Aggressive angiomyxoma of the inguinal region.
Aggressive angiomyxoma is a distinctive and very rare soft tissue tumor occurring almost exclusively in women. Only seven cases occurring in men have been previously reported. We herein report a case of a 74-year-old man who was admitted to our hospital presenting with a huge right inguinal mass that had grown over a 14-year period, in order to undergo surgical treatment for gastric cancer. The inguinal tumor was well-defined and demonstrated a glistening appearance on the cut surface. Histologically, the tumor was composed of bland-looking spindle and stellate cells with delicate cytoplasmic processes, which sparsely populated the fibromyxoid matrix. A prominent vascular component was also present. Immunohistochemically, the stromal cells stained consistently for vimentin and variably for muscle-specific actin, but not for alpha-smooth muscle actin, desmin, and S-100 protein. The gastric cancer was microscopically diagnosed to be papillary adenocarcinoma with serosal invasion and showing immunoreactivity for p53 protein, but not for aggressive angiomyxoma.


[Consumption habits of apiary products in an elder collective].
The aim of this study was to analyse the consumption habits of bee products such as: honey, bee pollen, royal jelly and propolis in the elderly of different places of Spain. Honey is an energetic food of its own, and it can also help to overcome several diseases; due to its components that have a beneficial effect in our health. These facts turn honey into a valuable constituent of one's nutrition specially in ancient people. This report demonstrates the knowledge and consumption habits of these persons. Date came from a questionnaire about preferences, places where they buy these products, time and amount of consumption, knowledge of the quality of these products, etc. The results suggest that the vast majority of the people inquired are regular consumers of honey and we also would like to underline the high rate of knowledge of its nutritional value and its medicinal qualities. However, most of the elderly inquired do not know about other apiary products such as bee propolis.


On the effects of temperature and pH on tropical and temperate holothurians.
Ocean acidification and increased ocean heat content has direct and indirect effects on marine organisms such as holothurians (sea cucumbers) that are vulnerable to changes in pH and temperature. These environmental factors have the potential to influence organismal performance and fitness at different life stages. Tropical and temperate holothurians are more vulnerable to temperature and pH than those from colder water environments. The high level of environmental variation observed in the oceans could influence organismal responses and even produce a wide spectrum of compensatory physiological mechanisms. It is possible that in these areas, larval survival will decline by up to 50% in response to a reduction of 0.5 pH units. Such reduction in pH may trigger low intrinsic growth rates and affect the sustainability of the resource. Here we describe the individual and combined effects that temperature and pH could produce in these organisms. We also describe how these effects can scale from individuals to the population level by using age-structured spatial models in which depensation can be integrated. The approach shows how physiology can improve the conservation of the resource based on the restriction of growth model parameters and by including a density threshold, below which the fitness of the population, specifically intrinsic growth rate, decreases.


Bronchial artery anatomy: preoperative 3D simulation with multidetector CT.
To preoperatively evaluate anatomic variations of the bronchial arteries by obtaining three-dimensional (3D) simulations with multidetector computed tomography (CT). This study was approved by the institutional review board, and written informed consent was obtained from all participants. Seventy-three consecutive patients with esophageal cancer underwent dynamic multidetector CT. The data were used to generate 3D simulations of the thoracic cavity. These images were then used to evaluate anatomic variations of the bilateral bronchial arteries and the mediastinal course in relation to the esophagus and trachea-bronchi. The preoperative CT findings were correlated with the thoracoscopic findings. CT depicted 118 right bronchial and 105 left bronchial arteries. The right bronchial arteries arose from the intercostal-bronchial trunk (IBT), thoracic aorta, common trunk of both bronchial arteries (CTB), and right subclavian artery in 61, 15, 38, and four cases, respectively, whereas the left bronchial arteries arose from the thoracic aorta, IBT, and CTB in 63, four, and 38 cases, respectively. The right bronchial arteries followed preferential courses through the mediastinum, depending on the parent artery: All 61 right bronchial arteries that arose from the IBT ran along the right side of the esophagus, dorsal to the trachea-main bronchi, whereas the majority of direct-origin and CTB-type right bronchial arteries and all left bronchial arteries ran along the left side of the esophagus. During right thoracoscopy, all bronchial arteries coursing along the right side of the esophagus were identified, whereas those coursing along the left side of the esophagus were frequently out of intraoperative view. Six small right bronchial arteries that were not detected at CT were discovered during surgery. Three-dimensional simulation with multidetector CT yields precise preoperative information regarding the anatomy of the bronchial arteries and their variants.


Interstitial deletion of chromosome 7p detected antenatally.
An interstitial deletion in chromosome 7(p13p15) detected in amniotic fluid cells is presented. After termination, the fetus was noted to have an asymmetrical skull, low set ears, a flattened nose, bifid thumbs and right big toe, pyloric adenomyosis, hypospadias, and simian creases. A brief comparison is made with previously reported cases involving deletions of 7p, including those associated with craniosynostosis.


Peritoneal macrophages are important for the early containment of Enterococcus faecium peritonitis in mice.
The increasing incidence of infections with multi-drug resistant Enterococcus faecium necessitates studies to increase knowledge on the pathogenesis of these infections. In this study, the contribution of peritoneal macrophages during E. faecium peritonitis was investigated. In an ex vivo setting, peritoneal macrophages harvested from C57BL/6 mice were responsive to, and able to phagocytose and kill, E. faecium. In vivo, peritoneal macrophages were depleted by intraperitoneal injection of clodronate-encapsulated liposomes, prior to inducing E. faecium peritonitis. Depletion of resident peritoneal macrophages caused a clear delay in peritoneal clearance of E. faecium with increased systemic dissemination. Mice depleted of peritoneal macrophages were able to recruit macrophages and neutrophils to the peritoneal cavity after infection, comparable to control mice. Furthermore, increased levels of peritoneal cytokines and chemokines were found in mice depleted of peritoneal macrophages. This study indicates that peritoneal macrophages are important in the early containment of E. faecium peritonitis and for the regulation of the inflammatory response.


A spatial-temporal approach for video caption detection and recognition.
We present a video caption detection and recognition system based on a fuzzy-clustering neural network (FCNN) classifier. Using a novel caption-transition detection scheme we locate both spatial and temporal positions of video captions with high precision and efficiency. Then employing several new character segmentation and binarization techniques, we improve the Chinese video-caption recognition accuracy from 13% to 86% on a set of news video captions. As the first attempt on Chinese video-caption recognition, our experiment results are very encouraging.


Diabetic nephropathy and antihypertensive treatment: what are the lessons from clinical trials?
Diabetic nephropathy is the most serious problem among current issues in nephrology, as 40% of the cases of end-stage renal disease are due to this entity. The close relationship between type 2 diabetes and hypertension makes the problem even more severe. The knowledge of the intrarenal effects of angiotensin II and the greater effect of angiotensin converting enzyme inhibitors (ACEI) on reducing albuminuria suggested in the past a trend toward preferable use of these drugs in diabetic nephropathy. The first relevant clinical trials yielded rather poor conclusions because of lack of blind randomization and short duration. Subsequent double-blind studies with adequate numbers of patients and sufficient duration underlined the importance of blood pressure (BP) control as well as the rather poor response of diabetic nephropathy to any treatment. In most of these studies, the changes in albuminuria or microalbuminuria were a substitute end point for the renal function. Three clinical trials using angiotensin II receptor blockers (ARB), planned specifically to monitor the progression of renal damage, have been recently published. They showed better renal protection by ARB, as compared with placebo or calcium channel blockers (CCB), beyond or independently of the BP reduction. Nevertheless, these recent trials, like the previous ones with similar results, invariably demonstrate slightly better control of BP in the groups of the active drug. Another issue is that the vast majority of the patients need so many nonstudy drugs to keep their pressure under control, that the isolation of advantageous effects of certain drugs seems unrealistic.


Trends in Pain Medication Prescriptions and Satisfaction Scores in Spine Surgery Patients at a Single Institution.
As the opioid crisis has gained national attention, there have been increasing efforts to decrease opioid usage. Simultaneously, patient satisfaction has been a crucial metric in the American health care system and has been closely linked to effective pain management in surgical patients. The purpose of this study was to examine rates of pain medication prescription and concurrent patient satisfaction in spine surgery patients. A total of 1729 patients undergoing spine surgery between June 25, 2017, and June 30, 2018, at a single institution by surgeons performing ≥20 surgeries per quarter, with medication data during hospitalization available, were assessed. Patients were evaluated for nonopioid pain medication prescription rates and morphine milligram equivalents (MME) of opioids used during hospitalization. Of the total cohort, 198 patients were evaluated for Press Ganey Satisfaction Survey responses. A χ2 test of independence was used to compare percentages, and 1-way analysis of variance was used to compare means across quarters. The mean total MME per patient hospitalization was 574.46, with no difference between quarters. However, mean MME per day decreased over time (P = .048), with highest mean 91.84 in Quarter 2 and lowest 77.50 in Quarter 4. Among all procedures, acetaminophen, nonsteroidal anti-inflammatory drugs, and steroid prescription rates increased, whereas benzodiazepine and γ-aminobutyric acid-analog prescriptions decreased. There were no significant differences between quarters for mean hospital ratings (P = .521) nor for responses to questions from the Press Ganey Satisfaction Survey regarding how often staff talk about pain (P = .164), how often staff talk about pain treatment (P = .595), or whether patients recommended the hospital (P = .096). There were also no differences between quarters for responses in all other patient satisfaction questions (P value range, .359-.988). Over the studied time period, opioid use decreased and nonopioid prescriptions increased during hospitalization, whereas satisfaction scores remained unchanged. These findings indicate an increasing effort in reducing opioid use among providers and suggest the ability to do so without affecting overall satisfaction rates. 4. The opioid epidemic has highlighted the need to reduce opioid usage in orthopedic spine surgery. This study reviews the trends for inpatient management of post-op pain in orthopedic spine surgery patients in relation to patient satisfaction. There was a significant increase in non-opioid analgesic pain medications, and a reduction in opioids during the study period. During this time, patient satisfaction as measured by Press-Ganey surveys did not show a decrease. This demonstrates that treatment of post-operative pain in orthopedic spine surgery patients can be managed with less opioids, more multimodal analgesia, and patient satisfaction will not be affected.


Comparison of telomerase and CD44 expression as diagnostic tumor markers in lesions of the thyroid.
The analysis of the tissue expression patterns of both the telomerase enzyme and the adhesion molecule CD44 has highlighted these molecules as potential tumor markers. In this study, the expression of these markers was analyzed in frozen tissue samples of the same human thyroid lesions, and the data were compared to evaluate their application to tumor diagnosis. The study analyzed 12 malignant specimens, including 5 papillary, 3 follicular, 2 anaplastic, 1 medullary, and 1 low-grade Hurthle cell carcinoma and 17 specimens from benign lesions, including cases of adenoma, hyperplasia, and Graves' disease. Telomerase expression was analyzed by assay of enzyme activity using the telomeric repeat amplification protocol and by reverse transcription-PCR detection of human telomerase reverse transcriptase (hTERT) mRNA. Nine of 12 (75%) malignant samples and the two Graves' disease samples were evaluated as positive for telomerase activity by the telomeric repeat amplification protocol assay. The presence of hTERT mRNA was detected in 8 (67%) of 12 malignant tissues and in 5 (29%) of 17 benign thyroid tissue samples. The expression of CD44 transcripts containing variant exons 7, 8, and 11 was evaluated by reverse transcription-PCR/Southern blot analysis. Of the 12 malignant samples, 9 (75%) included transcripts containing exon 7, 10 (83%) included transcripts containing exon 11, and 11 (92%) included transcripts containing exon 8. However, these CD44 exons were also present in transcripts in a high proportion of benign samples. Five (28%), 10 (59%), and 6 (35%) benign samples contained CD44 transcripts, including variant exons 7, 8, and 11, respectively. The measurement of telomerase activity proved to be the most specific for the detection of thyroid carcinoma in frozen tissue samples as a single analyte, but diagnostic accuracy was increased by the combination of telomerase and CD44 analyses.


The defining characteristics of Web 2.0 and their potential influence in the online vaccination debate.
The emergence of Web 2.0 has led to more and more Web-based resources demonstrating three defining characteristics: user participation, openness and network effects. This paper discusses these characteristics in the context of the online vaccination debate, explores how they structurally alter the way people might interact with vaccination information online, and describes ways in which such characteristics support particular tendencies in human decision making processes. Specifically, user participation supports the influence of narratives and personal accounts, openness shapes expectations for greater levels of detail and movement toward models of informed decision making, and network effects demonstrate the social nature of decision making, the influence of like-minded others and thus, the pitfalls of polarization in the online vaccination debate. Web 2.0 means that concerns about vaccination information online must expand beyond simply the possibility that people might access information of varying quality to incorporate a more comprehensive understanding of how people use current Web functionality, how such usage influences expectations about information sources and decision making processes, and the implications for communication strategies about vaccination.


Exploring the Incorporation of a Novel Cardiotoxicity Mobile Health App Into Care of Patients With Cancer: Qualitative Study of Patient and Provider Perspectives.
Cardiotoxicity is a limitation of several cancer therapies and early recognition improves outcomes. Symptom-tracking mobile health (mHealth) apps are feasible and beneficial, but key elements for mHealth symptom-tracking to indicate early signs of cardiotoxicity are unknown. We explored considerations for the design of, and implementation into a large academic medical center, an mHealth symptom-tracking tool for early recognition of cardiotoxicity in patients with cancer after cancer therapy initiation. We conducted semistructured interviews of >50% of the providers (oncologists, cardio-oncologists, and radiation oncologists) who manage cancer treatment-related cardiotoxicity in the participating institution (n=11), and either interviews or co-design or both with 6 patients. Data were coded and analyzed using thematic analysis. Providers indicated that there was no existing process to enable early recognition of cardiotoxicity and felt the app could reduce delays in diagnosis and lead to better patient outcomes. Signs and symptoms providers recommended for tracking included chest pain or tightness, shortness of breath, heart racing or palpitations, syncope, lightheadedness, edema, and excessive fatigue. Implementation barriers included determining who would receive symptom reports, ensuring all members of the patient's care team (eg, oncologist, cardiologist, and primary care) were informed of the symptom reports and could collaborate on care plans, and how to best integrate the app data into the electronic health record. Patients (n=6, 100%) agreed that the app would be useful for enhanced symptom capture and education and indicated willingness to use it. Providers and patients agree that a patient-facing, cancer treatment-related cardiotoxicity symptom-tracking mHealth app would be beneficial. Additional studies evaluating the role of mHealth as a potential strategy for targeted early cardioprotective therapy initiation are needed.


Platinum-based compounds and risk for cardiovascular toxicity in the elderly: role of the antioxidants in chemoprevention.
Cancer in elderly patients is an increasingly common problem. Older patients have more co-morbidity, therefore the toxic effects of chemotherapy treatment are less tolerable compared to younger patients. Platinum-based compounds (PBCs) are commonly used cytotoxic agents in the treatment of several solid tumors; however, their application is still limited in elderly patients, due to the risks in cardiovascular toxicity. The increased risk for myocardial ischemia, stroke, and vascular thrombosis linked with PBCs treatment is mainly due to reactive oxygen species (ROS) production and the subsequent induction of oxidative stress and switch to a prothrombotic condition. Recently, studies have shown a different genetic susceptibility in cardiovascular toxicity induced by therapy with PBCs. Antioxidants, such as vitamin E, selenium, lycopene, melatonin, and resveratrol, have been implicated in cancer treatment by their property to suppress the oxidant injury. Resveratrol, especially, has been shown to increase the antineoplastic activity of cisplatin. In addition, resveratrol's ability to activate the sirtuin1 (SIRT1) pathway has been heavily implicated in the mechanisms controlling longevity and quality of life in the aged population. This article reviews the current state of treatment with PBCs and their associated risk for cardiovascular disease. It discusses the most powerful antioxidant supplementation options as a possible strategy to reduce the cardiovascular toxicity effects of chemotherapy in the elderly.


Reductions in HIV risk among runaway youth.
Runaway youth are 6-12 times more likely to become infected with HIV than other youth. Using a quasi-experimental design, the efficacy of an HIV prevention program was evaluated over 2 years among 2 groups of runaways: (1) those at 2 shelters who received Street Smart, an intensive HIV intervention program, and (2) youth at 2 control shelters. Street Smart provided youth with access to health care and condoms and delivered a 10-session skill-focused prevention program based on social learning theory to youth. Prior to analysis of the intervention's outcomes, propensity scores were used to identify comparable subgroups of youth in the intervention (n = 101) and control conditions (n = 86). Compared to females in the control condition, females in the intervention condition significantly reduced their unprotected sexual acts at 2 years and alcohol use, marijuana use, and the number of drugs used over 12 months. Male adolescents in the intervention condition showed significant reductions in marijuana use over 6 months compared to control youth. Adolescent HIV prevention programs must proactively identify mechanisms for maintaining behavior change over the long-term, and innovative research designs are needed to allow examination of agency-level interventions.


10-year survey of 485 sterilisations. Part I--Sterilisation or hysterectomy?
A survey was made of all sterilisations performed in an obstetric and gynaecological unit in Dunfermline in 1965-74 to determine the outcome and complications. Altogether 547 women were sterilised by the modified Pomeroy method, and 485 (88.7%) were interviewed and examined. No sterilisation was followed by serious complications, and the incidence of even minor complications was low (4.12%). There were no subsequent pregnancies. Altogether 57 women had to be referred for gynaecological operations in the years after sterilisation but only 18 of these had to have hysterectomies. At interview 59 women were found to have gynaecological symptoms (menstrual disorders in 46), and examination showed that 83 women had a gynaecological condition, which was in most cases unsuspected by the patient. Most of these conditions were minor but three women had carcinoma-in-situ of the cervix. Although 46 women suffered menstrual disorders after sterilisation 104 had done so at some time before the operation. These results therefore offer little support for the wider use of hysterectomy as a form of sterilisation.


Do we need antiplatelet therapy in thrombocytosis? Pro. Diagnostic and pathophysiologic considerations for a treatment choice.
Thrombocytosis (defined as platelets >450 x 109/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodysplastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment.


Tuning the temperature dependence for switching in dithienylethene photochromic switches.
Diarylethene photochromic switches use light to drive structural changes through reversible electrocyclization reactions. High efficiency in dynamic photoswitching is a prerequisite for applications, as is thermal stability and the selective addressability of both isomers ring-opened and -closed diarylethenes. These properties can be optimized readily through rational variation in molecular structure. The efficiency with regard to switching as a function of structural variation is much less understood, with the exception of geometric requirements placed on the reacting atoms. Ultimately, increasing the quantum efficiency of photochemical switching in diarylethenes requires a detailed understanding of the excited-state potential energy surface(s) and the mechanisms involved in switching. Through studies of the temperature dependence, photoswitching and theoretical studies demonstrate the occurrence or absence of thermal activation barriers in three constitutional isomers that bear distinct π-conjugated systems. We found that a decrease in the thermal barriers correlates with an increase in switching efficiency. The origin of the barriers is assigned to the decrease in π-conjugation that is concomitant with the progress of the photoreaction. Furthermore, we show that balanced molecular design can minimize the change in the extent of π-conjugation during switching and lead to optimal bidirectional switching efficiencies. Our findings hold implications for future structural design of diarylethene photochromic switches.


Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis.
The E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2) is the immunodominant autoantigen of primary biliary cirrhosis. Whereas lipoylation of PDC-E2 is essential for enzymatic activity and predominates under normal conditions, other biochemical systems exist that also target the lysine residue, including acylation of fatty acids or xenobiotics and ubiquitinylation. More importantly, the immunogenicity can be affected by derivatization of the lysine residue, as the recognition of lipoylated PDC-E2 by patient autoantibodies is enhanced compared with octanoylated PDC-E2. Furthermore, our laboratory has shown that various xenobiotic modifications of a peptide representing the immunodominant region of PDC-E2 are immunoreactive against patient sera. The only purported regulatory system that prevents the accumulation of potentially autoreactive PDC-E2 is glutathionylation, in which the lysine-lipoic acid moiety is further modified with glutathione during apoptosis. Interestingly, this system is found in several cell lines, including HeLa, Jurkat, and Caco-2 cells, but not in cholangiocytes and salivary gland epithelial cells, both of which are targets for destruction in primary biliary cirrhosis. Hence, the failure of this or other regulatory system(s) may overwhelm the immune system with immunogenic PDC-E2 that can initiate the breakdown of tolerance in a genetically susceptible individual. In this review the authors survey the data available on the biochemical life of PDC-E2, with particular emphasis on the lysine residue and its known interactions with machinery involved in various posttranslational modifications.


Dehalogenimonas formicexedens sp. nov., a chlorinated alkane-respiring bacterium isolated from contaminated groundwater.
A strictly anaerobic, Gram-stain-negative, non-spore-forming bacterium designated NSZ-14T, isolated from contaminated groundwater in Louisiana (USA), was characterized using a polyphasic approach. Strain NSZ-14T reductively dehalogenated a variety of polychlorinated aliphatic alkanes, producing ethene from 1,2-dichloroethane, propene from 1,2-dichloropropane, a mixture of cis- and trans-1,2-dichloroethene from 1,1,2,2-tetrachloroethane, vinyl chloride from 1,1,2-trichloroethane and allyl chloride (3-chloro-1-propene) from 1,2,3-trichloropropane. Formate or hydrogen could both serve as electron donors. Dechlorination occurred between pH 5.5 and 7.5 and over a temperature range of 20-37 °C. Major cellular fatty acids included C18 : 1ω9c, C14 : 0 and C16 : 0. 16S rRNA gene sequence-based phylogenetic analysis indicated that the strain clusters within the class Dehalococcoidia of the phylum Chloroflexi, most closely related to but distinct from type strains of the species Dehalogenimonas alkenigignens (97.63 % similarity) and Dehalogenimonas lykanthroporepellens (95.05 %). A complete genome sequence determined for strain NSZ-14T revealed a DNA G+C content of 53.96 mol%, which was corroborated by HPLC (54.1±0.2 mol% G+C). Genome-wide comparisons based on average nucleotide identity by orthology and estimated DNA-DNA hybridization values combined with phenotypic and chemotaxonomic traits and phylogenetic analysis indicate that strain NSZ-14T represents a novel species within the genus Dehalogenimonas, for which the name Dehalogenimonas formicexedens sp. nov. is proposed. The type strain is NSZ-14T (=HAMBI 3672T=JCM 19277T=VKM B-3058T). An emended description of Dehalogenimonas alkenigignens is also provided.


Design and rationale of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study.
Edoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This study details the design of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study - a postauthorization observational study, which is part of the postapproval plan for edoxaban agreed with the European Medicines Agency. The ETNA-AF-Europe study (Clinicaltrials.gov: NCT02944019) is a multicenter, prospective, observational study that enrolled 13 980 patients with atrial fibrillation treated with edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). Patients treated with edoxaban were prospectively enrolled and will be followed up for 4 years with yearly follow-up visits. The primary objective of the ETNA-AF-Europe study is to assess the real-world safety of edoxaban by evaluating bleeding events, including intracranial hemorrhage; drug-related adverse events, such as hepatic events; and cardiovascular and all-cause mortality. In addition, efficacy will be assessed by recording major adverse cardiovascular events including stroke, systemic embolic events, transient ischemic attacks, and also VTE episodes, acute coronary syndromes, and hospitalizations related to cardiovascular condition. Event rates will be compared with event rates reported in the PREvention oF thromboembolic events-European Registry in Atrial Fibrillation in atrial fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, and in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48 study datasets.


Studying APOE ɛ4 Allele Dose Effects with a Univariate Morphometry Biomarker.
A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.


Interference of quorum sensing and virulence of the rice pathogen Burkholderia glumae by an engineered endophytic bacterium.
Many bacterial species are known to thrive within plants. Among these bacteria, a group referred to as endophytes provide beneficial effects to the host plants by the promotion of plant growth and the suppression of plant pathogens. Among 44 putative endophytic isolates isolated from surface-sterilized rice roots, Burkholderia sp. KJ006 was selected for further study because of a lack of pathogenicity to rice, a broad spectrum of antifungal properties, and the presence of the nifH gene, which is an indicator for nitrogen fixation. In an attempt to control Burkholderia glumae, a casual pathogen of seedling rot and grain rot of rice, an N-acyl-homoserine lactonase (aiiA) gene from Bacillus thuringiensis was introduced into Burkholderia sp. KJ006 given that the major virulence factor of Burkholderia glumae is controlled in a population-dependent manner (quorum sensing). The engineered strain KJ006 (pKPE-aiiA) inhibited production of quorum-sensing signals by Burkholderia glumae in vitro and reduced the disease incidence of rice seedling rot caused by Burkholderia glumae in situ. Our results indicate the possibility that a bacterial endophyte transformed with the aiiA gene can be used as a novel biological control agent against pathogenic Burkholderia glumae that are known to occupy the same ecological niche.


Results of a massive experiment on virtual currency endowments and money demand.
We use a 575,000-subject, 28-day experiment to investigate monetary policy in a virtual setting. The experiment tests the effect of virtual currency endowments on player retention and virtual currency demand. An increase in endowments of a virtual currency should lower the demand for the currency in the short run. However, in the long run, we would expect money demand to rise in response to inflation in the virtual world. We test for this behavior in a virtual field experiment in the football management game Top11. 575,000 players were selected at random and allocated to different "shards" or versions of the world. The shards differed only in terms of the initial money endowment offered to new players. Money demand was observed for 28 days as players used real money to purchase additional virtual currency. The results indicate that player money purchases were significantly higher in the shards where higher endowments were given. This suggests that a positive change in the money supply in a virtual context leads to inflation and increased money demand, and does so much more quickly than in real-world economies. Differences between virtual and real currency behavior will become more interesting as virtual currency becomes a bigger part of the real economy.


Acetylcholinesterase from Apis mellifera head. Evidence for amphiphilic and hydrophilic forms characterized by Triton X-114 phase separation.
The polymorphism of bee acetylcholinesterase was studied by sucrose-gradient-sedimentation analysis and non-denaturing electrophoretic analysis of fresh extracts. Lubrol-containing extracts exhibited only one form, which sedimented at 5 S when analysed on high-salt Lubrol-containing gradients and 6 S when analysed on low-salt Lubrol-containing gradients. The 5 S/6 S form aggregated upon removal of the detergent when sedimented on detergent-free gradients and was recovered in the detergent phase after Triton X-114 phase separation. Thus the 5 S/6 S enzyme corresponds to an amphiphilic acetylcholinesterase form. In detergent-free extracts three forms, whose apparent sedimentation coefficients are 14 S, 11 S and 7 S, were observed when sedimentations were performed on detergent-free gradients. Sedimentation analyses on detergent-containing gradients showed only a 5 S peak in high-salt detergent-free extracts and a 6 S peak, with a shoulder at about 7 S, in low-salt detergent-free extracts. Electrophoretic analysis in the presence of detergent demonstrated that the 14 S and 11 S peaks corresponded to aggregates of the 5 S/6 S form, whereas the 7 S peak corresponded to a hydrophilic acetylcholinesterase form which was recovered in the aqueous phase following Triton X-114 phase separation. The 5 S/6 S amphiphilic form could be converted into a 7.1 S hydrophilic form by phosphatidylinositol-specific phospholipase C digestion.


2D sandbox experiments of surfactant foams for mobility control and enhanced LNAPL recovery in layered soils.
The ability of surfactant foam to enhance mobility control and LNAPL recovery in a heterogeneous porous media was investigated through sandbox experiments with p-xylene used as LNAPL. A layered heterogeneous porous media was represented in a 2D sandbox filled with two layers of coarse and medium silica sand. Based on previous tests, the surfactant solution used was Ammonyx Lo at a concentration of 0.1% (w/w). The sandbox experimental program included tracer tests done under both uncontaminated and contaminated conditions, foam injection under uncontaminated conditions and surfactant solution and foam injection under contaminated conditions. Tracer tests indicated that the permeability contrast between sand layers was increased by LNAPL contamination. Foam injection under uncontaminated conditions presented a S-shaped front that indicated a better mobility control than the piston-shaped front obtained during tracer tests. During foam injection, complete sweep of the sandbox was achieved with 1.8pore volume (PV) compared to 2.8PV during tracer injection, thus indicating better mobility control with foam. Pre-flush of the contaminated sandbox with surfactant solution initiated p-xylene mobilization but no free phase was recovered at the effluent. A negligible p-xylene residual saturation was reached following foam injection in the contaminated sandbox. However, mass balance indicated a total recovery of only 48% of the initial p-xylene, thus indicating an underestimation of the recovery by volatilization. Recovery by volatilization was corrected, which gave the following proportions of LNAPL recovery mechanisms: 19% by mobilization, 16% by dissolution and 65% by volatilization. Results show the potential efficiency of foam remediation of LNAPL source zones in heterogeneous porous media. Still, further developments are needed prior to field scale application, which could benefit from in situ foam production that would simplify on-site operations.


The fine structure of Streptomyces coelicolor. II. The nuclear material.
Colonies and spore suspensions of Streptomyces coelicolor were fixed for electron microscopy by the method of Kellenberger, Ryter, and Séchaud (1958). In thin sections the nuclear regions have a lower average density than the cytoplasm and the outlines of these regions correspond well with the profiles of the chromatinic bodies observed with the light microscope. The nuclear regions contain fibrils, about 5 mmicro in diameter. In contrast, after fixation by the method of Palade (1952) the nuclear material is coagulated into irregular dense masses and tubular structures about 20 mmicro in diameter, lying in a nuclear "vacuole." The significance of these observations is discussed in relation to the observations of other workers on the fine structure of the nuclear material of other bacteria and the chromosomes of higher cells.


Role of N-terminal domain and accessory subunits in controlling deactivation-inactivation coupling of Kv4.2 channels.
We examined the relationship between deactivation and inactivation in Kv4.2 channels. In particular, we were interested in the role of a Kv4.2 N-terminal domain and accessory subunits in controlling macroscopic gating kinetics and asked if the effects of N-terminal deletion and accessory subunit coexpression conform to a kinetic coupling of deactivation and inactivation. We expressed Kv4.2 wild-type channels and N-terminal deletion mutants in the absence and presence of Kv channel interacting proteins (KChIPs) and dipeptidyl aminopeptidase-like proteins (DPPs) in human embryonic kidney 293 cells. Kv4.2-mediated A-type currents at positive and deactivation tail currents at negative membrane potentials were recorded under whole-cell voltage-clamp and analyzed by multi-exponential fitting. The observed changes in Kv4.2 macroscopic inactivation kinetics caused by N-terminal deletion, accessory subunit coexpression, or a combination of the two maneuvers were compared with respective changes in deactivation kinetics. Extensive correlation analyses indicated that modulatory effects on deactivation closely parallel respective effects on inactivation, including both onset and recovery kinetics. Searching for the structural determinants, which control deactivation and inactivation, we found that in a Kv4.2 Delta 2-10 N-terminal deletion mutant both the initial rapid phase of macroscopic inactivation and tail current deactivation were slowed. On the other hand, the intermediate and slow phase of A-type current decay, recovery from inactivation, and tail current decay kinetics were accelerated in Kv4.2 Delta 2-10 by KChIP2 and DPPX. Thus, a Kv4.2 N-terminal domain, which may control both inactivation and deactivation, is not necessary for active modulation of current kinetics by accessory subunits. Our results further suggest distinct mechanisms for Kv4.2 gating modulation by KChIPs and DPPs.


Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.
KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA). Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations. Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004). Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.


A multimedia activity model for ionizable compounds: validation study with 2,4-dichlorophenoxyacetic acid, aniline, and trimethoprim.
Fugacity models are widely adopted for the environmental exposure assessment of organic chemicals but are inconvenient for nonvolatile substances, such as ionizable chemicals. The activity approach is a robust alternative to the fugacity concept and provides the thermodynamically exact equations to describe the behavior of neutral and ionizable molecules in nonideal systems. A multimedia activity model applicable to neutral and ionizable molecules (MAMI) was developed and tested for 2,4-dichlorophenoxyacetic acid and the bases aniline and trimethoprim. The model features pH and ionic strength dependence and species-specific estimations of partition coefficients from physicochemical properties. Sorption estimates consider both lipophilic and electrical interactions. A realistic regional exposure scenario was simulated for the three test compounds, and model results were compared with results obtained with a conventional fugacity model and with monitoring data. The better performance of MAMI indicates that the activity approach can enlarge the applicability domain and improve model predictions of existing regional models. Model results, supported by experimental evidence, showed the importance of dissociation, electrical interactions in solids, humidity in air, and to a lesser extent salinity in seawater to describe the environmental fate of ionizable organic chemicals.


Stress and Depression in Ohio Social Workers during the COVID-19 Pandemic: The Buffering Role of Social Connectedness.
Although social workers have an elevated risk of infection with COVID-19, no previous studies have investigated the virus's impact on practitioners. Using survey data (N = 441), this study identified associations between stress, depression, and COVID-related factors and explored the role of social connectedness as a moderator for mental health among Ohio social workers. The results of the study showed that among social workers with a positive COVID-19 diagnosis, 70 percent experienced moderate/high levels of stress, and 37 percent met the criteria for clinical depressive symptoms. Results from the multiple regression analyses showed that perceived stress was positively associated with a positive COVID-19 diagnosis for social workers, and depression was positively associated with working with a client with a positive COVID-19 diagnosis. An interaction effect was also identified between social connectedness and social workers' mental health. These findings suggest that the provision of individual or organizational interventions that emphasize social connectedness can help to protect social workers' mental health.


The Elusive Path of Brain Tissue Oxygenation and Cerebral Perfusion in Harness Hang Syncope in Mountain Climbers.
Lanfranconi, Francesca, Luca Pollastri, Giovanni Corna, Manuela Bartesaghi, Massimiliano Novarina, Alessandra Ferri, and Giuseppe Andrea Miserocchi. The elusive path of brain tissue oxygenation and cerebral perfusion in harness hang syncope in mountain climbers. High Alt Med Biol. 18:363-371, 2017. Harness hang syncope (HHS) is a risk that specifically affects wide ranges of situations requiring safety harnesses in mountains. An irreversible orthostatic stasis could lead to death if a prompt rescue is not performed. We aimed at evaluating the risk of developing HHS and at identifying the characteristics related to the pathogenesis of HHS. Forty adults (aged 39.1 [8.2] years) were enrolled in a suspension test lasting about 28.7 (11.4) minutes. We measured cardiovascular parameters, and near infrared spectroscopy (NIRS) was used to assess cerebral hypoxia by changes in the concentration of oxyhemoglobin (Δ[HbO2]) and de-oxyhemoglobin (Δ[HHb]). In the four participants who developed HHS: (1) systolic and diastolic blood pressure showed ample oscillations with a final abrupt drop (∼30 mmHg); (2) Δ[HbO2] increased after 8-12 minutes of suspension and reached a plateau before HHS; and (3) Δ[HHb] decreased with a final abrupt increase before syncope. Participants who developed HHS failed to activate cardiovascular reflexes that usually safeguard O2 availability to match the metabolic needs of the brain tissue. Since cerebral hypoxia was detected as an early phenomenon by Δ[HbO2] and Δ[HHb] changes, NIRS measurement appears to be the most important parameter to monitor the onset of HHS.


Enhancements to commissioning techniques and quality assurance of brachytherapy treatment planning systems that use model-based dose calculation algorithms.
The current standard for brachytherapy dose calculations is based on the AAPM TG-43 formalism. Simplifications used in the TG-43 formalism have been challenged by many publications over the past decade. With the continuous increase in computing power, approaches based on fundamental physics processes or physics models such as the linear-Boltzmann transport equation are now applicable in a clinical setting. Thus, model-based dose calculation algorithms (MBDCAs) have been introduced to address TG-43 limitations for brachytherapy. The MBDCA approach results in a paradigm shift, which will require a concerted effort to integrate them properly into the radiation therapy community. MBDCA will improve treatment planning relative to the implementation of the traditional TG-43 formalism by accounting for individualized, patient-specific radiation scatter conditions, and the radiological effect of material heterogeneities differing from water. A snapshot of the current status of MBDCA and AAPM Task Group reports related to the subject of QA recommendations for brachytherapy treatment planning is presented. Some simplified Monte Carlo simulation results are also presented to delineate the effects MBDCA are called to account for and facilitate the discussion on suggestions for (i) new QA standards to augment current societal recommendations, (ii) consideration of dose specification such as dose to medium in medium, collisional kerma to medium in medium, or collisional kerma to water in medium, and (iii) infrastructure needed to uniformly introduce these new algorithms. Suggestions in this Vision 20/20 article may serve as a basis for developing future standards to be recommended by professional societies such as the AAPM, ESTRO, and ABS toward providing consistent clinical implementation throughout the brachytherapy community and rigorous quality management of MBDCA-based treatment planning systems.


Neighbourhood deprivation and access to alcohol outlets: a national study.
People living in poor areas suffer higher mortality than those in wealthy areas. Environmental factors partly explain this association, including exposure to pollutants and accessibility of healthcare. We sought to determine whether proximity to alcohol outlets varied by area deprivation in New Zealand. Roadway travel distance from each census unit to the nearest alcohol outlet was summarised according to socioeconomic deprivation for each area. Analyses were conducted by license type (pubs/bars, clubs, restaurants, off-licenses) and community urban-rural status. Strong associations were found between proximity to the nearest alcohol outlet and deprivation, there being greater access to outlets in more-deprived urban areas.


The concept of validity.
This article advances a simple conception of test validity: A test is valid for measuring an attribute if (a) the attribute exists and (b) variations in the attribute causally produce variation in the measurement outcomes. This conception is shown to diverge from current validity theory in several respects. In particular, the emphasis in the proposed conception is on ontology, reference, and causality, whereas current validity theory focuses on epistemology, meaning, and correlation. It is argued that the proposed conception is not only simpler but also theoretically superior to the position taken in the existing literature. Further, it has clear theoretical and practical implications for validation research. Most important, validation research must not be directed at the relation between the measured attribute and other attributes but at the processes that convey the effect of the measured attribute on the test scores.


Effect of passive concentration as instructional set for training enhancement of EEG alpha.
The technique of passive concentration, employed by autogenic training and Transcendental Meditation for achieving relaxation, was tested here as a technique for enhancing EEG alpha. Of 30 subjects displaying between 15% and 74% alpha in their resting EEGs recruited, 10 had to be eliminated. The remaining 20 constituted two groups. One was instructed only to attempt to maintain a tone indicating alpha but given no information about technique (control group). The other was given additional instructions in passive concentration (experimental group). Both were given four 5-min. trials a day for 4 consecutive days. Heart rate and skin conductance were measured to monitor autonomic arousal. The group receiving instructions in passive concentration had significantly less alpha than the control group, which did not increase amount of alpha above baseline. The reduction of alpha in the experimental group was interpreted as resulting from beginning long training periods (20 min. per day), a practice advocated by Transcendental Meditation but discouraged by autogenic training. It was concluded that the relevance of passive concentration for alpha enhancement is doubtful.


Risk factors for hospital-based surgical site infections.
Surgical site infections (SSIs) contribute to morbidity and are costly to the healthcare system. To identify factors associated with SSIs. Case-control study analyzing the Nationwide Readmission Database (NRD). We identified 45,445 SSIs. Infection rates were higher in those who were obese (BMI ≥ 30) (OR: 1.39, 95% CI 1.28-1.51), tobacco users (OR: 1.08, 95% CI 1.02-1.15), diagnosed with diabetes (OR: 1.16, 95% CI 1.10-1.22), with Elixhauser Comorbidity Index ≥ 2 (OR: 1.14, 95% CI 1.09-1.20), admitted to hospital for 4-6 days (OR: 1.35, 95% CI 1.29-1.42), in medium-size hospital (OR: 1.15, 95% CI 1.05-1.26), or large-size hospital (OR: 1.43, 95% CI 1.31-1.56). In contrast, patients who were 60-79 years old (OR: 0.78, 95% CI 0.73-0.84), 80 years or older (OR: 0.66, 95% CI 0.59-0.73), female (OR: 0.95, 95% CI 0.91-0.99), underweight (BMI < 18.5) (OR: 0.14, 95% CI 0.03-0.59), in a non-metropolitan hospital (OR: 0.83, 95% CI 0.75-0.91), self-pay (OR: 0.82, 95% CI 0.74-0.91), or covered by Medicare (OR: 0.86, 95% CI 0.80-0.91) had lower odds. Initial data entry to NRD is susceptible to human error. Patients who are obese, use tobacco, have multiple comorbidities, and have long hospital stays in medium-to-large-size hospitals are at risk of SSIs. Conversely, odds of SSIs are lower in females, age ≥ 60, BMI < 18.5, self-pay or Medicare (versus private insurance), or at smaller hospitals. Understanding factors associated with SSIs may help surgeons anticipate complications.


Management of pikeperch migrating over management areas in a Baltic archipelago area.
Pikeperch Sander lucioperca (L.) were tagged in an area where ten small independent management units regulate fisheries, in order to analyze the relevance of migrations for the management. A total of 465 fishes were tagged in connection with the spawning migration. The number of recaptures was 96. The distribution of recaptures between areas and that of total catches, estimated from questionnaire to housholds and, individuals in the survey area, were correlated. The comparison of tagging and recapture dates showed that the same pikeperch migrated to the spawning areas at the same time in two subsequent years, indicating the existence of individual spawning behavior. A modified yield/recruit-model demonstrated that in situations where the dispersal area of a pikeperch stock overlaps with several management areas, the risk of overfishing is very high. Management of this kind of fisheries needs cooperation between units as well as sound data on the movements of pikeperch to define the effects of fishing regulations.


Using Item Response Theory for Explainable Machine Learning in Predicting Mortality in the Intensive Care Unit: Case-Based Approach.
Supervised machine learning (ML) is being featured in the health care literature with study results frequently reported using metrics such as accuracy, sensitivity, specificity, recall, or F1 score. Although each metric provides a different perspective on the performance, they remain to be overall measures for the whole sample, discounting the uniqueness of each case or patient. Intuitively, we know that all cases are not equal, but the present evaluative approaches do not take case difficulty into account. A more case-based, comprehensive approach is warranted to assess supervised ML outcomes and forms the rationale for this study. This study aims to demonstrate how the item response theory (IRT) can be used to stratify the data based on how difficult each case is to classify, independent of the outcome measure of interest (eg, accuracy). This stratification allows the evaluation of ML classifiers to take the form of a distribution rather than a single scalar value. Two large, public intensive care unit data sets, Medical Information Mart for Intensive Care III and electronic intensive care unit, were used to showcase this method in predicting mortality. For each data set, a balanced sample (n=8078 and n=21,940, respectively) and an imbalanced sample (n=12,117 and n=32,910, respectively) were drawn. A 2-parameter logistic model was used to provide scores for each case. Several ML algorithms were used in the demonstration to classify cases based on their health-related features: logistic regression, linear discriminant analysis, K-nearest neighbors, decision tree, naive Bayes, and a neural network. Generalized linear mixed model analyses were used to assess the effects of case difficulty strata, ML algorithm, and the interaction between them in predicting accuracy. The results showed significant effects (P<.001) for case difficulty strata, ML algorithm, and their interaction in predicting accuracy and illustrated that all classifiers performed better with easier-to-classify cases and that overall the neural network performed best. Significant interactions suggest that cases that fall in the most arduous strata should be handled by logistic regression, linear discriminant analysis, decision tree, or neural network but not by naive Bayes or K-nearest neighbors. Conventional metrics for ML classification have been reported for methodological comparison. This demonstration shows that using the IRT is a viable method for understanding the data that are provided to ML algorithms, independent of outcome measures, and highlights how well classifiers differentiate cases of varying difficulty. This method explains which features are indicative of healthy states and why. It enables end users to tailor the classifier that is appropriate to the difficulty level of the patient for personalized medicine.


Updates on high-throughput molecular profiling for the study of rheumatoid arthritis.
The completion of the human genome mapping project has provided the necessary backdrop for the development of high-throughput array technologies. In contrast to the reductionist approach to studying the role of a particular molecule in a specific pathway, these technologies enable us to conduct a comprehensive survey of various molecular profiles across different cell types and individuals, placing us one step closer to understanding integrative regulatory networks and the workings of the cell as a whole.


Integrative measurement analysis via machine learning descriptor selection for investigating physical properties of biopolymers in hairs.
Integrative measurement analysis of complex subjects, such as polymers is a major challenge to obtain comprehensive understanding of the properties. In this study, we describe analytical strategies to extract and selectively associate compositional information measured by multiple analytical techniques, aiming to reveal their relationships with physical properties of biopolymers derived from hair. Hair samples were analyzed by multiple techniques, including solid-state nuclear magnetic resonance (NMR), time-domain NMR, Fourier transform infrared spectroscopy, and thermogravimetric and differential thermal analysis. The measured data were processed by different processing techniques, such as spectral differentiation and deconvolution, and then converted into a variety of "measurement descriptors" with different compositional information. The descriptors were associated with the mechanical properties of hair by constructing prediction models using machine learning algorithms. Herein, the stepwise model refinement via selection of adopted descriptors based on importance evaluation identified the most contributive descriptors, which provided an integrative interpretation about the compositional factors, such as α-helix keratins in cortex; and bounded water and thermal resistant components in cuticle. These results demonstrated the efficacy of the present strategy to generate and select descriptors from manifold measured data for investigating the nature of sophisticated subjects, such as hair.


Mapping the transcriptome: Realizing the full potential of spatial data analysis.
RNA sequencing in situ allows for whole-transcriptome characterization at high resolution, while retaining spatial information. These data present an analytical challenge for bioinformatics-how to leverage spatial information effectively? Properties of data with a spatial dimension require special handling, which necessitate a different set of statistical and inferential considerations when compared to non-spatial data. The geographical sciences primarily use spatial data and have developed methods to analye them. Here we discuss the challenges associated with spatial analysis and examine how we can take advantage of practice from the geographical sciences to realize the full potential of spatial information in transcriptomic datasets.


Mechanical stimulation and intercellular communication increases intracellular Ca2+ in epithelial cells.
Intercellular communication of epithelial cells was examined by measuring changes in intracellular calcium concentration ([Ca2+]i). Mechanical stimulation of respiratory tract ciliated cells in culture induced a wave of increasing Ca2+ that spread, cell by cell, from the stimulated cell to neighboring cells. The communication of these Ca2+ waves between cells was restricted or blocked by halothane, an anesthetic known to uncouple cells. In the absence of extracellular Ca2+, the mechanically stimulated cell showed no change or a decrease in [Ca2+]i, whereas [Ca2+]i increased in neighboring cells. Iontophoretic injection of inositol 1,4,5-trisphosphate (IP3) evoked a communicated Ca2+ response that was similar to that produced by mechanical stimulation. These results support the hypothesis that IP3 acts as a cellular messenger that mediates communication through gap junctions between ciliated epithelial cells.


PHACE syndrome in antenatally diagnosed posterior fossa anomaly.
PHACE is a neurocutaneous syndrome, an acronym to describe patients with facial segmental hemangiomas and other malformations. We describe a newborn antenatally diagnosed to have posterior fossa anomaly and subsequently as PHACE syndrome.


Catechol-O-methyltransferase and breast cancer risk.
Recent studies suggest that a polymorphism in catechol-O-methyltransferase (COMT) is associated with increased risk of breast cancer. Methylation by COMT is the principal pathway for inactivation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. We examined the association of COMT genotype and breast cancer risk in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 654 cases and 642 controls, with approximately equal numbers of African-American and white women and women under the age of 50 and aged 50 or over. Contrary to previous reports, we did not observe an association between one or more copies of the low activity COMT allele (COMT-L) and breast cancer risk. Multivariate relative risks (RRs) were 0.8 (95% confidence interval: 0.6-1.1) for COMT-HL and 0.8 (0.6-1.1) for COMT-LL, compared with the COMT-HH genotype. RRs for COMT did not differ among African-American and white women and we did not observe strong modification of RR estimates by menopausal status, body mass index, physical activity or other covariates. Our results suggest that COMT genotype is not related to breast cancer risk.


Knowledge, attitudes, and clinical practice of rheumatologists in vaccination of the at-risk rheumatology patient population.
Patients with inflammatory arthritis are at increased risk of infection. Much of the burden of infection in this population is vaccine preventable. A number of international rheumatology organizations have published expert recommendations for vaccination in adult patients. Despite this, reported vaccination rates remain low among patients with inflammatory arthritis. We sought to establish the knowledge, attitudes, and clinical practice of rheumatologists with respect to vaccination. Rheumatologists practicing in Ireland in 2009 were surveyed by postal questionnaire. Data collected was entered into Microsoft Excel and statistical analysis was carried out using SPSS18 software. Eighty (100%) practicing rheumatologists were surveyed. Response rate was 55% (44/80). Of those surveyed, 57% (25/44) had no written departmental vaccination guidelines. Although 90% of those surveyed agreed that the responsibility for ensuring vaccine compliance rests with health professionals, only 5% considered that the rheumatology clinic was the best setting in which to accomplish this. Half (50%, n = 22) of practicing rheumatologists do not inquire about vaccination history in the clinic, with a minority (9%, n = 4) recording vaccination history in their clinical notes. A significant percentage of rheumatologists do not perform screening about prior vaccination before initiation of either anti-tumor necrosis factor (34%) or disease-modifying antirheumatic disease (42%) therapy. Moreover, 57% (n = 25) considered the responsibility for vaccination the domain of the patients' general practitioners with the favored strategy to improve vaccine compliance being led by the primary care physicians (48%, n = 21). The practice of Irish rheumatologists with regard to vaccination in this survey was suboptimal. Most neither recommend nor record vaccination history in their clinical notes, with the majority feeling that the rheumatology clinic is not the appropriate setting in which to target strategies to improve vaccine compliance. Although a more proactive role needs to be taken by rheumatologists as the principal prescribers of immunosuppressive therapy on this issue, our survey respondents suggest that strategies to improve vaccine uptake should be developed outside the rheumatology clinic and, in particular, involve primary care. The circulation of currently available international guidelines on vaccination specific for rheumatology patients to primary care physicians should be used to inform practices to ensure improved vaccine compliance.


Negatively Skewed Locomotor Activity Is Related to Autistic Traits and Behavioral Problems in Typically Developing Children and Those With Autism Spectrum Disorders.
An important objective for researchers and clinicians is to gain a better understanding of the factors that underlie autism spectrum disorders (ASDs). It is possible that investigating objective and quantitative behavioral phenotypes and their relationship to clinical characteristics, such as autistic traits and other emotional/behavioral problems, might facilitate this process. Given this, in the current study we examined the link between locomotor dynamics and clinical characteristics, including autistic traits and emotional/behavioral problems, in children with ASD (n = 14) and typically developing (TD) children (n = 13). A watch-type actigraph was used to continuously measure locomotor activity which was assessed in terms of mean activity levels and the skewness of activity. Parents assessed quantitative autistic traits using the Japanese version of the Social Responsiveness Scale (SRS) and emotional and behavioral problems using the Japanese version of the Strengths and Difficulties Questionnaire (SDQ). Results showed that among all children, all-day activity was more negatively skewed, suggesting sporadic large all-day "troughs" in activity and was significantly correlated with the SRS social awareness subscale score (ρ = -0.446, p = 0.038). In addition, the more negatively skewed daytime locomotor activity was associated with the SDQ Hyperactivity Inattention subscale score (ρ = -0.493, p = 0.020). The results of this study indicate that investigating locomotor dynamics may provide one way to increase understanding of the neurophysiological mechanisms underlying the clinical characteristics of ASD.


Shetti, a simple tool to parse, manipulate and search large datasets of sequences.
Parsing and manipulating long and/or multiple protein or gene sequences can be a challenging process for experimental biologists and microbiologists lacking prior knowledge of bioinformatics and programming. Here we present a simple, easy, user-friendly and versatile tool to parse, manipulate and search within large datasets of long and multiple protein or gene sequences. The Shetti tool can be used to search for a sequence, species, protein/gene or pattern/motif. Moreover, it can also be used to construct a universal consensus or molecular signatures for proteins based on their physical characteristics. Shetti is an efficient and fast tool that can deal with large sets of long sequences efficiently. Shetti parses UniProt Knowledgebase and NCBI GenBank flat files and visualizes them as a table.


Oculoparalytic illusion: visual-field dependent spatial mislocalizations by humans partially paralyzed with curare.
In darkness, observers partially paralyzed with curare make large (greater thn 20 degrees) gaze- and dosage-dependent errors in visually localizing eye-level-horizontal and median planes, in matching the location of a sound to a light, and in pointing at a light. In illuminated, structured visual localization and pointing are accurate but errors in auditory-to-visual matches remain. Defects in extraretinal eye position information are responsible for all errors. The influence of extraretinal eye position information on visual localization is suppressed by a structured visual field but is crucial both in darkness and for intersensory localization if visual capture is prevented.


Retinal pigment epithelial cell DNA is damaged by exposure to benzo[a]pyrene, a constituent of cigarette smoke.
This study examined the effect of exogenous benzo[ a ]pyrene (BaP), an important constituent of cigarette smoke, on cultured bovine retinal pigment epithelial (RPE) cells. Evidence is presented for its metabolic conversion into benzo[ a ]pyrene diol epoxide (BPDE) and the consequent formation of potentially cytotoxic nucleobase adducts in DNA. Cultured RPE cells were treated with BaP at concentrations in the range of 0-100 microM. The presence of BaP was found to cause inhibition of cell growth and replication. BaP induced the expression of a phase I drug metabolizing enzyme which was identified as cytochrome P450 1A1 (CYP 1A1) by RT-PCR and by Western blotting. Coincident with the increased expression of CYP 1A1, covalent adducts between the mutagenic metabolite BPDE and DNA could be detected within RPE cells by immunocytochemical staining. Additional support for their formation was afforded by nuclease P1 enhanced (32)P-postlabelling assays on cellular DNA. Single-cell gel electrophoresis (comet) assays showed that exposure of RPE cells to BaP rendered them markedly more susceptible to DNA damage induced by broad band UVB or blue light laser irradiation. In the case of UVB, this is consistent with the photosensitization of DNA cleavage by nucleobase adducts of BPDE. Collectively, these findings imply that BaP has a significant impact on RPE cell pathophysiology and suggest mechanisms whereby exposure to cigarette smoke might cause RPE dysfunction and cell death, thus possibly contributing to degenerative disorders of the retina.


FFLOM: A Flow-Based Autoregressive Model for Fragment-to-Lead Optimization.
Recently, deep generative models have been regarded as promising tools in fragment-based drug design (FBDD). Despite the growing interest in these models, they still face challenges in generating molecules with desired properties in low data regimes. In this study, we propose a novel flow-based autoregressive model named FFLOM for linker and R-group design. In a large-scale benchmark evaluation on ZINC, CASF, and PDBbind test sets, FFLOM achieves state-of-the-art performance in terms of validity, uniqueness, novelty, and recovery of the generated molecules and can recover over 92% of the original molecules in the PDBbind test set (with at least five atoms). FFLOM also exhibits excellent potential applicability in several practical scenarios encompassing fragment linking, PROTAC design, R-group growing, and R-group optimization. In all four cases, FFLOM can perfectly reconstruct the ground-truth compounds and generate over 74% of molecules with novel fragments, some of which have higher binding affinity than the ground truth.


Current concepts in portal vein thrombosis: etiology, clinical presentation and management.
The aim of this article is to focus on etiology, risk factors, clinical presentation and classification systems of acute and chronic PVT as well as focusing on current diagnostic and therapeutic options for the management of acute and chronic PVT. PVT represents a serious clinical concern in cirrhotic patients and in those with specific local or systemic risk factors. The rate and extent of thrombus formation can significantly impact patient presentation and the resulting clinical outcomes. The presentation of acute PVT can range from abdominal pain to intestinal ischemia/infarction and even death, while chronic PVT can remain clinically silent. A number of imaging modalities including US, CT and MRI can be used to confirm the diagnosis. In addition to addressing underlying risk factors, AC therapy forms a cornerstone of treatment and has demonstrated efficacy in both acute and chronic settings. Proper caution should be used when initiating AC therapy in cirrhotic patients given their underlying coagulopathic status with attention now being paid to NOACs and LMWH. For patients with bowel ischemia, extensive thrombosis, contraindications or poor response to AC, or for those with co-morbidities that preclude AC, minimally invasive endovascular techniques offer alternative treatment options. Familiarity with the etiology, clinical presentation and classification of PVT optimize early detection and incorporate effective therapeutic options, the management of these complex patients should be undertaken by a multidisciplinary team. Minimally invasive catheter-based therapies and endovascular portosystemic shunt creation demonstrated efficacy in the treatment of AC-resistant patients and for patients with extensive or complicated disease.


Serogroups, atypical biochemical characters, colicinogeny and antibiotic resistance pattern of Shiga toxin-producing Escherichia coli isolated from diarrhoeic calves in Gujarat, India.
This study was designed to investigate the antibiotic resistance, colicinogeny, serotyping and atypical biochemical characteristics of 41 Shiga toxin-producing Escherichia coli (STEC) strains detected using polymerase chain reaction from 90 E. coli strains isolated from 46 diarrhoeic calves. The STEC strains belonged to 14 different serogroups. Seventeen per cent of the STEC strains carried the eaeA gene while 14.28% of the 49 non-STEC strains were eaeA positive. Twenty eight (68.29%) of the 41 STEC strains were rhamnose non-fermentors. All the STEC strains revealed resistance to at least three of the antibiotics tested. 100% resistance was found against kanamycin and cephalexin followed by cephaloridine, enrofloxacin, amikacin, ampicillin, tetracycline, ceftiofur, ciprofloxacin, colistin and co-trimoxazole. Eighteen (44%) of the STEC strains produced colicin and all these colicinogenic strains were resistant to three or more antibiotics. Eleven STEC strains (26.82%) showed urease activity. The results of this study suggest that diarrhoeic calves are an important reservoir of STEC strains that are potentially pathogenic for farm animals and humans. Moreover, rhamnose fermentation, colicinogeny and atypical biochemical behaviour, such as urease activity, may serve as important markers or diagnostic tools for epidemiological surveys to trace the source of infection in disease outbreaks.


Efficacy and tolerability of switching to ziprasidone from olanzapine, risperidone or haloperidol: an international, multicenter study.
To compare the effectiveness of a switch from haloperidol (N=99), olanzapine (N=82), or risperidone (N=104) to 12 weeks of treatment with 80-160 mg/day ziprasidone in patients with stable schizophrenia or schizoaffective disorder. Stable outpatients with persistent symptoms or troublesome side effects were switched using one of three 1-week taper/switch strategies as determined by the investigator. Efficacy was assessed using the Brief Psychiatric Rating Scale score, Clinical Global Impression, Positive and Negative Symptom Scale, Montgomery-Asberg Depression Rating Scale, and the Global Assessment of Functioning Scale, and tolerability by using standard measures of weight change, extrapyramidal symptoms, and laboratory findings. Suboptimal efficacy was the primary reason for switching. The preferred switch strategy was immediate discontinuation, and the preferred dosing regimen was 120 mg/day. Completer rates were 68, 60, and 86% in the haloperidol, risperidone, and olanzapine pre-switch groups, respectively. At week 12, a switch to ziprasidone resulted in statistically significant improvement from baseline on the Brief Psychiatric Rating Scale score, Clinical Global Impression-Improvement, Positive and Negative Symptom Scale, and Global Assessment of Functioning scales, reduction in extrapyramidal symptoms and a neutral impact on metabolic parameters. Switch from olanzapine and risperidone resulted in weight reduction and from haloperidol in some weight increase. In conclusion, oral ziprasidone of 80-160 mg/day with food was a clinically valuable treatment option for stable patients with schizophrenia or schizoaffective disorder experiencing suboptimal efficacy or poor tolerability with haloperidol, olanzapine, or risperidone.


Effects of Brucella ovis infection on semen characteristics of 16-month-old red deer stags.
To determine the effects of Brucella ovis infection on semen characteristics of 16-month-old red deer stags (Cervus elaphus). At monthly intervals during March, April and May, semen was collected using electro-ejaculation from 9 yearling red deer stags that had been artificially infected with B. ovis 3 months previously. In March, semen was also collected from 6 non-infected stags from the same peer group for comparison. Semen was evaluated for gross appearance, percentage of sperm showing forward motility, sperm morphology and sperm density/ml of semen, and the presence of white blood cells was determined. In addition, at the time of semen collection, the epididymes of each stag were palpated and lesions recorded. Grossly visible purulent material was present in semen from 6/9 infected stags and the percentage of sperm showing forward motility did not exceed 20% in any of these samples. Increased numbers of white blood cells and cellular debris were evident in semen from 8/9 infected stags. Compared with non-infected stags, sperm motility in semen from infected stags was significantly reduced (p<0.05). There were no differences in percentage of morphologically normal sperm between groups, but infected stags had more detached sperm heads present in semen than non-infected stags (p<0.05). Only 2 of the infected stags had lesions of epididymitis evident on scrotal palpation. B. ovis infection is likely to have a detrimental effect on stag semen quality. While there was variation between individual animals, overall sperm motility was decreased and semen from infected stags had increased numbers of white blood cells and detached sperm heads. The fertility of breeding stags may be reduced if they are infected with B. ovis and this possibility should be considered when investigating reproductive problems of deer.


QRS polarity on 12-lead surface ECG. A criterion for the differentiation of right and left posteroseptal accessory atrioventricular pathways.
In this study, we tried to disclose certain electrocardiogram (ECG) criteria that might be useful in the classification of posteroseptal accessory atrioventricular pathways as right and left in patients with pre-excitation in whom the accessory pathway localization was verified by subsequent successful ablation. Twenty such patients with posteroseptal accessory pathways (mean age 34.9 +/- 9.8; 11 male, 9 female) were included in the study. Localization of the accessory pathway was right posteroseptal in 13 (65%) and left posteroseptal in 7 (35%). Common to all these 20 patients with posteroseptal accessory pathways was a QRS polarity positive in lead L1 and negative in leads D3, aVL. In patients with right posteroseptal accessory pathways, QRS polarity was negative in lead V1 in all and positive in lead V2 in 90%. On the other hand, none of the patients with left posteroseptal accessory pathways showed negative QRS polarity in lead V1. In conclusion, these findings strongly suggest that in patients with pre-excitation, a QRS polarity negative in lead V1 and positive in lead V2 is an important surface ECG finding that signifies right-sided localization of a posteroseptal accessory pathway. In cases with left posteroseptal accessory pathways, QRS polarity in leads V1 and V2 has been found to be either biphasic or positive.


Use of pyocin 78-C2 in the treatment of Pseudomonas aeruginosa infection in mice.
Purified pyocin, administered parenterally to mice infected with sensitive strains of Pseudomonas aeruginosa, afforded significant protection against two of the three strains studied.


[Venoarterial perfusion without oxygenation as a means of mechanical aid to the heart in acute failure].
The efficacy of veno-arterial perfusion without oxygenation was established in experiments on dogs with a model of acute cardiac insufficiency. The overall index of circulation and the percentage of the heart participation in it is an important criterion of the effectiveness of shunting of the left ventricle. This criterion made it possible to determine the therapeutic role of veno-arterial perfusion without oxygenation in aiding the diseased ventricle even when the size of the shunt did not exceed 1/3 of the initial cardiac ejection.


Long-term efficient gene delivery using polyethylenimine with modified Tat peptide.
Polyethylenimine (PEI), a cationic polymer, has been widely studied and shown great promise as an efficient gene delivery vehicle. Likewise, the HIV-1 Tat peptide, a cell-permeable peptide, has been successfully used for intracellular gene delivery. To improve the favorable properties of these two vectors, we combine PEI with the modified Tat peptide sequence bearing histidine and cysteine residues (mTat). In vitro mTat/PEI-mediated transfection was evaluated by luciferase expression plasmid in two cell types. mTat/PEI produced significant improvement (≈5-fold) in transfection efficiency of both cell lines with little cytotoxicity when compared to mTat alone, PEI alone, or four commercial reagents. The particle size of mTat/PEI/DNA complex was significantly smaller than mTat or PEI alone, and it was correlated with higher transfection efficiency. Filipin III, an inhibitor of caveolae-mediated endocytosis, significantly inhibited mTat/PEI transfection. In contrast, chlorpromazine, an inhibitor of clathrin-mediated endocytosis, did not. This suggested caveolae-mediated endocytosis as the transfection mechanism. Furthermore, the results of in vivo studies showed that animals administered mTat/PEI/DNA intramuscularly had significantly higher and longer luciferase expression (≈7 months) than those with mTat/DNA, PEI/DNA, or DNA alone, without any associated toxicity. The combination of mTat with PEI could significantly improve transfection efficiency, expanding the potential use as a non-viral gene vector both in vitro and in vivo.


Perforin-dependent cytotoxic activity and lymphokine secretion by CD4+ T cells are regulated by CD8+ T cells.
Factors influencing the development of CD4+ T cell subpopulations with differing lymphokine profiles are well established. However, CD4+ cells can show both perforin- and Fas ligand-dependent cytotoxicity, and little is known about conditions favoring the development of these effector activities. We now report that CD8+ cells regulate the development of perforin-dependent cytotoxicity in CD4+ cells. CD4+ cells activated in either the presence or absence of CD8+ cells developed Fas ligand-dependent cytotoxic activity. However, CD4+ cells developed perforin-dependent cytotoxicity only in the absence of activated CD8+ cells. CD8+ cells also inhibited the development of IL-4-secreting CD4+ cells; however, there was no correlation between the expression of perforin-dependent cytotoxic activity and the ability to secrete IL-4, and perforin-dependent cytotoxic CD4+ cells represented only 10% of isolated clones. This suggests that the two characteristics are expressed in different CD4+ subsets and might be regulated by distinct effects of the CD8+ cells. In keeping with this, regulation of the lymphokine profile of CD4+ cells by CD8+ cells was consistent with mediation by IFN-gamma, but only when delivered at high concentrations requiring close proximity of the cells. In contrast, regulation of perforin-dependent cytotoxic activity of CD4+ cells by CD8+ cells seemed inconsistent with an IFN-gamma-dependent mechanism, suggesting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor. The characteristics of perforin-dependent CD4+ CTL and their regulation by activated CD8+ cells suggest that they represent a previously unrecognized subpopulation that plays a defensive role when a CD8+ cell response is absent.


Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions.
Active Src localization at focal adhesions (FAs) is essential for cell migration. How this pool is linked mechanistically to the large pool of Src at late endosomes (LEs)/lysosomes (LY) is not well understood. Here, we used inducible Tsg101 gene deletion, TSG101 knockdown, and dominant-negative VPS4 expression to demonstrate that the localization of activated cellular Src and viral Src at FAs requires the endosomal-sorting complexes required for transport (ESCRT) pathway. Tsg101 deletion also led to impaired Src-dependent activation of STAT3 and focal adhesion kinase and reduced cell migration. Impairment of the ESCRT pathway or Rab7 function led to the accumulation of active Src at aberrant LE/LY compartments followed by its loss. Analyses using fluorescence recovery after photo-bleaching show that dynamic mobility of Src in endosomes is ESCRT pathway-dependent. These results reveal a critical role for an ESCRT pathway-dependent LE/LY trafficking step in Src function by promoting localization of active Src to FAs.


Lesion symptom mapping at the regional level in patients with a meningioma.
The majority of meningioma patients suffer from presurgical cognitive deficits. Since meningiomas do not directly damage the brain, this is presumably caused by a functional integrity reduction of the surrounding brain tissue through perilesional edema and/or mass effect of the tumor. Tumor location is a key feature in determining neurological symptoms in brain tumor patients, but the relationship between meningioma location and cognitive performance remains unclear. This study aimed to identify brain areas where the presence of a meningioma forms a potential risk factor for worse cognitive performance as compared to meningiomas at other locations. Neuropsychological data (CNS Vital Signs) and MRI were collected in 224 meningioma patients one day before surgery. Sociodemographically corrected scores were calculated for 7 cognitive domains. Tumors were semiautomatically segmented and mapped into MNI-space for use in Statistical Region of Interest analyses. For each cognitive domain, we tested whether larger proportions of tumor overlap with each of the 150 defined regions were associated with worse performance. After multiple comparison (Bonferroni) and lesion volume correction, larger proportions of tumor overlap with both the left middle and superior frontal gyrus were associated with worse complex attention scores. Larger proportions of tumor overlap with the left middle frontal gyrus were associated with worse cognitive flexibility scores. For the other domains, no association between tumor overlap with a region and cognitive performance was found. The current results suggest that, compared to patients with a meningioma at other locations, patients with a meningioma at the left middle frontal gyrus are at potential risk for worse performance on cognitive flexibility and complex attention whereas patients with a meningioma at the left superior frontal gyrus are at potential risk for worse performance on complex attention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Lack of an absolute requirement for the native aryl hydrocarbon receptor (AhR) and AhR nuclear translocator transactivation domains in protein kinase C-mediated modulation of the AhR pathway.
Protein kinase C (PKC)-mediated modulation of the aryl hydrocarbon receptor (AhR) pathway was examined in CHOK1-derived L10.I cells stably transfected with the pGUDLUC6.1 reporter; pGUDLUC6.1 is solely controlled by four dioxin-responsive enhancer elements. Co treatment of L10.I cells with 10 nM 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and 81 nM phorbol 12-myristate 13-acetate (PMA), an activator of sn-1,2-diacylglyerol binding PKCs, enhanced transactivation of the reporter construct several-fold relative to cells treated with a saturating 10 nM TCDD dose alone; this effect was dubbed the "PMA effect." A domain swapping and deletional analysis of the native AhR and AhR nuclear translocator (ARNT) protein transactivation domains (TADs) was performed to determine if these domains are absolutely required for the AhR x ARNT dimer-mediated PMA effect in the L10.I model system; controls demonstrate the suitability of the L10.I model for these analyses and that endogenous AhR and ARNT levels are extremely low in this model. Transient coexpression of the AhR and ARNT-474-FLAG, an ARNT protein lacking the native ARNT TAD, in L10.I cells reveals the native ARNT TAD is not absolutely required for the AhR x ARNT-474-FLAG dimer to mediate the PMA effect. Transient coexpression of AhRDeltaCVP, a chimeric AhR protein in which the native AhR TAD has been replaced with the VP16 (herpes simplex virus protein 16) TAD (which control experiments demonstrate is unaffected by PMA), and ARNT in L10.I cells indicates that the native AhR TAD is not absolutely required for this AhRDeltaCVP x ARNT dimer to mediate the PMA effect. These observations strongly suggest that PKC-mediated modulation of the AhR pathway is not absolutely dependent on coactivators recruited to the AhR. ARNT dimer by the native TADs of the AhR and its heterodimerization partner ARNT.


Dynamic Functional Connectivity and Symptoms of Parkinson's Disease: A Resting-State fMRI Study.
Research has shown that dynamic functional connectivity (dFC) in Parkinson's disease (PD) is associated with better attention performance and with motor symptom severity. In the current study, we aimed to investigate dFC of both the default mode network (DMN) and the frontoparietal network (FPN) as neural correlates of cognitive functioning in patients with PD. Additionally, we investigated pain and motor problems as symptoms of PD in relation to dFC. Twenty-four PD patients and 27 healthy controls participated in this study. Memory and executive functioning were assessed with neuropsychological tests. Pain was assessed with the Numeric Rating Scale (NRS); motor symptom severity was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS). All subjects underwent resting-state functional magnetic resonance imaging (fMRI), from which dFC was defined by calculating the variability of functional connectivity over a number of sliding windows within each scan. dFC of both the DMN and FPN with the rest of the brain was calculated. Patients performed worse on tests of visuospatial memory, verbal memory and working memory. No difference existed between groups regarding dFC of the DMN nor the FPN with the rest of the brain. A positive correlation existed between dFC of the DMN and visuospatial memory. Our results suggest that dynamics during the resting state are a neural correlate of visuospatial memory in PD patients. Furthermore, we suggest that brain dynamics of the DMN, as measured with dFC, could be a phenomenon specifically linked to cognitive functioning in PD, but not to other symptoms.


Colourimetric-based method for the diagnosis of spinal muscular atrophy using gold nanoprobes.
Although numerous molecular methods for spinal muscular atrophy (SMA) detection have been exploited, most of them are laborious, time consuming and costly. Recently, gold nanoparticles (AuNPs) have attracted attention in the field of colourimetric bioanalysis, because AuNP aggregation can be tracked with the naked eye as well as ultraviolet-visible (UV-vis) peak analysis. Here, based on a non-cross linking platform, a colourimetric-based method was used to evaluate the capability of thiolated oligo-AuNPs (Au nanoprobes) to distinguish between normal individuals, carriers and those with SMA. In this platform, removal of the repulsive force of the Au nanoprobes using high salt concentration solutions forced them to aggregate. Amplified DNA products from 20 blood samples were hybridised with the Au nanoprobes. UV-vis spectra and peak analysis ratios of SMA-positive samples revealed that, following salt addition, the unhybridised Au nanoprobes progressively aggregated and their absorption peak shifted to longer wavelengths (P<0.05), observed as a colour change from red to violet-purple. In contrast, colourimetric discrimination between normal and carrier samples following salt addition was not possible because of the small differences in their spectra and aggregation indices. Using this method, patients can be screened in <30 min.


Role of TNF-alpha and extracellular ATP in THP-1 cell activation following allergen exposure.
Dendritic cells (DCs), including Langerhans cells (LCs), play a critical role in the induction phase of allergic contact hypersensitivity. Following exposure to chemical allergens in the skin, LCs undergo a maturation process leading to the up-regulation of expression of co-stimulatory molecules, such as CD86, CD54 and CD40. Our previous study revealed that chemical allergens induce phenotype alterations (e.g., CD86, CD54 and CD40) and cytokine production (TNF-alpha and IL-8) in THP-1 cells that possibly reflect the maturation of dendritic cells during skin sensitization. However, the physiological signals for phenotypic alterations by chemical allergens are still not fully understood. Therefore, in this study, we investigated the effect of TNF-alpha and extracellular ATP on THP-1 cell activation induced by chemical allergens. Kinetic studies revealed that TNF-alpha and IL-8 release occurred in a time-dependent manner with release of two cytokines beginning at 3 hr post-exposure to well-known haptens, DNCB and NiSO(4). While recombinant human TNF-alpha augmented CD54 and CD40 expression in a dose-dependent manner, rhTNF-alpha did not increase CD86 expression. Furthermore, neutralization of TNF-alpha activity strongly inhibited CD54 and CD40 expression induced by allergens. On the contrary, extracellular ATP induced the up-regulation of both CD86 and CD54 expression. In the presence of the P2 receptor antagonist suramin, the up-regulation of CD86 and CD54 expression by allergens was in part suppressed. Therefore, we postulate that not only TNF-alpha but also extracellular ATP may contribute to cell activation following allergen stimulation, which might reflect the mechanism by which DCs respond to allergens.