[Estimation of chloramphenicol in the working area air by high performance liquid chromatography].
Chloramphenicol (levomycetin) is a broad-spectrum antibiotic that is active against gram-positive and gram-negative microorganisms. At present, it is manufactured via organic synthesis. Working place air becomes polluted during the manufacture and use of medicines containing chloramphenicol. In the working place air, chloramphenicol is present as a disintegration aerosol and may provoke occupational diseases of varying severity in the exposed persons. A procedure has been determined to measure air chloramphenicol, by using high performance liquid chromatography. Aspiration through an AFA FPP-15 aerosol filter is a suitable device for air chloramphenicol sampling. The selected chloramphenicol is removed from the filter via triple methanol extraction in an ultrasound bath. The pooled extract is evaporated to dryness in a current of nitrogen and the dry residue is dissolved in the mobile phase containing acetonitrile : buffer (pH 4.8) = 30:70. The chloramphenicol determination procedure using reverse-phase liquid chromatography with ultraviolet detection at a wavelength of 275 nm has been developed and completely validated. Chromatographic conditions are given. The retention time of chloramphenicol is 6.5 min. The detection limit is 0.1 microg/cm3. The method is noted for a linear relationship between the concentration of chloramphenicol (microg/cm3) and the peak area (mm2) in the range of 1 to 20 microg/cm3.


Analysis of extracellular vesicles produced in the biofilm by the dimorphic yeast Pichia fermentans.
The yeast Pichia fermentans DISAABA 726 strain (P. fermentans) is a dimorphic yeast that under different environmental conditions may switch from a yeast-like to pseudohyphal morphology. We hypothesize that exosomes-like vesicles (EV) could mediate this rapid modification. EV are membrane-derived vesicles carrying lipids, proteins, mRNAs and microRNAs and have been recognized as important mediators of intercellular communication. Although it has been assumed for a long time that fungi release EV, knowledge of their functions is still limited. In this work we analyze P. fermentans EV production during growth in two different media containing urea (YCU) or methionine (YCM) where yeast-like or pseudohyphal morphology are produced. We developed a procedure to extract EV from the neighboring biofilm which is faster and more efficient as compared to the widely used ultracentrifugation method. Differences in morphology and RNA content of EV suggest that they might have an active role during dimorphic transition as response to the growth conditions. Our findings are coherent with a general state of hypoxic stress of the pseudohyphal cells.


Interaction of influenza and parainfluenza viruses with polycations, organic oligocations and chromosome preparations.
As evaluated by light scattering at 90 degrees, natural organic oligocations such as putrescine, spermidine and spermine interfered with myxovirus aggregates which were induced by the histone H2A and strongly amplified by shaking during incubation. In contrast, the synthetic oligocation 1.7-diamino heptane itself aggregated the virus particles, its action being unmodified by adding polycationic H2A in abundance. When human chromosome preparations treated with protamine solution and shaked during incubation were covered with a stable polycationic molecular layer, the chromosomes had become unstainable by the Giemsa method even if the dye was used in excess. Nevertheless, the affinity of influenza virus particles for protamine was so high that they were able to dissociate the protamine molecules from the preformed complexes reconstituting the affinity of chromosome preparations to Giemsa stain. The virus-caused shift in the staining ability of chromosomes did not occur when bacterial suspension was added instead of the viral one. The model of oligocationic relaxation and of polycation condensation accounting for the modulatory effects of polyamines is discussed.


Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations.
The kinetics and dynamics (inhibition of exercise tachycardia) of two controlled-release preparations of propranolol (Elanolol and Inderal LA) were examined in six normal volunteers. Conventional propranolol (Inderal) was also studied for comparison purposes. As compared to conventional propranolol (120 mg), single doses of Elanol (120 mg) and Inderal LA (160 mg) produced a smoother serum level profile, with lower and delayed peak times. Dose-corrected AUC0-24 values were greater after Elanol than after Inderal LA (651 +/- 147 vs 402 +/- 159 ng ml-1 h, means +/- s.e. mean, P greater than 0.05). The profile of inhibition of exercise tachycardia mirrored closely that of the serum levels. At steady state, all regimens studied (Inderal 40 mg three times daily; Elanol 120 mg once daily; Inderal LA 160 mg once daily) ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose-corrected AUC0-24 values were 797 +/- 148 ng ml-1 h after Inderal, 908 +/- 113 ng ml-1 h after Elanol and 602 +/- 122 ng ml-1 after Inderal LA. The bioavailability of Inderal LA was significantly lower than that of the other preparations. These results demonstrate that long-acting formulations of propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first-pass metabolism.


In-Silico Integration Approach to Identify a Key miRNA Regulating a Gene Network in Aggressive Prostate Cancer.
Like other cancer diseases, prostate cancer (PC) is caused by the accumulation of genetic alterations in the cells that drives malignant growth. These alterations are revealed by gene profiling and copy number alteration (CNA) analysis. Moreover, recent evidence suggests that also microRNAs have an important role in PC development. Despite efforts to profile PC, the alterations (gene, CNA, and miRNA) and biological processes that correlate with disease development and progression remain partially elusive. Many gene signatures proposed as diagnostic or prognostic tools in cancer poorly overlap. The identification of co-expressed genes, that are functionally related, can identify a core network of genes associated with PC with a better reproducibility. By combining different approaches, including the integration of mRNA expression profiles, CNAs, and miRNA expression levels, we identified a gene signature of four genes overlapping with other published gene signatures and able to distinguish, in silico, high Gleason-scored PC from normal human tissue, which was further enriched to 19 genes by gene co-expression analysis. From the analysis of miRNAs possibly regulating this network, we found that hsa-miR-153 was highly connected to the genes in the network. Our results identify a four-gene signature with diagnostic and prognostic value in PC and suggest an interesting gene network that could play a key regulatory role in PC development and progression. Furthermore, hsa-miR-153, controlling this network, could be a potential biomarker for theranostics in high Gleason-scored PC.


Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity.
Multiple lines of evidence indicate that PrPSc, found only in scrapie, is a necessary component of the infectious scrapie agent. Equally compelling is the evidence that its accumulation in the brain causes the neuropathology characteristic of scrapie. We measured the regional concentration of PrPSc in nine brain regions throughout the course of scrapie in the Syrian hamster following intrathalamic inoculation of prions. PrPSc was compared to the regional concentration of glial fibrillary acidic protein, a measure of reactive astrocytic gliosis. PrPSc was detected first in the thalamus 14 to 21 days postinoculation and next in the septum at 28 days. Initiation of PrPSc synthesis and accumulation in the thalamus was attributable to the inoculum and in the septum to ventricular spread of de novo synthesized PrPSc. The timing and pattern of PrPSc accumulation in all other brain regions suggested transmission along neuroanatomic pathways. Reactive astrocytic gliosis followed PrPSc accumulation in each region by 1 to 2 weeks. Brain PrPSc, determined by summing the concentrations in each brain region, correlated well with scrapie infectivity titers throughout the course of infection (correlation coefficient = 0.975; slope of linear regression line = 1.136). Our results support the hypothesis that PrPSc participates in both the etiology and pathogenesis of prion diseases.


Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.
RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.


Comparative evaluation of microshear bond strength of the caries-affected dentinal surface treated with conventional method and chemomechanical method (papain).
There is a growing interest in chemomechanical excavation (papain) in permanent molar teeth. There are several studies dealing with primary molar teeth. The aim of this study was to evaluate the influence of conventional method and Carie-care (chemomechanical method) on the microshear bond strength (μSBS) and the type of failure of an adhesive system to caries-affected dentin of permanent molar teeth. Twenty permanent molar teeth with carious lesions extending into the dentin were selected. Through the center of the carious lesion, teeth were sectioned mesiodistally and divided into two groups based on the method of caries excavation (conventional and chemomechanical method). The time required for the completion of excavation procedure was noted. Samples were again divided into two subgroups in each according to the method of restoration (Ketac N100 and Filtek Z350 composite). The bonded interface was subjected to μSBS testing in a universal testing machine. Fractured surfaces were examined under a stereomicroscope, and representative specimens were examined under scanning electron microscope for the type of failure. It was achieved with unpaired t-test and Kruskal-Wallis H-test at 5% level of significance. The μSBS values of Carie-care groups were similar to that of the conventional method. The μSBSs of resin composite were significantly (P < 0.001) more than that of resin glass ionomer bonded irrespective of the method of caries excavation. A papain-based chemomechanical agent can be used safely as a method for caries removal when employing conventional adhesive systems.


Global variation in the incidence and outcome of emergency medical services witnessed out-of-hospital cardiac arrest: A systematic review and meta-analysis.
To examine global variation in the incidence and outcomes of emergency medical services (EMS) witnessed out-of-hospital cardiac arrest (OHCA). We systematically reviewed four electronic databases for studies between 1990 and 5th April 2021 reporting EMS-witnessed OHCA populations. Studies were included if they reported sufficient data to calculate the primary outcome of survival to hospital discharge or 30-day survival. Random-effects models were used to pool incidence and survival outcomes, and meta-regression was used to examine sources of heterogeneity. Study quality was appraised using the Joanna Briggs Institute critical appraisal tools. The search returned 1178 non-duplicate titles of which 66 articles comprising 133,981 EMS-witnessed patients treated by EMS across 33 countries were included. All but one study was observational and only 12 studies (18%) were deemed to be at low risk of bias. The pooled incidence of EMS-treated cases was 4.1 per 100,000 person-years (95% CI: 3.5, 4.7), varying almost 4-fold across continents. The pooled proportion of survivors to hospital discharge or 30-days was 20% overall (95% CI: 18%, 22%; I2 = 98%), 43% (95% CI: 37%, 49%; I2 = 94%) for initial shockable rhythms and 6% (95% CI: 5%, 8%; I2 = 79%) for initial non-shockable rhythms. In the meta-regression analysis, only region and aetiology were significantly associated with survival. When compared to studies from North America, pooled survival was significantly higher in studies from Europe (14% vs. 26%; p = 0.04) and Australasia (14% vs. 31%, p < 0.001). We identified significant global variation in the incidence and survival outcome of EMS-witnessed OHCA. Further research is needed to understand the factors contributing to these variations.


Effect of overeating on plasma and urinary concentrations of norepinephrine.
This study examined the effect of overeating on plasma norepinephrine concentrations and urinary norepinephrine excretion in man, since overeating sucrose or fat increases norepinephrine turnover in rodents. Five normal subjects were overfed by 50% for 20 days, without substantially changing the proportions of protein, fat, and carbohydrate in the diet, after a control period of normal feeding. Sodium intake remained constant throughout the study. There was no effect of overfeeding on plasma norepinephrine concentrations when subjects were resting supine either before or after a meal. However, plasma norepinephrine concentrations after 10 min of orthostasis were 40% lower (P less than 0.05) at the end of overfeeding. Plasma norepinephrine concentrations during slow walking also tended to be lower during overfeeding, but this effect was not statistically significant. Mean 24-h norepinephrine and epinephrine excretion were not altered. These data do not support the hypothesis that overeating increases sympathetic nervous system activity in man.


[Cloning, expression, purification and activity assay of Trypanosoma brucei phenylalanyl-tRNA synthetase in Escherichia coli].
Phenylalany--tRNA synthetase is a key enzyme for protein synthesis in Trypanosoma. Its validation as an inhibition. target will enable the development of a new generation of anti-Trypanosoma drugs. However, little is known about the isolation of the Trypanosoma Phenylalanyl-tRNA synthetase. Here we report the cloning, expression, purification, and activity assay of Phenylalanyl-tRNA synthetase from Trypanosoma brucei in Escherichia coli host. We co-cloned the alpha-subunit and beta-subunit of Phenylalanyl-tRNA synthetase from Trypanosoma brucei genomic DNA into the co-expression vector pCOLADuet. We successfully expressed the Trypanosoma brucei Phenylalanyl-tRNA synthetase in E. coli host, purified the whole enzyme by Ni-Hind affinity column and verified it by Western blotting. In addition, we tested its enzymatic activity by isotope labeling. The whole work laid a solid foundation for in vitro the screening and optimization of Trypanosoma brucei phenylalanyl-tRNA synthetase inhibitors.


[Study on the expression of vitamin D receptor in bone of immature rats of disuse osteoporosis].
To study the expression of vitamin D receptor in bone of immobilized immature rat and explore the relation between disuse osteoporosis (DOP) and the expression of vitamin D receptor (VDR) in bone. Rats aging 4 weeks were immobilized by limb-tail fixation for 2 and 4 weeks respectively, and then the wet weight, gray weight, bone mineral density of femurs and tibiae were measured, the histopathological and histomorphological parameters also were detected, which were used to evaluate the effect of immobilization on bone content and bone structure of femurs and tibiae in growing rats. The VDR expression of femurs and tibiae in the growing rats was evaluated by immunohistochemistry and image analysis. The wet weight, gray weight, and bone mineral density of immobilized limbs in the growing rats were all lower than those in age-matched control groups (P < 0.05). There were rare, small and broken bone trabeculae found in the histological films of proximal tibial metaphysis of immobilized limbs, with decreased trabecular area and perimeter (P < 0.05), comparing with the age-macthed control groups. Over-expression of VDR in cellular plasma and nuclear membranes of osteoblasts was also found in the proximal metaphysis of right hind limb in immobilized growing rats. It is a definite method to establish animal model of DOP in young rats by leg-tail fixation; over-expression of Vitamin D receptors in growing bone of immobilized rat limbs means that the disorder of vittamin D endocrine system may be related to pathogenesis of DOP.


Perineal injuries and birth positions among 2992 women with a low risk pregnancy who opted for a homebirth.
Whether certain birth positions are associated with perineal injuries and severe perineal trauma (SPT) is still unclear. The objective of this study was to describe the prevalence of perineal injuries of different severity in a low-risk population of women who planned to give birth at home and to compare the prevalence of perineal injuries, SPT and episiotomy in different birth positions in four Nordic countries. A population-based prospective cohort study of planned home births in four Nordic countries. To assess medical outcomes a questionnaire completed after birth by the attending midwife was used. Descriptive statistics, bivariate analysis and logistic regression were used to analyze the data. Two thousand nine hundred ninety-two women with planned home births, who birthed spontaneously at home or after transfer to hospital, between 2008 and 2013 were included. The prevalence of SPT was 0.7 % and the prevalence of episiotomy was 1.0 %. There were differences between the countries regarding all maternal characteristics. No association between flexible sacrum positions and sutured perineal injuries was found (OR 1.02; 95 % CI 0.86-1.21) or SPT (OR 0.68; CI 95 % 0.26-1.79). Flexible sacrum positions were associated with fewer episiotomies (OR 0.20; CI 95 % 0.10-0.54). A low prevalence of SPT and episiotomy was found among women opting for a home birth in four Nordic countries. Women used a variety of birth positions and a majority gave birth in flexible sacrum positions. No associations were found between flexible sacrum positions and SPT. Flexible sacrum positions were associated with fewer episiotomies.


Stereotactic radiosurgery as a feasible treatment for intramedullary spinal arteriovenous malformations: a single-center observation.
Spinal cord intramedullary arteriovenous malformations are rare. For patients suffering from either hemorrhage or myelopathy, surgical or endovascular interventions are indicated. However, complete eradication of the nidus is often difficult because of its intramedullary location and complex angioarchitecture. In this report, we evaluate the feasibility and safety of stereotactic radiosurgery as a treatment modality for intramedullary spinal arteriovenous malformations (AVMs). Between 2010 and 2014, we performed stereotactic radiosurgery to treat four patients with intramedullary AVM and one with spinal arteriovenous metameric syndrome (one woman and four men; age range, 31-66 years). Three patients presented with myelopathy, and two suffered hemorrhages. Nidi were located in the cervical (three cases) and thoracic (two cases) spinal cord regions. Based on the angioarchitecture, surgery and endovascular embolization were indicated. When both modalities were deemed hazardous, radiosurgery using CyberKnife™ was offered. Radiation using marginal doses of 18 Gy was administered in three fractions. The mean follow-up period was 37.2 months (range, 16-62 months). After treatment, two of the three patients with myelopathy experienced either improvement or stabilization of their symptoms and one experienced worsening of dysesthesia. In two patients with hemorrhage, symptoms improved in one and remained stable in the other. No further hemorrhagic episodes were evident during follow-up. Follow-up angiograms showed marked shrinkage of the nidus located in the thoracic spinal cord in one case and angiographic stabilization in the others. As a treatment modality for intramedullary AVMs, CyberKnife™ is safe and can be considered when surgery or endovascular therapy is not indicated. To determine optimum radiation doses and protocols for treating spinal AVMs, further studies with more patients and long-term follow-up are required.


[Phase II clinical trial of sorafenib plus local chemotherapy in the treatment of metastatic renal cell carcinoma with pleural effusion].
To evaluate the safety and efficacy of sorafenib plus cisplatin in the treatment of metastatic renal cell carcinoma (mRCC) with pleural effusion. A total of 30 patients with mRCC (clear cell carcinoma) with pleural effusion from April 2009 to January 2011 were recruited. All received sorafenib 400 mg twice daily. And 11 patients in chemotherapy group received sorafenib plus local chemotherapeutic perfusion of cisplatin 40 mg weekly for 2 weeks while another 19 patients in control group received sorafenib alone. The response rate of pleural effusion was 10/11 for chemotherapy group versus 3/19 for control group (χ(2) = 13.097, P < 0.01). Followed up to April 30(th), 2011, 5 of 11 patients in chemotherapy group and 10 of 19 patients in control group died. Among those on sorafenib, the median overall survival time was 22 months (95%CI: 2.12 - 41.88) for local chemotherapy versus 9 months (95%CI: 8.20 - 9.80) without local therapy (P = 0.04). The most common events in local chemotherapy group were I-II thoracic pain, nausea and vomiting. And the incidence rates were 8/11 and 9/11 versus 4/19 and 3/19 respectively (P < 0.01). The main laboratory abnormalities were similar in two groups. The regimen of sorafenib plus pleural cavity perfusion of cisplatin is both effective and safe in the treatment of mRCC with pleural effusion. It may control local symptoms and achieve a better overall survival.


XPIWIT--an XML pipeline wrapper for the Insight Toolkit.
The Insight Toolkit offers plenty of features for multidimensional image analysis. Current implementations, however, often suffer either from a lack of flexibility due to hard-coded C++ pipelines for a certain task or by slow execution times, e.g. caused by inefficient implementations or multiple read/write operations for separate filter execution. We present an XML-based wrapper application for the Insight Toolkit that combines the performance of a pure C++ implementation with an easy-to-use graphical setup of dynamic image analysis pipelines. Created XML pipelines can be interpreted and executed by XPIWIT in console mode either locally or on large clusters. We successfully applied the software tool for the automated analysis of terabyte-scale, time-resolved 3D image data of zebrafish embryos. XPIWIT is implemented in C++ using the Insight Toolkit and the Qt SDK. It has been successfully compiled and tested under Windows and Unix-based systems. Software and documentation are distributed under Apache 2.0 license and are publicly available for download at https://bitbucket.org/jstegmaier/xpiwit/downloads/. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Effects of low-dose irradiation on enhancement of immunity by dendritic cells.
Low-doses of irradiation have been reported to have beneficial effects, particularly anti-tumor effects. In this paper, we show the effects of the low-dose irradiation on T cell activation induced by dendritic cells (DCs). DCs, which had been pre-irradiated at 0.02-1.0 Gy from a (137)Cs source, were cultured with allogeneic T cells, and the proliferation of T cells was then examined. The 0.05Gy-pre-irradiated DCs showed the highest proliferation capacity of T cells. The 0.05Gy-irradiation does not augment the expression of major histocompatibility complexes (MHCs) or costimulatory molecules on DCs, as with non-irradiated DCs or 1Gy-irradiated DCs, but does augment the production of IL-2, IL-12 and IFN-gamma DCs. These results suggest that the low-dose irradiation augments T cell-activation capacity through cytokine production by DCs, which might shift naïve helper T cells to Th1 cells.


Presence of pathogenicity islands and virulence genes of extraintestinal pathogenic Escherichia coli (ExPEC) in isolates from avian organic fertilizer.
Poultry litter is commonly used as fertilizer in agriculture. However, this poultry litter must be processed prior to use, since poultry have a large number of pathogenic microorganisms. The aims of this study were to isolate and genotypically and phenotypically characterize Escherichia coli from avian organic fertilizer. Sixty-four E. coli isolates were identified from avian organic fertilizer and characterized for ExPEC virulence factors, pathogenicity islands, phylogenetic groups, antimicrobial resistance, biofilm formation, and adhesion to HEp-2 cells. Sixty-three isolates (98.4%) showed at least one virulence gene (fimH, ecpA, sitA, traT, iutA, iroN, hlyF, ompT and iss). The predominant phylogenetic groups were groups A (59.3%) and B1 (34.3%). The pathogenicity island CFT073II (51.5%) was the most prevalent among the isolates tested. Thirty-two isolates (50%) were resistant to at least one antimicrobial agent. Approximately 90% of isolates adhered to HEp-2 cells, and the predominant pattern was aggregative adherence (74.1%). In the biofilm assay, it was observed that 75% of isolates did not produce biofilm. These results lead us to conclude that some E. coli isolates from avian organic fertilizer could be pathogenic for humans.


Patients With Idiopathic Scoliosis Run an Increased Risk of Schizophrenia.
Retrospective cohort study. To investigate a possible linkage between idiopathic scoliosis (IS) and schizophrenia in an adolescent population. There is an interesting link between schizophrenia and idiopathic scoliosis: schizophrenia is a disturbance of mental equilibrium, and scoliosis of physical equilibrium, both are multifactorial, genetically determined, start at a young age, and brain development is thought to play a role. Furthermore, both may be presenting symptoms of the genetic disorder 22q11 deletion syndrome. This study poses the question whether these two poorly understood disorders are related. A retrospective cohort study was conducted and consisted of 3,702 Swedish adolescents, collected from the National Patient Register, that underwent inpatient care for IS during 1997-2015. These were matched by age, sex, and date of diagnosis to 370,200 controls, collected from Swedish population data, and then followed up in the National Patient Register to identify in- and outpatient care for schizophrenia diagnosis. Follow-up time was calculated from first IS diagnosis date until date of schizophrenia diagnosis or end of follow-up. Cox proportional regression analysis was performed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for being diagnosed with schizophrenia. Over a median follow-up time of 9.5 years, 0.7% of patients with IS developed schizophrenia versus 0.5% of controls (p = .04). The risk of schizophrenia was significantly higher in patients with IS (HR, 1.52; 95% CI, 1.03-2.23). Using only hospitalized schizophrenia as event, the prevalence for schizophrenia was 0.5% versus 0.3% (p ≤.01; HR, 1.83; 95% CI, 1.17-2.84). This study suggests that patients with IS have increased risk of schizophrenia. Dissatisfaction with one's physical appearance might lead to psychological distress and provoke mental illness in predisposed persons. Alternatively, these two disorders may share a common genetic background. Level 2B.


The evolution of pain management in the critically ill trauma patient: Emerging concepts from the global war on terrorism.
The evolution of military medical care to manage polytrauma, critically ill-wounded warriors from the greater war on terrorism has been accompanied by significant changes in the diagnosis, management, and modulation of acute and chronic trauma-related pain. A paradigm shift in pain management includes early treatment of pain at the point of injury and throughout the continuum of care with a combination of standard and novel therapeutic interventions. These concepts are important for all critical care providers because they translate to most critically ill patients, including those resulting from natural disasters. Previous authors have reported a high incidence of moderate to severe pain and poor analgesia in intensive care units associated with sleep disturbances, tachycardia, pulmonary complications, increased stress response with thromboembolic incidents, and immunosuppression, increased intensive care unit and hospital stays, and needless suffering. Although opioids have traditionally been the cornerstone of acute pain management, they have potential negative effects ranging from sedation, confusion, respiratory depression, nausea, ileus, constipation, tolerance, opioid-induced hyperalgesia as well as potential for immunosuppression. Alternatively, multimodal therapy is increasingly recognized as a critical pain management approach, especially when combined with early nutrition and ambulation, designed to improve functional recovery and decrease chronic pain conditions. Multimodal therapy encompasses a wide range of procedures and medications, including regional analgesia with continuous epidural or peripheral nerve block infusions, judicious opioids, acetaminophen, anti-inflammatory agents, anticonvulsants, ketamine, clonidine, mexiletine, antidepressants, and anxiolytics as options to treat or modulate pain at various sites of action. With a more aggressive acute pain management strategy, the military has decreased acute and chronic pain conditions, which may have application in the civilian sector as well.


[Establishment of an Iron-overloaded Mouse Model with Tuberculosis and Analysis of the Iron Metabolism Index].
Objective To establish a mouse model of exogenous iron overload combined with tuberculosis(TB). Methods C57BL/6N mice were divided into negative control, low-, medium-, and high-dose iron groups and received intraperitoneal injection of iron dextran at 0, 3.75, 7.50, and 15.00 mg/dose(3 times/week for 4 weeks), respectively.After 4 weeks, the organ morphology and body weight of the mice were evaluated.The content of serum iron, ferritin, transferrin, and transferrin receptor was determined by ELISA.Heart, liver, spleen, lung, kidney, and small intestine were analyzed for tissue iron content and iron deposition pathology.Mycobacterium tuberculosis(Mtb)standard strain H37Rv was injected via tail vein to infect the mice receiving moderate-dose iron to establish an iron-overloaded mouse model of active TB.HE staining and Mtb culture were employed to analyze tuberculous lesions and bacterial loads of lung, spleen and liver tissues. Results The weight gain percentages of mice in the negative control, low-, medium-, and high-dose iron groups were 25.47%, 25.22%, 24.74%, and 21.36%, respectively, which was significantly lower in the high-dose group than in the negative control(F=17.235, P=0.027), low-dose(F=15.206, P=0.031), and medium-dose(F=11.061, P=0.036)groups.Liver had the highest iron content, followed by spleen, kidney, and small intestine.The iron content in heart and lung tissues of the low-dose group had no significant difference compared with those of the negative control group(F=19.023, P=0.715;F=23.193, P=0.902).Serum iron and ferritin in the iron-overloaded mice increased in a dose-dependent manner, while transferrin and transferrin receptor had no significant changes.HE and Prussian blue staining showed that the iron-overloaded mice had different degrees of iron deposition in tissues and high-dose iron caused liver and kidney damage.The lung(F=23.227, P=0.017), spleen(F=19.023, P=0.021), and liver(F=17.392, P=0.009)of the iron-overloaded mice with TB had a significantly shorter time of bacterial culture than those of the TB-infected mice without iron overload.The lung(F=21.012, P=0.007), spleen(F=20.173, P=0.002), and liver(F=19.091, P=0.005)of the iron-overloaded mice with TB had significantly higher bacterial loads than those of the TB-infected mice without iron overload. Conclusions The exogenous iron-overloaded mouse model with similar symptoms to patients with clinical iron overload can be established by intraperitoneal injection of medium-dose(7.50 mg/dose, 3 times/week for 4 weeks)iron dextran.Mtb injection through the tail vein can help construct a mouse model of iron overload combined with active TB.


GaS0.5Te0.5 monolayer as an efficient water splitting photocatalyst.
Herein, two-dimensional materials for photocatalytic water splitting are drawing more attention due to the larger surface areas for photocatalytic reactions and shorter migration distances for photogenerated carriers. In this present study, we systematically investigated the fundamental electronic properties of GaS1-xTex monolayers (x = 0, 0.125, 0.25, 0.5, 0.75, 0.875, and 1) for water splitting based on density functional theory (DFT) using the HSE06 functional. The simulation of the defect formation energy under each experimental synthetic condition shows that the Te substitutional impurity in GaS can be relatively easily realized under Ga-rich conditions. Our results show that the GaS0.5Te0.5 monolayer is a direct band gap (2.09 eV) semiconductor, which is attributed to the elevation of Te px/py states at the Γ point by the strain effect. Moreover, the GaS0.5Te0.5 monolayer has appropriate band edge alignment with respect to the water redox potentials in both acidic and neutral environments. Additionally, the carrier effective mass of the GaS0.5Te0.5 monolayer along the direction of Γ → K is smaller than those of pristine GaS and GaTe monolayers, which can cause the carriers to quickly transfer from the photogenerated center to the surface of the photocatalyst. These results imply that the GaS0.5Te0.5 monolayer is a promising candidate as a visible-light water splitting photocatalyst, which should be properly synthesized and tested in further experimental investigations.


Reduced Cortico-Cortical Resting-State Connectivity in Sensory Systems is related to Bodily Pain in Juvenile Fibromyalgia.
Juvenile-onset fibromyalgia (JFM) is a paradigmatic chronic pain condition for which the underlying neurobiological substrates are poorly understood. This study examined for the first time data-driven resting-state functional connectivity (rsFC) alterations in 37 female adolescents with JFM compared with 43 healthy female adolescents, and identified associations with bodily pain. Whole-brain voxel-wise rsFC alterations were assessed using the intrinsic connectivity contrast, a measure of node centrality at each voxel, and seed-based analyses for interpretability. We studied the relationship between rsFC alterations in somatosensory systems and location and extension of bodily pain. Adolescents with JFM had voxel-wise rsFC reductions in the paracentral lobule (PCL)/primary somatosensory cortex (S1) (T=4.89, pFWE<.001) and left midcingulate cortex (T=4.67, pFWE=.043). Post-hoc analyses revealed reduced rsFC spanning major cortical sensory hubs (T's>4.4, pFWE's<.030). Cortico-cortical rsFC reductions within PCL/S1 in JFM occurred in locations innervated by bodily areas where the pain was most frequent (F=3.15; pFDR=.029) and predicted widespread pain (T's>4.4, pFWE's<.045). Conversely, adolescents with JFM had increases in PCL/S1-thalamus (T=4.75, pFWE=.046) and PCL/S1-anterior insula rsFC (T=5.13, pFWE=.039). Reduced cortico-cortical sensory integration involving PCL/S1 and spanning the sensory systems may underly critical pain sensory features in youth with JFM. Reduced sensory integration is paralleled by augmented crosstalk between sensory and affective/salience-processing regions, potentially indicating a shift towards more affectively colored sensory experiences to the detriment of specific sensory discrimination. This article is protected by copyright. All rights reserved.


Thromboembolic complications at the onset of nephrotic syndrome.
Nephrotic syndrome is associated with hypercoagulable states and a subsequent high risk of venous and rarely arterial thromboembolism. Although venous thromboembolism has been a recognised risk, prevalence of pulmonary embolism in patients with nephrotic syndrome is based on data from different case series. Here we report a 5 year old child with nephrotic syndrome who developed life threatening cerebral dural venous sinus thrombosis and pulmonary embolism within a month of disease onset.


A predictive model for survival after in-hospital cardiopulmonary arrest.
In-hospital cardiopulmonary resuscitation (CPR) has seen a steady increase in the application of technology and techniques since the introduction of closed cardiac massage in 1960. Despite this progress, there has not been a demonstrated improvement in survival rates after in-hospital cardiac arrest over the last 40 years. Identification of prognostic factors associated with survival after a resuscitation attempt can help physician decisions and patients' end-of-life choices in a pre-arrest situation. Using an Utstein-based template we analyzed 219 consecutive adult attempted resuscitations in a large urban teaching hospital over a 3-year period. The main outcome measures were survival to discharge, 1 and 3 months. Backwards stepwise logistic regression was used to select baseline variables that predict survival at discharge, 1 and 3 months. Survival rates at discharge, 1 and 3 months were 15.1, 13.3, and 11.5%. Meaningful neurological status (cerebral performance score of 1) at discharge was achieved in 61% of survivors. Independent predictors of survival were: higher body-mass index (BMI), presence of chronic renal insufficiency (CRI), respiratory arrest, ventricular tachycardia/fibrillation (VT/VF) as initial rhythm and arrest early during the hospital stay. A risk model based on these variables demonstrated a significant fit between predicted and observed survival at discharge with goodness of fit test P-value of 0.87. Survival after in-hospital cardiopulmonary arrest is poor and can be estimated by using clinical variables. If validated in a large prospective trial, this score could help physicians in attempting resuscitation, patients and families in making end-of-life decisions and hospitals in resource allocation.


Lexico-semantic structure in vocabulary and its links to lexical processing in toddlerhood and language outcomes at age three.
Toddlerhood is marked by advances in several lexico-semantic skills, including improvements in the size and structure of the lexicon and increased efficiency in lexical processing. This project seeks to delineate how early changes in vocabulary size and vocabulary structure support lexical processing (Experiment 1), and how these three skills together (vocabulary size, structure, and lexical processing) relate to later language outcomes at age 3 (Experiment 2). Experiment 1 explored how the size and semantic structure of toddlers' vocabulary from 18 to 24 months (N = 61) predicted performance on two lexical processing tasks (semantically related and semantically unrelated trials). Denser semantic connectivity (i.e., global level connectivity between near and far neighbors) positively associated with semantic interference during semantically related lexical processing, whereas denser category structure (i.e., lower-level connectivity between near neighbors) facilitated lexical processing in semantically unrelated trials. In Experiment 2, a subset of the same children (N = 49) returned at age 36 months and completed a comprehensive assessment of their language skills using the Clinical Evaluation of Language Fundamental, Preschool 2 (CELF-P2). Here, earlier measures of lexico-semantic connectivity and lexical processing best predicted age 3 language skill. The findings support accounts that early vocabulary structure and lexical processing skills promote continued growth in language. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Assessment of reproductive and developmental effects of graphene oxide on Japanese medaka (Oryzias latipes).
Due to its unique properties, graphene oxide (GO) has potential for biomedical and electronic applications, however environmental contamination including aquatic ecosystem is inevitable. Moreover, potential risks of GO in aquatic life are inadequately explored. Present study was designed to evaluate GO as an endocrine disrupting chemical (EDC) using the model Japanese medaka (Oryzias latipes). GO was injected intraperitoneally (25-200 μg/g) once to breeding pairs and continued pair breeding an additional 21 days. Eggs laid were analyzed for fecundity and the fertilized eggs were evaluated for developmental abnormalities including hatching. Histopathological evaluation of gonads, liver, and kidneys was made 21 days post-injection. LD50 was found to be sex-dependent. Fecundity tended to reduce in a dose-dependent manner during early post-injection days; however, the overall evaluation showed no significant difference. The hatchability of embryos was reduced significantly in the 200 μg/g group; edema (yolk and cardiovascular) and embryo-mortality remained unaltered. Histopathological assessment identified black particles, probably agglomerated GO, in the gonads of GO-treated fish. However, folliculogenesis in stromal compartments of ovary and the composition of germinal elements in testis remained almost unaltered. Moreover, granulosa and Leydig cells morphology did not indicate any significant EDC-related effects. Although liver and kidney histopathology did not show GO as an EDC, some GO-treated fish accumulated proteinaceous fluid in hepatic vessels and induced hyperplasia in interstitial lymphoid cells (HIL) located in kidneys. GO agglomerated in medaka gonads after 21-days post-injection. However, gonad histopathology including granulosa and Leydig cells alterations were associated with GO toxicity rather than EDC effects.


Animal Models of Uveal Melanoma.
Animal models are crucial for the study of tumorigenesis and therapies in oncology research. Though rare, uveal melanoma (UM) is the most common intraocular tumor and remains one of the most lethal cancers. Given the limitations of studying human UM cells in vitro, animal models have emerged as excellent platforms to investigate disease onset, progression, and metastasis. Since Greene's initial studies on hamster UM, researchers have dramatically improved the array of animal models. Animals with spontaneous tumors have largely been replaced by engrafted and genetically engineered models. Inoculation techniques continue to be refined and expanded. Newer methods for directed mutagenesis have formed transgenic models to reliably study primary tumorigenesis. Human UM cell lines have been used to generate rapidly growing xenografts. Most recently, patient-derived xenografts have emerged as models that closely mimic the behavior of human UM. Separate animal models to study metastatic UM have also been established. Despite the advancements, the prognosis has only recently improved for UM patients, especially in patients with metastases. There is a need to identify and evaluate new preclinical models. To accomplish this goal, it is important to understand the origin, methods, advantages, and disadvantages of current animal models. In this review, the authors present current and historic animal models for the experimental study of UM. The strengths and shortcomings of each model are discussed and potential future directions are explored.


Flow cytometry vs. Ki67 labelling index in breast cancer: a prospective evaluation of 181 cases.
Excessive proliferation is one of the first steps in oncogenic activation and one of the most important biological features defining the aggressiveness of tumors. Quantifying the proportion of tumor cells in S-phase by means of flow cytometry has shown, in the past, to be useful for defining high-risk subgroups in breast cancer. Several antigens closely associated with proliferation are also detectable by means of immunohistochemistry, offering in theory an easy to perform and cheap alternative to flow cytometry for measuring proliferation. To test this hypothesis, we compared both methods prospectively in a series of breast cancers. We studied the proliferation rate of 181 breast cancers (152 ductal infiltrating, 17 lobular infiltrating, 12 other histological varieties), operated upon at our institution, by means of flow cytometry and the Ki67 labelling index, using the MIBI antibody. Ploidy (expressed as DNA content or DNA-index), S-phase fraction and the Ki67 labelling index were the variables of the study. The S-phase fraction was considered separately for diploid and aneuploid tumors, following the 1992 Maine Consensus guidelines and was judged abnormally elevated if higher than the 75th percentile for each group. The Ki67 labelling index was expressed as percent positive tumor cells, positive cells being those showing specific nuclear staining. DNA-ploidy and the Ki67 labelling index could be evaluated in all tumors. Of the total, 96 (53%) were diploid and 85 (47%) aneuploid. S-phase fraction could be measured in 172 out of the 181 tumors (95%). The 75th percentile cut-offs for diploid and aneuploid tumors were 9.9% and 15.8%, respectively. We found a significant correlation beween rising DNA content and increasing Ki67 index (r = 0.18; p = 0.022), as well as between the percentage of cells in S-phase of the whole tumor population and Ki67 (r = 0.22; p = 0.0055). A Ki67 cut-off of 50% or higher identified most aneuploid tumors, or a small group of diploid ones with a high S-phase fraction (specificity = 96.7%; positive predictive value 92.5%), however at the price of a very low sensitivity (62.6%). This was due to the presence of many aneuploid tumors with a low S-phase fraction. The Ki67 labelling index and S-phase fraction are significantly correlated. However, flow cytometry provides additional indirect information on tumor aggressiveness associated with DNA-ploidy. Further studies are needed to determine whether Ki67 alone is sufficient as a routinely applicable method.


When are abrupt onsets found efficiently in complex visual search? Evidence from multielement asynchronous dynamic search.
Previous work has found that search principles derived from simple visual search tasks do not necessarily apply to more complex search tasks. Using a Multielement Asynchronous Dynamic (MAD) visual search task, in which high numbers of stimuli could either be moving, stationary, and/or changing in luminance, Kunar and Watson (M. A Kunar & D. G. Watson, 2011, Visual search in a Multi-element Asynchronous Dynamic (MAD) world, Journal of Experimental Psychology: Human Perception and Performance, Vol 37, pp. 1017-1031) found that, unlike previous work, participants missed a higher number of targets with search for moving items worse than for static items and that there was no benefit for finding targets that showed a luminance onset. In the present research, we investigated why luminance onsets do not capture attention and whether luminance onsets can ever capture attention in MAD search. Experiment 1 investigated whether blinking stimuli, which abruptly offset for 100 ms before reonsetting--conditions known to produce attentional capture in simpler visual search tasks--captured attention in MAD search, and Experiments 2-5 investigated whether giving participants advance knowledge and preexposure to the blinking cues produced efficient search for blinking targets. Experiments 6-9 investigated whether unique luminance onsets, unique motion, or unique stationary items captured attention. The results found that luminance onsets captured attention in MAD search only when they were unique, consistent with a top-down unique feature hypothesis.


MRI differential diagnosis: bone metastases versus bone lesions due to malignant hemopathies.
Bone determinations are usually the first sign of disseminated cancers, whether is a hematological malignancy or other type of neoplasia. The aim of this paper is the possibility of differentiating the bone lesions from hematological malignancies by other malignancies that give bone metastases for the purpose to guide the clinician concerning causality of bone lesions. The research involved a retrospective study, which included 309 cases that were investigated by magnetic resonance imaging (MRI) at a segment of the spine, between 2010 and 2014, from which 137 were diagnosed with a form of hematological neoplasia, and the remaining had another form of cancer. Imaging aspect differs in these two study groups. Bone determinations due to malignant hemopathies (MH) were in general hypointense on T1-weighted sequences, iso- or hyperintense on T2-weighted sequences. On the other hand, bone metastases were hypo- or isointense on T1-weighted sequences, and had no specific signal intensity on T2-weighted sequences. In post-contrast images, all lesions showed contrast enhancement, with some differences. In terms of imagistic aspect, there are certain characteristics that can make a clear differentiation between bone determinations due to MH from the bone metastases, and some are found in the majority of the cases studied.


Detection of IgM and IgG against hepatitis E virus in serum and meat juice samples from pigs at slaughter in Bavaria, Germany.
Hepatitis E virus (HEV) is an emerging foodborne pathogen with domestic and wild pigs (and likely other species such as deer or rabbits) recognized as reservoir. Pathogenesis in pigs usually leads to an asymptomatic course of disease. Since there is no enzyme-linked immunosorbent assay (ELISA) kit for the detection of anti-HEV antibodies in pigs commercially available, the objective of this study was to assess the seroprevalence in fattening pigs at slaughter and at herd level using a newly developed ELISA based on genotype (GT) 1 and GT 3 in Bavaria, Germany. Based on 516 serum and 198 meat juice samples collected from different herds at four different Bavarian slaughterhouses, the overall seroprevalence of anti-HEV IgG in serum and meat juice samples was 68.6% and 67.6%, respectively. Analyzing the serum for the presence of anti-HEV IgM, 36/516 (7%) were positive for anti-HEV IgM. At herd level, most of the herds were seropositive for anti-HEV antibodies. The present study shows that HEV is widespread among the Bavarian pig population and that some pigs might test positive for anti-HEV IgM even at the age of slaughter. Also, meat juice serves as an equivalent matrix to serum to test for anti-HEV antibodies in pigs.


Covalent immobilization of lipase in organic solvents.
Lipase from Rhizopus sp. has been immobilized covalently on tresyl activated silica. Three different coupling media were evaluated: aqueous buffer, n-hexane, and a microemulsion based on n-hexane, aqueous buffer, and the nonionic surfactant triethylene glycol monododecyl ether. In addition, coupling via a very long, hydrophilic spacer arm, polyethylene glycol 1500 (PEG 1500), was compared with attachment to the silica via a short silane bridge only. The enzyme preparations were tested in hydrolysis and transesterification reactions. In the hydrolysis no marked differences in activity were found between the coupling media used. In the transesterification, on the other hand, the choice of immobilization medium had a very large effect on lipase activity, the preparation from microemulsion being the most active one. The use of the hydrophilic spacer had a large effect on activity in the hydrolysis reaction. Whereas direct coupling gave an activity of immobilized lipase of 26-34% of that of free enzyme, depending on the reaction medium, lipase bound via the spacer exhibited 56-67% activity. The latter values are considerably higher than previously reported in the literature for covalently immobilized lipase. The hydrophilic spacer had no effect on enzyme activity in the transesterification, however, a fact which is attributed to the hydrophobic medium of this reaction. The spacer is incompatible with the reaction medium and will, therefore, adsorb on the particles rather than stretch out into the bulk phase. The stability of the bound lipase was extremely good, no loss in activity being observed after a period of three weeks in aqueous solution of 37 degrees C.


Atomic Structure-Free Representation of Active Motifs for Expedited Catalyst Discovery.
To discover new catalysts using density functional theory (DFT) calculations, binding energies of reaction intermediates are considered as descriptors to predict catalytic activities. Recently, machine learning methods have been developed to reduce the number of computationally intensive DFT calculations for a high-throughput screening. These methods require several steps such as bulk structure optimization, surface structure modeling, and active site identification, which could be time-consuming as the number of new candidate materials increases. To bypass these processes, in this work, we report an atomic structure-free representation of active motifs to predict binding energies. We identify binding site atoms and their nearest neighboring atoms positioned in the same layer and the sublayer, and their atomic properties are collected to construct fingerprints. Our method enabled a quicker training (200-400 s using CPU) compared to the previous deep-learning models and predicted CO and H binding energies with mean absolute errors (MAEs) of 0.120 and 0.105 eV, respectively. Our method is also capable of creating all possible active motifs without any DFT calculations and predicting their binding energies using the trained model. The predicted binding energy distributions can suggest promising candidates to accelerate catalyst discovery.


[Oxidative stress and autophagy in SK-N-SH cells induced by manganese chloride or 1-methyl-4-phenylpyridinium: a comparative analysis].
Objective: To investigate the effect of manganese chloride (MnCl(2)) or 1-methyl-4-phenylpyridinium (MPP (+)) on oxidative stress and autophagy in human neuroblastomaSK-N-SH cells and the mechanism of the neurotoxicity of manganese. Methods: SK-N-SH cells were treated with MnCl(2) or MPP(+) at doses of 0.062 5, 0.125, 0.25, 0.5, 1.0, and 2.0 mmol/L for 24 hours, and MTT assay was used to measure cell viability. The cells weretreated with MnCl(2) or MPP(+) at doses of 0.125, 0.25, and 0.5 mmol/L for 24 hours, and flow cytometry was used to measure the content of reactive oxygen species (ROS) in cells, a laser scanning confocal microscope was used to observe autophagosome in cells, and Western blot was used to measure the expression of autophagy-related proteins P62 and LC3-II/LC3-I. Results: Compared with the control group, the 0.0625-2.0 mmol/L MnCl(2) and 0.125-2.0 mmol/L MPP (+) treatment groups had significant reductions in the viability of SK-N-SH cells, and the 0.25-2.0 mmol/L MnCl(2) treatment groups had significantly lower viability than the groups treated with the same doses of MPP(+) (all P<0.05) . Compared with the control group, the 0.125-0.25 mmol/L MnCl(2) and 0.125-0.5 mmol/L MPP(+) treatment groups had significant increases in the content of ROS, and the 0.25-0.5 mmol/L MPP(+) treatment groups had significantly higher content of ROS than the groups treated with the same doses of MnCl(2) (all P<0.05) . Compared with the control group, the 0.25-0.5 mmol/L MnCl(2) andMPP(+) treatment groups had significant increases in autophagy-related proteins LC3-II/LC3-I and significant reductions in P62 expression; the 0.125-0.5 mmol/L MPP(+) treatment groups had significantly higher LC3-II/LC3-I than the groups treated with the same doses of MnCl(2), and the 0.125 and 0.25 mmol/L MPP (+) treatment groups had significantly lower P62 expression than the groups treated with the same doses of MnCl(2) (all P<0.05) . Conclusion: Both MnCl(2) and MPP(+) can induce oxidative stress and autophagy in SK-N-SH cells, and MPP(+) has a significantly greater inductive effect on autophagy of SK-N-SH cells than MnCl(2).


Interaction of picolinamide fungicide primary metabolites UK-2A and CAS-649 with the cytochrome bc1 complex Qi site: mutation effects and modelling in Saccharomyces cerevisiae.
Fenpicoxamid and florylpicoxamid are picolinamide fungicides targeting the Qi site of the cytochrome bc1 complex, via their primary metabolites UK-2A and CAS-649, respectively. We explore binding interactions and resistance mechanisms for picolinamides, antimycin A and ilicicolin H in yeast by testing effects of cytochrome b amino acid changes on fungicide sensitivity and interpreting results using molecular docking. Effects of amino acid changes on sensitivity to UK-2A and CAS-649 were similar, with highest resistance associated with exchanges involving G37 and substitutions N31K and L198F. These changes, as well as K228M, also affected antimycin A, while ilicicolin H was affected by changes at G37 and L198, as well as Q22E. N31 substitution patterns suggest that a lysine at position 31 introduces an electrostatic interaction with neighbouring D229, causing disruption of a key salt-bridge interaction with picolinamides. Changes involving G37 and L198 imply resistance primarily through steric interference. G37 changes also showed differences between CAS-649 and UK-2A or antimycin A with respect to branched versus unbranched amino acids. N31K and substitution of G37 by large amino acids reduced growth rate substantially while L198 substitutions showed little effect on growth. Binding of UK-2A and CAS-649 at the Qi site involves similar interactions such that general cross-resistance between fenpicoxamid and florylpicoxamid is anticipated in target pathogens. Some resistance mutations reduced growth rate and could carry a fitness penalty in pathogens. However, certain changes involving G37 and L198 carry little or no growth penalty and may pose the greatest risk for resistance development in the field. © 2022 Society of Chemical Industry.


Dietary nitrate-induced increases in human muscle power: high versus low responders.
Maximal neuromuscular power is an important determinant of athletic performance and also quality of life, independence, and perhaps even mortality in patient populations. We have shown that dietary nitrate (NO3- ), a source of nitric oxide (NO), improves muscle power in some, but not all, subjects. The present investigation was designed to identify factors contributing to this interindividual variability. Healthy men (n = 13) and women (n = 7) 22-79 year of age and weighing 52.1-114.9 kg were studied using a randomized, double-blind, placebo-controlled, crossover design. Subjects were tested 2 h after ingesting beetroot juice (BRJ) either containing or devoid of 12.3 ± 0.8 mmol of NO3- . Plasma NO3- and nitrite (NO2- ) were measured as indicators of NO bioavailability and maximal knee extensor speed (Vmax ), power (Pmax ), and fatigability were determined via isokinetic dynamometry. On average, dietary NO3- increased (P < 0.05) Pmax by 4.4 ± 8.1%. Individual changes, however, ranged from -9.6 to +26.8%. This interindividual variability was not significantly correlated with age, body mass (inverse of NO3- dose per kg), body mass index (surrogate for body composition) or placebo trial Vmax or fatigue index (in vivo indicators of muscle fiber type distribution). In contrast, the relative increase in Pmax was significantly correlated (r = 0.60; P < 0.01) with the relative increase in plasma NO2- concentration. In multivariable analysis female sex also tended (P = 0.08) to be associated with a greater increase in Pmax. We conclude that the magnitude of the dietary NO3- -induced increase in muscle power is dependent upon the magnitude of the resulting increase in plasma NO2- and possibly female sex.


[The results of recent research in neurocutaneous syndromes].
Identification of NF1, TSC2 and TSC1 genes has enabled us to focus on their function and regulation. Evidence suggests that these genes are tumor suppressor genes. Malignant tissues in NF1 and hamartomatous tissues in TSC show "loss of heterozygosity" in NF1 and TSC1, 2 genes, respectively. In addition, in the Eker rat with hereditary renal carcinoma, a mutation in the TSC2 gene has been identified. In this review I mentioned briefly several issues to be clarified in the near future.


Zero CD4 count: a case of discordant CD4 response in a patient with well suppressed viral load.
Human immunodeficiency virus (HIV) positive patients continue to have raise in CD4 cell for several years after initiation of anti-retroviral therapy (ART). The discordant response of static or fall in CD4 cells in presence of well-suppressed viral load is an unusual finding. In this communication, we present a case report of an HIV patient in whom the repeated CD4 enumerations consistently showed zero/nil CD4 counts before and after the start of ART in spite of maximum viral suppression.


Reactive Granulomatous Dermatitis in a Child with Acute Lymphoblastic Leukemia.
Reactive granulomatous dermatitis (RGD) is an umbrella term to describe a reaction pattern characterized by skin-colored to erythematous papules, plaques, and nodules although other morphologies have been described. RGD has rarely been reported in children, and in this report, we present the case of a 3-year-old girl with acute lymphoblastic leukemia (ALL) who presented with firm, tender nodules, and ulcerated plaques on her extremities. Histopathologic examination showed foci of dense granulomatous inflammatory infiltrates composed of histiocytes, neutrophils, and multinucleate giant cells. The constellation of clinical symptoms, negative infectious workup, and histopathology support the diagnosis of RGD.


[Effect of obsidan on the systemic hemodynamics of dogs in ontogeny].
Investigations on dogs of different age have brought evidence that intravenous administration of 2 mg/kg of obsidan (propranolol hydrochloride) causes in 18-22-day old puppies a fall of arterial pressure due to a reduced cardiac ejection with little changing total vascular peripheral resistance. The frequency of the rhythm and conduction in the heart are slowed down. In dogs aged 3-5 years the arterial pressure remains unchanged, since the diminution of the cardiac output is attended by a greater vascular resistance.


Refractory generalized edema: an infrequent complication of long-term pergolide treatment for Parkinson disease.
Generalized edema is the result of increased interstitial fluid volume due to altered Starling forces or capillary endothelial damage. The authors present a patient with severe Parkinson disease who presented with increasing dyspnea, bilateral pleural effusion, and peripheral edema that was refractory to diuretics. Common causes of the severe loss of fluid into the extravascular space were ruled out and pergolide was suspected. Upon discontinuation of pergolide therapy, all signs of fluid retention resolved. This report emphasizes that pergolide should be considered a cause of otherwise unexplained generalized edema in patients with Parkinson disease on this therapy.


Degradation of collagen in lung tissue slices exposed to hyperoxia.
Exposure of animals to oxidant gases produces a mild emphysema, and O2-derived free radicals are capable of degrading connective tissues in vitro. It is postulated that degradation of connective tissue by O2-derived free radicals leads to emphysema in these models. To determine whether exposure of lung tissue slices to an oxidant gas results in degradation of collagen and to investigate factors mediating this degradation, we exposed lung tissue slices from normal rats to hyperoxia (95% O2, 5% CO2) and measured hydroxyproline release into the medium. After a 4-h exposure, the hydroxyproline released was 5.3 +/- 0.2 micrograms/g lung tissue (n = 10) in normoxia and 8.1 +/- 0.6 micrograms/g tissue (n = 13) in hyperoxia (p less than 0.05), suggesting degradation of collagen. The addition of 0.1% trypsin to the initial incubation medium caused a synergistic increase in hydroxyproline release from O2-exposed slices: normoxia/trypsin, 46.2 +/- 3.6 micrograms/g tissue (n = 10); hyperoxia/trypsin, 61.4 +/- 3.6 micrograms/g tissue (n = 11) (p less than 0.05). The addition of proteinase inhibitors completely suppressed the O2-induced release of hydroxyproline, suggesting that proteolytic enzymes are involved in hyperoxia-mediated degradation of lung collagen.


Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea.
Hearing relies on the transmission of auditory information from sensory hair cells (HCs) to the brain through the auditory nerve. This relay of information requires HCs to be innervated by spiral ganglion neurons (SGNs) in an exclusive manner and SGNs to be ensheathed by myelinating and non-myelinating glial cells. In the developing auditory nerve, mistargeted SGN axons are retracted or pruned and excessive cells are cleared in a process referred to as nerve refinement. Whether auditory glial cells are eliminated during auditory nerve refinement is unknown. Using early postnatal mice of either sex, we show that glial cell numbers decrease after the first postnatal week, corresponding temporally with nerve refinement in the developing auditory nerve. Additionally, expression of immune-related genes was upregulated and macrophage numbers increase in a manner coinciding with the reduction of glial cell numbers. Transient depletion of macrophages during early auditory nerve development, using transgenic CD11bDTR/EGFP mice, resulted in the appearance of excessive glial cells. Macrophage depletion caused abnormalities in myelin formation and transient edema of the stria vascularis. Macrophage-depleted mice also showed auditory function impairment that partially recovered in adulthood. These findings demonstrate that macrophages contribute to the regulation of glial cell number during postnatal development of the cochlea and that glial cells play a critical role in hearing onset and auditory nerve maturation.


Estimation of human fetal-placental unit metabolic rate by application of the Bohr principle.
The Bohr Principle via continuous indirect calorimetry was used to estimate human fetal-placental unit metabolic rate in 12 normal women undergoing elective caesarean section under continuous lumbar epidural anaesthesia. Maternal oxygen consumption decreased after umbilical cord clamping and after placental removal. Fetal-placental unit oxygen consumption was 10.7 +/- 1.3 ml/min per kg (mean +/- SEM). Fetal oxygen consumption was 6.8 +/- 1.4 ml/min per kg. Placental oxygen consumption was 37 +/- 12 ml/min per kg. Fetal-placental unit carbon dioxide production was 9.2 +/- 1.2 ml/min per kg. These mean values agree favourably with measurements of uterine and fetal metabolism from other mammalian species. Maternal minute ventilation decreased with removal of the fetal-placental unit, and this decrease was found to be linearly related to the fetal-placental unit carbon dioxide production.


Staphylococcus aureus growth and enterotoxin production during the manufacture of uncooked, semihard cheese from cows' raw milk.
Staphylococcus aureus growth and enterotoxin production during the manufacture of model Saint-Nectaire, Registered Designation of Origin Saint-Nectaire, and Registered Designation of Origin Salers cheeses, three types of uncooked, semihard, raw milk cheese, were investigated. Coagulase-positive staphylococci (SC+) grew rapidly during the first 6 h. Between 6 and 24 h, counts increased by less than 0.5 log CFU/ml. Raw milk counts ranged from undetectable (<10 CFU/ml) to 3.03 log CFU/ml. Maximal levels reached in cheese on day 1 ranged from 2.82 to 6.84 log CFU/g. The level of SC+ after 24 h was mainly influenced by the milk baseline SC+ level (correlation coefficient, r > 0.80) but pH at 6 h influenced the SC+ growth observed between 6 and 24 h (r > 0.70). Thus, the initial level of SC+ in raw milk should be maintained below 100 CFU/ml and best below 40 CFU/ml. To limit growth, acidification should be managed to obtain pH values around or below 5.8 at 6 h in Saint-Nectaire cheeses and around or below 6.3 at 6 h in Salers cheeses. Enterotoxins were only detected in two Salers cheeses whose SC+ counts on day 1 were 5.55 log CFU/g and 5.06 log CFU/g, respectively, and whose pH values at 6 h were high (approximately 6.6 and 6.5, respectively).


[Metalloproteases, vascular remodeling and atherothrombotic syndromes].
Defects in the synthesis and breakdown of the extracellular matrix (ECM) are now seen as key processes in the development of atherosclerosis and its thrombotic complications. Correlations have been observed between circulating levels of ECM biomarkers and the clinical manifestations of and risk factors for atherosclerosis. Several matrix metalloproteinases (MMPs), endopeptidases that can degrade the ECM, such as MMP-9 and MMP-10, play important roles in the pathophysiology of atherothrombosis and contribute to the expansion of abdominal aortic aneurysms. Moreover, they may also be useful biomarkers of atherosclerotic risk and serve as predictors of coronary and cerebrovascular disease recurrence. Although at present the effect of tissue inhibitors of MMPs (TIMPs) on cardiovascular disease prognosis is still uncertain, the ECM could be a promising therapeutic target in atherothrombotic disease, and several MMP inhibitors are currently undergoing clinical trials.


The regulated synthesis of versican, decorin, and biglycan: extracellular matrix proteoglycans that influence cellular phenotype.
The principal extracellular matrix (ECM) chondroitin/dermatan sulfate proteoglycans include members of two gene families--the large aggregating chondroitin sulfate proteoglycans (lecticans) and the small leucine-rich proteoglycans (SLRPs). These families of proteoglycans are widely distributed within the interstitial matrix, where they are known to bind a variety of both soluble and insoluble ligands. Extensive structural studies and data concerning the synthesis of these proteoglycans have been published over the last few years. This review focuses on the regulation of the expression of the lectican, versican, and the SLRPs--decorin and biglycan, as well--studied and widely distributed examples of these families of ECM proteoglycans. In addition, the effects of these proteoglycans on the formation of the ECM and the response of cells to growth factors and cytokines are examined as mechanisms by which versican, decorin and biglycan, both directly and indirectly influence cellular proliferation, migration, and phenotype.


[Strategies aiming to control hyperphosphatemia in chronic kidney disease].
Chronic kidney disease is known to be associated with phosphate retention. The mechanisms are complex and the early increase in serum phosphate levels in chronic kidney disease is not strictly related to the dietary phosphate load or to the degree of phosphate retention. It also implicates the activity of intestinal sodium-phosphate cotransporters, the degree of bone turnover and the retention and/or phosphate release from the skeleton, and the feedback mechanisms regulating the phosphaturia. Indeed, the increase in serum phosphate levels is only a reflection of underlying complex mechanisms, and many important factors play a role including parathyroid hormone, vitamin D, fibroblast growth factor 23 (FGF23), and others. Hyperphosphatemia increases the risk of cardiovascular morbidity and mortality in chronic kidney disease as well as in subjects with normal renal function. Oral phosphate binders are prescribed in patients with chronic kidney disease and in those treated by dialysis, to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational studies, they have been shown to decrease all-cause and cardiovascular mortality risk. However, different problems have been associated with currently available phosphate binders including the induction of a positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. The aim of this article is to provide an update review of the pathophysiological mechanisms leading and maintaining elevated serum phosphate levels in patients with chronic kidney disease and patients in dialysis, and the educational, nutritional, and therapeutic strategies that can be undertaken to control the hyperphosphatemia.


Denosumab in Giant Cell Rich Tumors of Bone: An Open-Label Multicenter Phase II Study.
Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab as GCTB. The primary objective of this study was to determine the efficacy of denosumab in patients with GCRTB that have recurred or require morbid surgery. In this open-label, multicenter, phase II trial, patients with GCRTB were included (June 2018-March 2020). Recruitment was stopped because of low accrual. Patients received denosumab (120 mg) subcutaneously (SC) on day 1 of every 4-week cycle with a loading dose of 120 mg SC on days 8 and 15. Three patients were enrolled. One withdrew consent before start of study. The remaining patients had central giant cell granuloma of the jawbone (CGCG). Median treatment duration was 15 cycles (range 12-18). In both subjects, improvement in ossification of lesions was seen. Median follow-up was 28.5 months (range 20-37). One patient developed a recurrence for which surgery was performed. Due to critical emerging real-world data of denosumab in GCRTBs, the study was prematurely stopped and not supportive of use of denosumab for this indication. (ClinicalTrials.gov Identifier: NCT03605199).


Direct Diagnostic Tests for Lyme Disease.
Borrelia burgdorferi was discovered to be the cause of Lyme disease in 1983, leading to seroassays. The 1994 serodiagnostic testing guidelines predated a full understanding of key B. burgdorferi antigens and have a number of shortcomings. These serologic tests cannot distinguish active infection, past infection, or reinfection. Reliable direct-detection methods for active B. burgdorferi infection have been lacking in the past but are needed and appear achievable. New approaches have effectively been applied to other emerging infections and show promise in direct detection of B. burgdorferi infections.


Factors and cost associated with atopic dermatitis in Nevada.
Objectives: Atopic dermatitis, or eczema, is an inflammatory illness that impacts individuals of all ages. The cost of treating AD and the impact on the quality of life have not been well documented in the state of Nevada. This study seeks to fill this gap by identifying factors that impact the cost of AD in the state utilizing clinical and patient demographics. Methods: ANOVA with Bonferroni adjustment was performed using a large hospital utilization database to examine the cost of AD in the state of Nevada across all hospital settings. Results: Several significant factors were associated with the overall cost of AD in Nevada, including hospital setting type (outpatient vs. inpatient), physician type, region, AD diagnosis level, and age (p < 0.05). Stratified analysis was performed by setting type. In the inpatient setting, region, diagnosis level, and records with age listed between 0 and 5 years remained significant (p < 0.05). In the outpatient setting, physician type, region, and African American race remained significant (p < 0.05). Conclusions: Data from this study indicate that the AD cost burden is dependent on both demographic and clinical factors in the state of Nevada. These differences suggest that patients with AD may encounter higher costs depending on age, race, and clinical factors.


Thrombin activatable fibrinolysis inhibitor (TAFI)--how does thrombin regulate fibrinolysis?
The thrombin-catalysed conversion of plasma fibrinogen into fibrin and the development of an insoluble fibrin clot are the final steps of the coagulation cascade during haemostasis. A delicate balance between coagulation and fibrinolysis determines the stability of the fibrin clot. Thrombin plays a central role in this process, it not only forms the clot but it is also involved in stabilizing the clot by activating thrombin activatable fibrinolysis inhibitor (TAFI). Activated TAFI protects the fibrin clot against lysis. Here we will discuss the mechanisms for regulation of fibrinolysis by thrombin. The role of the coagulation system for the generation of thrombin and for the activation of TAFI implies that defects in thrombin generation will directly affect the protection of clots against lysis. Thus, defects in activation of TAFI might contribute to the severity of bleeding disorders. Vice versa an increased activation of TAFI due to an increased rate of thrombin generation might lead to thrombotic disorders. Specific inhibitors of activated TAFI or inhibitors that interfere with the generation of thrombin might provide novel therapeutic strategies for thrombolytic therapy. Besides having a role in the regulation of fibrinolysis, TAFI may also have an important function in the regulation of inflammation, wound healing and blood pressure.


Fast transient analysis and first-stage collision-induced dissociation with the flowing atmospheric-pressure afterglow ionization source to improve analyte detection and identification.
The recent development of ambient desorption/ionization mass spectrometry (ADI-MS) has enabled fast, simple analysis of many different sample types. The ADI-MS sources have numerous advantages, including little or no required sample pre-treatment, simple mass spectra, and direct analysis of solids and liquids. However, problems of competitive ionization and limited fragmentation require sample-constituent separation, high mass accuracy, and/or tandem mass spectrometry (MS/MS) to detect, identify, and quantify unknown analytes. To maintain the inherent high throughput of ADI-MS, it is essential for the ion source/mass analyzer combination to measure fast transient signals and provide structural information. In the current study, the flowing atmospheric-pressure afterglow (FAPA) ionization source is coupled with a time-of-flight mass spectrometer (TOF-MS) to analyze fast transient signals (<500 ms FWHM). It was found that gas chromatography (GC) coupled with the FAPA source resulted in a reproducible (<5% RSD) and sensitive (detection limits of <6 fmol for a mixture of herbicides) system with analysis times of ca. 5 min. Introducing analytes to the FAPA in a transient was also shown to significantly reduce matrix effects caused by competitive ionization by minimizing the number and amount of constituents introduced into the ionization source. Additionally, MS/MS with FAPA-TOF-MS, enabling analyte identification, was performed via first-stage collision-induced dissociation (CID). Lastly, molecular and structural information was obtained across a fast transient peak by modulating the conditions that caused the first-stage CID.


Castration in the standing horse combining laparoscopic and conventional techniques.
Standing laparoscopic castration without orchidectomy has been shown to be a reliable method of castration in animals with abdominal cryptorchidism, but it cannot be recommended as a method of castration in those with inguinal cryptorchidism or normal males. An alternative laparoscopic method for the castration of horses with descended testes was developed. To report the results of laparoscopy-assisted abdominal transection of the spermatic cord and a modified open method in the standing horse for castration of descended testes in unilateral abdominal cryptorchids. Descriptive case series. Fifteen unilateral abdominal cryptorchids were castrated laparoscopically by performing intra-abdominal ligation of both spermatic cords. The spermatic cord of the cryptorchid testis was not transected. After intra-abdominal transection of the spermatic cord of the descended testis, the testis was removed by an open castration technique in the standing horse. Data collected included time taken to perform the surgical procedure, surgical complications and post-operative recovery. Abdominal testes were located on the right side in eight horses and on the left in seven. The surgical procedure was easy to perform and few intra- or post-operative complications were seen. Pulse and respiration rates and rectal temperatures remained within normal limits during the evaluation period in all but one animal, which displayed transient pyrexia. The scrotal and laparoscopic incisional wounds healed well without any signs of swelling or exudate. In one Warmblood, there was prolapse of subcutaneous tissue the day after surgery, which retracted in 3 days. The owners were contacted by telephone at 2-3 months after discharge. Post-operative recovery had been uneventful in all horses. This study included a small number of cases in which all surgeries were performed by or under the supervision of the same surgeon. Follow-up was limited to telephone reports from owners. A laparoscopic technique that is combined with an open scrotal incision to remove the descended testis in the standing horse was developed and shown to be a safe and reliable option for the castration of unilateral abdominal cryptorchids.


Addition of lipids to parenteral nutrition does not cause fungal infections.
Parenteral nutrition (PN) that includes lipid emulsion is considered to increase both bacterial and fungal central venous catheter-related bloodstream infections. This concept is based on several erroneous metrics: Reports in age-old literature at a time when preparing PN admixtures lacked stringent quality control, when its infusion, the techniques of insertion, maintenance of vascular access devices, and delivery systems were not well identified or enforced. Additionally, concepts of glucohomeostasis were different and higher glucose levels were accepted. We provide updated information with supporting literature to show that associating PN with lipids with an increase in bloodstream infections is not justified.


Pneumatosis intestinalis related to cytomegalo-virus infection--a new etiology?
Five patients who developed pneumatosis intestinalis in the course of a cytomegalo virus (CMV) infection after cadaveric kidney transplantation are described. Based on the fact that CMV is known to cause intestinal ulcers, we postulate a causal relationship between CMV and pneumatosis intestinalis.


The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function.
Although the BRCA1 tumor suppressor has been implicated in many cellular processes, the biochemical mechanisms by which it influences these diverse pathways are poorly understood. The only known enzymatic function of BRCA1 is the E3 ubiquitin ligase activity mediated by its highly conserved RING domain. In vivo, BRCA1 associates with the BARD1 polypeptide to form a heterodimeric BRCA1/BARD1 complex that catalyzes autoubiquitination of BRCA1 and trans ubiquitination of other protein substrates. In most cases, BRCA1-dependent ubiquitination generates polyubiquitin chains bearing an unconventional K6 linkage that does not appear to target proteins for proteasomal degradation. Since ubiquitin-dependent processes are usually mediated by cellular receptors with ubiquitin-binding motifs, we screened for proteins that specifically bind autoubiquitinated BRCA1. Here we report that the UBXN1 polypeptide, which contains a ubiquitin-associated (UBA) motif, recognizes autoubiquitinated BRCA1. This occurs through a bipartite interaction in which the UBA domain of UBXN1 binds K6-linked polyubiquitin chains conjugated to BRCA1 while the C-terminal sequences of UBXN1 bind the BRCA1/BARD1 heterodimer in a ubiquitin-independent fashion. Significantly, the E3 ligase activity of BRCA1/BARD1 is dramatically reduced in the presence of UBXN1, suggesting that UBXN1 regulates the enzymatic function of BRCA1 in a manner that is dependent on its ubiquitination status.


Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".
Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.


A Data-Driven Diagnostic Framework for Wind Turbine Structures: A Holistic Approach.
The complex dynamics of operational wind turbine (WT) structures challenges the applicability of existing structural health monitoring (SHM) strategies for condition assessment. At the center of Europe's renewable energy strategic planning, WT systems call for implementation of strategies that may describe the WT behavior in its complete operational spectrum. The framework proposed in this paper relies on the symbiotic treatment of acting environmental/operational variables and the monitored vibration response of the structure. The approach aims at accurate simulation of the temporal variability characterizing the WT dynamics, and subsequently at the tracking of the evolution of this variability in a longer-term horizon. The bi-component analysis tool is applied on long-term data, collected as part of continuous monitoring campaigns on two actual operating WT structures located in different sites in Germany. The obtained data-driven structural models verify the potential of the proposed strategy for development of an automated SHM diagnostic tool.


Noise-driven cellular heterogeneity in circadian periodicity.
Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.


Diffuse Extent of Peritubular Capillaritis in Late Antibody-Mediated Rejection: Associations With Levels of Donor-Specific Antibodies and Chronic Allograft Injury.
Recently, diffuse peritubular capillaritis (ptc) has been suggested to independently predict chronic transplant injury and loss, and although the ptc score is a diagnostic criterion for antibody-mediated rejection, the utility of diffuse ptc is under debate. We evaluated the diagnostic value of ptc characteristics in this cross-sectional study including 85 biopsies of patients with donor-specific antibodies (DSA). Biopsies were reevaluated for the extent (diffuse vs focal), score and leukocytic composition in relation to DSA binding strength (mean fluorescence intensity [MFI]_max). Chronic allograft injury (transplant chronic glomerulopathy [cg] or chronic lesion score CLS]) were associated with ptc features. Peritubular capillaritis was detected in 50% (76% mononuclear ptc). Peritubular capillaritis scores 1, 2, and 3 were present in 36%, 55%, and 9%, and focal or diffuse ptc in 36% or 64%. Diffuse ptc was associated with DSA MFI_max (median: 4407 vs 2419 [focal ptc; P = 0.04] or 1946 [no ptc; P = 0.004]), cg (58% vs no ptc 24% [P = 0.02]), and higher CLS (mean: 6.81 vs 4.67 [focal ptc, P = 0.01] or 5.18 [no ptc, P = 0.001]), respectively. The association of ptc score of 2 or greater with cg was slightly better than with diffuse ptc. Diffuse ptc and ptc score of 2 or greater remained independently related to cg after adjusting for DSA_MFI_max, C4d, or previous rejection episodes, however lost their independent relation after adjusting for total microcirculation scores. Diffuse ptc was the only ptc characteristic independently related to CLS. Our results emphasize the clinical relevance of reporting diffuse ptc, which may relate to DSA binding strength and potentially to chronic graft injury.


An unexpected silver triflate-catalyzed tandem reaction of N'-(2-alkynylbenzylidene)hydrazide with ketene.
An unexpected silver triflate-catalyzed tandem reaction of N'-(2-alkynylbenzylidene)hydrazide with ketene through 6-endo-cyclization, [3+2] cycloaddition and rearrangement is reported. This reaction proceeds efficiently to generate the molecular complexity with the formation of four bonds in a one-pot procedure.


Severe Parechovirus 3 Infections in Young Infants-Kansas and Missouri, 2014.
Infection with parechovirus type 3 (PeV3) can cause severe neurologic and sepsis-like illness in young infants; clinical and epidemiologic descriptions have been limited. We aimed to characterize PeV3 illness and explore risk factors for acquisition in a cluster of neonatal cases at Children's Mercy Hospital in Kansas City, Missouri. Cerebrospinal fluid specimens were obtained from infants aged <180 days who were hospitalized with sepsis-like illness or meningitis between June 1 and November 1, 2014. PeV-positive specimens were sequenced at the Centers for Disease Control and Prevention. We reviewed the medical and birth charts of the infants and performed face-to-face parent interviews. We analyzed characteristics according to infant age and intensive care admission status. We identified 35 cases of PeV infection in infants aged 5 to 56 days. Seven infants required intensive care (median age, 11 days vs 27 days among those who did not require intensive care; P = .0044). Six of these 7 infants had neurologic manifestations consistent with seizures, and all 6 of them were treated with acyclovir but subsequently tested negative for herpes simplex virus. Virus sequences formed 2 lineages, both of which were associated with severe illness. Half of the infants were reported to have household contacts who were ill during the week before onset. Infants aged ≤7 days at onset were more likely to have been delivered at the same hospital. PeV3 can cause severe neurologic illness in neonates, and younger infants are more likely to require intensive care. PeV3 should be considered along with herpes simplex virus and other pathogens when evaluating young infants with sepsis-like illness or meningitis. More widespread testing for PeV3 would enable us to gain a better understanding of the clinical scope and circulation of this virus.


Occupational ocular accidents amongst Greek endodontists: a national questionnaire survey.
To investigate amongst Greek endodontists, the incidence of ocular accidents during practice, the circumstances associated with them, the therapeutic measures taken after the accidents, their compliance with the use of eye protection and their eye care behaviour. One hundred and forty-seven endodontists met the inclusion criteria and were invited to participate in the survey. Data were gathered through interviews based on a questionnaire. Participants were asked for personal/professional data, information on ocular accidents in the past 5 years, post-accident actions and the type of eye protection used. Their eyesight status and frequency of ocular examination were also recorded. Data were analysed using chi-square test, independent samples t-test and logistic regression. The level of significance was set at P = 0.05. The response rate was 84%. Ocular accidents were reported by 73% of the participants. Amalgam and NaOCl were the foreign bodies most frequently associated with ocular accidents. Medical assistance was sought in 16% of the most recent accidents. No permanent eye damage was reported. Regular use of magnification (OR:0.305, 95%CI:0.123-0.754) and years of clinical experience (OR:0.191, 95%CI:0.066-0.551) were significant predictors for the incidence of ocular accidents. Adequate eye protection was utilized by 82% of endodontists. Endodontists with eyesight deficiencies attended more frequently for ocular examination (P = 0.018). A high percentage of endodontists experienced ocular accidents. Regular use of magnification and increasing years in practice were associated with a reduced risk of ocular accidents. The majority of endodontists reported using adequate eye protection.


Narrative Medicine Theory and Practice: the Double Helix Model.
The genesis of the medical humanities as a discrete academic discipline engendered a need for a theoretical framework, a function taken on by the growing narrative medicine movement. More recently, scholars have begun to develop a critical medical humanities, an analytical movement that emphasises the fundamental enmeshment of the sciences and humanities. Building on Helene Scott-Fordsmand's work on reversing the medical humanities, this paper develops an alternative to the current version of narrative medicine. We propose a new interpretive heuristic, the Double Helix Model, and place it in critical dialogue with the Columbia School's close reading based-approach. Through this new conceptual frame, we suggest that critical narrative medicine may empower clinicians to contribute to the reorientation of the roles of the sciences and humanities, benefiting providers, scholars and patients.


Augmented mechanical response of muscle thin-fiber sensory receptors recorded from rat muscle-nerve preparations in vitro after eccentric contraction.
Unaccustomed strenuous exercise, especially that from eccentric muscular work, often causes muscle tenderness, which is a kind of mechanical hyperalgesia. We developed an animal model of delayed-onset muscle soreness (DOMS) from eccentric muscular contraction (ECC) in rats and demonstrated the existence of muscle tenderness by means of behavioral pain tests and c-Fos protein expression in the spinal dorsal horn. The purpose of the present study was to examine whether the sensitivities of muscle thin-fiber sensory receptors to mechanical, chemical, and thermal stimuli were altered after repetitive ECC in a rat model of DOMS. ECC was caused in the animals by electrical stimulation of the common peroneal nerve innervating the extensor digitorum longus muscle (EDL) while the muscle was being stretched. Activities of single thin-fiber receptors (sensitive to pressure but insensitive to stretch, with conduction velocity slower than 2.0 m/s) were recorded from muscle (EDL)-nerve preparations in vitro 2 days after ECC when mechanical hyperalgesia was at its peak. The mechanical threshold of thin-fiber receptors was found to be very much lower in the ECC preparations than in the nontreated control (CTR) [median 65.4 mN (interquartile range [IQR]; 46.6-122.0 mN) in the CTR preparation vs. 38.2 mN (IQR; 26.8-55.8 mN) in the ECC, P < 0.001]. In addition, the total number of evoked discharges during a ramp mechanical stimulus, taken as an index of the magnitude of the mechanical response, nearly doubled in the ECC preparations compared with the CTR [24.7 spikes (IQR; 14.2-37.1 spikes) in the CTR preparation vs. 54.2 spikes (IQR; 24.3-89.0 spikes) in the ECC, P < 0.001]. In contrast, the numbers of discharges induced by chemical (pH 5.5, lactic acid, adenosine triphosphate, and bradykinin) and thermal (cold and heat) stimuli were not different between the two preparations. These results suggest that augmentation of the mechanical response in muscle thin-fiber sensory receptors might be related to the muscle tenderness in DOMS after ECC.