[Determination of intracellular pH by the distribution of benzoic acid in S. cerevisiae. Amino acid transport and proton gradient].
The internal pH (pHi) of Saccharomyces cerevisiae, wild type strain and its mutant rho- has been measured by the intra-extracellular distribution of 14C-benzoic acid. The values of pHi (external pH 4.5) change with the yeast strain and depend on the cellular metabolic conditions. The values of pHi and proton gradient in the wild type yeast are higher in energized than in starved cells: in energized cells pHi, 6.15 to 6.40, delta pH 1.65 to 1.90 or -97 to -112 mV; starved cells pH 5.90, delta pH 1.40 or -82 mV. In the rho- mutant, the values are lower than in the wild type yeast, in the same metabolic conditions. Energized rho- mutant cells, pH 6.05, delta pH 1.55 or -91 mV; starved cells, pHi 5.70, delta pH 1.20 or -71 mV. The proton conductors, DNP and PCP produce a decrease in pHi and delta pH and inhibition of L-leucine entrance by system S1, high affinity and low velocity and system S2, low affinity and high velocity. The obtained values of delta pH decrease and L-leucine transport inhibition, demonstrate that there is no strict relationship between the proton gradient across the cell membrane and the process of transport of L-leucine in yeast.


Unsupervised Domain Adaptation Using Fourier Phase Enhanced Training Images for Liver Tumors Detection in Multi-phase CT Images.
Computer-aided diagnostic methods, such as automatic and precise liver tumor detection, have a significant impact on healthcare. In recent years, deep learning-based liver tumor detection methods in multi-phase computed tomography (CT) images have achieved noticeable performance. Deep learning frameworks require a substantial amount of annotated training data but obtaining enough training data with high quality annotations is a major issue in medical imaging. Additionally, deep learning frameworks experience domain shift problems when they are trained using one dataset (source domain) and applied to new test data (target domain). To address the lack of training data and domain shift issues in multiphase CT images, here, we present an adversarial learning-based strategy to mitigate the domain gap across different phases of multiphase CT scans. We introduce to use Fourier phase component of CT images in order to improve the semantic information and more reliably identify the tumor tissues. Our approach eliminates the requirement for distinct annotations for each phase of CT scans. The experiment results show that our proposed method performs noticeably better than conventional training and other methods.


Glacial bottleneck and postglacial recolonization of a seed parasitic weevil, Curculio hilgendorfi, inferred from mitochondrial DNA variation.
Climatic changes during glacial periods have had a major influence on the recent evolutionary history of living organisms, even in the warm temperate zone. We investigated phylogeographical patterns of a weevil Curculio hilgendorfi (Curculionidae), a host-specific seed predator of Castanopsis (Fagaceae) growing in the broadleaved evergreen forests in Japan. We examined 2709 bp of mitochondrial DNA for 204 individuals collected from 62 populations of the weevil. Four major haplogroups were detected, in southwestern and northeastern parts of the main islands and in central and southern parts of the Ryukyu Islands. The demographic population expansion was detected for the two groups in the main islands but not for the Ryukyu groups. The beginning time of the expansion was dated to 39,000-59,000 years ago, which is consistent with the end of the last glacial period. Our data also demonstrated that the southwestern population of the main islands has experienced a more severe bottleneck and more rapid population growth after glacial ages than the northeastern population. At least three refugial areas in the main islands were likely to have existed during the last glacial periods, one of which had not previously been recognized by analyses of intraspecific chloroplast DNA variation of several plant species growing in the broadleaved evergreen forests. Our results represent the first phylogeographical and population demographic analysis of an insect species associated with the broadleaved evergreen forests in Japan, and reveal more detailed postglacial history of the forests.


Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The recently published Prostate Cancer Intervention versus Observation Trial (PIVOT) did not identify differences in prostate cancer-specific mortality or all-cause mortality among patients with low-risk disease managed conservatively vs those managed definitively; however, recently published data suggest that older men may harbour more aggressive disease than is identified at biopsy owing to sampling error and undergrading. Whether older men with apparent low-risk disease are placed at risk of prostate cancer-specific mortality when managed conservatively remains unknown. The study used population-level data to show that non-curative approaches for older men with low-risk prostate cancer do result in an increased risk of prostate cancer-specific mortality. Differences between our study and the PIVOT trial include the fact that we included a larger sample size, analysed the data using an 'as-treated' approach, and included a healthier cohort of men as evinced by lower 4-year all-cause mortality estimates in our study than in the PIVOT. Our results suggest that older men with apparent low-risk prostate cancer are at risk of undergrading, which probably explains the differences in prostate cancer-specific mortality observed between men managed conservatively vs those managed definitively. Our study suggests that alternative approaches to excluding occult, high grade prostate cancer are needed in such men. To evaluate whether older age in men with low-risk prostate cancer increases the risk of prostate cancer-specific mortality (PCSM) when non-curative approaches are selected as initial management. The study cohort consisted of 27 969 men, with a median age of 67 years, with prostate-specific antigen (PSA)-detected, low-risk prostate cancer (clinical category T1c, Gleason score ≤6, and PSA ≤10) identified by the Surveillance, Epidemiology and End Results programme between 2004 and 2007. Fine and Gray's competing risk regression analysis was used to evaluate whether management with non-curative vs curative therapy was associated with an increased risk of PCSM after adjusting for PSA level, age at diagnosis and year of diagnosis. After a median follow-up of 2.75 years, 1121 men died, 60 (5.4%) from prostate cancer. Both older age (adjusted hazard ratio [AHR] 1.05; 95% confidence interval (CI) 1.02-1.08; P < 0.001) and non-curative treatment (AHR 3.34; 95% CI 1.97-5.67; P < 0.001) were significantly associated with an increased risk of PCSM. Men > the median age experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent (P < 0.001); this finding was not seen in men ≤ the median age (P = 0.17). Pending prospective validation, our study suggests that non-curative approaches for older men with 'low-risk' prostate cancer result in an increased risk of PCSM, suggesting the need for alternative approaches to exclude occult, high grade prostate cancer in these men.


Analysis of Branched Amino Acids by UPLC as an Alternative Method for the Management of Patients with MUSD.
Maple syrup urine disease (MSUD) is a severe life-threatening metabolic disorder. Patients' poor outcomes could be prevented by early diagnosis and regular monitoring, which mainly depend on the analysis of branched amino acids (BCAAs) in plasma. The study aimed to test whether the analysis of BCAAs by ultra-performance liquid chromatography (UPLC) is an alternative to an analysis by ion-exchange chromatography (IEC) for the diagnosis and monitoring of MSUD. The two methods analyzed fifty plasma samples obtained from treated and untreated patients with MSUD. Data were analyzed using Passing-Bablok and Bland-Altman methods. The slope of the regression lines was equal or close to one for the three BCAAs, indicating no significant proportional differences between the two methods. A slight positive or negative bias was found for leucine and alloisoleucine, respectively. However, for each amino acid, one or two measurement pairs were out of statistical interval of agreement. Despite small analytical differences, the two methods could be considered in clinical agreement since the differences have no impact on the diagnosis and management of patients. UPLC and IEC methods are in clinical agreement for plasma BCAAs analysis. The UPLC method could be used simultaneously or interchangeably with the IEC method for diagnosing and monitoring MSUD patients. However, for reasons of practicability, the alternative method should only be used when the usual method cannot be carried out.


Nutritional interventions improve quality of life of caregivers of children with neurodevelopmental disorders.
Introduction: Children with neurodevelopmental disorders are at high risk for malnutrition. We aimed to investigate the impact of nutritional interventions to children with neurodevelopmental disorders and the quality of life of caregivers.Materials/Method: This is a prospective interventional study of 91 children with neurodevelopmental disorders. The children were separated into two groups: the intervention group and control group. The intervention group was selected from among children who had not been evaluated for nutrition and feeding problems by a pediatric gastroenterologist or dietician for the past one year. Children in the intervention group were called for follow-up visits and their nutritional intervention and anthropometric measurements were initiated by a pediatric gastroenterologist and dietician, at one month, three months, six months, and one year. The WHOQoL-BREF quality of life scale was completed by the caregivers of the children at baseline and at one year.Results: The intervention group had increased malnutrition (p < 0.001) and gastrointestinal system pathologies such as dysphagia (p < 0.001), constipation (p = 0.02), gastroesophageal reflux (p = 0.03) at baseline. After the nutritional intervention, 77.7% of the intervention group gained weight and 55.5% reached the target weight. The quality of life scale scores at baseline were lower among caregivers of the intervention group; however, they reached those of the control group after the nutritional intervention.Conclusion: Close multidisciplinary nutrition monitoring enables children with neurodevelopmental disorders to thrive appropriately and improves the quality of life of caregivers.


Evaluation of hip abductor and adductor strength in the elderly: a reliability study.
In elderly individuals an increased muscle strength contributes to the diminution of the falls risk and associated adverse events. An increasing interest in lateral control exists due to the fatal consequences of postero-lateral falls. Therefore a proper assessment of frontal plane hip muscle strength in elderly is important but remains challenging. Therefore we aimed to investigate the feasibility and repeatability of a hip abductor and adductor maximum voluntary isometric strength (MVIS) and rate of force generation (RFG) test in elderly. This represents an initial step in the development process of a new and clinically relevant test that could lead to more specific treatment protocols for this population. In this measurement focused study hip abduction (ABD) and adduction (ADD) MVIS and RFG were tested twice within one to three hours with a dynamometer fixed to a custom made frame in a geriatric population including fallers and non-fallers. Intraclass correlation coefficient (ICCagreement), standard error of measurement (SEM), and smallest detectable difference (SDD) were determined. All recruited persons (N = 76; mean age (SD) 80.46 (7.05) years old) completed the tests. The average time needed to complete the strength tests was 10.58 min. (1.56) per muscle group. The reliability of the hip ABD and ADD was high with ICC'sagreement ranging from 0.83 to 0.97. The SDD varied between 18.1 and 81.8% depending on the muscle group and type of strength that was evaluated. Hip abductor and adductor strength measures in older person are feasible and reliable. However, the significance of moderate changes in these measurements may be limited by the large SDD and SEM. Therefore, physical therapist should be careful when using this measure for assessing the progress of an individual person in a daily clinical use.


Disparities in Care: Impact of Socioeconomic Factors on Pancreatic Surgery: Exploring the National Cancer Database.
Studies have shown high-volume institutions have decreased mortality and increased survival for pancreatectomy. However, not all patients can travel to high-volume centers. Socioeconomic factors may influence treatment decisions. The goal of this study is to examine socioeconomic factors that determine where a patient is treated and how that location affects outcome. This is a retrospective study of the National Cancer Database of patients diagnosed with pancreatic cancer from 2004 to 2014. The primary outcome was to examine socioeconomic factors that predicted where a patient underwent their pancreatectomy. Patients treated at academic programs (APs) had to travel a mean distance of 80.9 miles, whereas patients treated at community programs (CPs) had to travel 31.7 miles (P < 0.0001). Spanish and Hispanic patients were less likely to travel to an AP (69% had surgery at an AP versus 76% of non-Hispanic patients, P < 0.001). Patients with higher comorbidities were also more likely to have care at CPs. Patients who had pancreatic cancer surgery at CPs were more likely to be Hispanic or with higher medical comorbidities. Those who had surgery at AP traveled further distances but had better perioperative outcomes and had an improvement in overall survival.


Evaluation of the 7th and 8th editions of the AJCC/UICC TNM staging systems for lung cancer in a large North American cohort.
The new 8th American Joint Committee on Cancer (AJCC)/International Union for Cancer Control (UICC) lung cancer staging system was developed and internally validated using the International Association for the Study of Lung Cancer (IASLC) database, but external validation is needed. The goal of this study is to validate the discriminatory ability and prognostic performance of this new staging system in a larger, independent non-small cell lung cancer (NSCLC) cohort with greater emphasis on North American patients. A total of 858,909 NSCLC cases with one malignant primary tumor collected from 2004 to 2013 in the National Cancer Database (NCDB) were analyzed. The primary coding guidelines of the Collaborative Staging Manual and Coding Instructions for the new 8th edition AJCC/UICC lung cancer staging system was used to define the new T, M and TNM stages for all patients in the database. Kaplan-Meier curves, Cox regression models and time-dependent receiver operating characteristics were used to compare the discriminatory ability and prognostic performance of the 7th and the revised 8th T, M categories and overall stages. We demonstrated that the 8th staging system provides better discriminatory ability than the 7th staging system and predicts prognosis for NSCLC patients using the NCDB. There were significant survival differences between adjacent groups defined by both clinical staging and pathologic staging systems. These staging parameters were significantly associated with survival after adjusting for other factors. The updated T, M, and overall TNM stage of the 8th staging system show improvement compared to the 7th edition in discriminatory ability between adjacent subgroups and are independent predictors for prognosis.


Metabolic reprogramming involves in transition of activated/resting CD4+ memory T cells and prognosis of gastric cancer.
Little is known on how metabolic reprogramming potentially prompts transition of activated and resting CD4+ memory T cells infiltration in tumor microenvironment of gastric cancer (GC). The study aimed to evaluate their interactions and develop a risk model for predicting prognosis in GC. Expression profiles were obtained from TCGA and GEO databases. An immunotherapeutic IMvigor210 cohort was also enrolled. CIBERSORT algorithm was used to evaluate the infiltration of immune cells. The ssGSEA method was performed to assess levels of 114 metabolism pathways. Prognosis and correlation analysis were conducted to identify metabolism pathways and genes correlated with activated CD4+ memory T cells ratio (AR) and prognosis. An AR-related metabolism gene (ARMG) risk model was constructed and validated in different cohorts. Flow cytometry was applied to validate the effect of all-trans retinoic acid (ATRA) on CD4+ memory T cells. Since significantly inverse prognostic value and negative correlation of resting and activated CD4+ memory T cells, high AR level was associated with favorable overall survival (OS) in GC. Meanwhile, 15 metabolism pathways including retinoic acid metabolism pathway were significantly correlated with AR and prognosis. The ARMG risk model could classify GC patients with different outcomes, treatment responses, genomic and immune landscape. The prognostic value of the model was also confirmed in the additional validation, immunotherapy and pan-cancer cohorts. Functional analyses revealed that the ARMG model was positively correlated with pro-tumorigenic pathways. In vitro experiments showed that ATRA could inhibit levels of activated CD4+ memory T cells and AR. Our study showed that metabolic reprogramming including retinoic acid metabolism could contribute to transition of activated and resting CD4+ memory T cells, and affect prognosis of GC patients. The ARMG risk model could serve as a new tool for GC patients by accurately predicting prognosis and response to treatment.


Mitochondria, Bioenergetics and Excitotoxicity: New Therapeutic Targets in Perinatal Brain Injury.
Injury to the fragile immature brain is implicated in the manifestation of long-term neurological disorders, including childhood disability such as cerebral palsy, learning disability and behavioral disorders. Advancements in perinatal practice and improved care mean the majority of infants suffering from perinatal brain injury will survive, with many subtle clinical symptoms going undiagnosed until later in life. Hypoxic-ischemia is the dominant cause of perinatal brain injury, and constitutes a significant socioeconomic burden to both developed and developing countries. Therapeutic hypothermia is the sole validated clinical intervention to perinatal asphyxia; however it is not always neuroprotective and its utility is limited to developed countries. There is an urgent need to better understand the molecular pathways underlying hypoxic-ischemic injury to identify new therapeutic targets in such a small but critical therapeutic window. Mitochondria are highly implicated following ischemic injury due to their roles as the powerhouse and main energy generators of the cell, as well as cell death processes. While the link between impaired mitochondrial bioenergetics and secondary energy failure following loss of high-energy phosphates is well established after hypoxia-ischemia (HI), there is emerging evidence that the roles of mitochondria in disease extend far beyond this. Indeed, mitochondrial turnover, including processes such as mitochondrial biogenesis, fusion, fission and mitophagy, affect recovery of neurons after injury and mitochondria are involved in the regulation of the innate immune response to inflammation. This review article will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after hypoxic-ischemic injury, as a means of identifying new avenues for clinical intervention.


A multivariate Baltic Sea environmental index.
Since 2001/2002, the correlation between North Atlantic Oscillation index and biological variables in the North Sea and Baltic Sea fails, which might be addressed to a global climate regime shift. To understand inter-annual and inter-decadal variability in environmental variables, a new multivariate index for the Baltic Sea is developed and presented here. The multivariate Baltic Sea Environmental (BSE) index is defined as the 1st principal component score of four z-transformed time series: the Arctic Oscillation index, the salinity between 120 and 200 m in the Gotland Sea, the integrated river runoff of all rivers draining into the Baltic Sea, and the relative vorticity of geostrophic wind over the Baltic Sea area. A statistical downscaling technique has been applied to project different climate indices to the sea surface temperature in the Gotland, to the Landsort gauge, and the sea ice extent. The new BSE index shows a better performance than all other climate indices and is equivalent to the Chen index for physical properties. An application of the new index to zooplankton time series from the central Baltic Sea (Latvian EEZ) shows an excellent skill in potential predictability of environmental time series.


Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis.
Glioma is one of the leading types of brain tumor, but few etiologic factors of primary glioma have been identified. Previous observational research has shown an association between viral infection and glioma risk. In this study, we used Mendelian randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infection and glioma. We conducted a two-sample bidirectional MR analysis using genome-wide association study (GWAS) data. Summary statistics data of glioma were collected from the largest meta-analysis GWAS, involving 12,488 cases and 18,169 controls. Single-nucleotide polymorphisms (SNPs) associated with exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted herpes zoster (caused by Varicella zoster virus (VZV) infection) significantly decreased risk of low-grade glioma (LGG) development (OR = 0.85, 95% CI: 0.76-0.96, P = 0.01, FDR = 0.04). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. This is one of the first and largest studies in this field. We show robust evidence supporting that genetically predicted herpes zoster caused by VZV infection reduces risk of LGG. The findings of our research advance understanding of the etiology of glioma.


Traumatic tricuspid valve papillary muscle case with concomitant acquired patent foramen ovale and covert right atrial rupture.
Cardiac trauma often occurs in motor vehicle accidents. A 50-year-old female driver was transported to our hospital with multiple trauma after a high-speed car accident. After admission to the intensive care unit, cardiac ultrasound examination revealed traumatic tricuspid valve papillary muscle rupture and patent foramen ovale, while Lancisi's sign was noted on physical examination. Surgical treatment was performed with valve annuloplasty and closure of the patent foramen ovale and a covert right atrial defect that was detected intraoperatively.


[Neonatal candidiasis: therapeutic options].
Diverse factors (such as preterm babies with low body weight staying for long-term periods at intensive care units, subjected to invasive procedures, receiving one or more antibiotic schemes, parenteral nutrition, etc.) are considered to pose a risk for the development of infections by opportunistic agents. Of the latter, Candida albicans is considered the main cause of neonatal candidiasis. The most frequently involved Candida species are C. albicans, C. parapsilosis and C. tropicalis. The advent of new antimycotic agents has increased the therapeutic possibilities for the treatment of candidiasis. Antimycotic agents used for the treatment of neonatal candidiasis include: amphotericin B deoxycolate, lipid-associated compounds of amphotericin B, fluconazole and itraconazol, and caspofungin.


Does the Factor Structure of IQ Differ Between the Differential Ability Scales (DAS-II) Normative Sample and Autistic Children?
The Differential Abilities Scales, 2nd edition (DAS-II) is frequently used to assess intelligence in autism spectrum disorder (ASD). However, it remains unknown whether the DAS-II measurement model (e.g., factor structure, loadings), which was developed on a normative sample, holds for the autistic population or requires alternative score interpretations. We obtained DAS-II data from 1,316 autistic individuals in the Simons Simplex Consortium and 2,400 individuals in the normative data set. We combined ASD and normative data sets for multigroup confirmatory factor analyses to assess different levels of measurement invariance, or how well the same measurement model fit both data sets: "weak" or metric, "strong" or scalar, and partial scalar if full scalar was not achieved. A weak invariance model showed excellent fit (Confirmatory Fit Index [CFI] > 0.995, Tucker Lewis Index [TLI] > 0.995, root mean square error of approximation [RMSEA] < 0.025), but a strong invariance model demonstrated a significant deterioration in fit during permutation testing (all p's<0.001), suggesting measurement bias, meaning systematic error when assessing autistic children. Fit improved significantly, and partial scalar invariance was achieved when either of the two spatial subtest (Recall of Designs or Pattern Construction) intercepts was permitted to vary between the ASD and normative groups, pinpointing these subtests as the source of bias. The DAS-II appears to measure verbal and nonverbal-but not spatial-intelligence in autistic children similarly as in normative sample children. These results may be driven by Pattern Construction, which shows higher scores than other subtests in the ASD sample. Clinicians assessing autistic children with the DAS-II should interpret verbal and nonverbal reasoning composite scores over the spatial score or General Composite Ability. Autism Res 2020, 13: 1184-1194. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Differential Abilities Scales, 2nd edition (DAS-II) is a popular intelligence quotient (IQ) test for assessing children with autism. This article shows that the DAS-II spatial standardized scores should be interpreted with caution because they hold a different meaning for autistic children. Verbal and nonverbal reasoning scores appear valid and to hold the same meaning for those with and without autism spectrum disorder.


A Multimodal Imaging Approach Demonstrates Reduced Midbrain Functional Network Connectivity Is Associated With Freezing of Gait in Parkinson's Disease.
Background: The pathophysiological mechanisms underlying freezing of gait (FOG) are poorly defined. MRI studies in FOG showed a distinct pattern of cortical atrophy and decreased functional connectivity (FC) within motor and cognitive networks. Furthermore, reduced rs-FC within midbrain, frontal, and temporal areas has been also described. This study investigated the patterns of whole-brain FC alterations within midbrain inter-connected regions in PD-FOG patients, and whether these patterns are linked to midbrain structural damage using a multi-modal imaging approach, combing structural and functional imaging techniques. Methods: Thirty three PD patients (16 PD-FOG, 17 PD noFOG), and 21 sex- and age-matched healthy controls (HCs) were prospectively enrolled. All subjects underwent MRI scan at 1.5T, whereas only PD patients underwent clinical and cognitive assessment. Grey matter (GM) integrity was measured using voxel-based morphometry (VBM). VBM findings served as basis to localize midbrain damage, and were further used as a seed region for investigating whole-brain FC alterations using rs-fMRI. Results: In rs-fMRI, patients with PD and FOG demonstrated significant decrease of midbrain-cortical FC levels in the R PCG, right postcentral, and supramarginal gyri compared to controls and the middle cingulate compared to noFOG group. Based on the regression analysis, MOCA, UPDRS-III total score, and FOG severity scores were associated with FC levels in several frontal, parietal and temporal regions. Discussion: The present results suggest that midbrain structural damage as well as decreased FC within the brainstem functional network might contribute to FOG occurrence in PD patients.


Assessment of the antireflection property of moth wings by three-dimensional transfer-matrix optical simulations.
The wings of the moth Cacostatia ossa (Ctenuchinae) are covered on both sides by non-close-packed nipple arrays which are known to act as broadband antireflection coatings. Experimental evaluation of the antireflection property of these biological structures is problematic because of the lack of a proper reference for reflectance measurements, i.e., a smooth surface made of the same material as the wing. Theoretical evaluation, on the other hand, is much more reliable provided that optical simulations are carried out on a realistic structural model of the wing. Based on detailed morphological characterizations, we established a three-dimensional (3D) model of the wing and used 3D transfer-matrix optical simulations in order to demonstrate the broadband antireflection property of the wings of Cacostatia ossa. Differences between hemispherical and specular reflectance spectra revealed that diffraction effects were not negligible for this structure although they did not jeopardize the antireflection efficiency. The influences of the backside corrugation and of the material's absorption on the reflectance spectrum were also studied. In addition, simulations based on an effective-medium model of the wing were carried out using a multilayer thin-film code. In comparison with the latter simulations, the 3D transfer-matrix simulations were found to be more accurate for evaluating the antireflection property.


Randomized controlled trials for Alzheimer disease and Parkinson disease.
The continuous increase in elderly and oldest-old population, and subsequent rise in prevalence of chronic neurological diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), are a major challenge for healthcare systems. These two conditions are the most prevalent neurodegenerative diseases in older persons and physicians should engage treatment for these patients. In this field, Randomized Clinical Trials (RCTs) specifically focused on elderly populations are still lacking. The aim of this study was to identify RCTs conducted among AD and PD and to examine the difference between mean age of enrollment and incidence of these two neurodegenerative diseases. We found that the scenario is different between PD and AD. In particular, the enrollment for PD trials seems to include younger persons than AD, although the incidence of both diseases is similar and highest after 80 years old. The consequence of these results could influence conclusive guidelines of treatment in older parkinsonian patients.


Leptin: pharmacological aspects in gynecology.
Hematic levels of leptin vary in relation to numerous metabolic factors and are able to interact in perfect synchrony with the hormones involved in the hypothalamus-pituitary-ovarian axis during the various phases of the reproductive cycle. In general it is maintained that the complex and multiple action mechanisms of leptin need to be clarified by further in-depth research studies. It is likely that valid pharmacological applications of leptin will be found for human use although it is too premature to talk about concrete pharmacological answers and to formulate the relative complete technical protocols. In medicine the therapeutic use of leptin for humans has been reported in only a few cases. In fact human recombinant leptin has already been administered in gynecology for hypothalamic amenorrhea with precise protocols. In addition, very recent studies have provided the basis for new strategies to be developed concerning the use of leptin to fight multiple sclerosis. At present there are considerable technical and economic problems in the production of leptin on a large scale. Most likely these problems will be overcome in the foreseeable future, and will involve new techniques related to genetics, cellular reprograming, and stem cells. In fact, new pharmacogenetic research has provided encouraging results for the production in industrial quantities of a more effective and fail-proof leptin. Even considering that norms have not yet been proposed for pharmacological interventions with leptin for use directly on humans, in our work we have studied by immunohistochemistry methods the distribution of leptin and its receptor (Ob-R) in the ovaries of the female dog as a biological model, in the pre- and postpubertal phases and in other phases of the ovarian cycle. Given the hypothesis that the information obtained from immunohistochemical localization of the hormone and its receptor in various ovarian structures is transferable to humans, it could be useful to define therapeutic protocols based on the effective role of leptin and its receptor in folliculogenesis.


Fermentable Dietary Fiber Promotes Helminth Infection and Exacerbates Host Inflammatory Responses.
Fermentable dietary fibers promote the growth of beneficial bacteria, can enhance mucosal barrier integrity, and reduce chronic inflammation. However, effects on intestinal type 2 immune function remain unclear. In this study, we used the murine whipworm Trichuris muris to investigate the effect of the fermentable fiber inulin on host responses to infection regimes that promote distinct Th1 and Th2 responses in C57BL/6 mice. In uninfected mice, dietary inulin stimulated the growth of beneficial bacteria, such as Bifidobacterium (Actinobacteria) and Akkermansia (Verrucomicrobia). Despite this, inulin prevented worm expulsion in normally resistant mice, instead resulting in chronic infection, whereas mice fed an equivalent amount of nonfermentable fiber (cellulose) expelled worms normally. Lack of expulsion in the mice fed inulin was accompanied by a significantly Th1-skewed immune profile characterized by increased T-bet+ T cells and IFN-γ production in mesenteric lymph nodes, increased expression of Ido1 in the cecum, and a complete absence of mast cell and IgE production. Furthermore, the combination of dietary inulin and high-dose T. muris infection caused marked dysbiosis, with expansion of the Firmicutes and Proteobacteria phyla, near elimination of Bacteroidetes, and marked reductions in cecal short-chain fatty acids. Neutralization of IFN-γ during infection abrogated Ido1 expression and was sufficient to restore IgE production and worm expulsion in inulin-fed mice. Our results indicate that, whereas inulin promoted gut health in otherwise healthy mice, during T. muris infection, it exacerbated inflammatory responses and dysbiosis. Thus, the positive effects of fermentable fiber on gut inflammation appear to be context dependent, revealing a novel interaction between diet and infection.


Somatodendritic 5-hydroxytryptamine1A (5-HT1A) autoreceptor function in major depression as assessed using the shift in electroencephalographic frequency spectrum with buspirone.
Positron emission tomography and post-mortem studies of the number of somatodendritic 5-hydroxytryptamine(1A) (5-HT(1A)) autoreceptors in raphé nuclei have found both increases and decreases in depression. However, recent genetic studies suggest they may be increased in number and/or function. The current study examined the effect of buspirone on the electroencephalographic (EEG) centroid frequency, a putative index of somatodendritic 5-HT(1A) receptor functional status, in a cohort of medication-free depressed patients and controls. A total of 15 depressed patients (nine male) and intelligence quotient (IQ)-, gender- and age-matched healthy controls had resting EEG recorded from 29 scalp electrodes prior to and 30, 60 and 90 min after oral buspirone (30 mg) administration. The effect of buspirone on somatodendritic 5-HT(1A) receptors was assessed by calculating the EEG centroid frequency between 6 and 10.5 Hz. The effect of buspirone on postsynaptic 5-HT(1A) receptors was assessed by measuring plasma growth hormone, prolactin and cortisol concentrations. Analysis of variance revealed a significantly greater effect of buspirone on the EEG centroid frequency in patients compared with controls (F1,28 = 6.55, p = 0.016). There was no significant difference in the neuroendocrine responses between the two groups. These findings are consistent with an increase in the functional status of somatodendritic, but not postsynaptic, 5-HT1A autoreceptors, in medication-free depressed patients in line with hypotheses based on genetic data. This increase in functional status would be hypothesized to lead to an increase in serotonergic negative feedback, and hence decreased release of 5-HT at raphé projection sites, in depressed patients.


Variant antigen genes of Trypanosoma brucei: genomic alteration of a spliced leader orphon and retention of expression-linked copies during differentiation.
Variant surface glycoprotein (VSG) gene expression in Trypanosoma brucei involves not only the sequential activation of individual VSG genes during mammalian bloodstream stage antigenic variation but also the regulation of gene expression during cyclic transmission through alternate mammalian and insect hosts. In the bloodstream stage, transcriptional activation of many VSG genes is correlated with the appearance of an additional copy of the gene in a novel genomic location, the expression-linked copy. The parasite loses the ability to synthesize VSG during differentiation from mammalian bloodstream to insect procyclic stage. Five different bloodstream populations were individually converted to procyclic forms. In each case, the procyclic cells retained the expression-linked copy of the bloodstream parent, and it remained in the same immediate genomic context. Transcripts homologous to the VSG structural gene exon were found in bloodstream stage RNA but not in procyclic RNA. Nevertheless, transcripts containing sequences homologous to the VSG mRNA spliced leader were abundant in both procyclic and bloodstream stage cells. When the genomic organization of sequences homologous to the VSG leader was examined, a specific alteration correlated with procylic differentiation was found. These data are discussed in light of biological studies on antigenic variation.


Spatio-temporal variation in click production rates of beaked whales: Implications for passive acoustic density estimation.
Passive acoustic monitoring has become an increasingly prevalent tool for estimating density of marine mammals, such as beaked whales, which vocalize often but are difficult to survey visually. Counts of acoustic cues (e.g., vocalizations), when corrected for detection probability, can be translated into animal density estimates by applying an individual cue production rate multiplier. It is essential to understand variation in these rates to avoid biased estimates. The most direct way to measure cue production rate is with animal-mounted acoustic recorders. This study utilized data from sound recording tags deployed on Blainville's (Mesoplodon densirostris, 19 deployments) and Cuvier's (Ziphius cavirostris, 16 deployments) beaked whales, in two locations per species, to explore spatial and temporal variation in click production rates. No spatial or temporal variation was detected within the average click production rate of Blainville's beaked whales when calculated over dive cycles (including silent periods between dives); however, spatial variation was detected when averaged only over vocal periods. Cuvier's beaked whales exhibited significant spatial and temporal variation in click production rates within vocal periods and when silent periods were included. This evidence of variation emphasizes the need to utilize appropriate cue production rates when estimating density from passive acoustic data.


Renal cell cancer metastases to esophagus and stomach successfully treated with radiotherapy and pazopanib.
Renal cell cancer has been rarely reported as a cause of gastric or esophageal metastases. They usually present with gastrointestinal bleeding and most cases have been managed surgically or endoscopically. We report the case of a 38-year-old man with a 4-year history of metastatic renal cell carcinoma admitted to the emergency room with melena and anemia. At endoscopy, three esophageal polypoid lesions (middle and distal thirds) and a 7 cm mass in the gastric fundus were identified. Biopsy revealed esophageal mucosa infiltrated by renal cell carcinoma. Radiotherapy was administered (30 Gy in 10 fractions), followed by pazopanib, with excellent tolerance and without new bleeding episodes. Computed tomography scan showed complete disappearance of the esophageal and fundic lesions at 3 months follow-up. Twenty-four months after being initiated on pazopanib, there is no radiological evidence of disease. This is the first reported case showing complete remission of gastric and esophageal metastases after treatment with radiotherapy and pazopanib.


[Optimization of alcohol precipitation technology of Biqiu granules based on index components and pharmacodynamics].
To evaluate the rationality of alcohol precipitation technology of Biqiu granule by investigating its effect on serum histamine, IgE, IL-4, IFN and TNF-α. The contents of cafferic acid and rosmarinic acid were used as the evaluation indexes, and some factors affecting index were firstly evaluated by Plackett-Burman design; then alcohol precipitation technology was further optimized by Box-Behnken design to determine the optimal alcohol precipitation conditions. The best alcohol precipitation conditions were as follows: the relative density of herb liquor was 1.15 (65 ℃); the concentration of alcohol was 70%, and standing time was 12 hours. Optimal alcohol precipitation technology of Biqiu granules determined by pharmacodynamic screening, Plackett-Burman and Box-Behnken design tests, was stable and feasible with good predictability, providing reliable basis for the industrialization production of Biqiu granules.


Influence of Different Measurements on the Ability of P-SAP and DES-OSA Scores to Detect Severe Obstructive Sleep Apnea.
Severe obstructive sleep apnea (sOSA) represents a risk factor of postoperative complications. Perioperative sleep apnea prediction (P-SAP) and DES-obstructive sleep apnea (DES-OSA) (DES being the acronym for 2 of the participating investigators and OSA for obstructive sleep apnea) scores were validated in the detection of such patients. They include the measurement of neck circumference (NC) and distance between thyroid and chin (DTC). The aim of this study was to evaluate the influence of the measurement method of NC and DTC on the ability of the 2 scores to detect sOSA. A total of 371 preoperative patients were enrolled. For each of them, 6 combinations of P-SAP and DES-OSA scores were evaluated. We compared the results of the 6 combinations with the data extracted from the polysomnography (PSG) if available. The ability of the score to detect sOSA patients was evaluated using sensitivity (Se), specificity (Sp), Youden index (YI), area under receiver operating characteristic curve (AUROC), the Probit model, and the Kappa coefficient of Cohen. A P < .05 was considered as significant, a Bonferroni correction was applied if needed. Three hundred and seventy-one patients had a PSG. The Se and the Sp of the DES-OSA score, and the Sp of the P-SAP score, in their ability to detect severe OSA patients, were influenced by the measurement method of the DTC and of the NC. Nevertheless, the AUROC, the Youden index, the Probit model, and the Kappa coefficient of Cohen are not influenced by the variability of measurement. This study highlights that the measurement method of NC and DTC can influence the results of the 2 scores. We conclude that a strict protocol for the measurement of NC and DTC should be applied (DTC measurement should be performed on a patient with a head in neutral position and the NC measurement should be performed at the cricoid level).


Influence of particle size and concentration on the diffuse backscattering of polarized light from tissue phantoms and biological cell suspensions.
We present experimental results that show the spatial variations of the diffuse-backscattered intensity when linearly polarized light is incident upon highly scattering media. Experiments on polystyrene-sphere and Intralipid suspensions demonstrate that the radial and azimuthal variations of the observed pattern depend on the concentration, size, and anisotropy factor g of the particles that constitute the scattering medium. Measurements performed on biological-cell suspensions show the potential of this method for cell characterization.


Brazilian spotted fever in cart horses in a non-endemic area in Southern Brazil.
Brazilian Spotted Fever (BSF) is an often fatal zoonosis caused by the obligate intracellular bacterium Rickettsia rickettsii. The disease is generally transmitted to humans by Amblyomma spp. ticks. Serological evidence of past infection by R. rickettsii has been reported in horses, but the pathogenicity of R. rickettsii in horses remains unknown. Cart horses are still widely used in urban and urban fringe areas in Brazil, and these animals may constitute suitable sentinels for BSF human in these areas, for example, in Sao Jose dos Pinhais, where the first BSF human case in the state of Parana was diagnosed. Serum samples were randomly obtained from 75 cart horses between April 2005 and June 2006 and were tested by means of the indirect immunofluorescence assay (IFA) for antibodies against rickettsia of the spotted fever group. A total of 9.33% of the animals were considered positive, with titers ranging from 64 to 1,024. These results indicate the presence of the agent in such areas, although at low rates.


Antibody-antigen binding kinetics. A model for multivalency antibodies for large antigen systems.
This work presents a theoretical analysis of the influence of multivalency of antigen on external mass transfer-limited binding kinetics to divalent antibody for biosensor applications to polycyclic-aromatic systems. Both cases are considered wherein the antigen is in solution and the antibody is either covalently or noncovalently attached to a cylindrical fiber-optic biosensor, and the antibody is in solution and the antigen is attached to the surface. Both single-step and dual-step binding processes are considered. The rate of attachment of antigen to antibody (or vice versa) is linear for the valencies (or reaction orders) analyzed in the time frame (100 min) considered. The rate of attainment of saturation levels of antigen or antibody in solution close to the surface is very rapid (within 20 min). An increase in the valency of the antigen in solution has the effect of decreasing the order of reaction (for valency, v > or = 1). An increase in the number of steps increases the order of reaction, as expected. An increase in the valency of the antigen in solution decreases the saturation level of the antigen close to the surface and the rate of antigen attachment to the antibody on the surface for all Damkohler numbers. A decrease in the diffusional limitations decreases the effect of valency (or reaction order) on saturation levels of Cs/C0. Nondimensional plots presented in the analysis help extend the analysis to different antigen-antibody systems. An increase in the valency of the antibody in solution has the effect of increasing the order of reaction (for v > 2). The effects in this case are reverse to those described earlier. For valency greater than 2, the reaction order is dependent on the antigen valency, whether it is in solution or immobilized on the surface. The general analysis presented here should be applicable to most surface reactions that involve ligand-receptor binding wherein multiple-binding sites are involved on either the receptor or the ligand.


Cathepsin S and Protease-Activated Receptor-2 Drive Alloimmunity and Immune Regulation in Kidney Allograft Rejection.
Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate protease-activated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed Cat-S expression in intrarenal mononuclear phagocytes. In vitro, Cat-S inhibition suppressed CD4 + T cell lymphocyte activation in a mixed lymphocyte assay. In vivo, we employed a mouse model of kidney transplantation that showed preemptive Cat-S inhibition significantly protected allografts from tubulitis and intimal arteritis. To determine the contribution of PAR-2 activation, first, Balb/c donor kidneys were transplanted into Balb/c recipient mice without signs of rejection at day 10. In contrast, kidneys from C57BL/6J donor mice revealed severe intimal arteritis, tubulitis, interstitial inflammation, and glomerulitis. Kidneys from Par2-deficient C57BL/6J mice revealed partial protection from tubulitis and lower intrarenal expression levels for Fasl, Tnfa, Ccl5, and Ccr5. Together, we conclude that Cat-S and PAR-2 contribute to immune dysregulation and kidney allograft rejection, possibly involving Cat-S-mediated activation of PAR-2 on recipient parenchymal cells in the allograft.


[Definition of 'quack' in the public debate on alternative medicine].
In May 1999 the Amsterdam Court of Justice decided that a retired internist and propagandist of his own alternative cancer therapy, could rightfully be called a quack by his critics. Recently this judgment was reversed on appeal. The first court used the medical definition of quackery: a treatment of which the supposed benefits are unsubstantiated. The court of appeal, however, took into consideration that to the general public calling someone a quack is an indication that this person is a swindler and practises medicine unlawfully. This definition is supported by the most authoritative Dutch dictionary. Apparently a different semantic interpretation of the term quack has led to these strongly diverging verdicts. The terms quack and quackery are indispensable in the public debate on alternative medicine.


Elastofibroma dorsi: ultrasound pattern in three patients.
Elastofibroma dorsi is a rare benign tumor with a prevalence in the female population. The tumor is composed of adipose and fibrous tissue. It is typically localized at the tip of the scapular and is more frequently bilateral. Even if there are only very few reports on this topic, the incidence of the tumor seems to be less rare than expected. Elastofibroma dorsi was identified in 1961 and the first study using diagnostic ultrasound technique was published in 1996, however, since then no other major work has been produced. The purpose of the paper is to present three cases of elastofibroma dorsi, all studied by ultrasound imaging, including color and power Doppler, and by fine needle aspiration biopsy. Furthermore, in one case i.v. contrast media (Levovist) was used, and in two cases a CT and MRI evaluation was also made. Surgical excision was not performed in any of the cases. The relevant follow up was performed by clinical and ultrasound tests. In all the cases the ultrasound pattern of the elastofibroma dorsi was very similar to the surrounding muscular tissue, and neither a clear cleavage surface nor a specific vascular pattern could be evidenced. The tumor was very difficult to define from the surrounding tissue, except for a more evident coarse pattern and the same happened for the CT and MR, where a layered pattern of fatty tissue was noted. In this small cohort the tumor was mainly monolateral. The ultrasound investigation, integrated with color and power Doppler permitted a correct diagnosis, which was confirmed by the fine needle biopsy. Therefore, the less expensive ultrasound diagnosis, as a major method of screening for elastofibroma dorsi, would seem to be a reasonable proposal.


Oral contraceptives, depressive and insomnia symptoms in adult women with and without depression.
Worldwide, oral contraceptive (OC) use is a very common form of birth control, although it has been associated with symptoms of depression and insomnia. Insomnia is a risk factor for major depressive disorder (MDD) but may also be a symptom of the disorder. Despite the large number of women who use OC, it is yet unknown whether women with previous or current diagnosis of depression are more likely to experience more severe depressive and insomnia symptoms during concurrent OC use than women without diagnosis of depression. This study examined associations between OC use and concurrent symptoms of depression (including atypical depression) and insomnia as well as between OC and prevalences of concurrent dysthymia and MDD. Participants were adult women with and without a history of MDD or dysthymia. We hypothesized that OC use is associated with concurrent increased severity of depressive symptoms and insomnia symptoms, as well as with an increased prevalence of concurrent diagnoses of dysthymia and MDD. We also hypothesized that a history of MDD or dysthymia moderates the relationship between OC use and depressive and insomnia symptoms. Measurements from premenopausal adult women from the Netherlands Study of Depression and Anxiety (NESDA) were grouped, based on whether participants were using OC or naturally cycling (NC). OC use, timing and regularity of the menstrual cycle were assessed with a structured interview, self-reported symptoms of depression (including atypical depression), insomnia with validated questionnaires, and MDD and dysthymia with structured diagnostic interviews. We included a total of 1301 measurements in women who reported OC use and 1913 measurements in NC women (mean age 35.6, 49.8% and 28.9% of measurements in women with a previous depression or current depression, respectively). Linear mixed models showed that overall, OC use was neither associated with more severe depressive symptoms (including atypical depressive symptoms), nor with higher prevalence of diagnoses of MDD or dysthymia. However, by disentangling the amalgamated overall effect, within-person estimates indicated increased depressive symptoms and depressive disorder prevalence during OC use, whereas between-person estimated indicated lower depressive symptoms and prevalence of depressive disorders. OC use was consistently associated with more severe concurrent insomnia symptoms, in the overall estimates as well as in the within-person and between-person estimates. Presence of current or previous MDD or dysthymia did not moderate the associations between OC use and depressive or insomnia symptoms. The study findings showed consistent associations between OC use and more severe insomnia symptoms, but no consistent associations between OC and depressive symptoms or diagnoses. Instead, post-hoc analyses showed that associations between OC and depression differed between within- and between person-estimates. This indicates that, although OC shows no associations on the overall level, some individuals might experience OC-associated mood symptoms. Our findings underscore the importance of accounting for individual differences in experiences during OC use. Furthermore, it raises new questions about mechanisms underlying associations between OC, depression and insomnia.


[A comparative study of two mental health services: relationships between popular participation and social representations related to the right to health].
The present paper originated from a qualitative study that analyzed social representations related to the right to health, expressed by users of two types of mental health services, one with participation by users and families and the other without such participation. The aim was to analyze such representations not only in relation to the awareness of the right to health, but also concerning associated factors, such as: popular participation; illness; public health care; perception of social intervention capacity; and concepts concerning the state. Social representations of the right to health involve expectations that the health system and the state meet their roles of ensuring care and support. Users of the mental health service without user/family participation tended to be more resigned and pessimistic. The group with participation views the service it has built as having characteristics denied by the official system and view advocacy as a possible alternative focus for forming new social representations.


Neutron yields from 155 MeV/nucleon carbon and helium stopping in aluminum.
Neutron fluences have been measured from 155 MeV/nucleon 4He and 12C ions stopping in an Al target at laboratory angles between 10 and 160 deg. The resultant spectra were integrated over angle and energy above 10 MeV to produce total neutron yields. Comparison of the two systems shows that approximately two times as many neutrons are produced from 155 MeV/nucleon 4He stopping in Al and 155 MeV/nucleon 12C stopping in Al. Using an energy-dependent geometric cross-section formula to calculate the expected number of primary nuclear interactions shows that the 12C + Al system has, within uncertainties, the same number of neutrons per interaction (0.99 +/- 0.03) as does the 4He + Al system (1.02 +/- 0.04), despite the fact that 12C has three times as many neutrons as does 4He. Energy and angular distributions for both systems are also reported. No major differences can be seen between the two systems in those distributions, except for the overall magnitude. Where possible, the 4He + Al spectra are compared with previously measured spectra from 160 and 177.5 MeV/nucleon 4He interactions in a variety of stopping targets. The reported spectra are consistent with previously measured spectra. The data were acquired to provide data applicable to problems dealing with the determination of the radiation risk to humans engaged in long-term missions in space; however, the data are also of interest for issues related to the determination of the radiation environment in high-altitude flight, with shielding at high-energy heavy-ion accelerators and with doses delivered outside tumor sites treated with high-energy hadronic beams.


Targeting mixed lineage kinases in ER-positive breast cancer cells leads to G2/M cell cycle arrest and apoptosis.
Estrogen receptor (ER)-positive tumors represent the most common type of breast cancer, and ER-targeted therapies such as antiestrogens and aromatase inhibitors have therefore been widely used in breast cancer treatment. While many patients have benefited from these therapies, both innate and acquired resistance continue to be causes of treatment failure. Novel targeted therapeutics that could be used alone or in combination with endocrine agents to treat resistant tumors or to prevent their development are therefore needed. In this report, we examined the effects of inhibiting mixed-lineage kinase (MLK) activity on ER-positive breast cancer cells and non-tumorigenic mammary epithelial cells. Inhibition of MLK activity with the pan-MLK inhibitor CEP-1347 blocked cell cycle progression in G2 and early M phase, and induced apoptosis in three ER-positive breast cancer cell lines, including one with acquired antiestrogen resistance. In contrast, it had no effect on the cell cycle or apoptosis in two non-tumorigenic mammary epithelial cell lines. CEP-1347 treatment did not decrease the level of active ERK or p38 in any of the cell lines tested. However, it resulted in decreased JNK and NF-κB activity in the breast cancer cell lines. A JNK inhibitor mimicked the effects of CEP-1347 in breast cancer cells, and overexpression of c-Jun rescued CEP-1347-induced Bax expression. These results indicate that proliferation and survival of ER-positive breast cancer cells are highly dependent on MLK activity, and suggest that MLK inhibitors may have therapeutic efficacy for ER-positive breast tumors, including ones that are resistant to current endocrine therapies.


Phase Behavior of Poly(ethylene oxide) in Room Temperature Ionic Liquids: A Molecular Simulation and Deep Neural Network Study.
The phase behavior of polymers in room temperature ionic liquids is a topic of considerable interest. In this work we study the phase diagram of poly(ethylene oxide) in four imidazolium ionic liquids (ILs) using molecular simulation. We develop united atom models for 1-butyl-2,3-dimethylimidazolium ([BMMIM]), 1-ethyl-2,3-dimethylimidazolium ([EMMIM]), and 1-ethyl-3-methylimidazolium ([EMIM]) in an analogous fashion to previously developed models for 1-butyl-3-methylimidazolium ([BMIM]) and tetrafluoroborate ([BF4]) using symmetry-adapted perturbation theory. At high temperatures we obtain the coexistence concentrations using an interface method where the polymer and IL are simulated in a large elongated box, and an interface between coexisting phases is formed. At lower temperatures we use a deep neural network (DNN) method. The input descriptors for the DNN are the cohesive energy of mixing, the volume change of mixing, and the coordination numbers between cation and polymer, all of which are obtained from simulations of mixed systems at a series of temperatures. The DNN is trained by using the phase-separated systems at high temperatures and a mixed phase at low temperatures. The method predicts a lower critical solution temperature which decreases as the alkyl chain length on the cation is decreased, consistent with experiment. The simulations show that methylation of the cation has little effect on the phase diagram. This is in contrast to what is seen in experiments but could be because the polymer chains in the simulations are too short. At low temperatures the chains display two conformational motifs, namely a crown ether conformation and a ring conformation, each of which can wrap the chain around a single cation. This provides the entropic penalty for mixing and a reason for demixing as the temperature is raised. Such conformations might not be possible for longer chains. The combination of data-driven techniques and molecular simulation shows promise in the study of the phase behavior and physical properties of complex fluids.


Scientific impact increases when researchers publish in open access and international collaboration: A bibliometric analysis on poverty-related disease papers.
The European & Developing Countries Clinical Trials Partnership (EDCTP), like many other research funders, requires its grantees to make papers available via open access (OA). This article investigates the effect of publishing in OA journals and international collaboration within and between European and sub-Saharan African countries on citation impact and likelihood of falling into the top 1% and top 10% most cited papers in poverty-related disease (PRD) research. Disease-specific research publications were identified in the Web of Science™ and MEDLINE using Medical Subject Heading (MeSH) terms. Data on the open accessibility of scientific literature were derived from 1science oaFindr. Publication data, including relative citation counts, were extracted for 2003-2015. Regression models were applied to quantify the relationship between relative citations and presence in the 1% and top 10% most cited papers versus OA and international collaboration. The results show that since 2003 papers on PRDs have become increasingly available in OA. Among all PRD areas, malaria research is most frequently published in OA and in international collaboration. The adjusted regression analyses show that holding other factors constant, publishing research in OA and in international collaboration has a significant and meaningful citation advantage over non-OA or non-international collaborative research. Publishing papers as part of a European-wide or European- sub-Saharan African collaboration increases research impact. In contrast, such collaboration advantage is not observed for research output involving sub-Saharan Africa only which seems to decrease research impact. Our results indicate that there is a real, measurable citation advantage for publishing PRD research in OA and international collaboration. However, the international collaboration advantage seems to be region-specific with increased research impact for European-wide and European-sub-Saharan African collaborations but a decrease in research impact of collaborations confined to sub-Saharan African research institutions. Further research is required to further verify this finding and to understand the underlying factors related to this observed decrease in research impact. To target future research capacity building activities in sub-Saharan Africa it is important to assess whether the observed decreased impact reflects the scientific competencies and geographic distribution of individual researchers or institutional-, national- or funder-specific research requirements.


[Deep neck abscess. Factors related to reoperation and mortality].
Deep neck abscesses are major complications that arise of odontogenic, pharyngeal, or cervicofacial foci, mainly in patients with morbidities that facilitate the spread to other spaces. Many of them require surgical treatment, and an appropriate evaluation and surgical drainage is required to obtain the best results. To identify factors which relate to reoperation and mortality in patient submitted to surgical treatment due to deep neck abscess. Review of all patients with deep neck abscess who underwent surgical treatment in a Head and Neck Surgery Department in a third-level hospital during a two year period. There were 87 patients, 44 of which were female. The median age was 49 years old. Thirty-five patients (40%) had comorbidities, diabetes mellitus being the most common, found in 30 (34%) patients. Twenty-one patients (24%) required reoperation (primarily due to inadequate surgical drainage). The risk factors identified with it were presence of comorbidities (mainly diabetes mellitus) (p< 0.05), multiple deep neck spaces involvement (p< 0.001) and an ASA score of three or above (p< 0.01). Eight patients died, for a mortality of 9%. The factors related to mortality were multiple deep neck spaces involvement (p< 0.01), bilateral involvement (p< 0.05) and reoperation (p< 0.001). Deep neck abscesses appropriate evaluation and a complete surgical drainage of all deep space neck abscesses are primordial to avoid reoperation and improve survival.


Injuries in female football players in top-level international tournaments.
Despite the growing popularity of women's football and the increasing number of female players, there has been little research on injuries sustained by female football players. Analysis of the incidence, characteristics and circumstances of injury in elite female football players in top-level international tournaments. Prospective survey. Injuries incurred in seven international football tournaments were analysed using an established injury report system. Doctors of all participating teams reported all injuries after each match on a standardised injury reporting form. The mean response rate was 95%. 387 injuries were reported from 174 matches, equivalent to an incidence of 67.4 injuries/1000 player hours (95% CI 60.7 to 74.1) or 2.2 injuries/match (95% CI 2.0 to 2.4). Most injuries (84%; 317/378) were caused by contact with another player. The injuries most commonly involved the lower extremity (n = 248; 65%), followed by injuries of the head and neck (n = 67, 18%), trunk (n = 33, 9%) and upper extremity (n = 32, 8%). Contusions (n = 166; 45%) were the most frequent type of injury, followed by sprains or ligament rupture (n = 96; 26%) and strains or muscle fibre ruptures (n = 31; 8%). The most common diagnosis was an ankle sprain. There were 7 ligament ruptures and 15 sprains of the knee. On average 1 injury/match (95% CI 0.8 to 1.2) was expected to result in absence from a match or training. The injury rate in women's top-level tournaments was within the range reported previously for match injuries in elite male and female players. However, the diagnoses and mechanisms of injury among the female players differed substantially from those previously reported in male football players.


Anti-basement membrane glomerulopathy in experimental trypanosomiasis.
The nature of kidney lesions in BD IX rats infected with Trypanosoma brucei was investigated. Proteinuria developed and increased up to 236 +/- 35 mg/24 hr at 7 wk after the infection. Antibodies were found to be deposited along the glomerular basement membrane (GBM) predominantly in a linear fashion, which changed to a more granular pattern 7 wk after the infection. At this stage of the disease, electron-dense deposits were found subendothelially along the GBM. In the sera and kidney eluates of diseased rats, anti-GBM antibodies were present. Enzyme-linked immunosorbent assay (ELISA) studies showed antibodies which reacted with GBM components laminin and type IV collagen and not with fibronectin. The antibody specificity was confirmed by using competitive and cross-absorption ELISA techniques, as well as immunoblotting. With the use of indirect immunofluorescence, no common antigenic sites were found on trypanosomes and GBM components. The observed linear immunofluorescence pattern seems to be caused by glomerular binding of antibodies directed against laminin and type IV collagen, which are known to be able to induce renal disease. Subendothelial complex formation in later stages of the disease might result from a molecular rearrangement of GBM components after in situ binding of the antibodies. The formation of auto-antibodies directed against laminin and type IV collagen is probably caused by restricted polyclonal B cell stimulation, a well known feature of trypanosomiasis.


Tissue models of peritoneal fibrosis.
To evaluate the utility of peritoneal pathologic samples, unrelated to peritoneal dialysis (PD) treatment, for the study of peritoneal fibrosis and inflammation. Comparative morphologic and immunohistochemical study of peritoneal pathologic samples unrelated to PD with peritoneal biopsies from PD patients with special emphasis on the expression of myofibroblastic and epithelial-to-mesenchymal transition markers. Regarding morphology, PD-related simple fibrosis was less cellular, with greater stromal hyalinization, determining a homogeneous, hypocellular aspect of the submesothelium. In contrast, non-PD fibrosis was more cellular with an extracellular matrix showing a dense and fibrillar quality with wide bundles of collagen. Hylinazing vasculopathy was only present in PD samples. Myofibroblastic differentiation and epithelial-to-mesenchymal transition were common findings in all situations of peritoneal fibrosis. Calponin and calretinin are useful cellular markers to study such fibrogenic mechanisms and correlate with other well-known markers such as a -SMA and cytokeratins. Their expression was much more intense in those samples showing acute inflammation (peritonitis). Non-PD models of peritoneal fibrosis seem very useful to evaluate important features of human peritoneal pathology such us fibrogenesis, and inflammation. Fibrogenic events such as myofibroblastic differentiation and epithelial-to-mesenchymal transition are evident in these tissue samples allowing us to use them as an accessible source for in vivo and ex vivo studies. Both events show their maximal expression in situations of acute inflammation supporting the important role that peritonitis episodes play in the progression of fibrosis.


High-resolution physicochemical characterization of different intravenous immunoglobulin products.
Intravenous immunoglobulin (IVIg) is a complex mixture drug comprising diverse immunoglobulins and non-IgG proteins purified from the plasma of thousands of healthy donors. Approved IVIg products on the market differ regarding source of plasma, isolation process, and formulation. These products are used widely, and often interchangeably, for the treatment of immunodeficiency and autoimmune and inflammatory diseases, but their mechanisms of action in different indications are not well understood. A primary limitation to understanding the therapeutic relevance of specific components within IVIg has been the limited resolution of analytics historically implemented to characterize its complex mixture. In this study, high-resolution analytics were applied to better understand the composition of IVIg and product variations. We characterized three approved IVIg products: Gammagard®, Privigen®, and Octagam®. Differences in the distribution of molecular weight species, IgG sequence variants, isoforms, glycoforms, and the repertoire of previously reported antibody specificities were identified. We also compared the effect of aging on these products to identify changes in size distribution and posttranslational modifications. This type of characterization may provide insights into the specific factors and components of IVIg that may influence its activity and ultimately lead to optimization of IVIg products for use in autoimmune diseases.


Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders.
We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders.


Hand dermatitis in a prospectively-followed cohort of hairdressing apprentices: final results of the POSH study. Prevention of occupational skin disease in hairdressers.
The incidence of hand dermatitis is high in the hairdressing trade; the individual disease burden is substantial, as are the costs of treatment, workers compensation and retraining programs. To evaluate the risk of developing occupational irritant hand dermatitis associated with several potential risk factors, namely constitution (atopy) and occupational exposure, an observational prospective population-based cohort study set in vocational training schools in northwest Germany, recruiting 2352 hairdressing apprentices, was performed. Unprotected wet work of more than 2 h per day is the major significant risk factor; low ambient absolute humidity is equally associated with a significantly increased risk. Compared to the youngest age group, risk diminishes with increasing age. Constitutional risk factors are difficult to evaluate because of selective dropout of atopic participants. For primary prevention, a population approach, improving working conditions and skin protection for all exposed, appears to be the most beneficial.


Radiation or chemotherapy cystitis with "pseudocarcinomatous" features.
The features of radiation or chemotherapy cystitis mimicking invasive urothelial cancer are not widely known. A search of the consultation files from our institution between January 1996 and September 2003 identified 20 patients with bladder biopsies showing cystitis mimicking invasive urothelial cancer. The mean age at diagnosis was 69 years (range, 40-85 years); 80% were males. Complete history was not available in 1 patient. Seventeen patients had a history of pelvic irradiation (15 prostate cancer and 2 endometrial cancer). Two patients had systemic chemotherapy (1 metastatic colon cancer and 1 mixed connective tissue disease). All patients presented with hematuria. The mean time from radiation and/or chemotherapy to presentation was 27 months (range, 0-84 months). All cases showed epithelial proliferation that mimicked invasive cancer within the lamina propria, with marked proliferation seen in 45% of cases. Mild to moderate nuclear pleomorphism was seen in all cases. A characteristic feature was the presence of pseudoinvasive urothelial nests wrapping around the vessels associated with fibrin deposition. Most cases did not show any mitoses (75%). Ulceration was seen in 39% of cases. All cases showed some degree of hemorrhage, fibrin deposition and fibrin thrombi, fibrosis, and acute and chronic inflammation, with hemosiderin identified in 60% of cases. Edema and vascular congestion were common features (95% and 80%, respectively). Thickened vessels and vascular changes associated with radiation injury were identified in 75% of cases. Seventeen patients were followed for a mean of 9 months (range, 0.25-37 months), and none developed bladder cancer. Radiation or chemotherapy cystitis can show epithelial proliferations that may be confused with invasive urothelial carcinomas. Other findings characteristic of radiation or chemotherapy cystitis, such as hemorrhage, fibrin, and vascular changes, are often seen in association with the epithelial proliferations and are helpful in distinguishing it from invasive cancer. Pathologists must be aware that these changes may be seen with a remote radiation or chemotherapy history, where this information may not be provided or known at the time of the biopsy evaluation.


Amniotic band syndrome and/or limb body wall complex: split or lump.
Six cases of amniotic band syndrome/limb body wall complex were studied in respect to clinicopathologic characteristics. The diagnosis was based on two out of three of the following manifestations: cranio facial clefts; limb body wall defects and amniotic band attachment. Four cases were stillborn and associated with internal defects, including central nervous system. Two cases had facial and limb defects and were live born (3-5 years old at examination). Phenotypic features of the stillborn cases were craniofacial clefting, thoracoabdominoschisis, amputation, ring constriction, amniotic band adhesion, placental adhesions, and internal malformations. Histology of bands revealed fibroconnective tissue as well as flattened epithelial cells together with neuroectodermal elements. Umbilical cord section revealed an abnormal number of vessels. When analyzing the observed data in relation to their etiology, it was found that amniotic disruption, vascular disruption or genetic disruption could explain the amniotic band syndrome/limb body wall complexes, alone or in combinations. A brief review of literature in search of pathogenesis is offered along with an etiopathogenetic model.


Embracing Allied Approaches to Public Health: Luxembourg's Industrial Elites and the Rockefeller Mission against Tuberculosis in France after the First World War.
The Rockefeller Commission for the Prevention of Tuberculosis in France played a key role in public health reforms in post-World War I France. In May 1920, one of the commission's traveling units whose goal was to bring health education to the French departments toured the Grand-Duchy of Luxembourg. This article discusses this ten-day campaign as a trigger for comprehensive public health reforms in Luxembourg. By the 1920s the steel industry had become the country's dominant economic sector, with the conglomerate Arbed as the main employer in constant need of a healthy workforce. A group of Luxembourgian anti-tuberculosis activists, spearheaded by the wife of the country's foremost industrialist, tried to benefit from the Rockefeller projects in France. Throughout the following decades, Luxembourgian anti-tuberculosis activists maintained close contacts with French experts. This article traces the transnational circulation of public health knowledge in the interwar period and elucidates Luxembourg's geostrategic repositioning after World War I.


Nuclear import of the Drosophila Rel protein Dorsal is regulated by phosphorylation.
In Drosophila, dorsal-ventral polarity is determined by a maternally encoded signal transduction pathway that culminates in the graded nuclear localization of the Rel protein, Dorsal. Dorsal is retained in the cytoplasm by the IkappaB protein, Cactus. Signal-dependent phosphorylation of Cactus results in the degradation of Cactus and the nuclear targeting of Dorsal. We present an in-depth study of the functional importance of Dorsal phosphorylation. We find that Dorsal is phosphorylated by the ventral signal while associated with Cactus, and that Dorsal phosphorylation is essential for its nuclear import. In vivo phospholabeling of Dorsal is limited to serine residues in both ovaries and early embryos. A protein bearing mutations in six conserved serines abolishes Dorsal activity, is constitutively cytoplasmic, and appears to eliminate Dorsal phosphorylation, but still interacts with Cactus. Two individual serine-to-alanine mutations produce unexpected results. In a wild-type signaling background, a mutation in the highly conserved PKA site (S312) produces only a weak loss-of-function; however, it completely destabilizes the protein in a cactus mutant background. Significantly, the phosphorylation of another completely conserved serine (S317) regulates the high level of nuclear import found in ventral cells. We conclude that the formation of a wild-type Dorsal nuclear gradient requires the phosphorylation of both Cactus and Dorsal. The strong conservation of the serines suggests that phosphorylation of other Rel proteins is essential for their proper nuclear targeting.


A rare case of hydatid cyst-associated AA amyloidosis and literature review of hydatid cyst-associated nephropathy.
Hydatid disease is an infective picture caused by echinococcus, which progresses with cysts in various organs, especially in the liver. Renal involvement is an unusual location in the course of the disease. Although mostly asymptomatic renal cysts are seen, rarely glomerular or tubular associated nephropathy develops. In addition, the development of amyloidosis has been shown previously in patients with untreated chronic hydatid cysts. We wanted to bring a 27-year-old female patient with a 10-year history of hydatid cyst and AA amyloidosis to the literature. In addition, in our literature review for hydatid disease-associated nephropathies, we brought together data from 12 studies involving a total of 21 cases. Of these cases, 3 were membranous glomerulonephritis (MGN), 5 were, membranoproliferative glomerulonephritis (MPGN), 1 was minimally change disease (MCD), 5 were AA amyloidosis (including our case), 3 were immunoglobulin A nephropathy (IgAN), 1 was tubulointerstitial nephritis (TIN), 1 was chronic kidney disease (CKD), 1 was TIN with mesangioproliferative glomerulonephritis (MesPGN), 1 was TIN with IgAN, 1 was MPGN with immunoglobulin M nephropathy (IgMN). In this way, we wanted to shed light on the relationship between Echinococcus and nephropathy. In this way, we wanted to emphasise the necessity of doing renal examinations in the follow-up of hydatid cyst patients.


Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia.
Arachidonic acid (AA) metabolites are implicated in the oncogenesis of several tumors, including prostate cancer. 15-Lipoxygenase-2 (15-LOX-2) is a novel AA-metabolizing enzyme with a limited tissue distribution, which includes prostate, lung, skin, and cornea. Previous studies have shown that 15-LOX-2 is present in benign prostate secretory cells and reduced in prostate adenocarcinoma and that production of the 15-LOX-2 metabolite 15S-hydroxyeicosatetraenoic acid is reduced in malignant compared with benign prostate. The objective of this study was to determine the frequency with which 15-LOX-2 immunostaining is reduced in prostate carcinoma and to correlate reduced expression with tumor differentiation (grade) and other pathologic parameters in radical prostatectomy specimens. Paraffin immunoperoxidase with a polyclonal antibody specific for 15-LOX-2 was performed on tumors and benign portions from 70 cases, and the percentage of tumor immunostaining for 15-LOX-2 was assessed. Whereas uniform 15-LOX-2 immunostaining was observed in secretory cells of benign glands, it was markedly reduced or absent in most adenocarcinomas: 23 of 70 tumors showed completely absent 15-LOX-2 immunostaining, and 45 of 70 cases showed negative immunostaining in more than 50% of the tumor. The extent of reduced 15-LOX-2 immunostaining correlated with tumor differentiation, with retained expression particularly in Gleason score 5 tumors versus a significant reduction of 15-LOX-2 in higher-grade tumors (mean +/- SD tumor 15-LOX-2 positive: Gleason score 5 = 67%+/-30%, Gleason score 6 = 16%+/-30%, Gleason score 7 = 23%+/-28%, Gleason score > or =8 = 41%+/-46%). In 16 cases with multifocal tumors or different foci of the same tumor with different grades, the higher-grade foci had significantly reduced 15-LOX-2 expression compared with the lower-grade foci. In peripheral zone tumors without complete loss of 15-LOX-2 expression, there was a significant inverse relationship between 15-LOX-2 immunostaining and tumor volume. There was not a significant correlation between 15-LOX-2 immunostaining and serum PSA or pathologic stage. In a subset of 27 cases, 15-LOX-2 expression in high-grade prostatic intraepithelial neoplasia (HGPIN) glands was significantly reduced compared with benign glands. These data show that in contrast to the uniform expression of 15-LOX-2 in differentiated secretory cells of benign prostate, reduced 15-LOX-2 is a common alteration in prostate carcinoma, and this correlates with tumor cell differentiation. That reduced expression is seen in HGPIN suggests that this may be an early alteration in carcinoma development.


Physical activity and risk of atrial fibrillation in the general population: meta-analysis of 23 cohort studies involving about 2 million participants.
Regular physical activity is well established to be associated with reduced risk of cardiovascular disease outcomes. Whether physical activity is associated with the future risk of atrial fibrillation (AF) remains a controversy. Using a systematic review and meta-analysis of published observational cohort studies in general populations with at least one-year of follow-up, we aimed to evaluate the association between regular physical activity and the risk of AF. Relevant studies were sought from inception until October 2020 in MEDLINE, Embase, Web of Science, and manual search of relevant articles. Extracted relative risks (RRs) with 95% confidence intervals (CIs) for the maximum versus the minimal amount of physical activity groups were pooled using random-effects meta-analysis. Quality of the evidence was assessed by GRADE. A total of 23 unique observational cohort studies comprising of 1,930,725 participants and 45,839 AF cases were eligible. The pooled multivariable-adjusted RR (95% CI) for AF comparing the most physically active versus the least physically active groups was 0.99 (0.93-1.05). This association was modified by sex: an increased risk was observed in men: 1.20 (1.02-1.42), with a decreased risk in women: 0.91 (0.84-0.99). The quality of the evidence ranged from low to moderate. Pooled observational cohort studies suggest that the absence of associations reported between regular physical activity and AF risk in previous general population studies and their aggregate analyses could be driven by a sex-specific difference in the associations - an increased risk in men and a decreased risk in women.Systematic review registration: PROSPERO 2020: CRD42020172814.


Intrinsic Functional Boundaries of Lateral Frontal Cortex in the Common Marmoset Monkey.
The common marmoset (Callithrix jacchus) is a small New World primate species that has been recently targeted as a potentially powerful preclinical model of human prefrontal cortex dysfunction. Although the structural boundaries of frontal cortex were described in marmosets at the start of the 20th century (Brodmann, 1909) and refined more recently (Paxinos et al., 2012), the broad functional boundaries of marmoset frontal cortex have yet to be established. In this study, we sought to functionally derive boundaries of the marmoset lateral frontal cortex (LFC) using ultra-high field (9.4 T) resting-state functional magnetic resonance imaging (RS-fMRI). We collected RS-fMRI data in seven (four females, three males) lightly anesthetized marmosets and used a data-driven hierarchical clustering approach to derive subdivisions of the LFC based on intrinsic functional connectivity. We then conducted seed-based analyses to assess the functional connectivity between these clusters and the rest of the brain. The results demonstrated seven distinct functional clusters within the LFC. The functional connectivity patterns of these clusters with the rest of the brain were also found to be distinct and organized along a rostrocaudal gradient, consonant with those found in humans and macaques. Overall, these results support the view that marmosets are a promising preclinical modeling species for studying LFC dysfunction related to neuropsychiatric or neurodegenerative human brain diseases.SIGNIFICANCE STATEMENT The common marmoset is a New World primate that has garnered recent attention as a powerful complement to canonical Old World primate (e.g., macaques) and rodent models (e.g., rats, mice) for preclinical modeling of the human brain in healthy and diseased states. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets, that is, how these circuitries are functionally divided and how those topologies compare to human circuitry. To our knowledge, this is the first study to demonstrate functional boundaries of the lateral frontal cortex and the corresponding network topologies in marmoset monkeys.


Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment.
Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.


Targeting cancer stem cells: protons versus photons.
Recent studies on cancer stem cells revealed they are tumorigenic and able to recapitulate the characteristics of the tumour from which they derive, so that it was suggested that elimination of this population is essential to prevent recurrences after any treatment. However, there is evidence that cancer stem cells are inherently resistant to conventional (photon) radiotherapy. Since the use of proton beam therapy in cancer treatment is growing rapidly worldwide, mainly because of their excellent dosimetric properties, the possibility could be considered that they also have biological advantages through preferential elimination of cancer stem cells.Indeed, a review of preclinical data suggest that protons and photons differ in their biological effects on cancer stem cells, with protons offering potential advantages, although the heterogeneity of cancer stem cells and the different proton irradiation modalities make the comparison of the results not so easy. Further research to understand the mechanisms underlying such effects is important for their possible exploitation in clinics and to perform proton beam therapy optimization.


Color-specific effects of intense laser exposure on visual evoked potentials in rhesus monkeys.
Color-specific visual impairments following exposure to intense laser flashes were investigated using visual evoked potentials (VEPs) recorded from four anesthetized rhesus monkeys. Steady-state VEPs were recorded from the primary visual cortex in response to counterphasing high-contrast sine-wave gratings composed of either luminance contrast (red-black, green-black, and blue-black) or chromatic contrast (red-green). The effects of laser flashes in the red (647 nm), green (514 nm), and blue (476 nm) regions of the visible spectrum were assessed. Only slight wavelength-specific effects were demonstrated, primarily for the red-black grating relative to the other two luminance gratings. Recovery functions for VEPs to the red-green chromatic grating were similar to those of the three luminance gratings. The results are discussed in terms of nonopponent (luminance) and opponent (chromatic) processing.


ReaxFF molecular dynamics simulation of thermal stability of a Cu3(BTC)2 metal-organic framework.
The thermal stability of a dehydrated Cu(3)(BTC)(2) (copper(II) benzene 1,3,5-tricarboxylate) metal-organic framework was studied by molecular dynamics simulation with a ReaxFF reactive force field. The results show that Cu(3)(BTC)(2) is thermally stable up to 565 K. When the temperature increases between 600 K and 700 K, the framework starts to partially collapse. The RDF analysis shows that the long range correlations between Cu dimers disappear, indicating the loss of the main channels of Cu(3)(BTC)(2). When the temperature is above 800 K, we find the decomposition of the Cu(3)(BTC)(2) framework. CO is the major product, and we also observe the release of CO(2), O(2), 1,3,5-benzenetricarboxylate (C(6)H(3)(CO(2))(3), BTC) and glassy carbon. The Cu dimer is stable up to 1100 K, but we find the formation of new copper oxide clusters at 1100 K. These results are consistent with experimental findings, and provide valuable information for future theoretical investigations of Cu(3)(BTC)(2) and its application in adsorption, separation and catalytic processes.


Disodium cromoglycate in immunological mast cell degranulation of mice: an experimental study.
Mast cell degranulation occurs at reproducible percentages when the specific antigen is injected into air bubbles of sensitized mice. A fourfold diminution of the degranulated mast cells was observed when 0.25 cc of a 1% solution of DSCG was injected into the bubble prior to the challenging injection. The difference is statistically significant.


Congenital Lobar Emphysema: An Approach of Anesthetic Management.
Congenital Lobar Emphysema (CLE) is a medical condition which is quiet rarely seen especially in neonates. The disease is characterized by over inflation of lungs which is produced due to inhibition of escape of inspired air from lungs. This condition usually occurs in infants due to partial obstruction of the bronchus and can be reversed with timely and planned anaesthetic management. Here in, we are presenting a case of an infant who was merely four months of age. CLE was affecting his left upper lobe since birth which was being treated as lobar pneumonia outside at some peripheral health center. The case presented to hospital with the symptoms acute respiratory distress and was taken up for urgent surgical management. Left upper lobectomy was performed which relived his symptoms. Case was discharged from hospital after 10 days of uneventful hospital stay. The case was challenging, as it involved careful and planned anaesthetic management of lung separation as well as prevention of hyperventilation of the un-involved lung.