New findings on the pollination biology of Mauritia flexuosa (Arecaceae) in Roraima, Brazil: linking dioecy, wind, and habitat.
Despite the ecological, economic, and cultural importance of the palm Mauritia flexuosa in Amazonia, knowledge of its reproductive biology is scarce. Previous observations of this species suggested beetles as the probable pollinator, but experimental work to confirm this hypothesis was lacking. • We investigated the floral biology and pollination of M. flexuosa in undisturbed forest, undisturbed savanna/forest ecotone, and fragmented savanna within plantations of the exotic tree, Acacia mangium, in northern Brazilian Amazonia. In each habitat, we examined floral biology, combined floral visitor observations with laboratory analyses, and performed anemophily and exclusion experiments. • Fruit set was significantly greater in the visitor exclusion treatment than in the wind + visitor exclusion treatment and significantly lower in the wind + visitor exclusion treatment than the open control, but there was no difference in fruit set between the visitor exclusion treatment and the control. We found no significant difference in pollen dispersal among the three habitats. The presence of A. mangium appears to have no immediate effect on pollination of M. flexuosa, although it may indirectly affect other aspects of this native's reproductive ecology. • Floral visitors of M. flexuosa are not pollinators. This dioecious palm depends on wind as its primary pollen vector. Wind pollination is not necessarily most effective in open habitats. These findings are important because they re-evaluate traditional assumptions of wind pollination and can improve management strategies of this natural resource in the Amazon.


Anti-oxidative and anti-apoptosis effects of egg white peptide, Trp-Asn-Trp-Ala-Asp, against H2O2-induced oxidative stress in human embryonic kidney 293 cells.
Peptides derived from egg white protein are well-known for their abundant species and biological properties. The aim of this study was to investigate the anti-oxidative and anti-apoptosis effects of (Trp-Asn-Trp-Ala-Asp) WNWAD, a pentapeptide derived from egg white ovomucin pepsin hydrolysates, against the oxidative stress induced by H2O2 in HEK-293 cells. Oxygen radical absorbance capacity (ORAC) results showed that WNWAD possessed extraordinary oxygen radical absorption capacity (with an ORAC value = 2.91 μM TE μM(-1)) in vitro. Then, at the cellular level, MTS assay results displayed that WNWAD dose-dependently inhibited H2O2-induced cellular oxidative stress in HEK-293 cells and fully recovered the oxidative damage induced by 400 μM H2O2 at a concentration of 1 μM. The 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probe assay further proved that WNWAD inhibited cellular oxidative stress by reducing intracellular ROS accumulation in intact HEK-293 cells. In addition, scanning electron microscopy (SEM) images showed that the morphology of HEK-293 cells under H2O2 treatment displayed a cell apoptosis phenotype, while WNWAD pretreatment prevented the development of this phenotype. Furthermore, Western blot results indicated that WNWAD up-regulated the level of the anti-apoptotic protein Bcl-2 and down-regulated the levels of apoptosis executor proteins, cleaved caspase-3 and cleaved PRAP, in H2O2-induced oxidative stress in HEK-293 cells. All the above results suggested that WNWAD protected HEK-293 cells against H2O2-induced oxidative stress by inhibiting intracellular ROS accumulation and blocking the ROS activated mitochondria-mediated cell apoptosis pathway.


Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma.
We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1α was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4.


More than a feeling: A unified view of stress measurement for population science.
Stress can influence health throughout the lifespan, yet there is little agreement about what types and aspects of stress matter most for human health and disease. This is in part because "stress" is not a monolithic concept but rather, an emergent process that involves interactions between individual and environmental factors, historical and current events, allostatic states, and psychological and physiological reactivity. Many of these processes alone have been labeled as "stress." Stress science would be further advanced if researchers adopted a common conceptual model that incorporates epidemiological, affective, and psychophysiological perspectives, with more precise language for describing stress measures. We articulate an integrative working model, highlighting how stressor exposures across the life course influence habitual responding and stress reactivity, and how health behaviors interact with stress. We offer a Stress Typology articulating timescales for stress measurement - acute, event-based, daily, and chronic - and more precise language for dimensions of stress measurement.


[The long way toward Mexican cardiology].
The evolution of medical thought from the precientific phase during Renaissance toward the beginning of scientific phase in the XVII Century is reviewed. This phase was dominated by the great event of the discovery of blood circulation. The irradiation of this doctrine was parallel to that of Copernican theory. Harvey, the starter of experimental method in medicine, graduated at the University of Padua, where previously studied Copernicus. There he was influenced by Galileo's teaching, from whom adopted the quantitative focussing for his physiological research. His monograph Exercitatio anatomica de motu cordis... was present in Mexico, although it is not possible to establish when it arrived here. Only in the physiological treatise of doctor Marcos Joseph Salgado (1727) the blood circulation is described following Harvey's doctrine. Studies in the cardiovascular field began here during French intervention at the same time of the development of our Academy of Medicine. The first observations, concerning the blood vessels, were of surgical interest. Between 1870 and 1900, around 30 thesis related to cardiovascular system were presented at Mexican Medical School and various books related to this field were published. At the end of XIX century and in the beginning of the XX, some cardiovascular pharmacological investigations were done at the National Medical Institute under the direction of Dr. Fernando Altamirano. However only toward the middle of XX century it was possible to create and sistematize a cardiological specialty, thanks to the foresight of Dr. Ignacio Chávez. Cardiology today constitutes a mother discipline fragmented in a great number of subspecialities, each one having own characteristics, methodology and focussing.


Hepatitis B virus infection and risk of gastric cancer: a systematic review and meta-analysis.
Hepatitis B virus (HBV) infection is a well-established risk factor for hepatocellular carcinoma. Recent studies have also suggested a higher risk of several extrahepatic cancers in patients with chronic HBV infection, including gastric cancer, even though the results are somewhat inconsistent. The current study was conducted to comprehensively investigate whether patients with HBV infection are at a higher risk of incident gastric cancer compared with individuals without HBV infection using systematic review and meta-analysis technique. Systemic literature review was conducted using EMBASE and MEDLINE database up to December 2019. Eligible studies had to be cohort studies that consisted of one group of patients with HBV infection and another group of individuals without HBV infection. Relative risk of incident gastric cancer between the groups must be reported. Point estimates and standard errors from each eligible study were combined together using the generic inverse variance method of DerSimonian and Laird. A total of 36,812 articles were identified. After two rounds of review, five articles with six cohorts of 120,995 HBV infected patients were included into the meta-analysis. The pooled analysis found that patients with HBV infection had a significantly higher risk of incident gastric cancer than individuals without HBV infection with the pooled risk ratio of 1.49 (95% CI, 1.20 - 1.85; I2=38%). A significantly increased risk of incident gastric cancer among patients with chronic HBV infection was observed in this systematic review and meta-analysis.


Recombinant Saccharomyces cerevisiae serves as novel carrier for oral DNA vaccines in Carassius auratus.
Oral delivery of DNA vaccines represents a promising vaccinating method for fish. Recombinant yeast has been proved to be a safe carrier for delivering antigen proteins and DNAs to some species in vivo. However, whether recombinant yeast can be used to deliver functional DNAs for vaccination to fish is still unknown. In this study, red crucian carp (Carassius auratus) was orally administrated with recombinant Saccharomyces cerevisiae harboring CMV-EGFP expression cassette. On day 5 post the first vaccination, EGFP expression in the hindgut was detected under fluorescence microscope. To further study whether the delivered gene could induce specific immune responses, the model antigen ovalbumin (OVA) was used as immunogen, and oral administrations were conducted with recombinant S. cerevisiae harboring pCMV-OVA mammalian gene expression cassette as gene delivery or pADH1-OVA yeast gene expression cassette as protein delivery. Each administration was performed with three different doses, and the OVA-specific serum antibody was detected in all the experimental groups by western blotting and enzyme-linked immunosorbent assay (ELISA). ELISA assay also revealed that pCMV-OVA group with lower dose (pCMV-OVA-L) and pADH1-OVA group with moderate dose (pADH1-OVA-M) triggered relatively stronger antibody response than the other two doses. Moreover, the antibody level induced by pCMV-OVA-L group was significantly higher than pADH1-OVA-M group at the same serum dilutions. All the results suggested that recombinant yeast can be used as a potential carrier for oral DNA vaccines and would help to develop more practical strategies to control infectious diseases in aquaculture.


Sensory potentials and sural nerve biopsy: a model evaluation.
Compound action potentials (CAPs) were recorded from the sural nerve prior to nerve biopsy in patients with various kinds of polyneuropathy. A previously developed volume conductor model for the CAP is applied to analyze the recorded CAPs in close relation with the morphological findings in the biopsy. First, the fiber diameter histograms obtained from the biopsy are used to simulate CAPs, by assuming a linear relation between fiber diameter and propagation velocity. It is concluded that the simulated CAPs deviate systematically from the recorded CAPs. Next, the assumption of a linear diameter-velocity relation is left, and the assumed fiber velocity distribution is adapted to obtain optimal model reconstructions of the recorded CAPs. It is concluded that the model is capable of reconstructing the recorded CAPs, including slow components and small polyphasic potentials in the case of severe fiber loss. It is demonstrated how the diameter histogram and the optimal velocity distribution can be combined to an empirical estimate of the diameter-velocity relation.


Differences in transcription patterns between induced pluripotent stem cells produced from the same germ layer are erased upon differentiation.
Little is known about differences between induced pluripotent stem cells produced from tissues originating from the same germ layer. We have generated human myoblast-derived iPS cells by retroviral transduction of human primary myoblasts with the OCT3/4, SOX2, KLF4 and MYC coding sequences and compared them to iPS produced from human primary fibroblasts. When cultivated in vitro, these iPS cells proved similar to human embryonic stem cells in terms of morphology, expression of embryonic stemness markers and gene promoter methylation patterns. Embryonic bodies were derived that expressed endodermal, mesodermal as well as ectodermal markers. A comparative analysis of transcription patterns revealed significant differences in the gene expression pattern between myoblast- and fibroblast-derived iPS cells. However, these differences were reduced in the mesenchymal stem cells derived from the two iPS cell types were compared.


Characterization of the Prk1 protein kinase from Schizosaccharomyces pombe.
We report the isolation and characterization of a protein kinase from the fission yeast Schizosaccharomyces pombe. The proposed Prk1 protein contains 352 amino acids and has significant homology to the Ume5p kinase (also known as Srb10p, Ssn3p and Are1p) of the budding yeast Saccharomyces cerevisiae, a cyclin-dependent kinase involved in regulating the transcription of a diverse set of genes. Disruption of the prk1 gene increases flocculation but does not appear to have any other significant effect on cell behaviour. This defect can be overcome by expressing the UME5 gene, indicating that Prk1 is the fission yeast homologue of Ume5p.


Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells.
ACE (kininase II) inhibitors have been shown to exert their beneficial cardiovascular effects via the inhibition of both angiotensin II formation and bradykinin breakdown. Because recent evidence suggests that ACE inhibitors may also interfere with B2 kinin receptor signaling and thus enhance the vascular response to bradykinin, we examined whether the distribution of B2 kinin receptors within the plasma membrane of native endothelial cells is affected by an ACE inhibitor. Localization of the B2 kinin receptor in membranes prepared from native porcine aortic endothelial cells was evaluated by means of specific [3H]bradykinin binding and immunoprecipitation of the B2 receptor from isolated membranes. Effects of bradykinin and ramiprilat on intracellular signaling were determined by monitoring the activation of the extracellularly regulated kinases Erk1 and Erk2 as well as [Ca2+]i increases in fura 2-loaded endothelial cells. Stimulation of native endothelial cells with bradykinin 100 nmol/L resulted in the time-dependent sequestration of the B2 receptor to caveolin-rich (CR) membranes, which was maximal after 5 minutes. Pretreatment with ramiprilat 100 nmol/L for 15 minutes significantly attenuated the recovery of B2 kinin receptors in CR membranes while increasing that from membranes lacking caveolin. This effect was not due to the inhibition of bradykinin degradation, because no effect was seen in the presence of an inhibitory concentration of the synthetic ACE substrate hippuryl-L-histidyl-L-leucine. Ramiprilat also decreased [3H]bradykinin binding to CR membranes when applied either before or after bradykinin stimulation. Moreover, ramiprilat resulted in reactivation of the B2 receptor in bradykinin-stimulated cells and induced a second peak in [Ca2+]i and reactivation of Erk1/2. The ACE inhibitor ramiprilat interferes with the targeting of the B2 kinin receptor to CR membrane domains in native endothelial cells. Therefore, effects other than the inhibition of kininase II may account for the effects of ramiprilat and other ACE inhibitors on the vascular system.


CO2 capture by ionic liquids - an answer to anthropogenic CO2 emissions?
Ionic liquids (ILs) are efficient solvents for the selective removal of CO2 from flue gas. Conventional, offthe-shelf ILs are limited in use to physisorption, which restricts their absorption capacity. After adding a chemical functionality like amines or alcohols, absorption of CO2 occurs mainly by chemisorption. This greatly enhances CO2 absorption and makes ILs suitable for potential industrial applications. By carefully choosing the anion and the cation of the IL, equimolar absorption of CO2 is possible. This paper reviews the current state of the art of CO2 capture by ILs and presents the current research in this field performed at the ChemTech Institute of the Ecole d'Ingénieurs et d'Architectes de Fribourg.


Preparing Primary Care Registered Nurse Preceptors for Emerging Care Coordination and Chronic Disease Self-Management Roles.
Nurse educators must prepare the future RN work-force to practice in emerging primary care roles. This program evaluation report describes the approach taken to develop and evaluate a novel preceptor education program designed to prepare RNs to precept nursing students in primary care coordination and disease self-management roles. The program was designed as a three-stage hybrid learning intervention with the goals of preparing RNs to (a) provide primary care coordination and disease self-management support and (b) precept nursing students. Evaluation tools were designed to reflect specific learning objectives of these goals pre- and postintervention. Preliminary evaluation data indicate the preceptor program provided a useful set of educational activities to prepare primary care RN preceptors for their new roles. Participants reported increased confidence levels in primary care coordination and disease self-management and student precepting responsibilities. Nursing students' evaluations showed positive primary care clinical experiences. [J Contin Educ Nurs. 2023;54(10):454-461.].


Therapeutic potential of anti-CD137 (4-1BB) monoclonal antibodies.
4-1BB (CD137) is an important T-cell stimulating molecule. The 4-1BB mAb or its variants have shown remarkable therapeutic activity against autoimmunity, viral infections, and cancer. Antibodies to 4-1BB have recently entered clinical trials for the treatment of cancer with favorable toxicity profile. In this article, we present a review documenting the efficacy and pitfalls of 4-1BB therapy. An extensive literature search has been made on 4-1BB, spanning two decades, and a comprehensive report is presented here highlighting the origins, biological effects, therapeutic potential, and mechanistic basis of targeting 4-1BB as well as the side effects associated with such therapy. Research so far indicates that 4-1BB is highly protective against various pathological conditions including cancer. However, a few important side effects of 4-1BB therapy such as liver toxicity, thrombocytopenia, anemia, and suppressive effects on certain immune competent cells should be taken into consideration before it is used for human therapy.


Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.
Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.


Prognostic markers in chronic lymphocytic leukemia: a comprehensive review.
The clinical course of individual CLL patients is highly variable, with life expectancies ranging from months to decades. Importantly, a significant subset of patients presents with low grade CLL, but will nevertheless develop a more aggressive and life-threatening disease. As these patients may potentially benefit from early treatment, it is crucial to assess patients' prognosis at diagnosis, allowing individual risk-adapted therapy. Reliable predictions of prognosis in an early stage of the disease have long been lacking in the clinical workup of CLL patients. During the last decades many efforts have been made to identify prognostic markers in CLL, resulting in a plethora of reports describing the predictive value of different parameters with regard to overall survival, disease progression and response to therapy. In this review, we attempt to provide an overview of the literature and we discuss the most important prognostic markers in CLL, from clinical staging systems and serum markers over proliferation markers and cytogenetics to more recent markers like the IgV(H) mutation status and its possible surrogate markers. Particular attention is paid to the advantages and drawbacks of all different markers, both from a clinical and from a technical point-of-view, highlighting the accomplishments as well as the remaining challenges in this rapidly evolving area of CLL research. Although the great majority of prognostic markers is not included in current international treatment guidelines, several of these markers deserve to be evaluated in prospective clinical trials and may eventually contribute to an improved clinical management of CLL patients.


Baseline Sleep Efficiency and Arousal Index Do Not Predict Who Will Benefit From Sedatives in Improving Positive Airway Pressure Adherence in Sleep Apnea to 90.
Positive airway pressure (PAP) is the preferred treatment for obstructive sleep apnea (OSA), but adherence is low. Educational or ongoing supportive intervention improves the number of PAP adherent patients from the 50% to the 70% range. A common side effect of PAP is increased awakenings. This prospective trial examined baseline polysomnographically derived sleep efficiency and arousal index in PAP adherent and nonadherent patients, and in patients needing sedating medicines to attain PAP adherence versus those who did not need such medicines. Patients with OSA were titrated on PAP during a polysomnography or treated with autotitrating PAP, followed by educational and supportive interventions. Patients with PAP related awakenings (patients describing waking up and taking PAP off in the middle of the night) or difficulty tolerating PAP were additionally treated with medicines that suppress arousals/awakenings (trazodone, mirtazapine, doxepin). A total of 120 of 151 (79%) new patients were ≥70% PAP adherent over a continuous 30-day period, typically within the first 90 days of starting PAP, without sedating medicines. Nineteen of the remaining patients were treated with medicines that suppress arousals and awakenings, and 16 became adherent, resulting in 136 (90%) of 151 new patients achieving adherence. There were no differences in baseline sleep efficiency or arousal index, between adherent and nonadherent patients, as well as between patients who needed sedating medicines for PAP adherence and those who did not. Adding medicines that suppress arousals and awakenings for patients having trouble tolerating PAP, increases the number of patients who are PAP adherent. The need for such medicines seems to be related to the PAP side effect of increased awakenings rather than baseline impaired sleep.


A one-year survey of mold growth inside twelve homes.
A survey was performed of the mold flora in the air and on the surfaces inside twelve homes throughout four seasons. There were significant variations of the mold flora in homes associated with the outdoor spore count, various rooms, carpeting, central air-conditioning and pets. We conclude that homes may be a source of perennial mold exposure.


[Protective effect of phloroglucinol on renal ischemia and reperfusion injury].
To investigate the effect and mechanisms of Phloroglucinol (PG) on renal ischemia and reperfusion injury (IRI). Forty-eight male Wistar rats were divided into 3 groups (16 rats per group): sham operated, saline-treated I/R (I/R), and PG-treated I/R (PG). I/R model: After removing the right kidney, renal I/R injury was induced by clamping the left renal artery for 45 min followed by reperfusion. The rats were administered with PG (30 mg/kg, intraperitoneally) or saline 15 min before renal ischemia. The blood and kidneys were harvested 6 and 24 h after reperfusion. Renal function and histologic changes of serum creatinine (SCr) and blood urea nitrogen(BUN)were assessed. Malondialdehyde (MDA),catalase (CAT),superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)were measured. Nuclear factor-kapa B (NF-κB) and caspase-3 in the kidneys were also measured. SCr and BUN were (103.9±10.4) μmol/L and (15.2±1.0) mmol/L in I/R group, and (81.8±13.4) μmol/L and (11.5±1.2) mmol/L in PG group 6 h after reperfusion. SCr and BUN were (154.9±12.1) μmol/L and (28.1±1.4) mmol/L in I/R group, (103.8±5.9) μmol/L and (16.0±1.0) mmol/L in PG group 24 h after reperfusion.PG treatment significantly attenuated renal dysfunction and histologic damage caused by I/R injury (P<0.05).The I/R-induced elevation in kidney MDA level decreased, where as reduced kidney SOD,CAT and GSH-Px were increased. What is more, the apoptotic tubular cells, the levels of active caspase-3,and active nuclear factor kappa B dramatically decreased after PG treatment. PG protects murine kidney I/R injury by suppressing oxidative stress, inflammation, and cell apoptosis.


Quantification of heterogeneity observed in medical images.
There has been much recent interest in the quantification of visually evident heterogeneity within functional grayscale medical images, such as those obtained via magnetic resonance or positron emission tomography. In the case of images of cancerous tumors, variations in grayscale intensity imply variations in crucial tumor biology. Despite these considerable clinical implications, there is as yet no standardized method for measuring the heterogeneity observed via these imaging modalities. In this work, we motivate and derive a statistical measure of image heterogeneity. This statistic measures the distance-dependent average deviation from the smoothest intensity gradation feasible. We show how this statistic may be used to automatically rank images of in vivo human tumors in order of increasing heterogeneity. We test this method against the current practice of ranking images via expert visual inspection. We find that this statistic provides a means of heterogeneity quantification beyond that given by other statistics traditionally used for the same purpose. We demonstrate the effect of tumor shape upon our ranking method and find the method applicable to a wide variety of clinically relevant tumor images. We find that the automated heterogeneity rankings agree very closely with those performed visually by experts. These results indicate that our automated method may be used reliably to rank, in order of increasing heterogeneity, tumor images whether or not object shape is considered to contribute to that heterogeneity. Automated heterogeneity ranking yields objective results which are more consistent than visual rankings. Reducing variability in image interpretation will enable more researchers to better study potential clinical implications of observed tumor heterogeneity.


Interleukin-11 receptor predicts post-operative clinical outcome in patients with early-stage clear-cell renal cell carcinoma.
To investigate the prognostic value of interleukin-11 receptor α chain in patients with early-stage clear-cell renal cell carcinoma. Interleukin-11 receptor α chain, a member of the gp130-dependent receptors, exerts pleiotropic oncogenic activities by promoting proliferation, angiogenesis and metastasis in many cancers. We retrospectively enrolled 293 patients (130 in the training cohort and 163 in the validation cohort) with early-stage (TNM Stage I + II) clear-cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathologic features, recurrence-free survival and overall survival were recorded. Interleukin-11 receptor α chain intensities were assessed by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves between groups. Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival and overall survival. The concordance index was calculated to assess predictive accuracy. In both training and validation cohorts, high interleukin-11 receptor α chain expression was associated with early recurrence (P = 0.004 and P = 0.015, respectively) and poor survival (P < 0.001 and P = 0.019, respectively) of patients with early-stage clear-cell renal cell carcinoma. Multivariate analyses confirmed that interleukin-11 receptor α chain expression was an independent prognostic factor for recurrence-free survival (P = 0.004) and overall survival (P = 0.001). The predictive accuracy of the Leibovich prognostic score was improved when interleukin-11 receptor α chain expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score. High Interleukin-11 receptor α chain expression is an independent predictor of poor clinical outcome in patients with early-stage clear-cell renal cell carcinoma, and the prognostic value is more prominent in those with low-risk disease.


miR-155-5p Implicates in the Pathogenesis of Renal Fibrosis via Targeting SOCS1 and SOCS6.
Renal fibrosis is associated with the reduction in the functional renal parenchyma and in most cases progresses to end-stage kidney failure, a devastating condition that requires lifelong dialysis or kidney transplantation. However, due to the extreme complexity in the pathogenesis of renal fibrosis and our limited knowledge, therapeutic options for renal fibrosis in the clinical setting are still scarce and often ineffective. Hence, further studies on the molecular mechanisms underlying renal fibrosis are compellingly needed. Multiple miRNAs have demonstrated to participate in kidney diseases in a TGF-β dependent or independent manner, but there is very little known about miR-155-5p on renal fibrosis. In the present study, we firstly explored the expression level and functions of miR-155-5p in the setting of renal fibrosis. Our research revealed that miR-155-5p is highly expressed in kidney tissues from patients and unilateral ureteral obstruction (UUO) rat models, and miR-155-5p knockdown significantly blocks renal fibrosis both in vivo and in vitro. In mechanism, our data demonstrate that miR-155-5p promotes renal fibrosis by increasing the phosphorylated activation of STAT3 via targeting SOCS1/6. Altogether, our findings highlight a miR-155-5p/SOCS/STAT3 axis in the pathogenesis of renal fibrosis, which may provide promising therapeutic targets for clinical prevention of this disease.


Atomistic oxidation mechanism of a carbon nanotube in nitric acid.
Motivated by recent experiments, we investigate how NO3-SWNT interactions become energetically favorable with varying oxidation state of a single-walled carbon nanotube (SWNT) using first-principles calculations. Chemisorption becomes less endothermic with respect to physisorption when the SWNT oxidation state is elevated. Importantly, the dissociative incorporation of an oxygen atom into the SWNT sidewall becomes highly favorable when the SWNT oxidation state is elevated from electron density depletion in the vicinity, as caused experimentally using electrochemical potential. The elevation of the SWNT oxidation state through accumulating local charge transfer from the surrounding molecules does not have the same effect. Our investigation reveals the crucial effects of the SWNT oxidation state in understanding the molecule-SWNT interaction.


Pulmonary mucinous cystadenoma complicated with infection: A rare case report.
Mucinous cystadenoma is a benign tumor that is commonly found in the pancreas, ovaries, or appendix, but is rarely encountered in the lungs. Worldwide, only a few reported cases of these tumors originate in the lungs. Herein, we analyzed the imaging features of a case of pulmonary mucinous cystadenoma (PMCA). To the best of our knowledge, this is the first reported case of PMCA complicated by significant infection. A 57-year-old man was admitted to our hospital with blood in sputum for more than 2 months. Serum laboratory examination showed significantly elevated leukocyte and tumor marker, carcinoembryonic antigen. Enhanced thoracic computed tomography and whole-body positron emission tomography/computed tomography showed a cystic-solid ill-defined mass in the right upper lung. The tumor was considered malignant, both clinically and radiologically. The patient underwent right upper lobe tumor resection and mediastinal lymph node dissection. Postoperative specimen pathology was diagnosed as PMCA with infection. The patient was not administered any further treatment. The patient was alive without any recurrence or metastasis of the tumor after 2 years of follow-up. Preoperative diagnosis of PMCA with atypical imaging and clinical manifestations is extremely difficult. This is the first reported case of PMCA complicated by a significant infection that was misdiagnosed preoperatively as a malignancy.


Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review.
Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient. Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity. Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.


Modulating mechanobiology as a therapeutic target for synovial fibrosis to restore joint lubrication.
Fibroses are disorders linked to persistence of myofibroblasts due to biochemical (e.g., Transforming growth factor-β) and biophysical cues (e.g., a stiff microenvironment). In the context of osteoarthritis, fibrotic changes in the joint-lining synovium have been linked with disease progression. The objective of this study was to probe synovial fibroblast mechanobiology and how essential functions (i.e., lubrication) are altered in fibrotic environments. Both ex vivo and in vitro synovium models were assessed for fibrotic and lubrication biomarkers to better understand the role of mechanobiology and lubrication. Additionally, in vitro, work on small molecules targeting mechanobiology was assessed. Our results indicated that modulating mechanobiology could rescue the fibrotic phenotype instigated by stiffening microenvironment that resulted in altered lubricant expression. A small molecule therapeutic, fasudil, blocked ROCK-mediated contractility and this inhibition of the fibrotic mechano-response of synovial fibroblasts restored proper lubrication function, providing insight into mechanisms of disease progression as well as a new avenue for therapeutic development. This study identifies synovial fibrosis as a condition that potentially has joint-wide deficits through inhibiting lubrication. Additionally, modulating mechanobiology (i.e., ROCK-mediated contractility) may pose a potential target for small molecule therapies that can be delivered to the joint space. Applied Biological Sciences.


Long-term results of surgery for temporal bone paragangliomas.
Assessment of the long-term results of surgery for temporal bone paragangliomas with special consideration of the patient's ability to cope with the functional deficits. Retrospective review of 36 patients who had undergone resection of a temporal bone paraganglioma 10 to 15 years previously. Assessment of the patients' subjective view of the functional outcome and quality of life by a questionnaire. Clinical records were reviewed regarding size of tumor, technique of surgery, supportive therapy, and tumor recurrence. Patients were sent a 50-item questionnaire evaluating their quality of life and the preoperative and postoperative function of cranial nerves VII through XII. A complete tumor removal was achieved in 30 patients (83%). There was only one tumor recurrence. The major negative effects of surgery involved hearing and dysphagia, which deterioriated in 14 and 12 patients, respectively. Thirty-five of the 36 patients (97%) reported that, despite deterioration, the cranial nerve deficits were still acceptable. Seventy-five percent of the patients regained their preoperative quality of life and 97% returned to their previous occupation in 1 to 2 years. The otologic extradural approach allowed complete tumor removal in 83%, with minimal perioperative morbidity. No surgically induced central nervous system lesions occured. Tracheostomy was avoided and all patients resumed oral feeding. Full rehabilitation after removal of class C and CD paragangliomas may take 1 to 2 years. However, the fact that 97% of the patients finally resumed normal social life showed the ability of most patients to cope with the sequelae of surgery even in class C and CD paragangliomas.


Role of the splanchnic bed in extracting circulating adrenaline and noradrenaline in normal subjects and in patients with cirrhosis of the liver.
Splanchnic extraction rates of adrenaline and noradrenaline were determined in seven normal subjects and in nine patients with cirrhosis of the liver using arterial-hepatic venous catherization . Both catecholamines were effectively removed when the blood passed through the splanchnic area: splanchnic fractional uptake of adrenaline in normal subjects was 90 +/- 3%, and lower for noradrenaline, 68 +/- 4% (P less than 0.001). Net splanchnic extraction rates were higher for noradrenaline (126 +/- 16 ng/min) than for adrenaline (40 +/- 10 ng/min, P less than 0.001), probably due to the higher arterial plasma levels of noradrenaline. Resting arterial adrenaline and noradrenaline levels were significantly higher in cirrhotic patients than in normal subjects (adrenaline: 121 +/- 27 vs 54 +/- 8 pg/ml, P less than 0.05; noradrenaline: 678 +/- 89 vs 251 +/- 26 pg/ml, P less than 0.005). Net splanchnic catecholamine uptake was increased in cirrhotic patients. The results demonstrate that the splanchnic bed in normal and cirrhotic subjects extracts plasma catecholamines efficiently; they suggest that elevated plasma catecholamines in cirrhosis are not the result of impaired splanchnic catecholamine removal.


Partial Preservation of Segment IV Confers No Benefit When Performing Extended Right Hepatectomy for Colorectal Liver Metastases.
Introduction. Reducing the volume of resected liver parenchyma may lead to lower morbidity and mortality. The aim of this study was to determine whether partial preservation of segment IV leads to improved outcomes when undertaking extended right hepatectomy for colorectal liver metastases (CRLM). Materials and Methods. A retrospective analysis of patients undergoing right-sided hepatectomy for CRLM was performed. Rates of 90-day mortality and organ dysfunction were compared in 117 patients undergoing right hepatectomy (n = 85), partially extended right hepatectomy with preservation of part of segment IV (n = 20), and fully extended right hepatectomy (n = 12). Results. The 90-day mortality rate of those undergoing right hepatectomy (3/85) was similar to that of those undergoing extended right hepatectomy (0/12) (P = 1.000) but lower than that of those undergoing partially extended right hepatectomy (4/20) (P = 0.024). The rates of hepatic and renal dysfunction were similar between patients undergoing right hepatectomy, partially extended or extended hepatectomy. Discussion. Preservation of part of segment IV confers little clinical benefit when performing extended right hepatectomy for CRLM.


[Application of temporary polyurethane-covered nitinol endoprosthesis in treating urethral stricture].
The incidence of urethral strictures and their recurrences is high. The effectiveness of optical urethrotomy in men is insufficient. Reconstructive urethroplasty is the "gold standard", but it is traumatic and accompanied by a prolonged period of rehabilitation. The results of using metal endourethral stents were unsatisfactory because of their incrustation and migration. This paper presents the results treating urethral strictures of various etiologies in 22 patients, who underwent optical urethrotomy with temporary placement of a new generation polyurethane-covered nitinol stents. After removing the stents from 3 to 8 months after implantation, there was a stable effect of preserving the urethral lumen. The recurrence of the stricture occurred in 1 case 1 month following the stent removal. In other cases, there were no recurrences over 1-3 year follow-up. We consider placing an internal stent as an alternative adjunctive treatment of patients with urethral strictures.


Deep learning for artery-vein classification in optical coherence tomography angiography.
Major retinopathies can differentially impact the arteries and veins. Traditional fundus photography provides limited resolution for visualizing retinal vascular details. Optical coherence tomography (OCT) can provide improved resolution for retinal imaging. However, it cannot discern capillary-level structures due to the limited image contrast. As a functional extension of OCT modality, optical coherence tomography angiography (OCTA) is a non-invasive, label-free method for enhanced contrast visualization of retinal vasculatures at the capillary level. Recently differential artery-vein (AV) analysis in OCTA has been demonstrated to improve the sensitivity for staging of retinopathies. Therefore, AV classification is an essential step for disease detection and diagnosis. However, current methods for AV classification in OCTA have employed multiple imagers, that is, fundus photography and OCT, and complex algorithms, thereby making it difficult for clinical deployment. On the contrary, deep learning (DL) algorithms may be able to reduce computational complexity and automate AV classification. In this article, we summarize traditional AV classification methods, recent DL methods for AV classification in OCTA, and discuss methods for interpretability in DL models.


Association of ERAP1 gene polymorphisms with the susceptibility to psoriasis vulgaris: A case-control study.
Psoriasis vulgaris (PsV), also known as plaque psoriasis, is a life-threatening autoimmune skin disease. Inflammatory factors may contribute to the development of PsV. Present study aimed to explore the association of endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms (rs26653 and rs27524) with PsV susceptibility in a Chinese Han population. Subgroup analysis was also performed based on the onset of PsV.Present case-control study included 143 patients with PsV and 149 healthy controls. Direct sequencing method was used for genotyping ERAP1 polymorphisms. Chi-squared test was used to estimate the association between ERAP1 polymorphisms and PsV susceptibility. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess association strength.The polymorphism rs26653 was positively correlated with PsV susceptibility (CC vs GG, P = .047, OR = 1.964, 95% CI = 1.006-3.834; C vs G, P = .042, OR = 1.403, 95% CI = 1.011-1.946). Meanwhile, its CC genotype and C allele were positively associated with the early onset of PsV (P = .036, OR = 2.080, 95% CI = 1.044-4.145; P = .034, OR = 1.443, 95% CI = 1.028-2.024) and increased PsV risk in the subgroup with family history (P = .029, OR = 2.149, 95% CI = 1.075-4.296; P = .027, OR = 1.466, 95% CI = 1.044-2.059).ERAP1 gene rs26653 polymorphism may increase the risk of PsV in Chinese Han population.


Perspectives on violence.
The worldwide rise in violence, especially that directed against females of all ages, led the World Health Organization (WHO) to undertake steps to deal with that problem. To do so, WHO adopted a public health approach. This entailed (1) developing a definition of violence, (2) devising a typology of violent acts, (3) creating a uniform database for reporting violence, and (4) promulgating a model for understanding violence and its attendant phenomena. This essay reviews, analyzes, and critiques those efforts.


DNA extraction and amplification from contemporary Polynesian bark-cloth.
Paper mulberry has been used for thousands of years in Asia and Oceania for making paper and bark-cloth, respectively. Museums around the world hold valuable collections of Polynesian bark-cloth. Genetic analysis of the plant fibers from which the textiles were made may answer a number of questions of interest related to provenance, authenticity or species used in the manufacture of these textiles. Recovery of nucleic acids from paper mulberry bark-cloth has not been reported before. We describe a simple method for the extraction of PCR-amplifiable DNA from small samples of contemporary Polynesian bark-cloth (tapa) using two types of nuclear markers. We report the amplification of about 300 bp sequences of the ITS1 region and of a microsatellite marker. Sufficient DNA was retrieved from all bark-cloth samples to permit successful PCR amplification. This method shows a means of obtaining useful genetic information from modern bark-cloth samples and opens perspectives for the analyses of small fragments derived from ethnographic materials.


Role of miR-383 and miR-146b in different propensities to obesity in male mice.
The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c, Acc1, Scd1 and Fasn) and upregulation of Cpt1α, Atp5c1, Cox7c and Cyp7a1 A stem-loop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid-treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3'untranslated region (3'UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb, respectively.


Opportunities and challenges for comparative effectiveness research (CER) with Electronic Clinical Data: a perspective from the EDM forum.
The Electronic Data Methods (EDM) Forum brings together perspectives from the Prospective Outcome Systems using Patient-specific Electronic data to Compare Tests and therapies (PROSPECT) studies, the Scalable Distributed Research Networks, and the Enhanced Registries projects. This paper discusses challenges faced by the research teams as part of their efforts to develop electronic clinical data (ECD) infrastructure to support comparative effectiveness research (CER). The findings reflect a set of opportunities for transdisciplinary learning, and will ideally enhance the transparency and generalizability of CER using ECD. Findings are based on 6 exploratory site visits conducted under naturalistic inquiry in the spring of 2011. Themes, challenges, and innovations were identified in the visit summaries through coding, keyword searches, and review for complex concepts. : The identified overarching challenges and emerging opportunities include: the substantial level of effort to establish and sustain data sharing partnerships; the importance of understanding the strengths and limitations of clinical informatics tools, platforms, and models that have emerged to enable research with ECD; the need for rigorous methods to assess data validity, quality, and context for multisite studies; and, emerging opportunities to achieve meaningful patient and consumer engagement and work collaboratively with multidisciplinary teams. The new infrastructure must evolve to serve a diverse set of potential users and must scale to address a range of CER or patient-centered outcomes research (PCOR) questions. To achieve this aim-to improve the quality, transparency, and reproducibility of CER and PCOR-a high level of collaboration and support is necessary to foster partnership and best practices as part of the EDM Forum.


Fumonisin in tortillas produced in small-scale facilities and effect of traditional masa production methods on this mycotoxin.
Four small tortilla plants were visited in Cameron County, Texas, where observations were made on their production methods. Samples of liquids and solids were collected at each stage of the nixtamalization process, and the pH was recorded. Samples were analyzed for fumonisin B(1) (FB(1)) using an immunoaffinity column/HPLC method chosen for its sensitivity for FB(1). It was found that production methods were highly variable among the producers visited, with major differences particularly in the amount of lime added and boiling times. As reported by others working in Mexico and Central America, FB(1) was found in some tortillas. This led to studies of the effects of the various recipes and across a greater range of initial FB(1) concentration/damaged corn than has typically been reported. Five initial concentrations of FB(1) were tested using irradiated corn kernels inoculated with Fusarium verticillioides MRC 826 as the source of FB(1). The amount of FB(1) detected in the masa and tortillas decreased as the concentration of Ca(OH)(2) increased, and boiling time had no apparent effect. Unexpectedly, as the initial concentrations were increased in the corn prior to nixtamalization, greater percentage reductions in FB(1) were observed.


Tumor-associated macrophages favor C26 murine colon carcinoma cell proliferation in an oxidative stress-dependent manner.
The role of tumor-associated macrophages (TAMs) in the development of colon carcinoma is still controversial. Therefore, the present study aimed to investigate the TAM‑driven processes that may affect colon cancer cell proliferation. To achieve this purpose, murine macrophages were co-cultured with C26 murine colon carcinoma cells at a cell density ratio that approximates physiological conditions for colon carcinoma development in vivo. In this respect, the effects of TAM-mediated angiogenesis, inflammation and oxidative stress on the proliferative capacity of C26 murine colon carcinoma cells were studied. To gain insight into the TAM-driven oxidative stress, NADPH oxidase, the main pro-oxidant enzyme in macrophages, was inhibited. Our data revealed that the stimulatory effects of TAMs on C26 cell proliferation may be related mainly to their pro-oxidant actions exerted by NADPH oxidase activity, which maintains the redox status and the angiogenic capacity of the tumor microenvironment. Additionally, the anti-inflammatory and pro-angiogenic effects of TAMs on tumor cells were found to create a favorable microenvironment for C26 colon carcinoma development and progression. In conclusion, our data confirmed the protumor role of TAMs in the development of colon carcinoma in an oxidative stress-dependent manner that potentiates the angiogenic capacity of the tumor microenvironment. These data may offer valuable information for future tumor-targeted therapies based on TAM 're-education' strategies.


Complex Problem Solving: What It Is and What It Is Not.
Computer-simulated scenarios have been part of psychological research on problem solving for more than 40 years. The shift in emphasis from simple toy problems to complex, more real-life oriented problems has been accompanied by discussions about the best ways to assess the process of solving complex problems. Psychometric issues such as reliable assessments and addressing correlations with other instruments have been in the foreground of these discussions and have left the content validity of complex problem solving in the background. In this paper, we return the focus to content issues and address the important features that define complex problems.


p-Si/W2C and p-Si/W2C/Pt photocathodes for the hydrogen evolution reaction.
p-Si/W2C photocathodes are synthesized by evaporating tungsten metal in an ambient of ethylene gas to form tungsten semicarbide (W2C) thin films on top of p-type silicon (p-Si) substrates. As deposited the thin films contain crystalline W2C with a bulk W:C atomic ratio of approximately 2:1. The W2C films demonstrate catalytic activity for the hydrogen evolution reaction (HER), and p-Si/W2C photocathodes produce cathodic photocurrent at potentials more positive than 0.0 V vs RHE while bare p-Si photocathodes do not. The W2C films are an effective support for Pt nanoparticles allowing for a considerable reduction in Pt loading. p-Si/W2C/Pt photocathodes with Pt nanoparticles achieve photocurrent onset potentials and limiting photocurrent densities that are comparable to p-Si/Pt photocathodes with Pt loading nine times higher. This makes W2C an earth abundant alternative to pure Pt for use as an electrocatalyst on photocathodes for the HER.


Relationship between alpha-naphthylisothiocyanate-induced liver injury and elevations in hepatic non-protein sulfhydryl content.
Acute administration of alpha-naphthylisothiocyanate (ANIT) to rats has been used as a model of intrahepatic cholestasis. The mechanism of toxicity of ANIT is unknown, although recent evidence suggests a causal or permissive role for glutathione (GSH) (Dahm LJ and Roth RA, Biochem Pharmacol 42: 1181-1188, 1991). In these studies, ANIT treatment elevated hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content, when liver injury was evident. The purpose of the present study was to characterize the effects of ANIT on hepatic NPSH content and to relate these changes to the development of liver injury. In rats fasted for 24 hr, administration of ANIT (100 mg/kg, per os [p.o.]) did not change hepatic NPSH content, bile flow, or serum measurements of total bilirubin concentration, alanine aminotransferase (ALT) activity, or gamma-glutamyltransferase (GGT) activity by 12 hr post-treatment relative to corn oil vehicle controls. However, by 24 hr after ANIT treatment, rats exhibited cholestasis and elevations in serum markers of liver injury. These markers were associated temporally with an increase in hepatic NPSH content, which consisted entirely of GSH. To determine whether the cholestasis caused by ANIT treatment might have caused the elevation of hepatic NPSH content, an extrahepatic cholestasis in rats was produced by ligation of the common bile duct. Bile duct ligation elevated hepatic NPSH content between 6 and 12 hr after ligation. Administration to rats of a non-hepatotoxic analog of ANIT, beta-naphthylisothiocyanate, also elevated hepatic NPSH content 24 hr after treatment. Taken together, these results indicate that the elevation in hepatic NPSH content after ANIT treatment is associated temporally with the onset of liver injury, but this elevation does not appear to participate causally in the mechanism of injury.


Use of Human-Centered Design Methodology to Develop a Digital Toolkit to Optimize Heart Failure Guideline-Directed Medical Therapy.
Guideline-directed medical therapies (GDMTs) improve quality of life and health outcomes for patients with heart failure (HF). However, GDMT utilization is suboptimal among patients with HF. The aims of this study were to engage key stakeholders in semistructured, virtual human-centered design sessions to identify challenges in GDMT optimization posthospitalization and inform the development of a digital toolkit aimed at optimizing HF GDMTs. For the human-centered design sessions, we recruited (a) clinicians who care for patients with HF across 3 hospital systems, (b) patients with HF with reduced ejection fraction (ejection fraction ≤ 40%) discharged from the hospital within 30 days of enrollment, and (c) caregivers. All participants were 18 years or older, English speaking, with Internet access. A total of 10 clinicians (median age, 37 years [interquartile range, 35-41], 12 years [interquartile range, 10-14] of experience caring for patients with HF, 80% women, 50% White, 50% nurse practitioners) and three patients and one caregiver (median age 57 years [IQR: 53-60], 75% men, 50% Black, 75% married) were included. Five themes emerged from the clinician sessions on challenges to GDMT optimization (eg, barriers to patient buy-in). Six themes on challenges (eg, managing medications), 4 themes on motivators (eg, regaining independence), and 3 themes on facilitators (eg, social support) to HF management arose from the patient and caregiver sessions. The clinician, patient, and caregiver insights identified through human-centered design will inform a digital toolkit aimed at optimizing HF GDMTs, including a patient-facing smartphone application and clinician dashboard. This digital toolkit will be evaluated in a multicenter, clinical trial.


Recognition of iconicity doesn't come for free.
Iconicity--resemblance between a symbol and its referent--has long been presumed to facilitate symbolic insight and symbol use in infancy. These two experiments test children's ability to recognize iconic gestures at ages 14 through 26 months. The results indicate a clear ability to recognize how a gesture resembles its referent by 26 months, but little evidence of recognition of iconicity at the onset of symbolic development. These findings imply that iconicity is not available as an aid at the onset of symbolic development but rather that the ability to apprehend the relation between a symbol and its referent develops over the course of the second year.


Samba II PCR testing for COVID-19 in pregnant women: a retrospective cohort study and literature review.
Asymptomatic carriage of COVID-19 in pregnant women has been reported and could lead to outbreaks in maternity units. We sought to ascertain the impact of rapid isothernal nucleic acid based testing for COVID-19 in an unselected cohort of pregnant women attending our maternity unit. We also assessed the correlation between community prevalence and asymptomatic carriage. Data for the retrospective cohort study were collected from a large UK tertiary maternity unit over a 4-week period using computerised hospital records. Literature searches were performed across multiple repositories. COVID-19 prevalence was extracted from online repositories. Nasopharyngeal and oropharyngeal swabs were obtained from 457/465 (98%) women during the study period. The median turnaround time for results was 5.3 h (interquartile range (IQR) 2.6-8.9 h), with 92% of the results returned within 24 h. In our cohort, only one woman tested positive, giving a screen positive rate of 0.22% (1/457; 95% CI: 0.04-1.23%). One woman who tested negative developed a fever postnatally following discharge but was lost to follow-up. From our literature review, we did not find any correlation between asymptomatic carriage in pregnant women and the reported regional prevalence of COVID-19. Testing using the SAMBA-II machine was acceptable to the vast majority of pregnant women requiring admission and had a low turnaround time. Asymptomatic carriage is low, but not correlated to community prevalence rates. Screening pregnant women on admission will remain an important component in order to minimise nosocomial infection.


Molecular analysis of the diversity of genus Psychrobacter present within a temperate estuary.
Many members of the genus Psychrobacter are endemic in extremely cold and saline environments and the genus has been described as only marginally successful in warmer habitats. In a previous study the Psychrobacter genus was, unexpectedly, the most frequently isolated bacterial genus from the sea-surface microlayer (SML) and the underlying water (UW) of a temperate estuary (Ria de Aveiro, Portugal). Here we analysed the diversity in Psychrobacter populations inhabiting this estuary. Samples were collected at three dates and three locations from sea-SML and UW. Isolated Psychrobacter strains were well-adapted to temperatures and salt concentrations above the ones described as optimal for most members of this genus. Hydrocarbon-degrading potential was not confirmed for these strains. We developed and optimized a reliable and specific denaturing gradient gel electrophoresis (DGGE)-based method for the analysis of Psychrobacter populations in aquatic systems. DGGE profiles inferred that Psychrobacter populations were very stable in the estuary, a strong indication for the presence of well-adapted phylotypes. The analysis of genus-specific clone libraries revealed a surprisingly high diversity among Psychrobacter in Ria de Aveiro. Results indicated that novel species were probably cultivated. Significant differences between sea-SML and UW Psychrobacter communities were revealed. Observed diversity trends may be related to environmental factors such as salinity and/or anthropogenic pressures such as contamination with hydrocarbons.


[Radiobiology base change: long term effects of ionizing radiation].
By definition, radiobiology studies energy transferring from ionizing radiations to biological material. For a long time, radiobiologists have mainly focused in physical issues and its impact on biological cells and tissues. Moreover, DNA damage, specifically of single and double strands (correctly or not restored by enzymatic repair processes), was studied through diverse mathematical models but only one experimental method: cell death measurement. Today, radiobiology has become again a strictly biological science, focused on the future of energy deposit. Genomic instability is the first step, as it studies the amplification over time of a gene signal in a clonal population derived from a single surviving cell after radiation exposure, independently of initial radiation doses. Bystander effect demonstrates that damage signals may be transmitted from irradiated to non-irradiated cells in a population with the same long term radio-induced effect. Abscopal effect is a reaction produced following irradiation, but occurring outside the site of radiation absorption (for example, from irradiated right lung to DNA damage of the left lung). Clastogenic factors are chromosome damaging substances which are present in irradiated patients's plasma. These data could change the fundamentals of radioprotection, as declared UNSCEAR during the 54th session of may 2006.


Induction of immunogenic cell death of tumors by newly synthesized heterocyclic quinone derivative.
Many cancer types are serious diseases causing mortality, and new therapeutics with improved efficacy and safety are required. Immuno-(cell)-therapy is considered as one of the promising therapeutic strategies for curing intractable cancer. In this study, we tested R2016, a newly developed heterocyclic quinone derivative, for induction of immunogenic tumor cell death and as a possible novel immunochemotherapeutic. We studied the anti-cancer effects of R2016 against LLC, a lung cancer cell line and B16F10, a melanoma cell line. LLC (non-immunogenic) and B16F10 (immunogenic) cells were killed by R2016 in dose-dependent manner. R2016 reduced the viability of both LLC and B16F10 tumor cells by inducing apoptosis and necrosis, while it demonstrated no cytotoxicity against normal splenocytes. Expression of immunogenic death markers on the cell surface of R2016 treated tumor cells including calreticulin (CRT) and heat shock proteins (HSPs) was increased along with the induction of their genes. Increased CRT expression correlated with dendritic cell (DC) uptake of dying tumor cells: the proportion of CRT+CD11c+cells was increased in the R2016-treated group. The gene transcription of Calr3, Hspb1, and Tnfaip6, which are related to immunogenicity induction of dead cells, was up-regulated in the R2016 treated tumor cells. On the other hand, ANGPT1, FGF7, and URGCP gene levels were down-regulated by R2016 treatment. This data suggests that R2016 induced immunogenic tumor cell death, and suggests R2016 as an effective anti-tumor immunochemotherapeutic modality.


The evolving role of mammary ductoscopy.
Mammary ductoscopy (MD) is an emerging technique that allows direct visualisation of the mammary duct system, and that produces sharp and clear video images and ductal washings for cytological analysis. There is a growing body of evidence that MD may have a role in the management of women with pathological nipple discharge, the guiding of breast conserving surgery for cancer, and the screening of high risk women. Further research is required to confirm these potential applications and the feasibility of its use in the rapid intervention and outpatient setting under local anaesthesia. Furthermore, the addition of molecular and genetic analysis of cells obtained by MD and the emergence of newer generations of microendoscopes are likely to enhance the use of this technique.


Psychosocial factors in alcohol use-related problems of working youth.
This study investigated the psychosocial correlates of alcohol use related problems in a sample of 581 working adolescents (N = 4405), recruited from five vocational schools in Ankara in June 2004 with the CAGE questionnaire, The Beck Depression Inventory, the Beck Hopelessness Scale, the Spielberger State Anxiety Scale, and the Coopersmith Self-Esteem Inventory. Using a multivariate analysis, the anxiety and hopelessness scores, and the length of stay in Ankara were found to be related to alcohol-use problems of the working youth. The study's limitations were noted and future research was suggested.


SPC25 may promote proliferation and metastasis of hepatocellular carcinoma via p53.
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis and high mortality. To identify key genes associated with HCC and the underlying mechanisms, we performed weighted correlation network analysis (WGCNA) of potential key genes of HCC. We identified 17 key genes closely related to HCC by yellow module combined with PPI analysis. Verification of the role of these genes revealed that SPC25 knockdown results in a significant decrease in proliferation and metastasis of HCC cells and increased protein levels of components of the p53 pathway in vitro. In summary, we identified that SPC25 is a potential tumor-promoting factor in HCC and may act via the p53 pathway.


Expression of recombinant rabbit IL-8 in Escherichia coli and establishment of the essential involvement of IL-8 in recruiting neutrophils into lipopolysaccharide-induced inflammatory site of rabbit skin.
In order to establish the pathophysiological roles of IL-8, rabbit IL-8 was expressed in Escherichia coli and purified to homogeneity by sequential chromatography on heparin agarose, CM-HPLC, and RP-HPLC. The purified recombinant rabbit IL-8 was homogeneous on SDS-PAGE and the ED50 of neutrophil chemotactic activity for rabbit peritoneal neutrophils was 2 ng/ml. The binding of 125I-labeled rabbit IL-8 to rabbit neutrophils was inhibited by unlabeled human IL-8 as well as rabbit IL-8 but not by another leucocyte chemotactic cytokine (chemokine), monocyte chemotactic and activating factor. Scatchard plot analysis of the binding of 125I-labeled rabbit IL-8 to rabbit peritoneal neutrophils revealed that the rabbit neutrophils have two affinity classes of receptors for IL-8 (Kd = 2.3 nM, 4.1 x 10(4) sites/cell; Kd = 18.0 nM, 11.4 x 10(4) sites/cell). It was found that a previously generated mouse anti-human IL-8 mAb, WS-4, inhibited the binding of 125I-labeled rabbit IL-8 to rabbit neutrophils, and blocked neutrophil chemotaxis in vitro in a specific and dose-dependent manner. An ELISA system for rabbit IL-8 was established using this mAb and guinea pig polyclonal antibodies to recombinant rabbit IL-8 to measure the levels of IL-8 in rabbit plasma. Intravenous administration of lipopolysaccharide (LPS) (100 micrograms) in rabbits caused the highest level of IL-8 in blood at around 2 h. Intravenous administration of WS-4 (10 mg) inhibited neutrophil infiltration at the site of LPS injection into the rabbit skin, suggesting that IL-8 is essential in the recruitment of neutrophils at sites of acute inflammation in vivo.


Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae.
In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs). KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin. In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37. In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.


Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes.
Sexual dysfunction induced by antipsychotic drug treatment is under investigated and under reported. This study aimed to determine the influence of genetic polymorphisms in the D2 dopamine receptor (DRD2) and endothelial nitric oxide synthase (eNOS) genes, and the possible role of blood prolactin concentrations on sexual function in schizophrenic patients. Male remitted schizophrenic patients (n = 100), who were living with a sexual partner and receiving antipsychotic drug monotherapy for at least 6 months, were assessed for sexual and erectile dysfunction using the Arizona Sexual Experience Scale and the five-item version of the International Index of Erectile Function. Blood samples were taken for plasma prolactin determination and genotyped for four polymorphisms: DRD2 (-141C Ins/Del and Taq1A) and eNOS gene (G894T and T-786C). The -141C Ins/Del, but not Taq1A, polymorphism of the DRD2 gene was significantly associated with sexual dysfunction with the del allele being less frequent in sexual dysfunction subjects. Neither of the eNOS polymorphisms, G894T or T-786C, was significantly associated with sexual or erectile dysfunction. Prolactin concentrations were significantly higher in patients with erectile dysfunction but did not reach significance in those with sexual dysfunction. Prolactin was also reduced in -141C Del allele carriers. The frequency and severity of sexual dysfunction in the patients receiving typical antipsychotics was significantly greater than those receiving risperidone or clozapine, while prolactin concentrations were significantly higher in subjects receiving risperidone compared with those receiving clozapine or typical antipsychotics. This is the first evidence indicating that antipsychotic drug treatment in men is associated with a variant in the DRD2 gene in which the -141C Del allele might be a protective factor. While this may, in part, be mediated by effects on prolactin, other factors are likely to contribute to the greater sexual dysfunction in patients receiving typical antipsychotics.


Identifying cohort differences in children undergoing partial intracapsular tonsillectomy vs traditional tonsillectomy for sleep disordered breathing.
Partial intracapsular tonsillectomy (PIT) is a well-established technique for reducing post-operative morbidity in pediatric patients with sleep disordered breathing (SDB). Although tonsillar re-growth rates are reported as low, risks of symptom recurrence or need for completion tonsillectomy are clear disadvantages when compared to traditional tonsillectomy (TT). We aim to identify cohort differences to better guide clinical decision making and identify patient-specific factors that may influence this decision. A secondary aim was to evaluate potential risk factors for tonsillar regrowth. Retrospective chart review of pediatric patients who underwent TT or PIT for SDB between 2015 and 2019 at a tertiary care academic medical center. Records were reviewed for age, gender, race, body mass index, comorbidities, diagnosis, apnea-hypopnea index, pre-operative Brodsky tonsil size, length of stay, post-operative hemorrhage, tonsillar regrowth, symptom recurrence, and need for completion tonsillectomy. 315 patients were included: 174 underwent TT and 141 underwent PIT. Patients undergoing TT were more likely to have a sleep study showing OSA (OR 3.01, p < 0.0001), asthma (OR 4.28, p = 0.000124), and other comorbidities (OR 4.06, p = 0.0258). The overall complication rate was 4.44% (14/315). Tonsillar regrowth was exclusive to the PIT group, occurring in 7/141 patients (4.96%). Age ≤4 years was significantly associated with increased risk of tonsillar regrowth (≤4 years: 7.69%, >4 years: 0%; p = 0.049). Race and pre-operative tonsil size were not associated with regrowth. Our study supports the low incidence of tonsillar regrowth in PIT and suggests an association with younger age. Moreover, we found that patients undergoing TT are more likely to be older, have OSA, asthma, and other comorbidities.


Deriving content-specific measures of room acoustic perception using a binaural, nonlinear auditory model.
Acousticians generally assess the acoustic qualities of a concert hall or any other room using impulse response-based measures such as the reverberation time, clarity index, and others. These parameters are used to predict perceptual attributes related to the acoustic qualities of the room. Various studies show that these physical measures are not able to predict the related perceptual attributes sufficiently well under all circumstances. In particular, it has been shown that physical measures are dependent on the state of occupation, are prone to exaggerated spatial fluctuation, and suffer from lacking discrimination regarding the kind of acoustic stimulus being presented. Accordingly, this paper proposes a method for the derivation of signal-based measures aiming at predicting aspects of room acoustic perception from content specific signal representations produced by a binaural, nonlinear model of the human auditory system. Listening tests were performed to test the proposed auditory parameters for both speech and music. The results look promising; the parameters correlate with their corresponding perceptual attributes in most cases.


Multicenter evaluation of the COBAS AMPLICOR HCV assay, an integrated PCR system for rapid detection of hepatitis C virus RNA in the diagnostic laboratory.
The benefits shown by the recent introduction of PCR for the in vitro diagnosis of hepatitis C virus (HCV) infection has prompted the development of standardized, ready-to-use assays that can be implemented in routine clinical laboratories. We have evaluated the clinical performance of COBAS AMPLICOR HCV (COBAS), the first instrument system that allows the automation of HCV RNA amplification and detection, to determine its performance in the routine laboratory setting. More than 2,000 specimens collected at five centers were analyzed in parallel by the COBAS and the manual AMPLICOR HCV (AMPLICOR) tests, and the results were compared with the results for biochemical and serological markers of HCV. In this study the two PCR systems showed the same accuracy, with a concordance rate of 99.8%. As expected, the correlation between serology and PCR was not absolute because the presence of anti-HCV antibodies may be associated with a latent or past infection. On the other hand, if the presence of confirmed anti-HCV antibodies and elevated alanine aminotransferase levels are taken as the "gold standard," indicating an active, ongoing infection, the COBAS and AMPLICOR tests show high and comparable sensitivities (100%) and specificities (98%), with positive and negative predictive values of 100 and 97%, respectively. During the study no false-positive reactions were detected. The use of an internal control allowed the identification of inhibitory substances that prevented amplification for 0.3 and 0.4% of samples tested by the COBAS and AMPLICOR tests, respectively. Compared to the manual system, the COBAS system allowed a significant reduction of hands-on time and could improve the overall laboratory work flow. In conclusion, these results support the use of the COBAS and AMPLICOR tests for the molecular diagnosis of active HCV infections.


Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma-aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4-guanidinobutanoic acid, and 2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5-dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.


Reduced skeletal muscle function is associated with decreased fiber cross-sectional area in the Cy/+ rat model of progressive kidney disease.
The combination of skeletal muscle wasting and compromised function plays a role in the health decline commonly observed in chronic kidney disease (CKD) patients, but the pathophysiology of muscle mass/strength changes remains unclear. The purpose of this study was to characterize muscle properties in the Cy/+ rat model of spontaneously progressive CKD. Leg muscle function and serum biochemistry of male Cy/+ (CKD) rats and their nonaffected littermates (NLs) were assessed in vivo at 25, 30 and 35 weeks of age. Architecture and histology of extensor digitorum longus (EDL) and soleus (SOL) muscles were assessed ex vivo at the conclusion of the experiment. We tested the hypothesis that animals with CKD have progressive loss of muscle function, and that this functional deficit is associated with loss of muscle mass and quality. Thirty-five-week-old CKD rats produced significantly lower maximum torque in ankle dorsiflexion and shorter time to maximum torque, and longer half relaxation time in dorsiflexion and plantarflexion compared with NL rats. Peak dorsiflexion torque (but not plantarflexion torque) in CKD remained steady from 25 to 35 weeks, while in NL rats, peak torque increased. Mass, physiologic cross-sectional area (CSA) and fiber-type (myosin heavy chain isoform) proportions of EDL and SOL were not different between CKD and NL. However, the EDL of CKD rats showed reduced CSAs in all fiber types, while only MyHC-1 fibers were decreased in area in the SOL. The results of this study demonstrate that muscle function progressively declines in the Cy/+ rat model of CKD. Because whole muscle mass and architecture do not vary between CKD and NL, but CKD muscles show reduction in individual fiber CSA, our data suggest that the functional decline is related to increased muscle fiber atrophy.


[Hormonal signal system of the lower eukaryotes].
The literary and the authors' own data on the structural and functional organization of hormonal signaling systems in the lower eukaryotes (yeasts, trypanosomes, ciliates, slide mold Dictyostelium discoideum) have been summarized and analysed. On the basis of a comparative analysis of the primary structures of signal proteins in the lower and higher eukaryotes (G-protein alpha-subunits, enzymes-cyclases-adenylyl and guanylyl cyclases) some possible pathways of the evolution of proteins are suggested. At the level of unicellular organisms, the main blocks of hormone-sensitive signaling systems of the higher eukaryotes were created. Moreover, signaling systems of the lower eukaryotes ar more invariant than these of the higher eukaryotes. It may be associated with the fact that of functional blocks, typical for signaling systems of multicellular animals, fungi and plants, were selected from the numerous variants of signaling system blocks of unicellular organisms.


Characterization of a molecular chaperone present in the eukaryotic flagellum.
Chlamydomonas flagella contain a molecular chaperone now identified as HSP70A, a major cytoplasmic isoform. HSP70A synthesis is upregulated by deflagellation, and its distribution in the flagellum overlaps with the IFT kinesin-II motor FLA10. HSP70A may chaperone flagellar proteins during transport, participating in the assembly and maintenance of the flagellum.


[Health projects managed by Nursing Coordinators: an analysis of contents and degree of success].
To describe the evolution and results of health projects run in hospitals and managed by Nursing Coordinators. A convenience sample of 13 north Italian hospital, and a sample of 56 Nursing Coordinators with a permanent position from at least 1 year, was contacted. The following information was collected with a structured interview: projects run in 2009, topic, if bottom up or top down, number of staff involved and state (ended, still running, stopped). In 2009 Nursing Coordinators started 114 projects (mean 1.8±1.2 each): 94 (82.5%) were improvement projects, 17 (14.9%) accreditation, and 3 (2.6%) research. The projects involved 2.732 staff members (73.7%; average commitment 84 hours); 55 (48.2%) projects were still running, 52 (45.6%) completed, for 5 (4.4%) there was no assessment and 2 (1.8%) had been stopped. Nurses are regularly involved in several projects. A systematic monitoring of the results obtained and stabilization strategies are scarce. Due to the large number of resources invested, a correct management and the choice of areas relevant for patients' problems and needs are pivotal.


Everolimus Implicated in Case of Severe Gastrointestinal Hemorrhage.
Breast cancer remains the leading cause of cancer and the third leading cause of cancer related deaths among our population with an estimated number of 246,660 new cases and 40,450 deaths in 2016. With treatment advancements, including targeted agents such as Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, survivability and quality of life continue to improve. However, with the use of these agents come adverse effects, some of which are still being characterized. Our case demonstrates recurrent episodes of gastrointestinal bleeding in a 60-year-old woman being treated with Everolimus for progressive metastatic breast cancer. On endoscopy, bleeding was secondary to erosive gastritis. Previous case reports have described bleeding due to gastric antral vascular ectasia (GAVE), which was described in two prior reported cases. In our case, bleeding also occurred on a reduced dose of Everolimus compared to what is previously reported (5 mg versus 10 mg). As a result of her gastrointestinal bleeding, she required multiple endoscopic interventions including argon plasma coagulation and multipolar heater probe to achieve hemostasis. This is the first case reported of gastrointestinal bleeding not consistent with GAVE and occurring while being on a reduced dose of Everolimus. It is important to document our case so that the Gastroenterology and Hematology communities can be educated and made aware for their patient populations on Everolimus.


Technology-based strategies for promoting clinical reasoning skills in nursing education.
Faculty face the demand of preparing nursing students for the constantly changing health care environment. Effective use of online, classroom, and clinical conferencing opportunities helps to enhance nursing students' clinical reasoning capabilities needed for practice. The growth of technology creates an avenue for faculty to develop engaging learning opportunities. This article presents technology-based strategies such as electronic concept mapping, electronic case histories, and digital storytelling that can be used to facilitate clinical reasoning skills.


The Hypoactivity Associated with the Repeated Exposure to Atrazine Is Related to Decreases in the Specific Binding to D1-DA Receptors in the Striatum of Rats.
The herbicide atrazine (ATR) has a potential toxic effect on the neuronal circuits of the brain, specifically on two major dopaminergic pathways: the nigrostriatal and mesolimbic circuits. In this work, we repeatedly exposed adult male Sprague-Dawley rats to 6 injections of 100 mg ATR/kg of body weight (for two weeks) and one saline injection two days after ATR administration. Locomotor activity was assessed for 15 minutes and/or 2 hours after ATR or saline injection and 2 months after the final ATR administration. The specific binding of [3H]-SCH23390 to D1-DA receptors and that of [3H]-Spiperone to D2-DA receptors in the dorsal and ventral striatum were assessed 2 days and 2 months after ATR treatment. ATR administration resulted in immediate, short- and long-term hypoactivity and reduced specific binding of [3H]-SCH23390 in the dorsal striatum of rats evaluated 2 months after the last ATR injection. The specific binding of [3H]-SCH23390 in the ventral striatum and the specific binding of [3H]-Spiperone in the dorsal and ventral striatum remained unchanged at 2 days or 2 months after ATR treatment. These results, together with previous findings of our group, indicate that the nigrostriatal system is a preferential target for ATR exposure.


Molecular chemical structure of barley proteins revealed by ultra-spatially resolved synchrotron light sourced FTIR microspectroscopy: comparison of barley varieties.
Barley protein structure affects the barley quality, fermentation, and degradation behavior in both humans and animals among other factors such as protein matrix. Publications show various biological differences among barley varieties such as Valier and Harrington, which have significantly different degradation behaviors. The objectives of this study were to reveal the molecular structure of barley protein, comparing various varieties (Dolly, Valier, Harrington, LP955, AC Metcalfe, and Sisler), and quantify protein structure profiles using Gaussian and Lorentzian methods of multi-component peak modeling by using the ultra-spatially resolved synchrotron light sourced Fourier transform infrared microspectroscopy (SFTIRM). The items of the protein molecular structure revealed included protein structure alpha-helices, beta-sheets, and others such as beta-turns and random coils. The experiment was performed at the National Synchrotron Light Source in Brookhaven National Laboratory (BNL, US Department of Energy, NY). The results showed that with the SFTIRM, the molecular structure of barley protein could be revealed. Barley protein structures exhibited significant differences among the varieties in terms of proportion and ratio of model-fitted alpha-helices, beta-sheets, and others. By using multi-component peaks modeling at protein amide I region of 1710-1576 cm-1, the results show that barley protein consisted of approximately 18-34% of alpha-helices, 14-25% of beta-sheets, and 44-69% others. AC Metcalfe, Sisler, and LP955 consisted of higher (P<0.05) proportions of alpha-helices (30-34%) than Dolly and Valier (alpha-helices 18-23%). Harrington was in between which was 25%. For protein beta-sheets, AC Metcalfe, and LP955 consisted of higher proportions (22-25%) than Dolly and Valier (13-17%). Different barley varieties contained different alpha-helix to beta-sheet ratios, ranging from 1.4 to 2.0, although the difference were insignificant (P>0.05). The ratio of alpha-helices to others (0.3 to 1.0, P<0.05) and that of beta-sheets to others (0.2 to 0.8, P<0.05) were different among the barley varieties. It needs to be pointed out that using a multi-peak modeling for protein structure analysis is only for making relative estimates and not exact determinations and only for the comparison purpose between varieties. The principal component analysis showed that protein amide I Fourier self-deconvolution spectra were different among the barley varieties, indicating that protein internal molecular structure differed. The above results demonstrate the potential of the SFTIRM to localize relatively pure protein areas in barley tissues and reveal protein molecular structure. The results indicated relative differences in protein structures among the barley varieties, which may partly explain the biological differences among the barley varieties. Further study is needed to understand the relationship between barley molecular chemical structure and biological features in terms of nutrient availability and digestive behavior.


Mapping and systematic appraisal of umbrella reviews in epidemiological research: a protocol for a meta-epidemiological study.
Umbrella review is one of the terms used to describe an overview of systematic reviews. During the last years, a rapid increase in the number of umbrella reviews on epidemiological studies has been observed, but there is no systematic assessment of their methodological and reporting characteristics. Our study aims to fill this gap by performing a systematic mapping of umbrella reviews in epidemiological research. We will perform a meta-epidemiological study including a systematic review in MEDLINE and EMBASE to identify all the umbrella reviews that focused on systematic reviews of epidemiological studies and were published from inception until December 31, 2022. We will consider eligible any research article which was designed as an umbrella review and summarized systematic reviews and meta-analyses of epidemiological studies. From each eligible article, we will extract information about the research topic, the methodological characteristics, and the reporting characteristics. We will examine whether the umbrella reviews assessed the strength of the available evidence and the rigor of the included systematic reviews. We will also examine whether these characteristics change across time. Our study will systematically appraise the methodological and reporting characteristics of published umbrella reviews in epidemiological literature. The findings of our study can be used to improve the design and conduct of future umbrella reviews, to derive a standardized set of reporting and methodological guidelines for umbrella reviews, and to allow further meta-epidemiological work. osf.io/sxzc6.


Structural and Electronic Factors Influencing the Selective Inhibition of COX-2.
Structural and electronic factors influencing the inhibition of cyclooxygenase-1 and -2 (COX-1/COX-2) were studied by means of Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking and Density Functional Theory (DFT). A series of structurally diverse compounds containing 209 molecules were classified in accordance with their inhibiting properties, as selectively inhibiting and non-selectively inhibiting COX-2 receptor agents (110 and 99 molecules, correspondingly). The results obtained from the ETM-NN calculations gave us possibility of selecting those pharmacophoric molecular fragments, which allow for the search of new selective inhibitors of COX-2 with high probability of realization. The final selection of pharmacophores and anti-pharmacophores found was taken as a basis for a system designed for the COX-2 inhibitory activity prediction. Analysis of the electron density distribution showed that more effective binding with COX-2 receptor was observed for selective inhibitors. To make an assessment of these interactions, calculations of stabilization energies were carried out for the ligand-receptor complexes. From the results of the docking and from the analysis of electronic structures of active sites of enzymes, some peculiarities of ligand-receptor binding and its influence on the selectivity of the COX-2 relative to COX-1 inhibition were elucidated. 95% of compounds were recognized correctly, as the most active ones, by the system of prediction designed. Thus, the system being the result of the study is capable of predicting the selective inhibitory activity of COX-2 successfully. As a consequence, it can be used both for computer screening and synthesis of potent inhibitors of COX-2 with molecular skeletons that may vary considerably.