Role and mechanism of ferroptosis in acute lung injury.
Ferroptosis is a new non-apoptotic cell death caused by the accumulation of dysregulated metabolism of ferric iron, amino acids or lipid peroxidation. Increasing studies suggest that ferroptosis is involved in the acute lung injury (ALI). This article aims to review the role of ferroptosis in ALI. ALI is a common respiratory disease and presents a high mortality rate. Inhibiting cell ferroptosis of lung improves the ALI. In addition, several signaling pathways are related to ferroptosis in ALI, involving in iron homeostasis, lipid peroxidation, and amino acid metabolism. Moreover, there are various key factors to regulate the occurrence of ferroptosis in ALI, such as ACSL4, NRF2, and P53. The ACSL4 promotes the ferroptosis, while the NRF2 alleviates the ferroptosis in ALI. The main effect of P53 is to promote ferroptosis. Accordingly, ferroptosis is involved in ALI and may be an important therapeutic target for ALI.


The effects of low-and high-frequency non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) on gastric slow waves evaluated using in vivo high-resolution mapping in porcine.
Gastric motility is regulated by an electrophysiological activity called slow-wave and neuronal innervations by the vagus nerve. Transcutaneous auricular vagal nerve stimulation (taVNS) has been demonstrated to have therapeutic potential for a wide range of medical conditions, including the management of gastric dysfunctions. The main objective of this study was to gain a better understanding of how non-invasive neuromodulation influences gastric slow wave under in vivo conditions. TaVNS protocols were applied in conjunction with 192-channel gastric bioelectrical mapping in porcine subjects under general anesthesia. The spatiotemporal profiles of gastric slow wave were assessed under two different taVNS protocols at 10 and 80 Hz. The taVNS protocols effectively altered the interval and amplitude of gastric slow waves, but not the velocity or the percentage of spatial dysrhythmias. In the subjects that responded to the protocols, the 10 Hz protocol was shown to normalize slow-wave propagation pattern in 90% of the subjects, whereas the 80 Hz protocol was shown to inhibit slow waves in 60% of the subjects. Chronic responses of gastric motility and slow waves in response to taVNS should be investigated using non-invasive means in conscious subjects in future.


Transmission of Blood Disease in Banana.
Banana Blood disease is a bacterial wilt caused by Ralstonia syzygii subsp. celebesensis and is an economically important disease in Indonesia and Malaysia. Transmission of this pathogen is hypothesized to occur through insects mechanically transferring bacteria from diseased to healthy banana inflorescences and other pathways involving pruning tools, water movement, and root-to-root contact. This study demonstrates that the ooze from the infected male bell and the sap from various symptomatic plant parts are infective, and the cut surfaces of a bunch peduncle, petiole, corm, pseudostem, and the rachis act as infection courts for R. syzygii subsp. celebesensis. In addition, evidence is provided that R. syzygii subsp. celebesensis is highly tool transmissible, that the bacterium can be transferred from the roots of a diseased plant to the roots of a healthy plant and transferred from the mother plant to the sucker. We provide evidence that local dispersal of Blood disease occurs predominantly through mechanical transmission by insects, birds, bats, or human activities from diseased to healthy banana plants and that long-distance dispersal occurs through the movement of contaminated planting material. Disease management strategies to prevent crop losses associated with this emerging disease are discussed based on our findings.


[Influence of surgical sanation of patients with destructive tuberculosis on the prevalence of tuberculosis and mortality].
To analyze the influence of surgical sanation of patients with destructive tuberculosis on the prevalence of tuberculosis and mortality. The strategy of treatment for new cases of destructive pulmonary tuberculosis was developed in the Perelman Department of Phthisiopulmonology and Thoracic Surgery of the Sechenov First Moscow State Medical University. This strategy was applied in the tuberculosis surgical department of the Tambov Regional Dispensary in 2013-2017. A register of patients with pulmonary destruction and bacterial excretion was developed and personal treatment plans were applied. Patients were divided into 3 groups depending on the treatment mode. The main group A consisted of patients who underwent surgical treatment. Surgery was not performed due to failure or discontinuation of treatment in the comparison group B. Group C included patients without indications or with contraindications for surgical treatment. Treatment efficacy considering destruction cavities closure and abacillation was 97.2% in group A, 41.4% in group B and 39.8% in group C. Surgical approach for patients with destructive tuberculosis reduced the number of patients in the register by 3.3 times (from 516 to 158) within 4 years. A significant reduction of the bacillary core allows breaking the infection chain, that affects the main epidemiological indicators. Reduced incidence of tuberculosis is observed in short-term period, but even greater impact of this factor should be expected in long-term follow-up. Surgical approach in complex treatment of destructive pulmonary tuberculosis is valuable to improve efficacy of management of these patients and reduce mortality rate.


In situ quantum dot growth on multiwalled carbon nanotubes.
The generation of nanoscale interconnects and supramolecular, hierarchical assemblies enables the development of a number of novel nanoscale applications. A rational approach toward engineering a robust system is through chemical recognition. Here, we show the in situ mineralization of crystalline CdTe quantum dots on the surfaces of oxidized multiwalled carbon nanotubes (MWNTs). We coordinate metallic precursors of quantum dots directly onto nanotubes and then proceed with in situ growth. The resulting network of molecular-scale "fused" nanotube-nanocrystal heterojunctions demonstrates a controlled synthetic route to the synthesis of complex nanoscale heterostructures. Extensive characterization of these heterostructures has been performed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, UV-visible spectroscopy, and X-ray diffraction (XRD).


L-GRAAL: Lagrangian graphlet-based network aligner.
Discovering and understanding patterns in networks of protein-protein interactions (PPIs) is a central problem in systems biology. Alignments between these networks aid functional understanding as they uncover important information, such as evolutionary conserved pathways, protein complexes and functional orthologs. A few methods have been proposed for global PPI network alignments, but because of NP-completeness of underlying sub-graph isomorphism problem, producing topologically and biologically accurate alignments remains a challenge. We introduce a novel global network alignment tool, Lagrangian GRAphlet-based ALigner (L-GRAAL), which directly optimizes both the protein and the interaction functional conservations, using a novel alignment search heuristic based on integer programming and Lagrangian relaxation. We compare L-GRAAL with the state-of-the-art network aligners on the largest available PPI networks from BioGRID and observe that L-GRAAL uncovers the largest common sub-graphs between the networks, as measured by edge-correctness and symmetric sub-structures scores, which allow transferring more functional information across networks. We assess the biological quality of the protein mappings using the semantic similarity of their Gene Ontology annotations and observe that L-GRAAL best uncovers functionally conserved proteins. Furthermore, we introduce for the first time a measure of the semantic similarity of the mapped interactions and show that L-GRAAL also uncovers best functionally conserved interactions. In addition, we illustrate on the PPI networks of baker's yeast and human the ability of L-GRAAL to predict new PPIs. Finally, L-GRAAL's results are the first to show that topological information is more important than sequence information for uncovering functionally conserved interactions. L-GRAAL is coded in C++. Software is available at: http://bio-nets.doc.ic.ac.uk/L-GRAAL/. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Glutamine: precursor or nitrogen donor for citrulline synthesis?
Although glutamine is considered the main precursor for citrulline synthesis, the current literature does not differentiate between the contribution of glutamine carbon skeleton vs. nonspecific nitrogen (i.e., ammonia) and carbon derived from glutamine oxidation. To elucidate the role of glutamine and nonspecific nitrogen in the synthesis of citrulline, l-[2-(15)N]- and l-[5-(15)N]glutamine and (15)N-ammonium acetate were infused intragastrically in mice. The amino group of glutamine labeled the three nitrogen groups of citrulline almost equally. The amido group and ammonium acetate labeled the ureido and amino groups of citrulline, but not the delta-nitrogen. D(5)-glutamine also infused in this arm of the study, which traces the carbon skeleton of glutamine, was utilized poorly, accounting for only 0.2-0.4% of the circulating citrulline. Dietary glutamine nitrogen (both N groups) incorporation was 25-fold higher than the incorporation of its carbon skeleton into citrulline. To investigate the relative contributions of the carbon skeleton and nonspecific carbon of glutamine, arginine, and proline to citrulline synthesis, U-(13)C(n) tracers of these amino acids were infused intragastrically. Dietary arginine was the main precursor for citrulline synthesis, accounting for approximately 40% of the circulating citrulline. Proline contribution was minor (3.4%), and glutamine was negligible (0.4%). However, the glutamine tracer resulted in a higher enrichment in the ureido group, indicating incorporation of nonspecific carbon from glutamine oxidation into carbamylphosphate used for citrulline synthesis. In conclusion, dietary glutamine is a poor carbon skeleton precursor for the synthesis of citrulline, although it contributes both nonspecific nitrogen and carbon to citrulline synthesis.


Anxiety disorders during pregnancy and postpartum.
Approximately 30% of women experience some type of anxiety disorder during their lifetime. Women with these disorders may experience profound changes in their symptoms during pregnancy and the postpartum period. In addition, some evidence exists that anxiety disorders can affect pregnancy outcomes. It is important that physicians understand the course of these disorders during pregnancy and available treatments so they can appropriately counsel women who are or intend to become pregnant. This article reviews the literature on the course of anxiety disorders during pregnancy and the postpartum period and presents guidelines for management.


A tool to evaluate patients' experiences of nursing care in Australian general practice: development of the Patient Enablement and Satisfaction Survey.
Australian health policy initiatives have increasingly supported the employment of nurses in general practice. An understanding of the impact of nursing care on patients in this setting is integral to assuring quality, safety and a patient-centred focus. The aim was to develop a survey to evaluate the satisfaction and enablement of patients who receive nursing care in Australian general practices. The survey was to be simple to administer and analyse, ensuring practicality for use by general practice nurses, doctors and managers. Two validated instruments formed the basis of the Patient Enablement and Satisfaction Survey (PESS). This survey was refined and validated for the Australian setting using focus groups and in-depth interviews with patients, and feedback from general practice nurses. Test-retest and alternate form methods were used to establish the survey's reliability. Feedback resulted in 14 amendments to the original draft survey. Questions that demonstrated a strong positive correlation for the test-retest and alternate form measures were included in the final survey. The PESS is a useful, practical tool for the evaluation of nursing care in Australian general practice, its validity and reliability established through a patient-centred research approach, reflective of the needs of patients accessing nursing services in this setting.


Monoclonal antibodies block murine IL-4 receptor function.
IL-4 is a cytokine which can induce B-lymphocyte proliferation, increase cell-surface Ia expression, and induce some activated B cells to differentiate and begin to secrete IgE. IL-4 binds specifically to a cell-surface receptor (IL-4R) on cells from a variety of lineages including T and B cells. In general both primary cells and in vitro cell lines express less than 5000 receptors per cell. Utilizing a subclone of the cytotoxic T cell line CTLL-2 expressing a high level of IL-4R, mAb against the murine IL-4R were prepared. Two mAb have been identified which have different properties. These antibodies, designated M1 and M2, recognize sequences specific to the murine IL-4R. Immunoprecipitation studies with M1 and M2 on CTLL-2 cells have identified the receptor as a Mr = 145,000 cell-surface protein. Similar results have been obtained with the recently isolated full length murine IL-4R cDNA expressed in COS-7 cells. In addition the antibodies are capable of inhibiting IL-4 binding. One antibody, M1, is also a potent inhibitor of IL-4-induced proliferation. These antibodies will be useful in dissecting a wide array of activities attributed to IL-4.


Unprecedented neptunyl(V) cation-directed structural variations in Np2Ox compounds.
Studies on transuranic oxides provide a particularly valuable insight into chemical bonding in actinide compounds, in which subtle differences between metal ions and oxygen atoms are of fundamental importance for the stability of these compounds as well as their existence. In the case of neptunium, it is still mainly limited to specific Np oxide compounds without periodicity in the formation of stable structures or different oxidation states. Here, we report a systematic global minimum search of Np2Ox (x = 1-7) clusters and the computational study of their electronic structures and chemical bonding. These studies suggest that Np(V) ion could play the structure-directing role, and thus the mixed-valent Np(III/V) in Np2O4 is predicted accessible. In comparison with lower oxidation state Np analogues, significant 5f-orbital covalent interactions with Np(V)O bonding are observed, which shows that these model neptunium oxides can provide new understandings into the behavior of 5f-electrons in chemical bonding and structural design.


Reversible colorimetric probes for mercury sensing.
The selectivity and sensitivity of two colorimetric sensors based on the ruthenium complexes N719 [bis(2,2'-bipyridyl-4,4'-dicarboxylate)ruthenium(II) bis(tetrabutylammonium) bis(thiocyanate)] and N749 [(2,2':6',2' '-terpyridine-4,4',4' '-tricarboxylate)ruthenium(II) tris(tetrabutylammonium) tris(isothiocyanate)] are described. It was found that mercury ions coordinate reversibly to the sulfur atom of the dyes' NCS groups. This interaction induces a color change in the dyes at submicromolar concentrations of mercury. Furthermore, the color change of these dyes is selective for mercury(II) when compared with other ions such as lead(II), cadmium(II), zinc(II), or iron(II). The detection limit for mercury(II) ions--using UV-vis spectroscopy--in homogeneous aqueous solutions is estimated to be approximately 20 ppb for N719 and approximately 150 ppb for N749. Moreover, the sensor molecules can be adsorbed onto high-surface-area mesoporous metal oxide films, allowing reversible heterogeneous sensing of mercury ions in aqueous solution. The results shown herein have important implications in the development of new reversible colorimetric sensors for the fast, easy, and selective detection and monitoring of mercuric ions in aqueous solutions.


[Melphalan pharmacokinetics during isolated limb regional perfusion in patients with skin melanoma and soft tissue sarcoma].
The study of pharmacokinetics of melphalan in the perfusate and blood plasma during isolated limb regional perfusion (ILRP) was carried out in patients with melanoma (n=21) and soft tissue sarcoma (n = 24). Melphalan was administered as 10 mg/l for a lower extremity and 13 mg/l for a upper extremity. Quantification of melphalan in perfusate and blood samples was performed by means of liquid chromatography/tandem mass spectrometry. 30 samples of the perfusate and 27 venous blood samples were analyzed. During the first 5 minutes of ILRP concentration of melphalan in the perfusate decreased to 13.2% of the initial value, and by the end of perfusion (60 minutes) it was 3.3%. The amount of melphalan in the blood plasma of the patients by the end of ILRP wasn't higher than 1.6% from the administered dose. That demonstrates minor systemic absorption of the drug during ILRP. Moreover melphalan concentration in the blood plasma during the perfusion was in average 0.015-0.223 mg/l which is significantly lower compared to the blood plasma concentrations after intravenous administration of melphalan. Thus ILRP procedure provided 97% of the melphalan dose accumulation in the soft tissues of a limb and in tumor tissues. Also pharmacokinetic advantage of melphalan over systemic administration of the drug was shown.


LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma.
Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.


Evaluation of pain and function after two home exercise programs in a clinical trial on women with chronic neck pain - with special emphasises on completers and responders.
Different types of exercises can help manage chronic neck pain. Supervised exercise interventions are widely used, but these protocols require substantial resources. The aim of this trial, which focused on adherence, was to evaluate two home exercise interventions. This parallel group randomized controlled trial included 57 women randomly allocated into two groups - a strength training group (STRENGTH, 34 subjects) and a stretching group (STRETCH, 23 subjects). The interventions focused on the neck and shoulder muscles and lasted for 12 months. The STRENGTH group performed weight training and ended each session with stretching exercises. These stretching exercises constituted the entirety of the STRETCH group's training session. Both groups were instructed to exercise three times per week. All the participants kept an exercise diary. In addition, all participants were offered support via phone and e-mail. The primary outcomes were pain intensity and function. The trial included a four- to six-month and a twelve-month follow-up. A completer in this study exercised at least 1,5 times per week during eight unbroken weeks. A responder in this study reported clinically significant improvements on pain and function. The statistical analyses used the Mann Whitney U-test, Wilcoxon signed-rank test, and X2 test. At four- to six-months, the numbers of completers were 19 in the STRENGTH group and 17 in the STRETCH group. At twelve months, the corresponding numbers were 11 (STRENGTH) and 10 (STRETCH). At four- to six-months, the proportions of subjects reporting clinically important changes (STRENGTH and STRETCH) were for neck pain: 47% and 41%, shoulder pain: 47% and 47%, function: 37% and 29%. At twelve months, the corresponding numbers were for neck pain: 45% and 40%, shoulder pain: 55% and 50%, function: 55% and 20%. No differences in the two primary outcomes between the two interventions were found, a finding that may be due to the insufficient statistical power of the study. Both interventions based on home exercises improved the two primary outcomes, but the adherences were relatively low. Future studies should investigate ways to improve adherence to home exercise treatments. ClinicalTrials.gov Id: NCT01876680.


More in sorrow than in anger: the British nurses' strike of 1988.
In early 1988 the nurses of Britain's National Health Service reached a peak of frustration. They took unprecedented industrial action to bring the state of nursing, and problems within the Health Service, to the attention of the nation. Throughout the crisis there was acrimonious debate between the Royal College of Nursing, which acts as both a professional association and a negotiating unit and opposed the strike, and the trade unions, which organized it. Their conflict undermined the nurses' solidarity and highlighted deep and complex tensions within the profession. On the day of action, labor withdrawal was widespread but inconsistent. In the end, the nurses made some gains, but most of their concerns were ignored. The government promoted the divisions between nursing unions; the media were critical of the nurses' actions; however, the labor movement supported them, and the British Medical Journal voiced the merits of the nurses' case. The struggle of the British nurses exemplifies issues and dilemmas facing nurses throughout the world. The increasing militancy of nurses in many countries reflects their dissatisfaction with pay, working conditions, and career opportunities. Many nurses are torn between the ideals of professionalism and the realities of their workplace and are ambivalent about the principles of collective bargaining. This article addresses these ambivalences and stresses the need to find creative solutions to match nurses' unique place in the political economy of health care.


Essential but Ill-Prepared: How the COVID-19 Pandemic Affects the Mental Health of the Grocery Store Workforce.
Frontline essential workers face elevated risks of exposure to COVID-19 because of the interactive nature of their jobs, which require high levels of interaction with the general public and coworkers. The impact of these elevated risks on the mental health of essential workers, especially outside the health care sector, is not well studied. To address this knowledge gap, we examined correlations between perceptions of workplace risks and mental health distress among grocery store workers in Arizona. We collected the first statewide sample of essential workers outside the health care sector focused on mental health and well-being. A total of 3344 grocery store workers in Arizona completed an online survey in July 2020. We used multiple regression models to identify demographic and work-based correlates of mental health distress. Levels of mental health distress among respondents were high: 557 of 3169 (17.6%) reported severe levels and 482 of 3168 (15.2%) reported moderate levels. Perceptions of workplace safety were strongly correlated with significantly reduced levels of mental health distress (ß = -1.44; SE = 0.20) and reduced perceived stress (ß = -0.97; SE = 0.16). Financially disadvantaged workers and employees aged <55 reported high levels of mental health distress. Perceptions of safety and protection in the workplace were significantly correlated with availability of safety trainings, social distancing, and policies governing customer behaviors. Lacking sufficient workplace protections, grocery store employees in Arizona experienced high levels of mental health distress during the COVID-19 pandemic. Providing clear federal and state policies to employers to guide implementation of workplace protections may help reduce sources of mental health distress.


Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins.
We describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based discovery (GE-FBD) uses selection of phage-displayed glycopeptides to dock a glycan fragment at the CRD and guide selection of synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 10(8) glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40-50-fold enhancement in affinity over methyl α-d-mannopyranoside (MeMan). Lectin array suggested specificity: Man-WYD derivative bound only to 3 out of 17 proteins—ConA, LcH, and PSA—that bind to Man. An X-ray structure of ConA:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking, but their extra-CRD binding modes are significantly different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.


Prevalence and Course of Treatment of Common Hip Diagnoses Presenting to a Sports Medicine Clinic.
Hip-related pain and pathology can have an overall negative impact on healthrelated quality of life. Prompt diagnosis and treatment of symptoms at the hip may expedite the recovery process and allow for an earlier return to normal activity. Knowing the prevalence of a condition can help facilitate the diagnostic process. However, the prevalence of hip diagnoses and associated courses of treatment have not been described. A retrospective study was performed on patients presenting to a sports medicine clinic. Information on demographics, duration of pain, course of treatment, history of previous injury or surgery, and mechanism of injury was collected. Multivariate linear regression and multivariate logistic regression were utilized to describe differences in course of treatment between diagnostic groups. Six hundred eighteen patients were included in this study, with 641 hips analyzed. Femoroacetabular impingement syndrome (FAIS) was the most frequent diagnosis (212 hips), followed by "musculotendinous pain" and "hip pain, not otherwise specified." Of those diagnosed with FAIS, 30.1% had secondary diagnoses in other categories. Home exercise programs were the most commonly prescribed treatment, followed by injections and physical therapy. Having a diagnosis of FAIS or chondrolabral pathology increased the odds of surgery. Femoroacetabular impingement syndrome was the most common diagnosis in our cohort and had the highest frequency of concurrent diagnoses. A combination of a home exercise program, injection, and physical therapy made up the typical course of treatment, while surgery was utilized less frequently.


The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection.
The association of inheritance of different apolipoprotein E (APOE, gene; apoE, protein) alleles with the risk and rate of onset of Alzheimer's disease (AD) is now well established and widely confirmed. While there are now a collection of hypotheses concerning the specific relationship of APOE polymorphisms to various phenotypic manifestations of AD, no single compelling theory has been tested and universally accepted. The only clear fact emerging during the past 6 years is that differences in APOE genotype affect the average rate of disease onset as a predictable function of the inheritance of this polymorphic gene. Methods now exist to enable experimental designs to study the metabolic effects of inheriting different APOE alleles, addressing what differences that may be present for many years, perhaps over the entire lifetime, can lead to earlier or later manifestations of the disease and are therapeutically tractable. This review summarizes part of an experimental approach to identify biological pathways influenced by the different APOE polymorphisms that are relevant to the pathogenesis of AD.


[Chemical and nutritional changes during preparation of whole corn tortillas prepared with instant flour obtained by extrusion process].
Chemical changes of some nutritional components (protein, total dietary fiber, vitamins, lysine, tryptophan, ether extract and fatty acids) of tortillas made from instant whole corn flour prepared by extrusion process (CINVESTAV process) were evaluated. The tortillas prepared by extrusion process were compared with tortillas made by traditional process and raw corn. The protein content of tortillas from both processes were statistically similar to those of the raw corn, although the traditional tortillas showed the lowest actual values. Tortillas from traditional process contained the lowest amount of total dietary fiber and available lysine. The loss of protein, crude fiber, total dietary fiber, available lysine, tryptophan, and vitamin contents during traditional tortillas process, was attributable to the partial loss of pericarp, aleurone and germ tissue during the process. Tortillas prepared by both processes showed loss of vitamins. The thermal treatment in both processes (traditional and extrusion) decreased the ether extract and fatty acids contents. Tortillas prepared by extrusion process showed better nutritional characteristics than traditional tortillas prepared by nixtamalization process.


YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling.
Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.


Fostemsavir: The first oral attachment inhibitor for treatment of HIV-1 infection.
The pharmacology, pharmacokinetics, and role in therapy of fostemsavir in management of HIV-1 infection are reviewed, with an emphasis on clinical efficacy and safety data from phase 2 and phase 3 clinical trials. Fostemsavir (Rukobia, ViiV Healthcare), is a prodrug of temsavir, a novel pyridine compound with potent activity against HIV-1. Fostemsavir, the first oral attachment inhibitor, was approved and granted the breakthrough therapy designation by the Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in heavily treatment-experienced adults. As absorption of temsavir is not altered with increased gastric pH, patients may take acid suppressive agents such as famotidine during fostemsavir therapy.Temsavir is primarily metabolized through hydrolysis but also via cytochrome P-450 (CYP) oxidation; therefore, coadministration of fostemsavir with strong CYP3A inducers such as rifampin, carbamazepine, phenytoin, mitotane, enzalutamide, or St John's wort is contraindicated because it may result in significantly lower temsavir exposure, which can ultimately impair virologic response. The most common adverse reactions associated with fostemsavir use include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbance. Fostemsavir may be an effective option for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Fostemsavir is a particularly attractive treatment option for patients who are no longer able to achieve viral suppression with use of currently available antiretroviral therapies and who are able to adhere to a twice-daily oral regimen.


Acute bacterial diseases.
The manner by which bacteria cause diarrhea has been clarified as a result of the understanding of mechanisms involved in fluid secretion. It is conceivable that many of the undiagnosed mass of diarrheal cases are in fact caused by E. coli or other organisms capable of eleborating an enterotoxin or of invading the epitehlial surfaces of the gastrointestinal tract. Confirmation of this concept would permit a better estimation of the importance of "viruses" in causing diarrhea. Proper treatment for bacterial diarrhea requires fluid replacement. Antibiotic therapy and antidiarrheal drugs need to be used with caution since they may worsen the diarrheal process or may complicate recovery.


[Antibiotic prophylaxis in patients with joint prostheses].
A systematic literature review was carried out in order to formulate a new Dutch guideline regarding policies for patients with a joint prosthesis who are to undergo a dental procedure. The research question was: Is antibiotic prophylaxis indicated in patients with a joint prosthesis who undergo dental procedures? The literature comprised studies in which patients with joint prostheses underwent a dental procedure resulting in hematogenous periprosthetic joint infection or in which a correlation between prophylactic antibiotics and hematogenous periprosthetic joint infection were described. The GRADE/AGREE II method was used to determine the strength of the evidence. A supplementary review of literature to gain further insight into pathophysiology, risk factors and risk intervention was carried out. The included studies did not provide any conclusive evidence that the use of antibiotic prophylaxis reduces the incidence of dental hematogenous periprosthetic joint infection. The results of the supplementary review of literature also supported the conclusion that antibiotic prophylaxis should be discouraged in dental procedures.


Central angiotensin (1-7) enhances baroreflex gain in conscious rabbits with heart failure.
In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of angiotensin (Ang) II, Ang-(1-7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1-7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1-7) on baroreflex control of heart rate and renal sympathetic nerve activity in conscious rabbits with CHF. We hypothesized that central Ang-(1-7) would improve baroreflex function in CHF. Ang-(1-7) (2 nmol/1 μL per hour) or artificial cerebrospinal fluid (1 μL per hour) was infused by an osmotic minipump for 4 days in sham and pacing-induced CHF rabbits (n=3 to 6 per group). Ang-(1-7) treatment had no effects in sham rabbits but reduced heart rate and increased baroreflex gain (7.4±1.5 versus 2.5±0.4 bpm/mm Hg; P<0.05) in CHF rabbits. The Ang-(1-7) antagonist A779 (8 nmol/1 μL per hour) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1-7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline renal sympathetic nerve activity was significantly lower, and baroreflex control of renal sympathetic nerve activity was enhanced in CHF rabbits receiving Ang-(1-7). These data suggest that augmentation of central Ang-(1-7) inhibits sympathetic outflow and increases vagal outflow in CHF, thus contributing to enhanced baroreflex gain in this disease state.


Triclosan elevates estradiol levels in serum and tissues of cycling and peri-implantation female mice.
Triclosan, an antimicrobial agent added to personal care products, can modulate estrogenic actions. We investigated whether triclosan affects concentrations of exogenous and endogenous estradiol. Female mice were given injections of triclosan followed by 1μCi tritium-labeled estradiol. Mice given daily 2-mg triclosan doses (57.9mg/kg/dose) showed significantly elevated radioactivity in tissues and serum compared to controls. A single dose of 1 or 2mg triclosan increased radioactivity in the uterus in both cycling and peri-implantation females. We also measured natural urinary estradiol at 2-12h following triclosan injection. Unconjugated estradiol was significantly elevated for several hours following 1 or 2mg of triclosan. These data are consistent with evidence that triclosan inhibits sulfonation of estrogens by interacting with sulfotransferases, preventing metabolism of these steroids into biologically inactive forms. Elevation of estrogen concentrations by triclosan is potentially relevant to anti-reproductive and carcinogenic actions of excessive estrogen activity.


Estimating Life Expectancy From Chinese Medicine Could Improve End-of-Life Care in Terminally Ill Cancer Patients.
Preparing for a good death is an important and meaningful concept in Chinese culture because people hope to know residual life to make effort for their unfinished business. However, the family of terminally ill patients with cancer may be annoyed and frustrated about unexpected bereavement if they have unresolved conflicts with the loved one, missing a chance for declaring love, untimely apologizing and saying goodbye. The study aimed to explore this difficult issue. The medical records of 121 deceased terminally ill patients with cancer at National Cheng Kung University Hospital between December 2010 and February 2012 were reviewed. The signs and awareness of dying among these patients were collected using palliative routine instruments in the hospice ward. The top 3 most prevalent dying signs were coolness and cyanosis (prevalence 98.3%, median period from the first documented dying sign to death 2 days, P = .028), mirror-like tongue (prevalence 94.2%, median period 5 days, P = .007), and earlobe crease (prevalence 93.4%, median period 4 days, P = .052). In addition, the prevalence of dying awareness was 71.1% (median period 4 days, P = .001). Furthermore, terminal agitation was identified more frequently in terminally ill patients with hepatoma and colon cancer (adjusted odds ratio = 3.240, P = .043), but turbid sclera with edema was noted more often in terminally ill patients with head and neck cancer (adjusted odds ratio = 5.698, P = .042). The results provide evidence to support clinical practice, offering knowledge and techniques to health care providers, and increasing quality of life for terminally ill patients with cancer.


[Nonuniform distribution and contribution of the P- and P/Q-type calcium channels to short-term inhibitory synaptic transmission in cultured hippocampal neurons].
In the present study, we investigated the sensitivity of GABAergic short-term plasticity to the selective P- and P/Q-type calcium channels blocker omega-agatoxin-IVA. To block the P-type channels we used 30 nM of this toxin and 200 nM of the toxin was used to block the P/Q channel types. The evoked inhibitory postsynaptic currents (eIPSC) were studied using patch-clamp technique in whole-cell configuration in postsynaptic neuron and local extracellular stimulation of single presynaptic axon by rectangular pulse. The present data show that the contribution of P- and P/Q-types channels to GABAergic synaptic transmission in cultured hippocampal neurons are 30% and 45%, respectively. It was shown that the mediate contribution of the P- and P/Q-types channels to the amplitudes of eIPSC is different to every discovered neuron. It means that distribution of these channels is non-uniform. To study the short-term plasticity of inhibitory synaptic transmission, axons of presynaptic neurons were paired-pulse stimulated with the interpulse interval of 150 ms. Neurons demonstrated both the depression and facilitation. The application of 30 nM and 200 nM of the blocker decreased the depression and increased facilitation to 8% and 11%, respectively. In addition, we found that the mediate contribution of the P- and P/Q-types channels to realization of synaptic transmission after the second stimuli is 4% less compared to that after the first one. Therefore, blocking of both P- and P/Q-types calcium channels can change the efficiency of synaptic transmission. In this instance it facilitates realization of the transmission via decreased depression or increased facilitation. These results confirm that the P- and P/Q-types calcium channels are involved in regulation of the short-term inhibitory synaptic plasticity in cultured hippocampal neurons.


Cutaneous adverse reaction during lithium treatment: a case report and updated systematic review with meta-analysis.
To present a new case of adverse cutaneous reaction during lithium treatment and to update the systematic review and meta-analysis of the incidence of this adverse reaction. We conducted a systematic search (performed in September 2016) for peer-reviewed articles in English indexed in Medline (2011-present). Meta-analytical estimates were obtained using the "Metafor" package. Ms. H., a 31-year-old Caucasian woman with BD1, was admitted to the inpatient unit for a full-blown psychotic episode and treated with carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d., and risperidone 4 mg q.d. with clinical improvement. After 12 days from the start of psychopharmacological treatment, she manifested a cutaneous reaction that motivated the stop of carbamazepine treatment, as well as the increase in lithium carbonate dose (750 mg q.d.). Risperidone dose remained unvaried. Since the skin lesion persisted after 8 days from withdrawal of carbamazepine, the private practitioner stopped also lithium carbonate treatment (de-challenge), maintaining risperidone treatment. The cutaneous reaction resolved spontaneously after six days from withdrawal of lithium carbonate. Subsequently, the worsening of psychopathological conditions motivated a new admission during which lithium carbonate was reintroduced (16 days after its suspension) (re-challenge). On the following day, we observed an itching erythematous maculopapular rash involving the trunk, the four limbs, and the oral mucosa. Our case of an erythematous maculopapular rash during lithium treatment was the first to present a challenge-de-challenge-re-challenge sequence that suggests causality. Although meta-analysis does not point to an increased rate of adverse skin reaction during lithium treatment, clinicians should not neglect to monitor cutaneous symptoms during lithium treatment.


Coastal Erosion and Flood Coping Mechanisms in Southern Thailand: A Qualitative Study.
Communities in coastal regions are affected by the impacts of extreme climatic events causing flooding and erosion. Reducing the impacts of flood and erosion in these areas by adopting coping strategies that fortify the resilience of individuals and their localities is desirable. This study used summative content analysis to explore the coping mechanisms of coastal communities before, during, and after various dangers relating to flooding and erosion. The findings from the study show that effective surveillance systems, disaster preparedness, risk mapping, early warning systems, availability of databases and functional command systems, as well as reliable funding are essential to efficiently cope with hazards of coastal flooding and erosion. As flooding and erosion have been predicted to be more severe due to climate change in the coming years, the adoption of effective natural and artificial mechanisms with modern technologies could help coastal regions to be more resilient in coping with the dangers associated with flooding and erosion. Pragmatic policies and programs to this end by actors are critical to averting crises induced by flooding and erosion in coastal areas.


Exploring Anopheles gut bacteria for Plasmodium blocking activity.
Malaria parasite transmission requires the successful development of Plasmodium gametocytes into flagellated microgametes upon mosquito blood ingestion, and the subsequent fertilization of microgametes and macrogametes for the development of motile zygotes, called ookinetes, which invade and transverse the Anopheles vector mosquito midgut at around 18-36 h after blood ingestion. Within the mosquito midgut, the malaria parasite has to withstand the mosquito's innate immune response and the detrimental effect of its commensal bacterial flora. We have assessed the midgut colonization capacity of five gut bacterial isolates from field-derived, and two from laboratory colony, mosquitoes and their effect on Plasmodium development in vivo and in vitro, along with their impact on mosquito survival. Some bacterial isolates activated the mosquito's immune system, affected the mosquito's lifespan, and were capable of blocking Plasmodium development. We have also shown that the ability of these bacteria to inhibit the parasites is likely to involve different mechanisms and factors. A Serratia marcescens isolate was particularly efficient in colonizing the mosquitoes' gut, compromising mosquito survival and inhibiting both Plasmodium sexual- and asexual-stage through secreted factors, thereby rendering it a potential candidate for the development of a malaria transmission intervention strategy.


Lysosomal hydrolases of the epidermis. 6. Changes in disease.
The activities of 14 acid hydrolases have been measured in normal and diseased human epidermis. Our findings were as follows: (i) Increased hydrolase activity was common in lesions; the clinically uninvolved skin of patients, however, invariably showed normal values. (2) The pattern of change was independent of the nature of the didease, the arylsulphatases and beta-glucosidase usually showing the greatest elevations. (3) The magnitude of the changes differed from disease to disease, being most marked in the lesions of psoriasis. (4) Ichthyosiform erythroderma was exceptional in showing elevated levels of the galactosidases and cathepsins B1 and D. We suggest that (with the exception of ichthyosiform erythroderma) the abnormalities which we have observed may be related to the proliferative rate of the epidermis.


Ion-activated, Gelrite-based in situ ophthalmic gels of pefloxacin mesylate: comparison with conventional eye drops.
The purpose of our work was to develop an ophthalmic delivery system of a flouroquinolone antibiotic, pefloxacin mesylate, based on the concept of ion-activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle, that gels in the presence of mono- or divalent-cations present in the lacrimal fluid, was used as the gelling agent. The developed formulation was compared with marketed eye drops in efficacy of treatment of bacterial conjunctivitis that was induced artificially in rabbits. The formulations were evaluated for rheological characteristics, in vitro release behavior, antimicrobial efficacy, and efficacy against bacterial conjunctivitis. We found that in situ gelling formulations passed the test for sterility. The formulations exhibited a first-order release pattern over 12 hr in in vitro release studies. The developed formulation was effective against selected micro-organisms in antimicrobial efficacy studies. The shelf lives of formulation was >2 years. The formulation demonstrated better therapeutic efficacy compared with standard eye drops because it improved the clinical parameters monitored for prolonged periods. The developed formulations can be considered as a viable alternative to conventional eye drops.


Goat semen cryopreservation with rainbow trout seminal plasma supplemented lecithin-based extenders.
The objective of this study was to determine the optimum concentrations of rainbow trout seminal plasma (RTS) supplemented extenders for goat semen quality at post-thaw and after incubation. Five sexually mature Saanen goat (Capra aegagrus hircus) were used for semen collection. Pooled semen was diluted with soybean lecithin-based extender without RTS (control) or supplemented with different concentrations of RTS (1%, 2%, 4% or 8%), at a final concentration of 150 × 106 spermatozoon/ml. Sperm motility, plasma membrane functional integrity (HOST), damaged acrosome (PSA-FITC), mitochondrial activity (rhodamine123) and DNA integrity (TUNEL) were evaluated. Spermatological parameters were evaluated at post-thaw and after 6 hr incubation. RTS8 group preserved sperm motility, acrosomal integrity, plasma membrane functional integrity and mitochondrial function better than the control group (p < .05). The study demonstrated that RTS supplemented lecithin-based extenders have useful effects on goat spermatozoa. In addition, the results of the current study represented the positive effect of using 8% RTS supplemented extender.


Establishing the importance of oil-membrane interactions on the transmembrane diffusion of physicochemically diverse compounds.
The diffusion process through a non-porous barrier membrane depends on the properties of the drug, vehicle and membrane. The aim of the current study was to investigate whether a series of oily vehicles might have the potential to interact to varying degrees with synthetic membranes and to determine whether any such interaction might affect the permeation of co-formulated permeants: methylparaben (MP); butylparaben (BP) or caffeine (CF). The oils (isopropyl myristate (IPM), isohexadecane (IHD), hexadecane (HD), oleic acid (OA) and liquid paraffin (LP)) and membranes (silicone, high density polyethylene and polyurethane) employed in the study were selected such that they displayed a range of different structural, and physicochemical properties. Diffusion studies showed that many of the vehicles were not inert and did interact with the membranes resulting in a modification of the permeants' flux when corrected for membrane thickness (e.g. normalized flux of MP increased from 1.25±0.13μgcm(-1)h(-1) in LP to 17.94±0.25μgcm(-1)h(-1)in IPM). The oils were sorbed differently to membranes (range of weight gain: 2.2±0.2% for polyurethane with LP to 105.6±1.1% for silicone with IHD). Membrane interaction was apparently dependent upon the physicochemical properties including; size, shape, flexibility and the Hansen solubility parameter values of both the membranes and oils. Sorbed oils resulted in modified permeant diffusion through the membranes. No simple correlation was found to exist between the Hansen solubility parameters of the oils or swelling of the membrane and the normalized fluxes of the three compounds investigated. More sophisticated modelling would appear to be required to delineate and quantify the key molecular parameters of membrane, permeant and vehicle compatibility and their interactions of relevance to membrane permeation.


Lactobacillus plantarum improves lipogenesis and IRS-1/AKT/eNOS signalling pathway in the liver of high-fructose-fed rats.
In the present study, we investigated the influence of Lactobacillus plantarum and Lactobacillus helveticus supplementation on lipogenesis, insulin signalling and glucose transporters in liver of high-fructose-fed rats. Fructose was given to the rats as a 20% solution in drinking water for 15 weeks. Lactobacillus plantarum and L. helveticus supplementations were performed by gastric gavage once a day during final 6 weeks. Dietary high-fructose increased hepatic weight, lipid accumulation and FASN expression as well as caused a significant reduction in IRS-1 expression, pAKT/total AKT and peNOS/total eNOS ratios, but an elevation in GLUT2 and GLUT5 mRNAs in the liver. Lactobacillus plantarum supplementation decreased hepatic weight, triglyceride content and FASN expression as well as improved IRS-1/AKT/eNOS pathway and GLUT2 expression in the liver of high-fructose-fed rats. However, L. helveticus supplementation exerted a restoring effect on lipid accumulation by decreasing FASN expression, and regulating effect on IRS-1 and GLUT2 expressions.


An Exploratory Study of Inhalers and Injectors Who Used Black Tar Heroin.
AIMS: To undertake an exploratory study to examine the characteristics of patients in narcotic treatment programs who started their use of black tar heroin either as inhalers or as injectors and to compare them with those who started as inhalers but shifted to injecting. Other studies in this area have used subjects using other forms of heroin more amenable to inhaling. PARTICIPANTS, DESIGN, AND MEASUREMENT: A purposive sample of 199 patients in 6 methadone programs in Texas were interviewed in 2002-2003 using a structured instrument. FINDINGS: At admission to treatment, those who were heroin inhalers were more likely to be African American, to live with their families, to have income from wages, and to report fewer days of problems on most of the ASI measures. Those who shifted from inhaling to injecting were more likely to be Hispanic and to have had mental health problems that interfered with their lives and to have had less nurturing while growing up. Injectors were older at this treatment admission, had more treatment episodes and more times in jail, and were more likely to have hepatitis C, AIDS, or gonorrhea. There were high levels of physical and mental problems and histories of traumatization as children and adults for almost all the respondents. Males were as likely as females to have been sexually abused as children or as adults. CONCLUSIONS: The high rates of mental and physical problems among all the clients interviewed showed the need for comprehensive services to be delivered within the substance abuse treatment programs. Histories of trauma and sexual abuse should be addressed for both male and female clients.


Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome.
Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS). Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance). In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.


Parathyroid hormone inhibits phosphate transport in OK cells but not in LLC-PK1 and JTC-12.P3 cells.
Na+-dependent phosphate transport and its response to parathyroid hormone (PTH) has been investigated in three continuous cell lines of renal epithelial origin (LLC-PK1, JTC-12.P3, and OK). The apparent Km for phosphate was similar, but the maximal transport rate (Vmax) was markedly different in the three cell lines. PTH and forskolin produced an increase of cellular adenosine 3',5'-cyclic monophosphate (cAMP) in all cell lines, but Na+-dependent phosphate transport was inhibited exclusively in the OK cells (a threefold reduction of influx after 4 h of exposure to 10(-10) M PTH). The change in phosphate transport is accounted for by a lowered Vmax (30.8 +/- 5.3 vs. 10.2 +/- 1.1 pmol X mg-1 X 3 min-1). The reduction in phosphate transport was reversible, such that 5 h after removal of PTH the Vmax had increased threefold over the inhibited state. Addition of PTH did not alter Na+-dependent L-alanine influx in the OK cells. Experiments with apical membrane vesicles showed that the change in Vmax occurred at the membrane level. It is concluded that the regulatory event responsible for PTH-reduced phosphate transport is beyond cAMP. Of the cell lines studied, only OK cells have a complete regulatory cascade.


Purification and characterization of five snake venom metalloproteinases from Egyptian Echis pyramidum pyramidum venom.
New five P-III snake venom metalloproteinases (SVMPs): EpyB2 (62 kDa), EpyB3 (62+23 kDa), EpyB4 (60 kDa), EpyB5 (67 kDa) and EpyB6 (66 kDa) of the most dangerous viper, Echis pyramidum pyramidum (Epy), were purified and characterized in a set of biochemical assays. The SVMPs were purified by applying a protocol of two successive chromatographic steps. Three purified SVMPs "EpyB2, EpyB4, and EpyB5" have hemorrhagic activity with MHDs, 7 μg, 7.6 μg and 15 μg, respectively; furthermore, they have high preference towards fibronectin, collagen, gelatin, fibrin and hemoglobin substrates compared with non-hemorrhagic SVMPs (EpyB3 and EpyB6). All the purified SVMPs showed remarkable thermal and pH stability, inhibited by metalloproteinase inhibitors and Zn(2+), Mn(2+), Ni(2+), Co(2+), Cu(2+), and Hg(2+). The purified SVMPs act as α-fibrinogenases, prothrombin activators and procoagulants. In conclusion, Epy venom has multiple SVMPs that are responsible for hemorrhagic events and thus represent a significant health hazard for victims of envenomation, however, they may be useful for treating diseases involving abnormal blood clot formation.


Bayesian inference for two-part mixed-effects model using skew distributions, with application to longitudinal semicontinuous alcohol data.
Semicontinuous data featured with an excessive proportion of zeros and right-skewed continuous positive values arise frequently in practice. One example would be the substance abuse/dependence symptoms data for which a substantial proportion of subjects investigated may report zero. Two-part mixed-effects models have been developed to analyze repeated measures of semicontinuous data from longitudinal studies. In this paper, we propose a flexible two-part mixed-effects model with skew distributions for correlated semicontinuous alcohol data under the framework of a Bayesian approach. The proposed model specification consists of two mixed-effects models linked by the correlated random effects: (i) a model on the occurrence of positive values using a generalized logistic mixed-effects model (Part I); and (ii) a model on the intensity of positive values using a linear mixed-effects model where the model errors follow skew distributions including skew- t and skew-normal distributions (Part II). The proposed method is illustrated with an alcohol abuse/dependence symptoms data from a longitudinal observational study, and the analytic results are reported by comparing potential models under different random-effects structures. Simulation studies are conducted to assess the performance of the proposed models and method.


Cellvibrio fontiphilus sp. nov., isolated from a spring.
A bacterial strain, designated MVW-40T, was isolated from Maolin Spring in Taiwan and characterized using a polyphasic taxonomy approach. Cells of strain MVW-40T were Gram-negative, strictly aerobic, motile by a single polar flagellum and bright yellow-pigmented rods with pointed ends. Growth occurred at 15-40 °C (optimum, 20-30 °C), at pH 6-9 (optimum, pH 6) and with 0-2 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain MVW-40T belonged to the genus Cellvibrio and showed the highest levels of sequence similarity with respect to Cellvibrio mixtussubsp. mixtus ACM 2601T (98.1 %) and Cellvibrio fibrivorans R-4079T (97.2 %). Strain MVW-40T contained summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 0 and C18 : 1ω7c as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, two uncharacterized aminophospholipids, two uncharacterized phospholipids and an uncharacterized lipid. The DNA G+C content of the genomic DNA was 52.8 mol%. The DNA-DNA hybridization value for strain MVW-40T with C. mixtussubsp. mixtus ACM 2601T and C. fibrivorans R-4079T was less than 45 %. On the basis of the phylogenetic inference and phenotypic data, strain MVW-40T should be classified as a novel species, for which the name Cellvibrio fontiphilus sp. nov. is proposed. The type strain is MVW-40T (=BCRC 80977T=LMG 29557T=KCTC 52237T).


Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats.
Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine- or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclo-oxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDO-induced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels.


Exhaled nitric oxide, total serum IgE and allergic sensitization in childhood asthma and allergic rhinitis.
Exhaled nitric oxide (eNO) levels are correlated with several markers of atopy and inflammatory activity in the airways, but the relationship between eNO and total serum IgE has not been fully elucidated in the context of allergic sensitization. The aim of this study was to investigate the relationship between eNO, total serum IgE and allergic sensitization in childhood asthma and allergic rhinitis. eNO levels, lung function, skin prick tests and total serum IgE were determined in 109 children (mean age, 10.4 yr) with mild intermittent asthma and in 41 children (mean age, 10.1 yr) with allergic rhinitis; 25 healthy non-atopic children were recruited as controls. eNO levels (median) were significantly higher in patients with asthma (22.7 p.p.b.) and in those with allergic rhinitis (15.3 p.p.b.) than in healthy controls (5.9 p.p.b.). Children with allergic asthma had higher eNO levels than children with allergic rhinitis. A significant positive correlation was found between eNO and total serum IgE (asthma, r = 0.42, p < 0.0001; allergic rhinitis, r = 0.31, p < 0.01), and between eNO and the number of positive skin prick tests (asthma, r = 0.31, p < 0.0001; allergic rhinitis, r = 0.39, p < 0.01). eNO levels were better correlated with total IgE than with the number of positive skin prick tests. This correlation was independent of allergic sensitization. High total serum IgE represents a specific and predictive marker of eNO increase in children with asthma or allergic rhinitis. This finding adds further support to the hypothesis that increased serum IgE could be a marker itself of airway inflammation in patients with allergic disease.


Comparison of Vaginal versus Oral Estradiol Administration in Improving the Visualization of Transformation Zone (TZ) during Colposcopy.
Colposcopy is an important diagnostic tool in the evaluation of patients with abnormal pap smears. However, in 10-20% transformation zone (TZ)/squamo-columnar junction is not completely visualized and these patients are deemed to have an incomplete colposcopy examination. Such patients usually require conization, a procedure associated with significant morbidity. Various agents like misoprostol, estrogens and laminaria tents have been used in the past to overcome the non-visualization of TZ. The present study was conducted with the aim to compare the efficacy of vaginal versus oral estradiol administration in overcoming incomplete colposcopy. Forty patients with non/partially visualized TZ during colposcopy were recruited for the study. These patients were randomly distributed into two groups: In Group I, 25μg estradiol was administered intravaginally daily for seven consecutive days followed by a repeat colposcopy on day 8. In Group II, a seven day course of 25μg oral estradiol was followed by a repeat colposcopy on day 8. The efficacy of the two regimens in improving visualization of the TZ on colposcopy and their adverse effect profile was compared. Vaginal estradiol had an overall efficacy of 70% in improving visualization of the TZ as compared to oral estradiol which was effective in 50% of patients (p-value-0.19). Major adverse effects in both the group of patients were nausea and vaginal discharge with no significant differences among the two groups. Both vaginal and oral estrogens had comparable efficacy and similar adverse effect profile in improving visualization of the TZ.


Dynamic connectivity among cortical layers in local and large-scale sensory processing.
Cortical processing of sensory stimuli typically recruits multiple areas, but how each area dynamically incorporates activity from other areas is not well understood. We investigated interactions between cortical columns of bilateral primary sensory regions (S1s) in rats by recording local field potentials and multi-unit activity simultaneously in both S1s with electrodes positioned at each cortical layer. Using dynamic connectivity analysis based on Granger-causal modeling, we found that, shortly after whisker stimulation (< 10 ms), contralateral S1 (cS1) already relays activity to granular and infragranular layers of S1 in the other hemisphere, after which cS1 shows a pattern of within-column interactions that directs activity upwards toward superficial layers. This pattern of predominant upward driving was also observed in S1 ipsilateral to stimulation, but at longer latencies. In addition, we found that interactions between the two S1s most strongly target granular and infragranular layers. Taken together, the results suggest a possible mechanism for how cortical columns integrate local and large-scale neocortical computation by relaying information from deeper layers to local processing in superficial layers.


Clinical characterization of patients with PRPF31-related retinitis pigmentosa and asymptomatic carriers: a cross-sectional study.
To describe the clinical phenotype of retinitis pigmentosa (RP) caused by PRPF31-variants and clinical characterization of asymptomatic PRPF31 carriers. We conducted a descriptive cross-sectional deep phenotyping study. We included subjects with PRPF31 variants predicted to be disease-causing, both individuals with RP and asymptomatic carriers. Participants underwent a comprehensive clinical examination of standard visual function parameters (visual acuity, contrast sensitivity, Goldmann visual field), full-field stimulus threshold (FST), full-field electroretinogram (ff-ERG), and a structural investigation with slit lamp and multimodal imaging. We used Spearman correlation analyses to evaluate associations between quantitative outcomes. We included 21 individuals with disease-causing PRPF31-variants: 16 symptomatic and 5 asymptomatic subjects. The symptomatic subjects demonstrated a typical RP phenotype with constricted visual fields, extinguished ff-ERG, and disrupted outer retinal anatomy. FST was impaired and correlated significantly with other outcome measures in RP subjects. Structure-function correlations with Spearman correlation analysis showed moderate correlation coefficients due to a few outliers in each analysis. The asymptomatic individuals had normal best-corrected visual acuity and visual fields, but showed reduced ff-ERG amplitudes, borderline FST sensitivity, and structural abnormalities on OCT and fundoscopy. RP11 has a typical RP phenotype but varies in terms of severity. FST measurements correlated well with other functional and structural metrics and may be a reliable outcome measure in future trials as it is sensitive to a broad range of disease severities. Asymptomatic carriers showed sub-clinical disease manifestations, and our findings underline that reported non-penetrance in PRPF31-related RP is not an all-or-none phenomenon.


Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer.
To evaluate the safety and efficacy of gemcitabine and cisplatin in combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant therapy before radical cystectomy (RC) in muscle-invasive bladder cancer. Patients with clinical T2-4aN0/XM0 muscle-invasive bladder cancer eligible for RC were enrolled. The initial six patients received lead-in pembrolizumab 200 mg once 2 weeks prior to pembrolizumab 200 mg once on day 1, cisplatin 70 mg/m2 once on day 1, and gemcitabine 1,000 mg/m2 once on days 1 and 8 every 21 days for four cycles. This schedule was discontinued for toxicity and subsequent patients received cisplatin 35 mg/m2 once on days 1 and 8 without lead-in pembrolizumab. The primary end point was pathologic downstaging (< pT2N0) with null and alternative hypothesis rates of 35% and 55%, respectively. Secondary end points were toxicity including patient-reported outcomes, complete pathologic response (pT0N0), event-free survival, and overall survival. Association of pathologic downstaging with programmed cell death ligand 1 staining was explored. Thirty-nine patients were enrolled between June 2016 and March 2020 (72% cT2, 23% cT3, and 5% cT4a). Patients received a median of four cycles of therapy. All patients underwent RC except one who declined. Twenty-two of 39 patients (56% [95% CI, 40 to 72]) achieved < pT2N0 and 14 of 39 (36% [95% CI, 21 to 53]) achieved pT0N0. Most common adverse events (AEs) of any grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%). One patient had new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Clinicians consistently under-reported AEs when compared with patients. Neoadjuvant gemcitabine and cisplatin plus pembrolizumab met its primary end point for improved pathologic downstaging and was generally safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo is ongoing.


Optical rectification effect in 1D metallic photonic crystal slabs with asymmetric unit cell.
Photo-induced voltage due to photon drag effect is investigated for metallic photonic crystal slabs (PCS) with symmetric and asymmetric unit cells. In the symmetric structure, the signal is antisymmetric as a function of the incident angle, while in the asymmetric structure it is asymmetric. When the laser beam is normally incident to the sample, the photovoltage is observed only for PCS with asymmetric unit cells and its laser wavelength dependence is readily described in terms of uneven diffraction. The phenomenon can be referred to as optical rectification due to photonic scale asymmetry.


Intestinal epithelial glucocorticoid receptor promotes chronic inflammation-associated colorectal cancer.
Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial GC receptor (GR), but not whole intestinal tissue GR, promoted chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In patients with colorectal cancer, GR was enriched in intestinal epithelial cells and high epithelial cell GR levels were associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increased macrophage infiltration, improved tissue recovery, and enhanced antitumor response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice developed fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early phase of tissue injury delayed recovery and accelerated the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling repressed acute colitis but promoted chronic inflammation-associated colorectal cancer. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that, although synthetic GC treatment for IBD should be used with caution, there is a therapeutic window for GC therapy during colorectal cancer development in immunocompetent patients.


[The aged and job perspectives. An exploration].
The expulsion of older people from the labour market is observed with some resignation by policy-makers. One of the consequences is the lack of opportunities for older people to participate in social life. This process of expulsion started as far back as the mid-sixties. Initially the Disablement Acts, and more recently the Unemployment Acts and Early Retirement measures were used to this end. After describing these processes, attention is paid to the rehabilitation activities for the older people who are entitled to payments according to the Disablement Acts. Some empirical data are presented. It is shown that hardly any activities have been undertaken that result in the rehabilitation of older disabled people. This situation has contributed to create an atmosphere in which the opinion prevails that older people are superfluous in the labour market. Taking into account the development of employment in agriculture, manufacturing and services, there are perspectives for older people to work in the service sector.


Gut environment changes due to androgen deprivation therapy in patients with prostate cancer.
It is estimated that by 2040 there will be 1,017,712 new cases of prostate cancer worldwide. Androgen deprivation therapy (ADT) is widely used as a treatment option for all disease stages. ADT, and the resulting decline in androgen levels, may indirectly affect gut microbiota. Factors affecting gut microbiota are wide-ranging; however, literature is scarce on the effects of ADT on gut microbiota and metabolome profiles in patients with prostate cancer. To study the changes of gut microbiome by ADT, this 24-week observational study investigated the relationship between testosterone levels and changes in gut microbiota in Japanese patients with prostate cancer undergoing ADT. Sequential faecal samples were collected 1 and 2 weeks before ADT, and 1, 4, 12, and 24 weeks after ADT. Blood samples were collected at almost the same times. Bacterial 16 S rRNA gene-based microbiome analyses and capillary electrophoresis-time-of-flight mass spectrometry-based metabolome analyses were performed. In total, 23 patients completed the study. The α- and ß-diversity of gut microbiota decreased significantly at 24 weeks after ADT (p = 0.017, p < 0.001, respectively). Relative abundances of Proteobacteria, Gammaproteobacteria, Pseudomonadales, Pseudomonas, and concentrations of urea, lactate, butyrate, 2-hydroxyisobutyrate and S-adenosylmethionine changed significantly after ADT (p < 0.05). There was a significant positive correlation between the abundance of Proteobacteria, a known indicator of dysbiosis, and the concentration of lactate (R = 0.49, p < 0.01). The decline in testosterone levels resulted in detrimental changes in gut microbiota. This dysbiosis may contribute to an increase in frailty and an increased risk of adverse outcomes in patients with prostate cancer.


Seeing the Best or Worst in Others: A Measure of Generalized Other-Perceptions.
How positively or negatively people generally view others is key for understanding personality, social behavior, and psychopathology. Previous research has measured generalized other-perceptions by relying on either explicit self-reports or judgments made in group settings. With the current research, we overcome the limitations of these past approaches by introducing a novel measurement instrument for generalized other-perceptions: the Online-Tool for Assessing Perceiver Effects (O-TAPE). By assessing perceivers' first impressions of a standardized set of target people displayed in social network profiles or short video sequences, the O-TAPE captures individual differences in the positivity of other-perceptions. In Study 1 (n = 219), the instrument demonstrated good psychometric properties and correlations with related constructs. Study 2 (n = 142) replicated these findings and also showed that the O-TAPE predicted other-perceptions in a naturalistic group setting. Study 3 (n = 200) refined the nomological network of the construct and demonstrated that the O-TAPE is invulnerable to effects of social desirability.


Phosphorylation of phosphatase inhibitor-2 at centrosomes during mitosis.
Inhibitor-2 (I-2) is a regulator of protein phosphatase type-1 (PP1), known to be phosphorylated in vitro by multiple kinases. In particular Thr72 is a Thr-Pro phosphorylation site conserved from yeast to human, but there is no evidence that this phosphorylation responds to any physiological signals. Here, we used electrophoretic mobility shift and immunoblotting with a site-specific phospho-Thr72 antibody to establish Thr72 phosphorylation in HeLa cells and show a 25-fold increase in phosphorylation during mitosis. Mass spectrometry demonstrated I-2 in actively growing HeLa cells was also phosphorylated at three other sites, Ser120, Ser121, and an additional Ser located between residues 70 and 90. In vitro kinase assays using recombinant I-2 as a substrate showed that the Thr72 kinase(s) was activated during mitosis, and sensitivity to kinase inhibitors indicated that the principal I-2 Thr72 kinase was not GSK3 but instead a member of the cyclin-dependent protein kinase family. Immunocytochemistry confirmed Thr72 phosphorylation of I-2 during mitosis, with peak intensity at prophase, and revealed subcellular concentration of the phospho-Thr72 I-2 at centrosomes. Together, the data show dynamic changes in I-2 phosphorylation during mitosis and localization of phosphorylated I-2 at centrosomes, suggesting involvement in mammalian cell division.


Ovary Development and Cold Tolerance of the Invasive Pest Drosophila suzukii (Matsumura) in the Central Plains of Kansas, United States.
Environmental challenges presented by temperature variation can be overcome through phenotypic plasticity in small invasive ectotherms. We tested the effect of thermal exposure to 21, 18, and 11°C throughout the whole life cycle of individuals, thermal exposure of adults reared at 25°C to 15 and 11°C for a 21-d period, and long (14:10 hr) and short (10:14 hr) photoperiod on ovary size and development in Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) cultured from a recently established population in Topeka, Kansas (United States). Examination of the response to temperature and photoperiod variation in this central plains population provides insight into the role of phenotypic plasticity in a climate that is warmer than regions in North America where D. suzukii was initially established. We found both low temperature and short photoperiod resulted in reduced ovary size and level of development. In particular, reduced ovary development was observed following exposure to 15°C, indicating that ovary development in females from the central plains population is more sensitive to lower temperature compared with populations examined from the northern United States and southern Canada. We also provide evidence that D. suzukii reared at 25°C are capable of short-term hardening when exposed to -6°C following 4°C acclimation, contrary to previous reports indicating flies reared at warm temperatures do not rapidly-cold harden. Our study highlights the central role of phenotypic plasticity in response to winter-like laboratory conditions and provides an important geographic comparison to previously published assessments of ovary development and short-term hardening survival response for D. suzukii collected in cooler climates.


Stress induced gastrointestinal bleeding in a pediatric intensive care unit: which risk factors should necessitate prophilaxis?
The aim of this study was to determine the frequency and the risk factors of stress induced gastrointestinal bleeding (GIB) in critically ill children, and to investigate the effect of prophilaxis. The setting was a 14-beded, tertiary care PICU. Records of 182 children admitted consecutively from December 2012 to May 2013 were retrospectively reviewed. 136 patients were eligible. The age ranged from 40 days to 18 years. Diagnosis, demographic data, risk factors, administration of prophilaxis, drugs used in medication, prescence and degree of GIB and complications were recorded. The male-female ratio was 1.3. Mean age was 5.9. Mean PRISM III score was 12.2 and 49.3% had PRISM Score ≥10. Most frequent diagnosis was infectious diseases. Sixtyone (44.9%) children received prophylaxis in which antacids was used in 28 (45.9%), sucralfate in 18 (29.5%), proton pomp inhibitors (PPIs) in 51 (83.6%) and 5 (8.2%) received H2 reseptor antagonist. The incidence of GIB was 15.4% (N.=21), in which 66.7% (N.=14) were mild, 23.8% (N.=5) were moderate, 4.8% (N.=1) was significant and 4.8% (N.=1) was massive. In children who received prophylaxis 17 (27.9%) cases developed GIB. Mechanical ventilation was found to be the only risk factor significantly associated with stress induced GIB. Also; mechanical ventilation and trauma was strongly significant (P<0.001) and coagulopathy/thrombocytopenia, PRISM III ≥10, renal and hepatic failure, hypotension, and heart failure/arrhythmia was found to be associated with the development of GIB in critically ill children (P<0.05). GIB is a serious concern for PICU clinicians and intensivists are confused about the conflicting evidence supporting prophilaxis. We believe that prophylaxis could be beneficial for mechanically ventilated children. Also trauma, coagulopathy/thrombocytopenia, PRISM III≥10, renal and hepatic failure, hypotension, and heart failure/arrhythmia must be kept in mind as risk factors requiring attention in PICU setting.


Fresh blood for everyone? Balancing availability and quality of stored RBCs.
Effective, prolonged ex vivo storage of red blood cells is an essential requirement for inventory management of each nation's blood supply. Current blood storage techniques are the development of a century of research. Blood undergoes metabolic and structural deterioration during prolonged ex vivo storage. Current regulatory requirements for the limit of blood storage do not consider oxygen delivery or clinical outcomes. Recently, concern that stored blood may produce adverse outcomes in recipients has sparked renewed interest in studies that can evaluate the clinical impact of fresh vs. stored blood. In 2008, a retrospective study of outcomes among transfused patients undergoing cardiac surgery suggested that blood stored for more than 14 days prior to transfusion led to higher perioperative mortality compared with blood stored for less than 14 days. Here, we critically examine the details of the above-mentioned study. Numerous substantial flaws in data analysis and presentation may have led to an erroneous conclusion about the effect of blood storage age and perioperative mortality. Given the fundamental importance of a safe and adequate blood supply to national healthcare, the question of the proper storage age for blood should be studied using a prospective study design.


[Effect of selenium on myocardial function and structure in mice within ischemic and hypoxic environment].
The experiment was designed to study the protective effect of selenium on myocardial function and ultrastructure changes of fetal mouse heart model under ischemic and hypoxic circumstances. The results showed that selenium can prolong the period of heart surviving and beating. Results via lanthanum probe technique indicated that selenium is able to maintain the functional integrity of the myocardial cell membrane as well as the mitochondria membrane. Ultrastructure changes under REM suggested that selenium may play a role in delaying the development of irreversible myocardial injury and to promote protein synthesis and the repairment of the injured cells.


A positive update on COVID-19 booster vaccine willingness among Danes.
Based on survey data from September 2021, we recently reported that an estimated 90% (weighted total) of vaccinated (completed or scheduled) adult Danes were also willing to receive a COVID-19 booster vaccine, once offered. This survey was, however, fielded before booster vaccination was recommended to the general adult population in Denmark, which may have resulted in an underestimation of booster vaccine willingness. Therefore, we conducted a follow-up survey targeting the same individuals. The follow-up survey wave was fielded in December 2021 using the same methods as in the September 2021 wave. Using data from participants responding to both survey waves, we compared COVID-19 booster vaccine willingness between the waves by means of paired t-test. A total of 1,429 invitees (58%) responded to the follow-up survey. Among those, 1,324 (93%) had also responded to the initial survey on COVID-19 booster vaccine willingness. At follow-up, among the 95% reporting to be vaccinated or that COVID-19 vaccination was scheduled, a weighted proportion of 95% indicated that they were willing to receive the booster vaccine once offered. Booster vaccine willingness at follow-up (December 2021) had statistically significantly increased (p less-than 0.001) compared with the initial survey (September 2021). Almost all of the COVID-19-vaccinated Danes seem willing to receive a booster dose of the vaccine, which bodes very well for the COVID-19 immunisation state in Denmark. The study was funded by a grant from the Novo Nordisk Foundation. not relevant.


Interaction between the Number of Chemotherapy Cycles and Brachytherapy Dose/Volume Parameters in Locally Advanced Cervical Cancer Patients.
Scarce data exist on concurrent chemotherapy in locally advanced cervical cancer (LACC) patients (pts) treated with image-guided adaptive brachytherapy (IGABT). We examined the effect of a number of chemotherapy cycles and their interaction with brachytherapy dose/volume parameters. Clinical records of 209 consecutive pts treated for a LACC were reviewed. Pts received CRT concurrently with cisplatin 40 mg/m² or carboplatin AUC2. An additional cycle could have been delivered during the pulse-dose rate (PDR)-IGABT. The impact of a number of chemotherapy cycles on outcome was examined, as well as the interactions with dose volume parameters. The number of cycles was four in 55 (26.3%) pts, five in 154 (73.7%) including 101 receiving the fifth cycle during IGABT. Median follow-up was 5.5 years. Pts receiving five cycles had a better outcome on all survival endpoints, including three year local control rate (93.9% vs. 77.2%; p < 0.05). In the subgroup, only pts with tumor FIGO (Fédération Internationale de Gynécologie Obstétrique) stage ≤IIB or with CTVHR > 25 cm3 had a better outcome. Pts receiving four cycles with D90CTVHR > 80GyEQD2 had the same locoregional control-(LRC) as those receiving five cycles and achieving D90CTVHR ≤ 80 GyEQD2 (p = 0.75). An optimal propensity score matching the balance for the FIGO stage, CTVHR volume and D90CTVHR confirmed the effect, with the largest life expectancy benefit for locoregional failure-free survival (absolute gain: 1.5 years; p = 0.017). Long-term radiation-induced toxicity was not increased. Increasing the total number of cycles from 4 to 5 improved LFS, suggesting a place for systemic strategies aimed at in-field cooperation. Delivering an additional cycle at the time of brachytherapy did not increase morbidity and there permitted an increase in chemotherapy dose intensity.


Liver involvement in systemic lupus erythematosus: case review of 40 patients.
Subclinical liver involvement is frequent in systemic lupus erythematosus (SLE). We sought to determine the presence of endstage liver disease in patients with SLE. We carried out a retrospective chart review of our cohort of patients with SLE. Endstage liver disease was defined as presence or development of cirrhosis, portal hypertension, or hepatic encephalopathy. Forty patients with liver enzyme abnormalities were identified. Major clinical diagnostic groups were drug-induced (n = 4), viral hepatitis (hepatitis B or C and cytomegalovirus; n = 8), nonalcoholic fatty liver disease (NAFLD; n = 8), autoimmune hepatitis (AIH; n = 6), primary biliary cirrhosis (PBC; n = 3), and miscellaneous [n = 11; liver involvement from infection (2), cryptogenic cirrhosis (2), lymphoma (1), and indeterminate (6)]. There were no differences in mean age, total and direct bilirubin, or aspartate aminotransferase and alkaline phosphatase levels. Alanine aminotransferase levels were higher in the miscellaneous group. Biopsies were performed in 20 patients and showed changes of NAFLD (n = 5), AIH (n = 4), PBC (n = 3), hepatitis C (n = 3), and cryptogenic cirrhosis (n = 2), and 1 each with phenytoin-induced liver injury, hepatic granulomas due to systemic candidiasis, and lymphomatous involvement of the liver. The median followup was 44 months (range 10-576). The estimated 5-year serious liver disease-free survival was 93% (95% confidence interval 84%-100%). Eight patients died. Mortality was not directly related to liver disease in any patient. Complications of portal hypertension, cirrhosis, and hepatic encephalopathy are rare manifestations of SLE unless coexistent liver disease such as NAFLD, viral hepatitis, or AIH is present.


Targeting Extracellular Bacterial Proteases for the Development of Novel Antivirulence Agents.
As resistance to clinically available antibiotics persistently increases, applying new strategies to target pathogenic bacteria are paramount to design effective drugs. Bacterial proteases play vital roles in cell viability and stress response, contributing to the pathogenicity of the resistant bacteria. Targeting these extracellular enzymes by antivirulence therapy is a prominent strategy in combating multi-drug resistant bacteria. By preventing the colonization and infiltration of the host, this method can lower selection pressure and reduce resistance development significantly. Here, we review the role of bacterial proteases, the rise of antivirulence therapy and we report on the development of novel antivirulence agents targeting two key virulence factors: elastase B (LasB) from Pseudomonas aeruginosa and collagenase H (ColH) from Clostridium histolyticum.


Report of a spinal extradural arteriovenous fistula with double radiculomedullary venous drainage: therapeutic implications and role of intraoperative spinal angiography.
Low-flow spinal extradural arteriovenous fistulas (SEAVFs) are frequently misdiagnosed as spinal dural arteriovenous fistulas (SDAVFs), and their true prevalence is unknown. The principal feature distinguishing low-flow SEAVFs from SDAVFs is the location of the shunt, which involves a pouch of epidural plexus in SEAVFs and a radiculomedullary vein (RMV) in SDAVFs. A venous hypertensive myelopathy comparable to the one observed with SDAVFs develops when the arterialized venous pouch of an SEAVF is connected to an RMV. Depending on the size of the epidural pouch, a low-flow SEAVF may uncommonly drain into multiple RMVs. The authors present an observation of a low-flow SEAVF whose double radiculomedullary drainage was revealed only after intraoperative digital subtraction angiography, and they discuss the surgical implications of this anatomical configuration.


Postural Coordination during Socio-motor Improvisation.
Human interaction often relies on socio-motor improvisation. Creating unprepared movements during social interaction is not a random process but relies on rules of synchronization. These situations do not only involve people to be coordinated, but also require the adjustment of their posture in order to maintain balance and support movements. The present study investigated posture in such a context. More precisely, we first evaluated the impact of amplitude and complexity of arm movements on posture in solo situation. Then, we assessed the impact of interpersonal coordination on posture using the mirror game in which dyads performed improvised and synchronized movements (i.e., duo situation). Posture was measured through ankle-hip coordination in medio-lateral and antero-posterior directions (ML and AP respectively). Our results revealed the spontaneous emergence of in-phase pattern in ML direction and antiphase pattern in AP direction for solo and duo situations. These two patterns respectively refer to the simultaneous flexion/extension of the ankles and the hips in the same or opposite direction. It suggests different functional roles of postural coordination patterns in each direction, with in-phase supporting task performance in ML (dynamical stability) and antiphase supporting postural control in AP (mechanical stability). Although amplitude of movement did not influence posture, movement complexity disturbed postural stability in both directions. Conversely, interpersonal coordination promoted postural stability in ML but not in AP direction. These results are discussed in terms of the difference in coupling strength between ankle-hip coordination and interpersonal coordination.