal of this systematic literature review was to enhance understanding of substance use, service use, and treatment among Latino subgroups to improve access to care and treatment outcomes in an era of health care reform. The authors used 13 electronic databases and manually searched the literature from January 1, 1978, to May 30, 2013. One hundred (69%) of 145 primary research articles met the inclusion criteria. Two blinded, independent reviewers scored each article. Consensus discussions and a content expert reconciled discrepancies. Current rates of alcohol and substance abuse among Latinos are comparable to or surpass other U.S. ethnic groups. Disparities in access and quality of care are evident between Latinos and other ethnic groups. As a heterogeneous group, Latinos vary by geographic region in terms of substance of choice and their cultural identity takes precedence over general ethnic identity as a likely determinant of substance abuse behaviors. There is growing research interest in systems influencing treatment access and adherence among racial/ethnic and gender minority groups. However, studies on Latinos' service use and immediate treatment outcomes have been both limited in number and inconsistent in findings. This review identified human capital, quality of care, and access to culturally responsive care as key strategies to eliminate disparities in health and treatment quality. Implications are discussed, including the need for effectiveness studies on Latinos served by systems of care that, under health care reform, are seeking to maximize resources, improve outcomes, and reduce variation in quality of care.


Agricultural pesticide accidents and prevention in Ecuador.
Accidents due to the misuse and abuse of agricultural pesticides is a worldwide problem. Although data gaps exist, there is an ever-growing body of information on the incidence and nature of pesticide-caused poisonings in the developing countries of the world. The information gathered in a field study in Ecuador, South America, among rural-based users of pesticides contributes to the understanding of the problem. Factors that contribute to accidental poisonings are detailed and described and are related to accident prevention efforts.


Endogenous Delta/Theta Sound-Brain Phase Entrainment Accelerates the Buildup of Auditory Streaming.
In many natural listening situations, meaningful sounds (e.g., speech) fluctuate in slow rhythms among other sounds. When a slow rhythmic auditory stream is selectively attended, endogenous delta (1‒4 Hz) oscillations in auditory cortex may shift their timing so that higher-excitability neuronal phases become aligned with salient events in that stream [1, 2]. As a consequence of this stream-brain phase entrainment [3], these events are processed and perceived more readily than temporally non-overlapping events [4-11], essentially enhancing the neural segregation between the attended stream and temporally noncoherent streams [12]. Stream-brain phase entrainment is robust to acoustic interference [13-20] provided that target stream-evoked rhythmic activity can be segregated from noncoherent activity evoked by other sounds [21], a process that usually builds up over time [22-27]. However, it has remained unclear whether stream-brain phase entrainment functionally contributes to this buildup of rhythmic streams or whether it is merely an epiphenomenon of it. Here, we addressed this issue directly by experimentally manipulating endogenous stream-brain phase entrainment in human auditory cortex with non-invasive transcranial alternating current stimulation (TACS) [28-30]. We assessed the consequences of these manipulations on the perceptual buildup of the target stream (the time required to recognize its presence in a noisy background), using behavioral measures in 20 healthy listeners performing a naturalistic listening task. Experimentally induced cyclic 4-Hz variations in stream-brain phase entrainment reliably caused a cyclic 4-Hz pattern in perceptual buildup time. Our findings demonstrate that strong endogenous delta/theta stream-brain phase entrainment accelerates the perceptual emergence of task-relevant rhythmic streams in noisy environments.


Surface properties of binary mixtures of some pulmonary surfactant components.
The dynamic surface pressure-area properties of pure and binary mixed films of rac-1,2-dipalmitoyl-glycero-3-phosphocholine, 1,2-diocoyl-sn-glycero-3-phosphocholine and cholesterol were investigated at 23 degrees C and 37 degrees C. The pure films and binary mixtures of rac-1,2-dipalmitoyl-glycero-3-phosphocholine: 1,2-dioeoyl-sn-glycero-3-phosphocholine and rac-1,2-dipalmitoyl-glycero-3-phosphocholine:cholesterol were characterized both for dilute surface initial concentrations of 150 Angstrom 2/molecule and for surface excess initial values of 15-50 Angstrom 2/molecule. The results show that the addition of 1,2-dioeoyl-sn-glycero-3-phosphocholine or cholesterol in a binary film with rac-1,2 dipalmitoyl-glycero-3-phosphocholine acts to improve the surface reentry and respreading properties over those of pure rac-1,2-dipalmitoyl-glycero-3-phosphocholine films upon dynamic compression past collapse. This effect is even more pronounced at 37 degrees C than at 23 degrees C, as demonstrated by the application of a collapse plateau ratio criterion. The enhanced dynamic respreading correlates with the effect of 1,2-dioleoyl-sn-glycero-3-phosphocholine and cholesterol in decreasing the gel to liquid crystal transition temperature of rac-1,2-dipalmitoyl-glycero-3-phosphocholine water dispersons, as well as with their facilitation of post-collapse dynamic surface pressure relaxation in binary films with rac-1,2-dipalmitoyl-glycero-3-phosphocholine.


Short- and Long-Term Intestinal Complications After Combined Pancreas-Kidney Transplantation.
Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice in patients with type 1 diabetes and end-stage renal disease, because it improves survival and quality of life. Currently, enteric exocrine drainage is the most commonly used method. Intestinal complications continue to be a major cause of posttransplant morbidity despite improvements in surgical technique. This study analyzed early and late intestinal complications related to SPK transplantation. We performed a retrospective analysis of 100 adult patients undergoing SPK transplantation between January 2009 and December 2019. We performed systemic venous drainage and exocrine enteric drainage with duodenojejunostomy. Statistical analysis was performed using SPSS v2. This study was performed in accordance with the Declaration of Istanbul and the 1964 Declaration of Helsinki. Informed consent was obtained from all participants involved in the study. Intestinal complications were reported in 18 patients. Ten patients (10%) had the following early intestinal complications including: ileus (n = 4), intestinal obstruction (n = 2), graft volvulus (n = 1), duodenal graft fistula (n = 1), and jejunal fistula after pancreas transplantation (n = 1). Two cases required relaparotomy: graft repositioning with Roux-en-Y conversion (n = 1) and Y-roux conversion (n = 1). Eight patients had repeated episodes of intestinal obstruction (8%), of whom 2 required surgery for resolution with 100% postoperative mortality. SPK transplantation with enteric drainage via duodenojejunostomy has a low rate of short- and long-term postoperative intestinal complications. Surgery in patients with recurrent intestinal obstruction has a high mortality risk and should be performed in reference transplant centers.


Parity Violation Energy of Biomolecules - V: Protein Metal Centers.
The parity-violation difference between mirror images of chiral metal centers found in naturally occurring proteins and enzymes is computed at the Dirac-Hartree-Fock level, for both equilibrium and transition state configurations. The systems, selected on the likelihood of yielding high parity violation energies based on atomic mass and coordination geometry, are extracted from: type I Blue Copper Protein active site, Zn and Cd Carbon Anhydrase, Ni Acetyl-Coenzyme-A Synthase, and Mo based CO-Dehydrogenase. Our values provide an approximate upper limit to possible parity-violation effects in biological systems based on static effects.


Distribution and Co-localization of endosome markers in cells.
Clathrin mediated endocytosis is one pathway for internalization of extracellular nano materials into cells [1, 2]. In this pathway, proteins attached to receptors and the internalized materials are encapsulated in clathrin coated membrane vesicles that subsequently fuse with or transform into intracellular compartments (early and late endosomes) as their contents are being directed to the lysosomes for degradation. The following proteins are commonly used to mark the pathway at various stages: Rab5 (early endosome), Rab7 (late endosome), and LAMP-1 (lysosome). In this work, we studied the distribution and co-localization of these marker proteins in two cell lines (C2C12 and A549) to determine whether these markers are unique for specific endosome types or whether they can co-exist with other markers. We estimate the densities and sizes of the endosomes containing the three markers, as well as the number of marker antibodies attached to each endosome. We determine that the markers are not unique to one endosome type but that the extent of co-localization is different for the two cell types. In fact, we find endosomes that contain all three markers simultaneously. Our results suggest that the use of these proteins as specific markers for specific endosome types should be reevaluated. This was the first successful use of triple image cross correlation spectroscopy to qualitatively and quantitatively study the extent of interaction among three different species in cells and also the first experimental study of three-way interactions of clathrin mediated endocytic markers.


Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.
Interactions between RNA molecules and proteins are critical to many cellular processes and are implicated in various diseases. The RNA-peptide complexes are good model systems to probe the recognition mechanism of RNA by proteins. In this work, we report studies on the binding-unbinding process of a helical peptide from a viral RNA element using nonequilibrium molecular dynamics simulations. We explored the existence of various dissociation pathways with distinct free-energy profiles that reveal metastable states and distinct barriers to peptide dissociation. We also report the free-energy differences for each of the four pathways to be 96.47 ± 12.63, 96.1 ± 10.95, 91.83 ± 9.81, and 92 ± 11.32 kcal/mol. Based on the free-energy analysis, we further propose the preferred pathway and the mechanism of peptide dissociation. The preferred pathway is characterized by the formation of sequential hydrogen-bonding and salt-bridging interactions between several key arginine amino acids and the viral RNA nucleotides. Specifically, we identified one arginine amino acid (R8) of the peptide to play a significant role in the recognition mechanism of the peptide by the viral RNA molecule.


Disproportionating enzyme (4-alpha-glucanotransferase; EC 220.127.116.11) of potato. Purification, molecular cloning, and potential role in starch metabolism.
Disproportionating enzyme (D-enzyme, 4-alpha-glucanotransferase; EC 22.214.171.124) has been purified to homogeneity from potato tubers and its activity characterized. The enzyme catalyzes the transfer of maltooligosaccharides from one 1,4-alpha-D-glucan molecule to another, or to glucose. Maltooligosaccharides are effective donor molecules, but short chain amylose and amylopectin may also function as donors. Enzyme activity is not affected by inorganic phosphate, 3-phosphoglycerate, or hexose phosphates. A cDNA clone encoding the enzyme was isolated using oligonucleotide probes derived from partial peptide sequences of the purified enzyme. The identity of the cDNA clone was confirmed by expression in Escherichia coli resulting in D-enzyme activity. The amino acid sequence deduced from the cDNA shows significant homology with a 4-alpha-glucanotransferase from Streptococcus. The deduced sequence indicates the presence of an amino-terminal plastid transit peptide of 52 amino acid residues and a mature polypeptide of 524 residues. D-enzyme mRNA is present in leaves, stems, roots, and stolons but is most abundant in developing and mature tubers. The amount of mRNA in leaves increases in response to light and to sucrose added to the medium. These results are discussed in terms of the function of D-enzyme in potato starch metabolism.


Population genetics and phylogenetic relationships of beetles (Coleoptera: Histeridae and Staphylinidae) from the Sonoran Desert associated with rotting columnar cacti.
Dozens of arthropod species are known to feed and breed in the necrotic tissues (rots) of columnar cacti in the Sonoran Desert. Because the necrotic patches are ephemeral, the associated arthropods must continually disperse to new cacti and therefore the populations of any given species are expected to show very little local genetic differentiation. While this has been found to be true for the cactophilic Drosophila, the evolutionary histories and characteristics of other arthropods inhabiting the same necrotic patches, especially the beetles, have yet to be examined. Here we used nucleotide sequence data from segments of the mitochondrial 16S rRNA and cytochrome c oxidase subunit I (COI) genes to examine population structure and demographic history of three sympatric beetle species (Coleoptera: Histeridae and Staphylinidae) collected on senita cactus (Lophocereus schottii) from six widely-separated localities on the Baja California peninsula of northwestern Mexico. Two histerids, Iliotona beyeri and Carcinops gilensis, and an unidentified staphylinid, Belonuchus sp., showed little or no population structure over a broad geographic area on the peninsula, consistent with the prediction that these beetles should show high dispersal ability. Demographic tests revealed varying levels of historical population expansion among the beetle species analyzed, which are discussed in light of their ecologies and concurrent biogeographic events. Additionally, phylogenetic analyses of COI sequences in Carcinops collected on a variety of columnar cacti from both peninsular and mainland Mexico localities revealed several species-level partitions, including a putative undescribed peninsular species that occurred sympatrically with C. gilensis on senita.


Multiecho sequence for velocity imaging in inhomogeneous rf fields.
The unambiguous determination of velocities with spatial resolution in a multiecho PFG NMR sequence strongly depends on the homogeneity of the B1 field. This affects, in particular, the use of surface coils that bear considerable potential for on-line flow monitoring where a fast-imaging sequence can become vital. However, even with most rf coils dedicated for imaging applications, B1 inhomogeneities are sufficiently large to generate severe problems in performing velocity-imaging experiments. In this paper, the use of a combination of different phase cycles in Carr-Purcell sequences is discussed. The suggested phase cycling scheme tolerates large flip angle imperfections arising in inhomogeneous B1 fields, and thus allows acquisition of a maximum number of echoes within a pulse train. The performance of the velocity-imaging sequence is proven by using phantom samples developing known laminar flow patterns.


Effect on an Oral Nutritional Supplement with β-Hydroxy-β-methylbutyrate and Vitamin D on Morphofunctional Aspects, Body Composition, and Phase Angle in Malnourished Patients.
This is a retrospective study of data from clinical practice to observe the effect of a high-calorie, high-protein oral nutritional supplement (ONS) with β-hydroxy-β-methylbutyrate (HMB) on nutritional status, body weight, and muscle-related parameters in 283 adult patients with or at risk of malnutrition under standard of care, 63% being cancer patients. They were recommended to increase physical activity and energy and protein intake from regular diet plus two servings per day of a specialized ONS enriched with HMB or standard ONS for up to 6 months. Dietary records, adherence and tolerance to ONS, nutritional status, body composition, handgrip strength, and blood analysis at the beginning and the end of the intervention were recorded. This program improved nutritional status from 100% malnourished or at risk of malnutrition at baseline to 80% well-nourished at final visit. It also increased body weight by 3.6-3.8 kg, fat-free mass by 0.9 to 1.3 kg, and handgrip strength by 4.7 to 6.2 kg. In a subgroup of patients (n = 43), phase angle (PhA), and body cell mass (BCM) increased only in the patients receiving the ONS enriched with HMB (0.95 (0.13) vs. -0.36 (0.4), and 2.98 (0.5) vs. -0.6 (1.5) kg, mean difference (SE) from baseline for PhA and BCM, respectively), suggesting the potential efficacy of this supplement on muscle health.


Chlordiazepoxide metabolite accumulation in liver disease.
Chlordiazepoxide 40mg daily was used to prevent delerium tremens in a 64-year-old female with alcoholic liver disease. After 20 days, the drug was stopped because of the onset of progressive drowsiness. The kinetics of chloridazepoxide were within the predicted range for patients with liver disease, but the elimination half-lives of desmethylchlordiazepoxide and demoxepam were greatly prolonged at 346 hours and 150 hours, respectively. It is suggested that metabolite accumulation may have contributed to the coma, which is an unusual reaction to chlordiazepoxide.


[Endobronchial administration of adrenaline in cardiopulmonary resuscitation: pharmacokinetic and dynamic studies in the dog].
The present animal study was designed to investigate the pharmacokinetic behavior of epinephrine after endobronchial (e.b.) and intravenous (i.v.) administration and its correlation to pharmacodynamic measurements. We found the effectiveness of e.b.-epinephrine (100 micrograms/kg BW) to be in the same magnitude as i.v.-epinephrine (100 micrograms/kg BW) with only a slight delay in the pharmacodynamic onset of a few seconds. The bioavailability of e.b.-administration of epinephrine was in the range of 80-85%. The therapeutic effect of e.b.-epinephrine (100 micrograms/kg BW) lasted much longer (30 min) when compared to i.v.-epinephrine (10 micrograms/kg BW) where the pharmacodynamic effect was terminated after 3 to 5 min. For the clinical situation of cardiopulmonary resuscitation a dose of 2-3 mg epinephrine in 5-10 ml of physiological saline instilled deeply into the bronchial system should be considered as alternative administration technique with fast onset and good effectiveness.


Front gardens to car parks: changes in garden permeability and effects on flood regulation.
This study addresses the consequences of widespread conversion of permeable front gardens to hard standing car parking surfaces, and the potential consequences in high-risk urban flooding hotspots, in the city of Southampton. The last two decades has seen a trend for domestic front gardens in urban areas to be converted for parking, driven by the lack of space and increased car ownership. Despite media and political attention, the effects of this change are unknown, but increased and more intense rainfall, potentially linked to climate change, could generate negative consequences as runoff from impermeable surfaces increases. Information is limited on garden permeability change, despite the consequences for ecosystem services, especially flood regulation. We focused on eight flooding hotspots identified by the local council as part of a wider urban flooding policy response. Aerial photographs from 1991, 2004 and 2011 were used to estimate changes in surface cover and to analyse permeability change within a digital surface model in a GIS environment. The 1, 30 and 100 year required attenuation storage volumes were estimated, which are the temporary storage required to reduce the peak flow rate given surface permeability. Within our study areas, impermeable cover in domestic front gardens increased by 22.47% over the 20-year study period (1991-2011) and required attenuation storage volumes increased by 26.23% on average. These increases suggest that a consequence of the conversion of gardens to parking areas will be a potential increase in flooding frequency and severity - a situation which is likely to occur in urban locations worldwide.


Preparation, characterization, and desalination study of polystyrene membrane integrated with zeolite using the electrospinning method.
The novel composite membranes of Styrofoam (polystyrene) integrated with natural zeolite particles were produced using the electrospinning method for desalination purposes. The product was then characterized using FTIR, XRD, and TGA. Subsequently, the effect of different zeolite concentrations, namely 0, 5, 10, 15, 20, and 30 wt.% on its morphological structure and effectiveness was determined. Desalination of artificial seawater was carried out using the gravitational filtration principle to confirm the membrane's capabilities, after which its performance was evaluated using 4 wt.% NaCl solution. The morphological analysis showed that the composite membrane obtained has a smooth surface with microdomains on a few parts, which indicates the presence of zeolite. The result showed that the product integrated with 30 wt.% zeolites had the best performance in the desalination of artificial seawater. This was determined by comparing the conductivity value of the seawater before and after the process. The conductivity led to an 82.63% decrease using 30 wt.% zeolites. The developed polystyrene membrane embedded with zeolite has good thermal stability, hence, it can be used for desalination.


Emerging Diagnostics and Therapeutics for Invasive Fungal Infections.
Recently, there have been significant advances in the diagnosis and management of invasive fungal infections. Compared with traditional fungal diagnostics, molecular assays promise improved sensitivity and specificity, the ability to test a range of samples (including noninvasive samples, ie, blood), the detection of genetic mutations associated with antifungal resistance, and the potential for a faster turnaround time. Antifungals in late-stage clinical development include agents with novel mechanisms of action (olorofim and fosmanogepix) and new members of existing classes with distinct advantages over existing antifungals in toxicity, drug-drug interactions, and dosing convenience (oteseconazole, opelconazole, rezafungin, ibrexafungerp, encochleated amphotericin B).


Horizontal cells of the pigeon retina.
Two types of horizontal cells are seen in Golgi-impregnated retinas of the pigeon. Type I horizontal cells are compact, "brush-shaped," and have an axon ending as an irregular spinous arborization. The majority of the dendrites terminate in the distal part of the outer plexiform layer (OPL) as clusters which contact cones, but some terminate as single expansions in the proximal part of the OPL. The axon terminal spines are found only in the distal part of the OPL and contact both rods and cones. Pigeon Type I horizontal cells are Cajal's "brush-shaped" cells, and their axon terminals resemble Cajal's "stellate" cells. Type II horizontal cells have irregular, wavy, multi-branched dendrites, appear horizontally flattened, and lack axons. The dendrites terminate in the proximal part of the OPL as isolated spines and contact only cones. The Type II horizontal cells of the pigeon have not been previously described in the avian retina.


Suppression of mouse miRNA-222-3p in response to Echinococcus multilocularis infection.
During Echinococcus multilocularis infection, serum miR-222-3p is dramatically downregulated, but its role is yet to be established. Here the expression of miR-222-3p in the spleen of infected mice was shown to be significantly decreased in response to parasite infection (p < 0.05). Using RAW264.7 macrophages, it was further demonstrated that E. multilocularis crude antigens significantly inhibited miR-222-3p expression (p < 0.01). In macrophages transfected with a miR-222-3p inhibitor, NO secretion was moderately decreased compared with the control (p < 0.05). Although all the pro- and anti-inflammatory cytokine genes tested kept constant in expression, four key genes involved in the LPS/TLR4 signaling pathway were significantly down- or up-regulated in transfected cells (p < 0.05), including CD14, TLR4, TICAM2 and AP-1. These results suggest that downregulated miR-222-3p is capable of modulating macrophage immune functions, possibly contributing to the pathogenesis during E. multilocularis infection.


Improvement of Ficin-Based Inhibitive Enzyme Assay for Toxic Metals Using Response Surface Methodology and Its Application for Near Real-Time Monitoring of Mercury in Marine Waters.
Potentially toxic metals pollution in the Straits of Malacca warrants the development of rapid, simple and sensitive assays. Enzyme-based assays are excellent preliminary screening tools with near real-time potential. The heavy-metal assay based on the protease ficin was optimized for mercury detection using response surface methodology. The inhibitive assay is based on ficin action on the substrate casein and residual casein is determined using the Coomassie dye-binding assay. Toxic metals strongly inhibit this hydrolysis. A central composite design (CCD) was utilized to optimize the detection of toxic metals. The results show a marked improvement for the concentration causing 50% inhibition (IC50) for mercury, silver and copper. Compared to one-factor-at-a-time (OFAT) optimization, RSM gave an improvement of IC50 (mg/L) from 0.060 (95% CI, 0.030-0.080) to 0.017 (95% CI, 0.016-0.019), from 0.098 (95% CI, 0.077-0.127) to 0.028 (95% CI, 0.022-0.037) and from 0.040 (95% CI, 0.035-0.045) to 0.023 (95% CI, 0.020-0.027), for mercury, silver and copper, respectively. A near-real time monitoring of mercury concentration in the Straits of Malacca at one location in Port Klang was carried out over a 4 h interval for a total of 24 h and validated by instrumental analysis, with the result revealing an absence of mercury pollution in the sampling site.


Whiplash injuries and the potential for mechanical instability.
Whiplash injury to the cervical spine is poorly understood. Symptoms often do not correlate to the clinical findings. It has been hypothesized that the long-term clinical symptoms associated with whiplash have their basis in mechanical derangement of the cervical spine caused at the time of trauma. Before such a hypothesis can be proven, one needs to document and quantify the soft tissue injuries of the cervical spine in whiplash. The purpose of the study was to quantify the mechanical changes that occur in the cervical spine specimen as a result of experimental whiplash trauma. Utilizing a whiplash trauma model, injuries to human cadaveric cervical spine specimens (C0-T1 or C0-C7) were produced by increasingly severe traumas. The flexibility tests determined the motion changes at each intervertebral level in response to 1.0 Nm pure flexion-extension moment. Parameters of range of motion (ROM) and neutral zone (NZ) were determined before and after each trauma. Significant flexibility increases first occurred in the lower cervical spine after 4.5-g rear-end (anteriorly directed) acceleration of the T1 vertebra. At this acceleration magnitude, extension ROM and NZ at C5-C6 increased (P < 0.05) by 98% and 160% respectively. There was also a tendency (P < 0. 1) for the extension NZ at C0-C1 and C6-C7 levels to increase after the 6.5-g acceleration by 52% and 241% respectively. There were no such tendencies for the ROM parameter. We have identified the threshold and sites of whiplash injury to the cervical spine. This information should help the clinician make more precise diagnoses in the case of whiplash trauma patients.


The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy.
Indoleamine 2,3-dioxygenase (IDO, also referred to as IDO1) has been demonstrated to be a normal endogenous mechanism of acquired peripheral immune tolerance in vivo. In the field of oncology, IDO expression and/or activity has been observed in several cancer types and has usually been associated with negative prognostic factors and worse outcome measures. This manuscript reviews current available data on the role of IDO in cancer and the current results obtained with IDO inhibition, both in animal models and in phase 1 and 2 clinical trials in humans. Preliminary results with IDO inhibitors, usually combined with other anti-cancer drugs, seem encouraging. Further studies are needed to clarify the conditions in which IDO inhibitors can be of value as an anti-cancer strategy. In addition, further research should address whether the expression of IDO in tissue or blood can be a marker to select patients who can benefit most from IDO inhibition.


Highly Regio- and Enantioselective Hydrosilylation of gem-Difluoroalkenes by Nickel Catalysis.
The synthesis of small organic molecules with a difluoromethylated stereocenter is particularly attractive in drug discovery. Herein, we have developed an efficient method for the direct generation of difluoromethylated stereocenters through Ni0 -catalyzed regio- and enantioselective hydrosilylation of gem-difluoroalkenes. The reaction also represents the enantioselective construction of carbon(sp3 )-silicon bonds with nickel catalysis, which provides an atom- and step-economical synthesis route of high-value optically active α-difluoromethylsilanes. This protocol features readily available starting materials and commercial chiral catalysis, broad substrates spanning a range of functional groups with high yield (up to 99 % yield) and excellent enantioselectivity (up to 96 % ee). The enantioenriched products undergo a variety of stereospecific transformations. Preliminary mechanistic studies were performed.


Nest-dwelling ectoparasites reduce antioxidant defences in females and nestlings of a passerine: a field experiment.
Ectoparasites may imply a cost in terms of oxidative stress provoked by inflammatory responses in hosts. Ectoparasites may also result in costs for nestlings and brooding females because of the direct loss of nutrients and reduced metabolic capacity resulting from parasite feeding activities. These responses may involve the production of reactive oxygen and nitrogen species that may induce oxidative damage in host tissues. Our goal was to examine the effect of ectoparasites in terms of oxidative stress for nestlings and adult females in a population of pied flycatchers Ficedula hypoleuca. We manipulated the entire nest ectoparasite community by reducing ectoparasite loads in some nests through a heating treatment and compared them with a control group of nests with natural loads. A marker of total antioxidant capacity (TAS) in plasma and total levels of glutathione (tGSH) in red blood cells as well as a marker of oxidative damage in plasma lipids (malondialdehyde; MDA) were assessed simultaneously. Levels of tGSH were higher in heat-treated nests than in controls for both females and nestlings. Higher TAS values were observed in females from heat-treated nests. In nestlings there was a negative correlation between TAS and MDA. Our study supports the hypothesis that ectoparasites expose cavity-nesting birds to an oxidative challenge. This could be paid for in the long term, ultimately compromising individual fitness.


Identification of a novel 7-cis-11-trans-lipoxin A4 generated by human neutrophils: total synthesis, spasmogenic activities and comparison with other geometric isomers of lipoxins A4 and B4.
Addition of (15S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15-HETE) and the ionophore A23187 (2.5 microM) to human neutrophils led to the formation of both lipoxin A4 and lipoxin B4 as well as a novel 5,6,15-trihydroxyeicosatetraenoic acid. The new compound was identified using an improved isolation and detection system and its basic structure was determined by physical methods. On the basis of biosynthetic considerations, geometric isomers of lipoxin A4 and lipoxin B4 were prepared by total synthesis. Comparison of these synthetic materials with the neutrophil-derived product showed that the new compound is (5S,6R,15S)-trihydroxy-9,11,13-trans-7-cis-eicosatetraenoic acid or the 7-cis-11-trans-isomer of LXA4 (7-cis-11-trans-LXA4). LXA4, 11-trans-LXA4, 7-cis-LXA4 and 7-cis-11-trans-LXA4 all evoked dose-dependent (0.1-10 microM) contractions of the guinea pig lung strip, whereas 6-cis-LXB4 and 6-cis-8-trans-LXB4 relaxed this preparation. LXA4 and 7-cis-LXA4 were approx. 10-times more potent than the compounds with 11-trans geometry. However, all four double-bond isomers of LXA4 caused contractions which, based upon pharmacological evidence, appeared to involve specific activation of the same site as cysteinyl-containing leukotrienes. In conclusion, 7-cis-11-trans-LXA4 was isolated and identified as a novel biologically active eicosanoid formed by human neutrophils.


Comparative evaluation of ATB Fungus 2 and Sensititre YeastOne panels for testing in vitro Candida antifungal susceptibility.
ATB Fungus 2 and SensititreYeastOne are commercial methods for antifungal susceptibility testing of yeasts. The agreement between these two methods was assessed with a total of 133 Candida strains (60 Candida albicans, 18 Candida dubliniensis, 29 Candida glabrata, and 26 Candida krusei). MIC endpoints were established after 24 h of incubation at 36-/+1 degrees C by each method. Intra-laboratory reproducibility of both methods was excellent (=or>99%). Overall agreement between ATB Fungus 2 and Sensititre YeastOne 3 MICs (within 2 dilutions) was 91.2-97.7% for amphotericin B, 5-fluorocytosine and itraconazole, and 82.7% for fluconazole. The categorical agreement when ATB Fungus 2 results were compared to those by SensititreYeastOne 3 was 93.2-98.5% for 5-fluorocytosine and amphotericin B, but lower for the triazoles (72.9-75.9%). This easy to perform method could be an alternative for routine use in the clinical microbiology laboratory for susceptibility testing of common Candida spp.


Do Surgeons Accurately Predict Level of Activity in Patients With Distal Radius Fractures?
One factor influencing the management of distal radius fractures is the functional status of the patient. The purpose of this study was to assess the agreement between patient and surgeon assessments of patient activity level in patients sustaining a distal radius fracture. Ninety-seven patients were included, with a mean age of 58.5 years (range, 18-92 years). Patients completed the International Physical Activity Questionnaire, a validated survey that provides a score of low, moderate, or high activity levels. Treating surgeons provided an independent assessment using the same scale. Agreement between patient and surgeon assessments was evaluated using a weighted kappa-statistic, with a secondary analysis using logistic regression models to assess odds of surgical treatment. Interrater agreement between surgeons and patients demonstrated only "fair" agreement, with a kappa-statistic of 0.33. Predictive models showed that surgeons accurately identified 73% of "high activity" patients but failed to correctly identify more than 41% of patients rated as "moderate activity" or "low activity." There was a correlation between surgical intervention and increasing physical activity status as assessed by the surgeon; however, the magnitude of this effect was unclear (odds ratio, 2.14; 95% confidence interval, 1.07-4.30). This relationship was no longer significant after adjusting for age, Charlson comorbidity index, and fracture class. There was no association between surgical intervention and physical activity status when using the status provided by the patient. Surgeon assessment of patient activity level does not have strong agreement with patients' independent assessment. Surgeons are most accurate at identifying "high activity level" patients but lack the ability to identify "moderate activity level" or "low activity level" patients. Recognition of surgeon assessment of patient activity level as flawed can stimulate improved dialog between patients and physicians, ultimately improving the shared decision-making process.


Electrocardiographic Changes in Children with Multisystem Inflammation Associated with COVID-19: Associated with Coronavirus Disease 2019.
To analyze findings and trends on serial electrocardiograms (ECGs) in multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease taken during the course of illness and at follow-up. We included all children presenting with MIS-C at a single center with 3 or more ECGs taken during the course of their illness. We measured ECG intervals (PR, QRSd, and QTc) and amplitudes (R-, S-, and T-waves) on each ECG and documented any arrhythmias and ST-segment changes. A majority of children (n = 42, 67%) showed ECG changes. The most common findings were low QRS amplitudes and transient T-wave inversion. ST changes were uncommon and included ST-segment elevation consistent with pericarditis in 1 child and acute coronary ischemia in 1 child. Arrhythmias were seen in 13 children (21%) but were benign with the exception of 1 child who was compromised by an atrial tachycardia requiring support with extracorporeal membrane oxygenation. No children were found to have high-grade atrioventricular block. MIS-C is associated with electrocardiographic changes over the course of the illness, with low amplitude ECGs on presentation, followed by transient T-wave inversion, particularly in the precordial leads. There was a low prevalence of ST-segment changes and tachyarrhythmias.


Vascular Integrity in the Pathogenesis of Brain Arteriovenous Malformation.
Brain arteriovenous malformation (bAVM) is an important cause of intracranial hemorrhage (ICH), particularly in the young population. ICH is the first clinical symptom in about 50 % of bAVM patients. The vessels in bAVM are fragile and prone to rupture, causing bleeding into the brain. About 30 % of unruptured and non-hemorrhagic bAVMs demonstrate microscopic evidence of hemosiderin in the vascular wall. In bAVM mouse models, vascular mural cell coverage is reduced in the AVM lesion, accompanied by vascular leakage and microhemorrhage. In this review, we discuss possible signaling pathways involved in abnormal vascular development in bAVM.


Retinal microvasculopathy in human immunodeficiency type 1 (HIV)-infected children.
To report two cases of retinal peripheral lesions in vertically HIV-infected children. Complete ophthalmological examinations were performed in both cases over a period of four years. We found retinal peripheral lesions in four eyes of two patients who were referred to us for routine examination. Both cases showed focal, segmental and white patches around the vessel wall in the far periphery and at the equator. These findings hardly changed after 3.5 and 2.5 years of follow-up, respectively. We suppose the cause of these lesions is an immune-mediated reaction. Even although there is a low incidence of retinal alterations in pediatric patients infected by HIV, we believe that complete and systematic ophthalmic examinations should be performed in these children.


On the topical problems of species in general and in relation to helminths.
In the light of the present knowledge of species, the author suggests to accept ten features of species and the general definition of species proposed by Zavadsky (1961, 1968), together with the definition by Mayr (1940) characterizing more concretely the species at the level of biparentally reproducing organisms. The definition by Timofeeff-Ressovsky et al. (1973) may be used for exclusively autogamous species of helminths. From the viewpoint of the species as a taxonomic unit, the paper presents proposals for establishment of a practical standard which would better suit the theoretical idea about the helminth species than it was the case till the present.


Expression of cyclooxygenase-2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro-inflammatory cytokines.
Cyclooxygenase-2 (COX-2) is involved in the biosynthesis of prostanoids in the course of inflammatory reactions. This isoenzyme is regulated at the transcription level and many cells express COX-2 upon challenge with lipopolysaccharide (LPS) or pro-inflammatory cytokines. Since hepatocytes respond to LPS and pro-inflammatory stimuli, we investigated the expression of COX-2 in foetal and adult hepatocytes upon challenge with these substances. COX-2 was expressed in foetal hepatocytes incubated with LPS, tumour necrosis factor-alpha and interleukin-1beta. This response rapidly decreased after birth and was absent in hepatocytes from animals aged 2 days or more and treated under identical conditions. The expression of COX-2 was determined at the mRNA, protein and enzyme activity levels using Northern and Western blot, and following the synthesis of prostaglandin E2, respectively. The use of NS 398, a specific pharmacological inhibitor of COX-2, confirmed the expression of this isoenzyme in activated foetal hepatocytes. Synergism in COX-2 expression was observed between LPS, tumour necrosis factor-alpha and interleukin-1beta. Interleukin-6 and permeant analogues of cyclic AMP failed to induce COX-2 or to synergize with LPS. Also, transforming growth factor-beta inhibited the LPS- and pro-inflammatory cytokines-dependent expression of COX-2. These results indicate that foetal hepatocytes are competent to express COX-2 upon challenge with pro-inflammatory stimuli, a process lost completely in hepatocytes isolated from animals aged 2 days.


Insulin and C-peptide plasma levels in patients with severe chronic pancreatitis and fasting normoglycemia.
The aim of the present study was to evaluate insulin secretion by the pancreatic B cell in a group of patients with severe chronic pancreatitis and without overt diabetes. For this purpose we have measured plasma insulin and C-peptide peripheral levels in the fasting state and after a 100-g oral glucose load in 10 patients with severe chronic pancreatitis and fasting normoglycemia, and in 10 sex-, age-, and weight-matched healthy controls. As compared to normal subjects, patients with chronic pancreatitis showed: (1) significantly higher plasma glucose levels after oral glucose load (area under the plasma glucose curve 1708 +/- 142 vs 1208 +/- 47 mmol/liter X 240 min, P less than 0.005); (2) plasma insulin levels significantly higher at fasting (0.11 +/- 0.008 vs 0.08 +/- 0.005 nmol/liter, P less than 0.01) but not after oral glucose administration (area under the plasma insulin curve 79 +/- 12 vs 88 +/- 16 nmol/liter X 240 min); (3) significantly lower plasma C-peptide concentrations both in the fasting state (0.15 +/- 0.01 vs 0.54 +/- 0.05 nmol/liter, P less than 0.001) and after oral glucose load (area under the plasma C-peptide curve 211 +/- 30 vs 325 +/- 37 nmol/liter X 240 min, P less than 0.05). The finding of diminished plasma C-peptide levels suggests that chronic pancreatitis is associated with an impaired B-cell function even in the absence of overt diabetes. The increased or unchanged plasma insulin levels in spite of decreased plasma C-peptide concentrations indicate that in chronic pancreatitis insulin metabolism is reduced, most likely within the liver.


Ethnic variation and variability of fetal nasal bone length at 11-15 weeks of gestation in a Brazilian population: preliminary results.
To evaluate the maternal ethnic influence and the intra and interobserver reproducibility of the nasal bone length measurement at 11-15 weeks of gestation in a Brazilian population. A cross-sectional study with 171 normal pregnant women at 11-15 weeks was performed. Nasal bone was transabdominally measured in all cases. The patients were separated into three racial groups (White, Black and Asian) according to maternal ethnicity. The intraobserver variability was calculated through the repeated measurement of 55 fetuses by a single observer, and the interobserver variability was calculated through 44 measurements by two observers. The ANOVA test was used to compare the three racial groups. To calculate the variability, the intraobserver correlation coefficient (intra-CC), the interclass correlation coefficient (inter-CC) with 95% confidence interval, and the Bland-Altman plots were used. No statistically significant difference could be observed among the three races as for nasal bone length measurement (P = 0.934). The intraobserver variability was considered very good [intra-CC 0.92-IC 95% (0.902; 0.947)], as well as the interobserver variability [inter-CC 0.91-IC 95% (0.873; 0.940)]. There is no significant difference in nasal bone length measurement among the three races analyzed. Nasal bone length measurement is reproducible.


Scanning tunnelling microscopy studies of beta-amyloid fibril structure and assembly.
Alzheimer's disease is in part characterised by the deposit of beta-amyloid peptide in the form of fibrils in the brain. In this study, the scanning tunnelling microscope (STM) has been used to provide high resolution images of synthetic fibril structure and formation as a function of time. Short fibrils are observed following brief peptide incubation times. At longer incubation periods ribbon like filaments were observed. These results suggest that beta-amyloid self-assembly is an ordered process, with a correlation between time of incubation and length of beta-amyloid filament growth.


A Phase 2 Study of Camrelizumab for Advanced Hepatocellular Carcinoma: Two-Year Outcomes and Continued Treatment beyond First RECIST-Defined Progression.
In a multicenter, open-label, parallel-group, randomized, phase 2 study for pretreated advanced hepatocellular carcinoma (HCC), camrelizumab showed potent antitumor activity and acceptable safety profile. The aim of this report was to provide long-term data and evaluate potential benefit of treatment with camrelizumab beyond progression. From November 15, 2016, to November 16, 2017, 217 patients received camrelizumab 3 mg/kg intravenously every 2 or 3 weeks. Treatment beyond first Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression (TBP) with camrelizumab was allowed. At data cutoff of December 16, 2019 (>2 years after the last patient enrollment; median duration of follow-up, 13.2 months [IQR 5.7-25.8]), 14 (43.8%) of the 32 responses per blinded independent central review were ongoing. The median duration of response was not reached (range 2.5-30.5 + months). The ongoing response rates at 12, 18, and 24 months were 68.3% (95% confidence interval [CI] 47.7-82.2), 59.8% (95% CI 38.8-75.6), and 53.1% (95% CI 31.0-71.0), respectively. The median overall survival (OS) was 14.2 months (95% CI 11.5-16.3). The 18- and 24-month OS rates were 41.3% (95% CI 34.6-47.9) and 33.7% (95% CI 27.3-40.2), respectively. Of the 172 patients who experienced RECIST-defined progression per investigator, 102 received TBP, while 70 did not (non-TBP). The median OS was 16.9 months (95% CI 13.3-22.6) in the TBP group versus 9.4 months (95% CI 5.8-14.8) in the non-TBP group, and the 18- and 24-month OS rates were 47.5% (95% CI 37.3-56.9) versus 33.1% (95% CI 22.3-44.3) and 38.8% (95% CI 29.2-48.4) versus 23.2% (95% CI 13.8-34.1), respectively. No new safety signals of camrelizumab were observed. With prolonged follow-up, camrelizumab continues to demonstrate the durable response and long survival in pretreated advanced HCC patients with manageable toxicities, especially in those who continued the treatment beyond first RECIST-defined progression.


Preliminary Results of Multi-Institutional Phase 1 Dose Escalation Trial Using Single-Fraction Stereotactic Partial Breast Irradiation for Early Stage Breast Cancer.
We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival. From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence. This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline.


Mechanisms and strategies to overcome multiple drug resistance in cancer.
One of the major problems in chemotherapy is multidrug resistance (MDR) against anticancer drugs. ATP-binding cassette (ABC) transporters are a family of proteins that mediate MDR via ATP-dependent drug efflux pumps. Many MDR inhibitors have been identified, but none of them have been proven clinically useful without side effects. Efforts continue to discover not toxic MDR inhibitors which lack pharmacokinetic interactions with anticancer drugs. Novel approaches have also been designed to inhibit or circumvent MDR. In this review, the structure and function of ABC transporters and development of MDR inhibitors are described briefly including various approaches to suppress MDR mechanisms.


Inpatient satisfaction with nursing care in a backward region: a cross-sectional study from northwestern China.
The aim of the study was to examine the level of patient satisfaction with nursing care and identify the factors affecting satisfaction from the inpatient's perspective in a backward region of China. This was a cross-sectional study. The study was conducted at a tertiary hospital located in northwest China. Patients admitted to the ward for at least 48 hours were chosen to participate in the survey. The Newcastle Satisfaction with Nursing Care Scale was used. Data were collected from 219 patients. The overall inpatient satisfaction with nursing care was 78.15±4.74. Patients were more satisfied with nurses who respected their privacy and treated them as individuals (67.7%). Patients were least satisfied with the type of information nurses gave them (11.7%) and with the sufficient awareness of their needs. Patients who were married, had a history of hospitalisation, surgery and were taken charge of by junior nurses had higher satisfaction. The overall level of patient satisfaction was moderate. Patient-centred individualised care and providing sufficient information model of care are needed. There was a need for nurses to be aware of patients' individualised care needs and to provide them with more information. This study may suggest/urge hospital administrators, policymakers and nurses to be more sensitive with patients' married status, history of hospitalisation and surgery, the professional title of in charged nurses when care is provided. Ultimately to achieve better outcome of patients' hospitalisation.


Large tunable image-charge effects in single-molecule junctions.
Metal/organic interfaces critically determine the characteristics of molecular electronic devices, because they influence the arrangement of the orbital levels that participate in charge transport. Studies on self-assembled monolayers show molecule-dependent energy-level shifts as well as transport-gap renormalization, two effects that suggest that electric-field polarization in the metal substrate induced by the formation of image charges plays a key role in the alignment of the molecular energy levels with respect to the metal's Fermi energy. Here, we provide direct experimental evidence for an electrode-induced gap renormalization in single-molecule junctions. We study charge transport through single porphyrin-type molecules using electrically gateable break junctions. In this set-up, the position of the occupied and unoccupied molecular energy levels can be followed in situ under simultaneous mechanical control. When increasing the electrode separation by just a few ångströms, we observe a substantial increase in the transport gap and level shifts as high as several hundreds of meV. Analysis of this large and tunable gap renormalization based on atomic charges obtained from density functional theory confirms and clarifies the dominant role of image-charge effects in single-molecule junctions.


Effect of Brachiaria decumbens as a novel supplementation on the production performance of broiler chickens.
The primary goal of this research was to elucidate the novel influence of Brachiaria decumbens supplementation on broiler chicken growth performance, nutritional digestibility, cecal microbiota, intestinal histomorphology, carcass characteristics, and meat quality. A total of 300 male day-old Ross 308 broiler chickens were randomly subjected to six different treatment groups having five replicates per treatment with 10 birds in each replicate. In treatment 1, broiler chickens were fed commercial diets with no added additives; in treatment 2, broiler chickens were offered commercial diets containing 100 mg/kg of the antibiotic oxytetracycline. However, in treatments 3, 4, 5, and 6, broiler chickens received similar commercial diets supplemented with 25 mg/kg, 50 mg/kg, 75 mg/kg, and 100 mg/kg of B. decumbens ground leaf powder, respectively, without antibiotics. Throughout the 42-day trial, the body weight gain and total feed intake for each replicate were recorded every week to determine the growth performance. Then, on 21th and 42nd day, ten broilers from each treatment (two in each replicate) were randomly selected and slaughtered to assess the digestibility of nutrients, histomorphology of the small intestine, the population of the cecal microbiota, carcass characteristics, as well as quality of both breast and drumstick muscle. There were differences (p < 0.05) in the growth performance, apparent ileal nutrient digestibility, intestinal histomorphology, carcass characteristics, and meat quality. Animals supplemented with 25 mg/kg of B. decumbens had higher growth performance and better ileal nutrient digestibility of protein, fiber, and ether extract, as well as higher villi height and carcass percentage with superior meat quality. Besides, the growth of E. faecalis during the starter phase was inhibited. In summary, B. decumbens supplementation at 25 mg/kg may be suggested as an optimal dose of as a prophylactic as well as an alternative for antibiotic growth promoter in stimulating the productivity of commercial broilers. This unconventional phytobiotic supplementation could be the key to replacing unnecessary antibiotics used in poultry feed.


Migration intentions among Portuguese junior doctors: Results from a survey.
Migration of health personnel during periods of economic crisis represents a challenge for policymakers in origin and destination countries. Portugal is going through a period of economic hardship and much has been speculated about an increase in junior doctors' migration during this period. Using a questionnaire administered to a sample of Portuguese junior doctors who were still in the general residency (1st-year after medical school), we aim at determining the prevalence of migration intentions among Portuguese junior doctors and to identify the most important drivers of career choice for those who are considering emigrating in the near future. In our sample, 55% of Portuguese junior doctors are considering working abroad in the coming 10 years. Several variables were associated with an intention to work abroad: female sex (odds ratio [OR] 0.559; 95% confidence interval [CI] 0.488-0.640), the National Medical Exam score (OR 0.978; 95% CI 0.961-0.996;), having studied abroad (OR 1.756; 95% CI 1.086-2.867) and considering income and research opportunities as key factors for future specialty choice (OR 1.356; 95% CI 1.132-1.626; OR 2.626; 95% CI 1.228-4.172). Our study warns of the shortages the country may face due to doctors' migration and the main factors behind migration intentions in Portugal. Developing physician retention strategies is a priority to appropriately address these factors.


A lipid mixing assay to accurately quantify the fusion of outer membrane vesicles.
The intermixing of phospholipids from opposing bilayers, or membrane fusion, is a naturally occurring process that can be leveraged to produce hybrid vesicle systems. Optimizing the production of these hybrid vesicles requires accurate, sensitive, and quantitative methods of the lipid mixing that occurs during fusion. A fluorescence-based assay that uses octadecyl-rhodamine B chloride to measure lipid mixing, or R18 assay, was developed by Hoekstra to investigate viral entry almost four decades ago. However, the R18 assay has so far only been used to measure heterotypic fusion events. Consequently, the fusion efficiencies that are calculated from the R18 assay underestimate the total number of fusion events and the true efficiency of vesicle fusions. In this article, we outline the experimental format and data analysis that is necessary to perform the R18 fusion assay and to accurately and reliably measure the true total fusion efficiency of outer membrane vesicles isolated from the Nissle 1917 strain of E. coli.


MELD predictive value of alterations of brain perfusion during liver transplantation.
The systemic circulation of patients with liver failure is characterized by low vascular resistance and a compensatorily increased cardiac output. In addition, some patients show functional loss of the autoregulation system for cerebral blood flow, creating enhanced risk during orthotopic liver transplantation (OLT), a possible cause of the high incidence of central nervous system complications after OLT. Sixteen consecutive patients undergoing OLT were enrolled and characterized by the Child-Pugh (CTP), the MELD, and the HCC-adjusted-MELD score before surgery. OLT was performed with the "piggyback" technique. Brain perfusion and oxygenation was monitored by NIRO300 by Hamamatsu. This instrument detects concentration changes in oxygenated hemoglobin (DeltaHbO(2)), deoxygenated hemoglobin (DeltaHHb), and total volume of hemoglobin (DeltaHbT). It also calculates the tissue oxygenation index (TOI), namely HbO(2)/HbT expressed as a percentage, and the tissue hemoglobin index (THI). The lowest levels of brain perfusion were recorded at the washout, DeltaHbO(2) = -13.95 (-20/-5.3) micromol L(-1) and TOI = 51.5 (35.2/70.7)%, while immediately after, at reperfusion, the highest peaks were observed: DeltaHbO(2) was 0.16 (16.9/13) micromol L(-1); DeltaHbT was 1.1 (22.3/11.8) mumol L(-1); and TOI was 73.6 (78.1/65.3)%. Patients with more severe liver deficiency scores showed higher levels of brain perfusion and oxygenation during surgery. Both the MELD and the CTP score predict alterations in brain perfusion.


Chromosomal and allozymic diagnosis of three species of Drosophila. Drosophila pseudoobscura, D. persimilis, and D. miranda.
Techniques are presented for distinguishing the sibling species D. pseudoobscura, D. persimilis, and D. miranda in two ways: by differences in the banding sequence of salivary chromosomes, and by the frequencies of allozymes at certain diagnostic loci.


Two New Highly Oxygenated Spirostanol Saponins from Paris polyphylla var. stenophylla.
Phytochemical investigation of the rhizomes of Paris polyphylla var. stenophylla led to the isolation of two new highly oxygenated spirostanol saponins, named paristenosides A (1) and B (2), together with seven known compounds. Their structures were established mainly on the base of NMR spectroscopic techniques and mass spectrometry, as well as chemical methods. In addition, the cytotoxicity of the two new saponins was tested. Two new highly oxygenated spirostanol saponins, paristenosides A (1) and B (2), were isolated from the rhizomes of Paris polyphylla var. stenophylla. Their structures were established mainly based on NMR spectroscopic techniques and mass spectrometry, as well as chemical methods.


Regulation of human IL-18 gene expression: interaction of PU.1 with GC-box binding protein is involved in human IL-18 expression in myeloid cells.
Interleukin-18 (IL-18) is a pro-inflammatory cytokine which participates in host defense against a variety of infections as well as in chronic inflammation including autoimmune diseases. However, little is known about human IL-18 regulation at the gene level. We have previously demonstrated that sodium butyrate, a bacterial fermentation product, induces IL-18 production via the proximal region of the promoter. In this study we investigated the molecular mechanisms for basal and sodium butyrate-induced expression of IL-18 in human myeloid cells. Two regulatory regions, a consensus binding site for PU.1 and a GC-rich region, are required for basal IL-18 promoter activity in human myeloid cells. PU.1 bound to the PU.1 consensus binding site in electrophoretic mobility shift assays, and overexpression of PU.1 led to activation of the IL-18 promoter through this site. Mutation analysis revealed that the GC-rich region, but not PU.1 site, participates in sodium butyrate-induced transactivation. Furthermore, DNA pull-down experiments and the critical spacing of the two binding sites suggest that formation of a protein complex involving both cis elements and the respective binding proteins might be crucial for human IL-18 expression.


High frequency of HPV genotypes 59, 66, 52, 51, 39 and 56 in women from Western Mexico.
Human papillomavirus infection is an important factor associated with cervical cancer (CC) development. The prevalence and genotype distribution vary greatly worldwide. Examining local epidemiological data constitutes an important step towards the development of vaccines to prevent CC. In this work, we studied the prevalence of HPV genotypes in women from Western Mexico with the COBAS 4800 and/or Linear Array Genotyping Test (LA). The samples analysed in this study represent a population from Western Mexico, which includes six different states. Our approach was first to test for HPV in cervical samples from women who attended their health clinic for routine gynaecological studies (open-population, n = 3000) by utilizing COBAS 4800. Afterwards, 300 of the HPV-positive samples were randomly selected to be genotyped with LA; finally, we genotyped samples from women with cervical intraepithelial neoplasia grade 1 (CIN 1, n = 71) and CC (n = 96) with LA. Sociodemographic data of the diverse groups were also compared. The overall HPV prevalence among the open-population of women as determined by COBAS 4800 was 12.1% (n = 364/3000). Among the HPV-positive samples, single infections (SI) with HPV16 were detected in 12.4% (n = 45/364), SI with HPV18 were detected in 1.4%, and infection with at least one of the genotypes included in the high-risk HPV pool was detected in 74.5% of the cases. LA analysis of the samples showed that in addition to HPV genotypes 16 and 18, there was a high prevalence of HPV genotypes 59, 66, 52, 51, 39 and 56 in women from Western Mexico. With respect to the sociodemographic data, we found statistically significant differences in the number of pregnancies, the use of hormonal contraceptives and tobacco intake. Our data indicate that there is a high prevalence of HPV genotypes which are not covered by the vaccines currently available in Mexico; therefore, it is necessary to include HPVs 59, 66, 51, 39 and 56 in the design of future vaccines to reduce the risk of CC development. It is also essential to emphasize that the use of hormonal contraceptives and tobacco smoking are risk factors for CC development in addition to the presence of HPV.


Effect of habitat quality on the ecological behaviour of a temperate-living primate: time-budget adjustments.
Barbary macaques, like other non-human primates living in highly seasonal temperate environments, display high monthly variations in their diet. In addition, their diet changes according to the habitat type they colonize and to the degree of habitat degradation due to resource exploitation by local people, in particular through pastoralism. We studied the time-budget adjustments of wild Barbary macaques in three cedar-oak forests impacted by different intensities of grazing pressure from goats and sheep. We examined how diet variations influenced the time monkeys spent in their activities and their day range lengths (i.e. their energy costs). At three studied sites, diet composition and time budgets showed marked seasonal variations. Diet composition had a strong influence on monkeys' time budget. In the forest where pastoralism was the highest, diet included a greater proportion of underground resources, shrub fruit and acorns, which led to an increase in the time spent foraging and moving, as well as an important increase in day range lengths. Energy costs were therefore higher in a degraded environment than in a suitable habitat. The monkeys living in forests subjected to pastoralism took advantage of increased day lengths to spend more time searching for food. However, in the forest with the highest pastoralism pressure, although monkeys spent more time foraging, they spent less time feeding than monkeys at the other sites. In addition, they appeared to have reached the limits of the available time they could devote to these activities, as their diurnal resting time was at its lowest level over several months. Temperature variations did not appear to modify monkeys' time budgets. In the least favourable habitat, saving time from resting activity allowed monkeys to maintain a relatively high level of social activity, partly linked to rearing constraints.


Histamine modulates salivary secretion and diminishes the progression of periodontal disease in rat experimental periodontitis.
We have recently reported that experimental periodontitis (EP) reduced methacholine-induced submandibular gland (SMG) salivary secretion. The aim of the present study was to determine whether histamine could prevent SMG impairment produced by EP. Bilateral EP was induced for 2 weeks and histamine treatment (0.1 mg/kg subcutaneously) was started 5 days before the end of the experimental period in male rats. The histamine effects on periodontitis-altered functional and histological parameters of SMG and on periodontal bone loss were evaluated. Histamine treatment partially reversed the methacholine-induced salivation reduction produced by EP while preventing SMG histological damage. Histamine's effect on SMG was associated with an increased proliferation rate (2.2 ± 0.3 vs. 0.2 ± 0.2 proliferative cells per field, P < 0.001). Furthermore, histamine completely prevented enhanced EP-induced apoptosis (1.0 ± 0.4 vs. 60.9 ± 4.6 apoptotic cells per field, P < 0.001). The protective effect exerted by histamine on SMG functionality is associated with attenuation of lingual and vestibular bone loss (0.66 ± 0.04 vs. 0.97 ± 0.06 mm; P < 0.001). Histamine is able to reduce periodontitis-induced damage to SMG and bone structure.


Ensuring access to justice: the need for community paralegals to end AIDS by 2030.
The HIV response has long recognized that certain "key populations" such as individuals in detention, adolescent girls and young women, sex workers, people who use drugs, LGBTQ individuals, migrants and others face higher barriers to access to, uptake of, and retention in HIV prevention and treatment services. One approach to addressing these barriers is the training of community paralegals to advocate for the rights of individuals and to address discrimination in health settings. Community paralegal programmes have been able to successfully address rights violations that impact access to health services and underlying determinants of health across a range of countries and populations, focusing upon issues such as discrimination and the denial of health services; unlawful detention of outreach workers, sex workers, persons who use drugs and men who have sex with men; and harmful traditional practices and gender-based violence. In addition to resolving specific cases, evaluations of paralegal programmes have found that these programmes increased legal literacy among key populations at risk of HIV and increased understanding of human rights among healthcare providers, resulting in improved access to HIV services. Some evaluations have noted challenges related to the sustainability of paralegal programmes similar to those raised with community health worker programmes more broadly. To achieve global HIV goals, funding for legal literacy and paralegal programmes should be increased and interventions should be rigorously evaluated. Efforts should target discrimination in access to HIV prevention and treatment and criminalization of key populations, two key barriers to ensuring access to HIV prevention and treatment services.


Unusual CNS and orbital metastases of neuroblastoma.
Although neuroblastoma is a common childhood malignancy with frequent metastatic disease, involvement of the CNS and eye are unusual findings. Recently, we encountered two such cases. One of the patients had undergone bone marrow transplantation. The long term effects of this treatment regarding behavior of the tumor and subsequent metastatic pattern have yet to be determined. The second patient presented with apparent congenital neuroblastoma. Both of these tumors were extremely aggressive in nature, and could represent variations of the usual metastatic pattern of neuroblastoma.