Exploring the Biomedical Applications of Biosynthesized Silver Nanoparticles Using Perilla frutescens Flavonoid Extract: Antibacterial, Antioxidant, and Cell Toxicity Properties against Colon Cancer Cells.
The present study reports the biomimetic synthesis of silver nanoparticles (AgNPs) using a simple, cost effective and eco-friendly method. In this method, the flavonoid extract of Perilla frutescens (PFFE) was used as a bioreduction agent for the reduction of metallic silver into nanosilver, called P. frutescens flavonoid extract silver nanoparticles (PFFE-AgNPs). The Ultraviolet-Visible (UV-Vis) spectrum showed a characteristic absorption peak at 440 nm that confirmed the synthesis of PFFE-AgNPs. A Fourier transform infrared spectroscopic (FTIR) analysis of the PFFE-AgNPs revealed that flavonoids are involved in the bioreduction and capping processes. X-ray diffraction (XRD) and selected area electron diffraction (SAED) patterns confirmed the face-centered cubic (FCC) crystal structure of PFFE-AgNPs. A transmission electron microscopic (TEM) analysis indicated that the synthesized PFFE-AgNPs are 20 to 70 nm in size with spherical morphology and without any aggregation. Dynamic light scattering (DLS) studies showed that the average hydrodynamic size was 44 nm. A polydispersity index (PDI) of 0.321 denotes the monodispersed nature of PFFE-AgNPs. Further, a highly negative surface charge or zeta potential value (-30 mV) indicates the repulsion, non-aggregation, and stability of PFFE-AgNPs. PFFE-AgNPs showed cytotoxic effects against cancer cell lines, including human colon carcinoma (COLO205) and mouse melanoma (B16F10), with IC50 concentrations of 59.57 and 69.33 μg/mL, respectively. PFFE-AgNPs showed a significant inhibition of both Gram-positive (Listeria monocytogens and Enterococcus faecalis) and Gram-negative (Salmonella typhi and Acinetobacter baumannii) bacteria pathogens. PFFE-AgNPs exhibited in vitro antioxidant activity by quenching 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) free radicals with IC50 values of 72.81 and 92.48 µg/mL, respectively. In this study, we also explained the plausible mechanisms of the biosynthesis, anticancer, and antibacterial effects of PFFE-AgNPs. Overall, these findings suggest that PFFE-AgNPs have potential as a multi-functional nanomaterial for biomedical applications, particularly in cancer therapy and infection control. However, it is important to note that further research is needed to determine the safety and efficacy of these nanoparticles in vivo, as well as to explore their potential in other areas of medicine.


The Eutherian Pseudoautosomal Region.
The pseudoautosomal region (PAR) is a unique segment of sequence homology between differentiated sex chromosomes where recombination occurs during meiosis. Molecular and functional properties of the PAR are distinctive from the autosomes and the remaining regions of the sex chromosomes. These include a higher rate of recombination than genome average, bias towards GC-substitutions and increased interindividual nucleotide divergence and mutations. As yet, the PAR has been physically demarcated in only 28 eutherian species representing 6 mammalian orders. Murid rodents have the smallest, gene-poorest and most diverged PARs. Other eutherian PARs are largely homologous but differ in size and gene content, being the smallest in equids and human/simian primates and much larger in other eutherians. Because pseudoautosomal genes escape X inactivation, their dosage changes with sex chromosome aneuploidies, whereas phenotypic effects of the latter depend on the size and gene content of the PAR. Thus, X monosomy is more viable in mice, humans and horses than in species with larger PARs. Presently, little is known about the functions of PAR genes in individual species, though human studies suggest their involvement in early embryonic development. The PAR is, thus, of evolutionary, genetic and biomedical significance and a 'research hotspot' in eutherian genomes.


Disease modifying drugs targeting β-amyloid.
At this time there are no effective methods to alter the disease course in Alzheimer's disease. All FDA approved interventions are for symptomatic relief only. However, it is an exciting time as many agents in development have theorhetical potential to impact the disease course. This review discusses some of the agents that have been in clinical trials, particularly those that affect amyloid processing. Some agents have failed while others still provide hope. Since amyloid is the peptide most closely linked to disease pathogenesis, it is possible that some of the anti-amyloid agents will impact the disease progression in a meaningful way.


Whole-exome sequencing as a diagnostic tool in a family with episodic ataxia type 1.
Complex neurologic phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. Whole-exome sequencing can be applied to investigate the "diagnostic odyssey" cases. These cases involve patients with rare diseases that likely have a genetic etiology but have failed to be diagnosed by clinical evaluation and targeted gene testing. We describe such a case, a 22-year-old man who had mild intellectual developmental disability and episodes of jerking ataxic movements that affected his whole body. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to Mayo Clinic in Jacksonville, Florida, WES was applied for genetic determination of the unknown disorder in the proband and his biological parents and sister. Additional clinical evaluation, magnetic resonance neuroimaging, electromyography, and electroencephalography of the proband were performed to verify the phenotype after the WES results were available. To our knowledge, this is the first report of the application of WES to facilitate the diagnosis of episodic ataxia type 1. This case illustrates that WES supported by clinical data is a useful and time-saving tool in the evaluation of patients with rare and complex hereditary disorders.


[Precise surgery].
Surgery has passed through an intuitive and an empirical era and has now entered its modern phase. The enormous progress in biomedicine, the rise of evidence-based medicine and the consensus on the need for humanistic patient care, have laid a foundation for a new surgical paradigm. Based on a series of studies and practices, we advocated the concept of 'Precision Surgery'. It covers the entire operation-centered surgical practice. The strategy of precision surgery is to seek a balance of maximizing the removal of the target lesion, while maximizing the functional liver remnant and minimizing surgical invasiveness. We propose that the concept of precision surgery should be considered for wider application within liver surgery and various surgical fields, and finally realize the multi-objective optimization with certainty-based practice to ensure maximized recovery for each patient.


Higher professional education for general practitioners: postal questionnaire survey.
There is no consensus about whether higher professional education (HPE) is necessary for general practitioners (GPs) to complete their vocational training. To investigate beliefs about the need for HPE, its funding, duration, curriculum, and whether new principals (NPs) are eligible to undertake it. A confidential postal questionnaire was sent to senior partners, GP registrars, NPs, GP trainers, and GP tutors, principally in the old South West region of England, and nationally to other 'academic' GPs. Of 1199 GPs, 750 (62.6%) replied; 561 (79.2%) responders agreed with the principle of HPE for NPs, especially members of the Royal College of General Practitioners and academic GPs; senior partners (SPs) were less likely to agree (all P < 0.001). Of 700 GPs, 331 (50.3%) believed that HPE should last one or two years, 66.4% agreed that NPs should have a major input into the HPE curriculum, and 54.6% agreed that health authorities should be major sources of funding, together with the postgraduate deans (29.9%). GP tutors and trainers should have the main responsibility for teaching HPE. The principal barriers to setting up a HPE course are the financial cost, the time cost, difficulty in changing the status quo, and various practical problems. The facilitatory influences are: the enthusiasm of the NPs and of their clinical colleagues, an appropriate educational environment, a high quality clinical base, and recognition that NPs have specific needs. Of 668 GPs, 89.7% would release NPs if an HPE course were free and locums were paid, although SPs were less likely to agree (P < 0.001); if the HPE course cost the practice money, then only 30.6% would release NPs. If adequately externally funded, then there is widespread support for HPE with most GPs willing to release NPs. NPs and existing GP teachers should decide the curriculum. Its aim should be to provide educational support for NPs during the transition from GP registrar to fully-trained GP principal.


[Application of quantum-chemical methods to prediction of the carcinogenicity of chemical substances].
A version of logical-combinatorial JSM type intelligent system was used to predict the presence and the degree of a carcinogenic effect. This version was based on combined description of chemical substances including both structural and numeric parameters. The new version allows for the fact that the toxicity and danger caused by chemical substances often depend on their biological activation in the organism. The authors substantiate classifying chemicals according to their carcinogenic activity, and illustrate the use of the system to predict the carcinogenicity of polycyclic aromatic hydrocarbons using a model of bioactivation via the formation of diolepoxides, and the carcinogenicity of halogenated alkanes using a model of bioactivation via oxidative dehalogenation. The paper defined the boundary level of an energetic parameter, the exceeding of which correlated with the inhibition of halogenated alkanes's metabolism and the absence of carcinogenic activity.


How Does Birth Order and Number of Siblings Affect Fertility? A Within-Family Comparison Using Swedish Register Data.
This study examines how the sibling constellation in childhood is associated with later fertility behaviour of men and women in Sweden. Administrative register data are used to investigate how birth order affects completed fertility, how the number of siblings and birth order jointly affect completed fertility, and in both cases if there are gender differences in these relationships. Our data consist of all fully biologically related siblings in Sweden whose mothers were born between 1915 and 1935 (the younger generation is born primarily in the 1940s, 1950s and 1960s; N = 1,472,813). To study the direct effect of birth order on fertility, sibling comparison models are applied, while to analyse the joint effect of number of siblings and birth order, the sample was stratified by birth order. Results show that higher birth order has a negative effect on completed fertility for women; hence, earlier-born women show overall higher fertility than later-born women. Parity transitions indicate that later-born women are less likely to have two or more children, while no overall gradient for men can be found. The number of siblings is more positively associated with completed fertility for firstborn than for later-born individuals. We conclude that the position in the family of origin can be seen as an additional factor that influences fertility, although effect sizes are rather small.


Long-term effects of budesonide or nedocromil in children with asthma.
Antiinflammatory therapies, such as inhaled corticosteroids or nedocromil, are recommended for children with asthma, although there is limited information on their long-term use. We randomly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide (311 children), 8 mg of nedocromil (312 children), or placebo (418 children) twice daily. We treated the participants for four to six years. All children used albuterol for asthma symptoms. There was no significant difference between either treatment and placebo in the primary outcome, the degree of change in the forced expiratory volume in one second (FEV1, expressed as a percentage of the predicted value) after the administration of a bronchodilator. As compared with the children assigned to placebo, the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity (FVC, expressed as a percentage) before the administration of a bronchodilator (decline in FEV1:FVC, 0.2 percent vs. 1.8 percent). The children given budesonide also had lower airway responsiveness to methacholine, fewer hospitalizations (2.5 vs. 4.4 per 100 person-years), fewer urgent visits to a caregiver (12 vs. 22 per 100 person-years), greater reduction in the need for albuterol for symptoms, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medications were needed. As compared with placebo, nedocromil significantly reduced urgent care visits (16 vs. 22 per 100 person-years) and courses of prednisone. The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group (22.7 vs. 23.8 cm, P=0.005); this difference was evident mostly within the first year. The height increase was similar in the nedocromil and placebo groups. In children with mild-to-moderate asthma, neither budesonide nor nedocromil is better than placebo in terms of lung function, but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil. The side effects of budesonide are limited to a small, transient reduction in growth velocity.


Population pharmacokinetics of ivermectin after mass drug administration in lymphatic filariasis endemic communities of Tanzania.
Ivermectin (IVM) is a drug of choice used with albendazole for mass drug administration (MDA) to halt transmission of lymphatic filariasis. We investigated IVM pharmacokinetic (PK) variability for its dose optimization during MDA. PK samples were collected at 0, 2, 4, and 6 h from individuals weighing greater than 15 kg (n = 468) receiving IVM (3-, 6-, 9-, or 12 mg) and ALB (400 mg) during an MDA campaign in Tanzania. Individual characteristics, including demographics, laboratory/clinical parameters, and pharmacogenetic variations were assessed. IVM plasma concentrations were quantified by liquid-chromatography tandem mass spectrometry and analyzed using population-(PopPK) modeling. A two-compartment model with transit absorption kinetics, and allometrically scaled oral clearance (CL/F) and central volume (Vc /F) was adapted. Fitting of the model to the data identified 48% higher bioavailability for the 3 mg dose compared to higher doses and identified a subpopulation with 97% higher mean transit time (MTT). The final estimates for CL/F, Vc /F, intercompartment clearance, peripheral volume, MTT, and absorption rate constant for a 70 kg person (on dose other than 3 mg) were 7.7 L/h, 147 L, 20.4 L/h, 207 L, 1.5 h, and 0.71/h, respectively. Monte-Carlo simulations indicated that weight-based dosing provides comparable exposure across weight bands, but height-based dosing with capping IVM dose at 12 mg for individuals with height greater than 160 cm underdoses those weighing greater than 70 kg. Variability in IVM PKs is partly explained by body weight and dose. The established PopPK model can be used for IVM dose optimization. Height-based pole dosing results in varying IVM exposure in different weight bands, hence using weighing scales for IVM dosing during MDA is recommended.


Effects of Napping on Alertness, Cognitive, and Physical Outcomes of Karate Athletes.
It has been suggested that napping is the best recovery strategy for athletes. However, researches on the impacts of napping on athletic performances are scarce. The aim of this study was to determine the effects of a 30-min nap after a partial sleep deprivation, or a normal night condition, on alertness, fatigue, and cognitive and physical outcomes. Thirteen national-level male karate athletes were randomized to experience nap and no-nap conditions, after either a reference or a partial sleep deprivation night. The nap lasted 30 min at 1:00 PM. The postnap testing session started at 2:00 PM by quantifying subjective alertness and fatigue. Cognitive and physical performances were respectively measured before and after the karate-specific test (KST) by simple reaction time (SRT) test, lower reaction test (LRT), mental rotation test (MRT), squat jump (SJ), and counter movement jump (CMJ) tests. After a reference night, the nap improved alertness and cognitive outcomes (SRT, LRT, and MRT). No effects on subjective fatigue and physical performances were found. After a partial-sleep deprivation, the nap restored subjective alertness and the decrement in performances caused by sleep loss in most of the tests (MRT, LRT, and KST), but no effects were observed in subjective fatigue and CMJ. After the fatigue induced by KST, there was an ergogenic effect of the nap on the physical performances (CMJ and SJ), and a partial psychogenic effect on the cognitive performances (LRT). A 30-min nap enhances cognitive outcomes. It is also an effective strategy to overcome the cognitive and physical deteriorations in performances caused either by sleep loss or by fatigue induced by exhaustive trainings in the afternoon.


Involvement of Ca(2+) in antiarrhythmic effect of ischemic preconditioning in isolated rat heart.
We investigated the relationship between the effects of ischemic preconditioning (IPC) and Ca(2+) preconditioning (CPC) on reperfusion-induced arrhythmias. In the control group (noPC), Langendorff-perfused rat hearts were subjected to 5-min zero-flow global ischemia (I) followed by 15-min reperfusion (I/R). In ischemic preconditioning groups (IPC), the hearts were subjected to three cycles of 3-min global ischemia and 5-min reperfusion. In the CPC group, the hearts were exposed to three cycles of 3-min perfusion of higher Ca(2+) (2.3 mmol/l Ca(2+)) followed by 5-min perfusion of normal 1.3 mmol/l Ca(2+), and the hearts were then subjected to I/R. Verapamil was administered in several hearts of the IPC group (VR+IPC). Ventricular arrhythmias upon reperfusion were less frequently seen in the IPC and CPC groups than in the noPC and VR+IPC groups. IPC and CPC could attenuate conduction delay and enhance shortening of the monophasic action potential duration during ischemia. The ventricular fibrillation threshold measured at 1-min reperfusion was significantly higher in the IPC and CPC groups than in the noPC and VR+IPC groups. Verapamil completely abolished the salutary effects of IPC. These results demonstrate that Ca(2+) plays an important role in the antiarrhythmic effect of IPC during reperfusion.


The metabolic syndrome and the risk of venous thrombosis: a case-control study.
The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. In a case-control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.


Development of a privacy and security policy framework for a multistate comparative effectiveness research network.
Comparative effectiveness research (CER) conducted in distributed research networks (DRNs) is subject to different state laws and regulations as well as institution-specific policies intended to protect privacy and security of health information. The goal of the Scalable National Network for Effectiveness Research (SCANNER) project is to develop and demonstrate a scalable, flexible technical infrastructure for DRNs that enables near real-time CER consistent with privacy and security laws and best practices. This investigation began with an analysis of privacy and security laws and state health information exchange (HIE) guidelines applicable to SCANNER participants from California, Illinois, Massachusetts, and the Federal Veteran's Administration. A 7-member expert panel of policy and technical experts reviewed the analysis and gave input into the framework during 5 meetings held in 2011-2012. The state/federal guidelines were applied to 3 CER use cases: safety of new oral hematologic medications; medication therapy management for patients with diabetes and hypertension; and informational interventions for providers in the treatment of acute respiratory infections. The policy framework provides flexibility, beginning with a use-case approach rather than a one-size-fits-all approach. The policies may vary depending on the type of patient data shared (aggregate counts, deidentified, limited, and fully identified datasets) and the flow of data. The types of agreements necessary for a DRN may include a network-level and data use agreements. The need for flexibility in the development and implementation of policies must be balanced with responsibilities of data stewardship.


Factors associated with adolescent mental health service need and utilization.
To determine the association of parent, family, and adolescent variables with adolescent mental health service need and utilization. Correlates of adolescent mental health service utilization, self-perceived need and unmet need were investigated in a general population sample of 1,120 Dutch adolescents aged 11 to 18 years (78% response rate). 3.1% of the sample had been referred for mental health services within the preceding year, and 3.8% reported unmet need. 7.7% of adolescents at risk for psychopathology, and 17.8% of those indicating a need for help, had been referred. Family stress and adolescent's self-reported problems were most strongly associated with service need and utilization. Internalizing problems, female gender, and low education level were associated with self-perceived unmet need. Adolescent ethnicity and competence in activities and school were associated with service use, but did not influence service need, while the opposite effect was found for adolescent age and parental psychopathology. In designing intervention programs aimed at increasing adolescent mental health service use, distinctions should be made between efforts focused at adolescents not recognizing their problems, and those with unmet need.


Extension for Community Healthcare Outcomes Uruguay: A New Strategy to Promote Best Primary Care Practice for Autism.
Introduction. In Uruguay, the special care required for children with neurodevelopmental disorders presents difficulties including lack of access to specialists and rehabilitation services. Project ECHO (Extension for Community Healthcare Outcomes) connects primary care clinicians from remote areas to specialists to enable them to treat complex conditions through ongoing education and mentoring. Objective. To share the experience of the ECHO Autism program during the first 2 years of implementation. Methods. Analysis of ECHO Autism clinics from June 2015 to June 2017 including clinical cases presented participants' self-perception of changes in skills and competences. Results. Twenty clinical cases were presented: mean age 4.5 years; 15 were males; and 17 with medical and psychiatric comorbidities. After ECHO Autism implementation, a statistically significant improvement in participants' self-perception of skills and competences was observed. Conclusions. ECHO Autism in Uruguay is a meaningful approach to autism care and offers improved access to best practice care.


Predicting Impact Outcomes and Maximum Spreading of Drop Impact on Heated Nanostructures Using Machine Learning.
Accurate prediction of droplet behavior upon impact on a heated nanostructured surface is vital for various industrial applications. In this study, we leverage multiple data-driven machine learning (ML) techniques to model the impact outcome and droplet spreading, employing existing experimental data. Our approach incorporates a comprehensive range of critical control parameters, such as the impact velocity (V), surface temperature (Ts), nanopillars' packing fraction (ϕ), and surface roughness (r). We obtain optimal results when utilizing the artificial neural network classification (ANNC) to construct a phase diagram that encompasses all of the experimental impact behaviors. Additionally, we utilize the support vector regression (SVR) method to model the maximum spreading factor (βmax) as a function of the Weber number (We), defined as the ratio of droplet kinetic to surface energy, and Ts for each surface combination. Consistent with previous experimental observations, our results illustrate that nanostructures not only introduce distinct impact behaviors, such as central jetting, but also influence the boundaries among the deposition, rebound, and splashing regimes within the phase diagram. An increase in ϕ at a constant r promotes deposition and spreading events, while increasing r at a constant ϕ results in enhanced heat transfer to promote the Leidenfrost effect for the rebound regime and a greater disturbance of the liquid lamella to trigger splashing. The SVR prediction reveals the existence of a We-number threshold governed by the nanostructure parameters. Beyond this threshold, the maximum spreading factor (βmax) of a spreading droplet becomes independent of the surface temperature (Ts) as We increases, suggesting that fluid properties are likely the dominating factors influencing the spreading dynamics in the extreme We range.


The influence of bilateral sagittal split ramus osteotomy on submental-cervical aesthetics.
The effect of orthodontic-surgical treatment on submental-cervical region was evaluated in a very limited number of studies. The aim of this study was to evaluate submental-cervical soft tissue contour changes following mandibular advancement and set-back procedures via bilateral sagittal split ramus osteotomy. Sixty-seven patients were included in this study. Group 1 consisted of 27 skeletal Class II patients who underwent mandibular advancement surgery, whereas Group 2 consisted of 40 skeletal Class III patients who underwent mandibular set-back surgery. Various linear and angular measurements were performed on pre-operative and sixth month post-operative cephalometric radiographs. A new method was used to evaluate the amount of sagging at submental region. The submental length did not change in Group 1; however, it decreased significantly in Group 2 (P < 0·05). The angle between submental plane and facial plane decreased to 95·9° from 98·8° in Group 1(P < 0·05), whereas it increased to 93·1° from 88·2° in Group2 (P < 0·05). The change of submental soft tissue sag was almost stable in Group 1, while 0·34 mm increase of sag was observed in Group 2. This increase was not statistically significant (P > 0·05). Mandibular set-back and advancement procedures do not remarkably change the submental sag following approximately 6 mm jaw movement. Although mandibular advancement did not significantly effect submental length, soft tissue followed mandibular set-back with a ratio of 1:1 at C-point to projection of soft tissue pogonion and 1:0·7 at C-point to soft tissue menton distances.


Long-term treatment of social phobia with clonazepam.
Twenty-six socially phobic outpatients were treated with clonazepam for the relief of symptoms. At evaluation, which took place after an average of 11.3 months of continuous treatment, 22 (84.6%) patients showed good improvement and 4 (14.4%) showed no improvement or were not recovered. The dose declined over time, from a peak mean of 2.1 mg/day to a mean of 0.94 mg/day at follow-up. Side effects are described, along with individual case descriptions that illustrate important aspects of the use of benzodiazepines for the treatment of social phobia.


Demands for multidimensional information on the work environment: A methodological framework for regular studies.
Development of methodologies for making economic decisions on designing work environment studies is a theoretical challenge for researchers in occupational health sciences. There are well-defined tools available in the relevant literature for analysis of cost-efficiency associated with the assessment of an occupational exposure of interest. However, these analytical tools are not appropriate for holistic studies of the work environment as a multidimensional reality. This article introduces an appropriate methodology for designing cross-sectional comprehensive studies of the work environment, in order to optimize the production of information on the psychosocial, ergonomic, and physical dimensions of the work environment in regular studies. The employment of a translog cost-utility function is suggested as a suitable way to provide cost-minimized designs for regular studies which are aimed at providing or developing multidimensional information systems of the work environment. The translog cost-utility function is not subject to predetermined restrictions, but has a flexibility property allowing it to be transformed to any specification that is adaptable to the specific work environmental characteristics and research requirements. The translog cost-utility function is an appropriate econometric model for optimizing the production of multidimensional information on occupational exposures in regular cross-sectional workplace studies.


Subterranean movement inferred by temporary emigration in Barton Springs salamanders (Eurycea sosorum).
Movement behavior is an important aspect of animal ecology but is challenging to study in species that are unobservable for some portion of their lives, such as those inhabiting subterranean environments. Using four years of robust-design capture-recapture data, we examined the probability of movement into subterranean habitat by a population of endangered Barton Springs salamanders (Eurycea sosorum), a species that inhabits both surface and subterranean groundwater habitats. We tested the effects of environmental variables and body size on survival and temporary emigration, using the latter as a measure of subterranean habitat use. Based on 2,046 observations of 1,578 individuals, we found that temporary emigration was higher for larger salamanders, 79% of which temporarily emigrated into subterranean habitat between primary sampling intervals, on average. Body size was a better predictor of temporary emigration and survival compared to environmental covariates, although coefficients from lower ranked models suggested turbidity and dissolved oxygen may influence salamander movement between the surface and subsurface. Surface population dynamics are partly driven by movement below ground and therefore surface abundance estimates represent a fraction of the superpopulation. As such, while surface habitat management remains an important conservation strategy for this species, periodic declines in apparent surface abundance do not necessarily indicate declines of the superpopulation associated with the spring habitat.


Nuclear factories for signalling and repairing DNA double strand breaks in living fission yeast.
In mammalian and budding yeast cells treated with genotoxic agents, different proteins implicated in detecting, signalling or repairing DNA lesions form nuclear foci. We studied foci formed by proteins involved in these processes in living fission yeast cells, which is amenable to genetic and molecular analysis. Using fluorescent tags, we analysed subnuclear localisations of the DNA damage checkpoint protein Rad9, of the homologous recombination protein Rad22 and of PCNA, which are implicated in many aspects of DNA metabolism. After inducing double strand breaks (DSBs) with ionising radiations, Rad22, Rad9 and PCNA form a low number of nuclear foci. Rad9 recruitment to foci depends on the presence of Rad1, Hus1 and Rad17, but is independent of downstream checkpoint effectors and of homologous recombination proteins. Likewise, Rad22 and PCNA form foci despite inactive homologous recombination repair and impaired DNA damage checkpoint. Rad22 and Rad9 foci co-localise completely, whereas PCNA co-localises with Rad22 and Rad9 only partially. Foci do not disassemble in cells unable to repair DNA by homologous recombination. Thus, in fission yeast, DSBs are detected by the DNA damage checkpoint and are repaired by homologous recombination at a few spatially confined subnuclear compartments where Rad22, Rad9 and PCNA concentrate independently.


Effects of hypocalcemia on diaphragmatic strength generation.
We studied the effects of hypocalcemia on diaphragmatic force and diaphragm blood flow (Qdi) in 12 anesthetized dogs. The diaphragm was electrically stimulated with intramuscular electrodes surgically implanted in the ventral surface of each hemidiaphragm. The transdiaphragmatic pressure (Pdi) during supramaximal (50 V) 2-s stimulations applied over a frequency range of 10-100 Hz was measured with balloon catheters during tracheal occlusion at functional residual capacity. A catheter was placed via the femoral vein into the left inferior phrenic vein, and Qdi was measured by timed volume collections of left inferior venous effluent. A catheter was introduced in a femoral artery to monitor blood pressure (BP). In five additional dogs, the force generated by the sartorius muscle during electrical stimulation was also studied concomitantly to diaphragmatic force. The animals were mechanically ventilated throughout the experiment, and the arterial blood gases and pH were maintained constant. Hypocalcemia was induced by a continuous infusion of EGTA (70 mg X kg-1 X h-1), which led to a progressive decrease (P less than 0.0001) of ionized calcium plasmatic level from 2.21 +/- 0.4 meq/1 during control to 1.69 +/- 0.06, 1.25 +/- 0.5, and 1.07 +/- 0.5 meq/1 after 30, 60, and 120 min, respectively. Hypocalcemia decreased progressively Pdi, which amounted to 84 +/- 3 (P less than 0.001) and 98 +/- 2% of control values for the low frequencies (10 and 20 Hz) and the high frequencies (50 and 100 Hz), respectively, after 30 min of EGTA infusion and to 74 +/- 5 and 79 +/- 6% for the low and high frequencies, respectively, after 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)


Programmable matter by folding.
Programmable matter is a material whose properties can be programmed to achieve specific shapes or stiffnesses upon command. This concept requires constituent elements to interact and rearrange intelligently in order to meet the goal. This paper considers achieving programmable sheets that can form themselves in different shapes autonomously by folding. Past approaches to creating transforming machines have been limited by the small feature sizes, the large number of components, and the associated complexity of communication among the units. We seek to mitigate these difficulties through the unique concept of self-folding origami with universal crease patterns. This approach exploits a single sheet composed of interconnected triangular sections. The sheet is able to fold into a set of predetermined shapes using embedded actuation. To implement this self-folding origami concept, we have developed a scalable end-to-end planning and fabrication process. Given a set of desired objects, the system computes an optimized design for a single sheet and multiple controllers to achieve each of the desired objects. The material, called programmable matter by folding, is an example of a system capable of achieving multiple shapes for multiple functions.


P450-mediated O-demethylated metabolite is responsible for rat hepatobiliary toxicity of pyridyltriazine-containing PI3K inhibitors.
The dysregulation of phosphatidylinositol 3-kinase (PI3K)-dependent pathways is implicated in several human cancers making it an attractive target for small molecule PI3K inhibitors. A series of potent pyridyltriazine-containing inhibitors of class Ia PI3Ks were synthesized and a subset of compounds was evaluated in exploratory repeat-dose rat toxicology studies. Daily oral dosing of compound 1: in Sprague Dawley rats for four consecutive days was associated with hepatobiliary toxicity that included biliary epithelial hyperplasia and hypertrophy, periductular edema, biliary stasis, and acute peribiliary inflammatory infiltrates. These histological changes were associated with clinical pathology changes that included increased serum liver enzymes, total bile acids, and bilirubin. The predominant clearance pathway of 1: was shown in vitro and in a bile-duct cannulated rat (14)C-ADME study to be P450-mediated oxidative metabolism. An O-demethylated pyridine metabolite, M3: , was identified as a candidate proximal metabolite that caused the hepatotoxicity. Co-administration of the pan-P450 inhibitor 1-aminobenzotriazole with 1: to rats significantly reduced the formation of M3: and prevented liver toxicity, whereas direct administration of M3: reproduced the toxicity. Structural changes were introduced to 1: to make the methoxypyridine ring less susceptible to P450 oxidation (compound 2: ), and addition of a methyl group to the benzylic carbon (compound 3: ) improved the pharmacokinetic profile. These changes culminated in the successful design of a clinical candidate 3: (AMG 511) that was devoid of liver toxicity in a 14-day rat toxicity study. Herein, we describe how a metabolism-based structure-activity relationship analysis allowed for the successful identification of a PI3K inhibitor devoid of off-target toxicity.


Primary cultures of female swine genital epithelial cells in vitro: a new approach for the study of hormonal modulation of Chlamydia infection.
Previous studies have demonstrated that female reproductive hormones influence chlamydial infection both in vivo and in vitro. Due to the reduced availability of human genital tissues for research purposes, an alternative hormone-responsive model system was sought to study chlamydial pathogenesis. Mature female swine eliminated from breeding programs were selected as the animals of choice because of the similarity of a sexually transmitted disease syndrome and sequelae in swine to a disease syndrome and sequelae found in humans, because of the near identity of a natural infectious chlamydial isolate from swine to Chlamydia trachomatis serovar D from humans, and because a pig's epithelial cell physiology and the mean length of its estrous cycle are similar to those in humans. Epithelial cells from the cervix, uterus, and horns of the uterus were isolated, cultivated in vitro in Dulbecco's minimum essential medium-Hanks' F-12 (DMEM-F-12) medium with and without exogenous hormone supplementation, and analyzed for Chlamydia suis S-45 infectivity. The distribution of chlamydial inclusions in swine epithelial cells was uneven and was influenced by the genital tract site and hormone status. This study confirmed that, like primary human endometrial epithelial cells, estrogen-dominant swine epithelial cells are more susceptible to chlamydial infection than are progesterone-dominant cells. Further, the more differentiated luminal epithelial cells were more susceptible to infection than were glandular epithelial cells. Interestingly, chlamydial growth in mature luminal epithelia was morphologically more active than in glandular epithelia, where persistent chlamydial forms predominated. Attempts to reprogram epithelial cell physiology and thereby susceptibility to chlamydial infection by reverse-stage, exogenous hormonal supplementation were unsuccessful. Freshly isolated primary pig epithelial cells frozen at -80 degrees C in DMEM-F-12 medium with 10% dimethyl sulfoxide for several weeks can, after thawing, reform characteristic polarized monolayers in 3 to 5 days. Thus, primary swine genital epithelia cultured ex vivo appear to be an excellent cell model for dissecting the hormonal modulation of several aspects of chlamydial pathogenesis and infection.


R & d in the United States: its strengths and challenges.
The promise of technology for improving the quality of life has never been greater, and American science and technology has led the way toward fulfillment of that promise. Now this preeminence is threatened by forces that may affect technological progress throughout the world. It is up to those of us in science, industry, and government to strengthen the institutions that have made us the leaders and to restore our initiative.


Stability and correlates of the California Verbal Learning Test for a sample of normal elderly persons.
The test-retest stability of the California Verbal Learning Test was examined for a normal elderly sample of 28 men and 74 women along with the correlation for total recall with scores on selected variables. Mean age was 72 yr. The test was re-administered after one year. Mean total recall did not change; the stability coefficient was .64. Coefficients for the other scores ranged considerably (.27 for recognition hits to .62 for perseverations) and were compared with prior research findings. Recall was moderately correlated with scores on the North American Reading Test, Trails B, visual reproductions, and subjective memory ability.


Three Level Thoracolumbar Spondylectomy for Recurrent Giant Cell Tumour of the Spine: A Case Report.
Giant cell tumour (GCT) is a benign tumour but can be locally aggressive and with the potential to metastasise especially to the lungs. Successful treatments have been reported for long bone lesions; however, optimal surgical and medical treatment for spinal and sacral lesions are not well established. In treating spinal GCTs, the aim is to achieve complete tumour excision, restore spinal stability and decompress the neural tissues. The ideal surgical procedure is an en bloc spondylectomy or vertebrectomy, where all tumour cells are removed as recurrence is closely related to the extent of initial surgical excision. However, such a surgery has a high complication rate, such as dura tear and massive blood loss. We report a patient with a missed pathological fracture of T12 treated initially with a posterior subtraction osteotomy, who had recurrence three years after the index surgery and subsequently underwent a three level vertebrectomy and posterior spinal fusion.


Low 24-hour adiponectin and high nocturnal leptin concentrations in a case-control study of community-dwelling premenopausal women with major depressive disorder: the Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression (POWER) study.
Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and antiatherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were (1) to establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; (2) to assess whether there is a relationship between adiponectin and MDD; and (3) to explore the temporal relationships among adiponectin, leptin, corticotropin, and cortisol secretion. We conducted a case-control study of community-dwelling premenopausal women with DSM-IV MDD (n = 23) and age- and body mass index (BMI)-matched control subjects (n = 23). Main outcome measures were circulating concentrations of adiponectin, leptin, corticotropin, and cortisol measured hourly for 24 hours. Subjects were recruited from July 1, 2001, to February 28, 2003. Women with MDD had approximately 30% lower mean 24-hour concentration of adiponectin than did control subjects. Adiponectin concentration was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, mean nocturnal leptin concentration was higher in the MDD versus control groups. Mean leptin concentration was inversely related to cortisol and adiponectin concentrations, both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between corticotropin and cortisol concentrations was stronger in women with MDD than in control subjects, a finding consistent with hypothalamic-pituitary-adrenal (HPA) axis activation in MDD. In premenopausal women with MDD, reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis.


Cognitive functions in major depression and Parkinson disease.
To investigate the importance of major depression in the production of cognitive deficits in patients with Parkinson disease (PD). A comprehensive neuropsychological and psychiatric assessment was conducted in 19 patients with PD and major depression, 31 patients with PD without depression, 27 patients with major depression but without PD, and 12 age-comparable healthy controls. Outpatient clinic. Patients with major depression (with or without PD) had significantly more severe cognitive deficits than both healthy controls and patients with PD without depression on tests of verbal fluency and auditory attention, while patients with PD and major depression had significantly more severe deficits on tasks of abstract reasoning and set alternation compared with the other 3 groups. Major depression in patients with PD is associated with significant deficits on specific cognitive tasks. While some of these deficits may be explained by the presence of major depression, frontal lobe-related cognitive impairments may result from an interaction between neuropathologic factors in PD and the mechanism of major depression.


Value of PET-CT in avoiding multimodality therapy in operable cervical cancer.
Posttreatment morbidity of multimodality therapy is substantially higher than either radical surgery or chemoradiation alone. Preoperative prediction of positive nodes limits optimal selection of the primary treatment modality. Computed tomography (CT) and magnetic resonance imaging have been tried for nodal assessment with modest results. Positron emission tomography (PET) combined with CT seems to be promising in this regard. This clinicopathologic study assesses the value of PET-CT in predicting nodal metastasis and avoiding multimodality therapy. Eighty patients with clinically operable cervical cancer underwent PET-CT during the preoperative evaluation followed by radical hysterectomy. Adjuvant chemoradiation was administered when indicated by histopathologic findings. The histopathologic finding of the pelvic nodes was correlated with the PET-CT findings for nodal metastasis. The chi2 test was used as the test of significance in the statistical analysis. Of 62 patients found PET-CT negative for nodal disease, 52 were true negative, whereas 10 were false negative on histopathologic examination. On the other hand, 14 of 18 patients found PET-CT positive for nodal disease were true positives. Specificity, sensitivity, positive predictive value, and negative predictive value of PET-CT in nodal assessment were found to be 92.8, 58.33, 77.7, and 83.8, respectively. Twenty-four patients (30%) with pelvic nodes positive for disease on histopathologic examination were administered adjuvant chemoradiation. Had we operated only on those patients who were PET-CT negative for nodal disease, 10 of 62 patients would have required adjuvant chemoradiation for positive nodes. Eighteen patients found PET-CT positive for nodal disease would be treated with primary chemoradiation. Inclusion of PET-CT in the decision-making process for primary surgery versus primary chemoradiation would allow 87.5% patients to receive a single modality of treatment (65%, only surgery; 22.5%, only chemoradiation) and the proportion of patients requiring multimodality treatment would reduce significantly from 30% to 12.5% (P < 0.01). Positron emission tomography combined with CT in the evaluation of operable cervical cancer can help in the optimal selection of patients for surgery such that multimodality treatment with its attendant increase in morbidity is avoided.


Hands on the Medical Informatics Initiative Core Data Set - Lessons Learned from Converting the MIMIC-IV.
With the steady increase in the connectivity of the healthcare system, new requirements and challenges are emerging. In addition to the seamless exchange of data between service providers on a national level, the local legacy data must also meet the new requirements. For this purpose, the applications used must be tested securely and sufficiently. However, the availability of suitable and realistic test data is not always given. Therefore, this study deals with the creation of test data based on real electronic health record data provided by the Medical Information Mart for Intensive Care (MIMIC-IV) database. In addition to converting the data to the current FHIR R4, conversion to the core data sets of the German Medical Informatics Initiative was also presented and made available. The test data was generated to simulate a legacy data transfer. Moreover, four different FHIR servers were tested for performance. This study is the first step toward comparable test scenarios around shared datasets and promotes comparability among providers on a national level.


Interconnections between Sigma B, agr, and proteolytic activity in Staphylococcus aureus biofilm maturation.
Staphylococcus aureus is a proficient biofilm former on host tissues and medical implants. We mutagenized S. aureus strain SH1000 to identify loci essential for ica-independent mechanisms of biofilm maturation and identified multiple insertions in the rsbUVW-sigB operon. Following construction and characterization of a sigB deletion, we determined that the biofilm phenotype was due to a lack of sigma factor B (SigB) activity. The phenotype was conserved in a sigB mutant of USA300 strain LAC, a well-studied community-associated methicillin-resistant S. aureus isolate. We determined that agr RNAIII levels were elevated in the sigB mutants, and high levels of RNAIII expression are known to have antibiofilm effects. By introducing an agr mutation into the SH1000 or LAC sigB deletion strain, S. aureus regained biofilm capacity, indicating that the biofilm phenotype was agr dependent. Protease activity is linked to agr activity and ica-independent biofilm formation, and we observed that the protease inhibitors phenylmethylsulfonyl fluoride and alpha-macroglobulin could reverse the sigB biofilm defect. Similarly, inactivating genes encoding both the aureolysin and Spl extracellular proteases in the sigB mutant restored biofilm capacity. Due to the growing link between murein hydrolase activity and biofilm maturation, autolysin zymography was performed, which revealed an altered profile in the sigB mutant; again, the phenotype could be repaired through protease inactivation. These findings indicate that the lack of SigB activity results in increased RNAIII expression, thus elevating extracellular protease levels and altering the murein hydrolase activity profile. Altogether, our observations demonstrate that SigB is an essential regulator of S. aureus biofilm maturation.


PPARδ activation attenuates hepatic steatosis in Ldlr-/- mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity.
PPARδ regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPARδ agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr(-/-) mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA β-oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPKβ1(-/-) hepatocytes. However, FA oxidation was only partially reduced in AMPKβ1(-/-) hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPARδ-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPKβ1(-/-) hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinflammatory M1 state, which was reversed by GW1516 intervention. Thus, PPARδ agonist treatment inhibits the progression of preestablished hepatic steatosis.


Bearing Fault Diagnosis Using Multidomain Fusion-Based Vibration Imaging and Multitask Learning.
Statistical features extraction from bearing fault signals requires a substantial level of knowledge and domain expertise. Furthermore, existing feature extraction techniques are mostly confined to selective feature extraction methods namely, time-domain, frequency-domain, or time-frequency domain statistical parameters. Vibration signals of bearing fault are highly non-linear and non-stationary making it cumbersome to extract relevant information for existing methodologies. This process even became more complicated when the bearing operates at variable speeds and load conditions. To address these challenges, this study develops an autonomous diagnostic system that combines signal-to-image transformation techniques for multi-domain information with convolutional neural network (CNN)-aided multitask learning (MTL). To address variable operating conditions, a composite color image is created by fusing information from multi-domains, such as the raw time-domain signal, the spectrum of the time-domain signal, and the envelope spectrum of the time-frequency analysis. This 2-D composite image, named multi-domain fusion-based vibration imaging (MDFVI), is highly effective in generating a unique pattern even with variable speeds and loads. Following that, these MDFVI images are fed to the proposed MTL-based CNN architecture to identify faults in variable speed and health conditions concurrently. The proposed method is tested on two benchmark datasets from the bearing experiment. The experimental results suggested that the proposed method outperformed state-of-the-arts in both datasets.


Sodium fluoride mimics effects of both agonists and antagonists on intact human platelets by simultaneous modulation of phospholipase C and adenylate cyclase activity.
Using intact human platelets, we studied the effect of sodium fluoride (NaF) on platelet aggregation and release reaction and correlated the functional changes to intracellular events specific for either agonist-induced or antagonist-induced platelet responses. At lower concentrations, with a peak activity between 30 and 40 mmol/L, NaF induced aggregation and release of adenosine 5'-triphosphate (ATP) that was associated with increased formation of inositol phosphates, a rise in cytosolic free Ca2+, and phosphorylation of 20-kd and 40-kd proteins. At NaF concentrations greater than 40 mmol/L, aggregation and ATP release decreased dose-dependently in parallel with a decrease in Ca2+ mobilization, whereas neither inositol phosphate formation nor 40-kd protein phosphorylation was reduced. At these concentrations, NaF caused a dose-dependent transient rise in platelet cyclic adenosine 3',5'-monophosphate (cAMP) levels that was sufficient to account for the observed reduction in Ca2+ mobilization, aggregation, and ATP release. Stimulated cAMP levels started declining rapidly within 30 seconds of addition of NaF, however. Similarly, prostacyclin (PGI2)-induced cAMP accumulation was temporarily enhanced but subsequently suppressed by NaF, suggesting either stimulation of a cAMP phosphodiesterase or delayed inhibition of adenylate cyclase. Evidence for the latter was provided by the finding that NaF pretreatment of platelets resulted in partial inhibition of PGI2-stimulated cAMP formation in the presence of the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX). We conclude that NaF exerts a dual (stimulatory and inhibitory) effect on adenylate cyclase in intact platelets that is accompanied by simultaneous activation of a phosphoinositide-specific phospholipase C; in addition, a cAMP phosphodiesterase may be activated.


Antigens from Taenia crassiceps cysticerci used in complement fixation, enzyme-linked immunosorbent assay, and western blot (immunoblot) for diagnosis of neurocysticercosis.
Antigens from Taenia solium cysticerci for the immunodiagnosis of cysticercosis are scarce and difficult to obtain. We studied the reliability of antigens from Taenia crassiceps cysticerci as a substitute for those from T. solium in three diagnostic tests: complement fixation, enzyme-linked immunosorbent assay, and Western blot (immunoblot). Precision rates of the three tests of 93, 99, and 96%, respectively, were found. Cysticerci from T. crassiceps can be easily obtained in large quantities and can be effectively used for the diagnosis of human neurocysticercosis.


A guide to direct mechanocatalysis.
Direct mechanocatalysis (DM) describes solvent-free catalytic reactions that are initiated by mechanical forces in mechanochemical reactors such as ball mills. The distinctive feature of DM is that the milling materials, e.g. the milling balls themselves are the catalyst of the reaction. In this article we follow the historical evolution of this novel concept and give a guide to this emerging, powerful synthesis tool. Within this perspective we seek to highlight the impact of the relevant milling parameters, the nature of the catalyst and potential additives, the scope of reactions that are currently accessible by this method, and the thus far raised hypotheses on the underlying mechanisms of direct mechanochemical transformations.


Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla.
Chloroquine, a widely used anti-malaria drug, has gained popularity for the treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV). Unfortunately, chloroquine may also negatively impact renal function for patients whose fluid and electrolyte homeostasis is already compromised by diseases. Chronic administration of chloroquine also results in polyuria, which may be explained by suppression of the antidiuretic response of vasopressin. Several of the transporters responsible for concentrating urine are vasopressin-sensitive including the urea transporters UT-A1 and UT-A3, the water channel aquaporin-2 (AQP2), and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg(-1)·day(-1) of chloroquine for 4 days. Twenty-four hour urine output was twofold higher, and urine osmolality was decreased by twofold in chloroquine-treated rats compared with controls. Urine analysis of treated rats detected the presence chloroquine as well as decreased urine urea and cAMP levels compared with control rats. Western blot analysis showed a downregulation of AQP2 and NKCC2 transporters; however, UT-A1 and UT-A3 abundances were unaffected by chloroquine treatment. Immunohistochemistry showed a marked reduction of UT-A1 and AQP2 in the apical membrane in inner medullary collecting ducts of chloroquine-treated rats. In conclusion, chloroquine-induced polyuria likely occurs as a result of lowered cAMP production. These findings suggest that chronic chloroquine treatment would exacerbate the already compromised fluid homeostasis observed in diseases like chronic kidney disease.


[Fungal flora in a hospital environment].
The airborne fungal flora was studied in different departments of a hospital by using a slit sampler (Casella, London) where the measured volume of air is impacted to the surface of culture medium contained in Petri dishes. Colonies were counted after 3 days incubation at 25 degrees C and 37 degrees C. Many species of hyphomycetes were identified. The main fungi isolated were Cladosporium sp (especially C. cladosporioides), Penicillium sp., Alternaria alternata, Aspergillus sp. (A. flavus, A. niger, A. fumigatus). The results show that the variability of the spore number is related to the ventilation. The number of spores found indoors seemed proportional to those present outdoors in naturally ventilated rooms. The results are quite different in the air-conditioned wards. Also, there might be a correlation between the counts and the activity and occupation of wards.


New auxin analogs with growth-promoting effects in intact plants reveal a chemical strategy to improve hormone delivery.
Plant growth depends on the integration of environmental cues and phytohormone-signaling pathways. During seedling emergence, elongation of the embryonic stem (hypocotyl) serves as a readout for light and hormone-dependent responses. We screened 10,000 chemicals provided exogenously to light-grown seedlings and identified 100 compounds that promote hypocotyl elongation. Notably, one subset of these chemicals shares structural characteristics with the synthetic auxins, 2,4-dichlorophenoxyacetic acid (2,4-D), and 1-naphthaleneacetic acid (1-NAA); however, traditional auxins (e.g., indole-3-acetic acid [IAA], 2,4-D, 1-NAA) have no effect on hypocotyl elongation. We show that the new compounds act as "proauxins" akin to prodrugs. Our data suggest that these compounds diffuse efficiently to the hypocotyls, where they undergo cleavage at varying rates, releasing functional auxins. To investigate this principle, we applied a masking strategy and designed a pro-2,4-D. Unlike 2,4-D alone, this pro-2,4-D enhanced hypocotyl elongation. We further demonstrated the utility of the proauxins by characterizing auxin responses in light-grown hypocotyls of several auxin receptor mutants. These new compounds thus provide experimental access to a tissue previously inaccessible to exogenous application of auxins. Our studies exemplify the combined power of chemical genetics and biochemical analyses for discovering and refining prohormone analogs with selective activity in specific plant tissues. In addition to the utility of these compounds for addressing questions related to auxin and light-signaling interactions, one can envision using these simple principles to study other plant hormone and small molecule responses in temporally and spatially controlled ways.


Design Rule for Improved Open-Circuit Voltage in Binary and Ternary Organic Solar Cells.
Mixing different compounds to improve functionality is one of the pillars of the organic electronics field. Here, the degree to which the charge transport properties of the constituent materials are simply additive when materials are mixed is quantified. It is demonstrated that in bulk heterojunction organic solar cells, hole mobility in the donor phase depends critically on the choice of the acceptor material, which may alter the energetic disorder of the donor. The same holds for electron mobility and disorder in the acceptor. The associated mobility differences can exceed an order of magnitude compared to pristine materials. Quantifying these effects by a state-filling model for the open-circuit voltage (VOC) of ternary Donor:Acceptor1:Acceptor2 (D:A1:A2) organic solar cells leads to a physically transparent description of the surprising, nearly linear tunability of the VOC with the A1:A2 weight ratio. It is predicted that in binary OPV systems, suitably chosen donor and acceptor materials can improve the device power conversion efficiency (PCE) by several percentage points, for example from 11 to 13.5% for a hypothetical state-of-the-art organic solar cell, highlighting the importance of this design rule.


Sterol regulatory element binding proteins in fungi: hypoxic transcription factors linked to pathogenesis.
Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors whose proteolytic activation is controlled by the cellular sterol concentration. Mammalian SREBPs are activated in cholesterol-depleted cells and serve to regulate cellular lipid homeostasis. Recent work demonstrates that SREBP is functionally conserved in fungi. While the ability to respond to sterols is conserved, fungal SREBPs are hypoxic transcription factors required for adaptation to a low-oxygen environment. In the fission yeast Schizosaccharomyces pombe, oxygen regulates the SREBP homolog Sre1 by independently controlling both its proteolytic activation and its degradation. SREBP is also required for adaptation to hypoxia in the human pathogens Cryptococcus neoformans and Aspergillus fumigatus. In these organisms, SREBP is required for virulence and resistance to antifungal drugs, making the SREBP pathway a potential target for antifungal therapy.


Attachment Strategies and Neuroendocrine Biomarkers in Obese Children.
Quality of the parent-infant relationship influences the mechanisms of development of the child's physiological stress regulation. This study explored associations between attachment strategies and both cortisol and thyroid stimulating hormone, hypothesized to be respectively a potential mediator and a potential intervening variable of the mother-child relationship in obese children. A sample of 83 obese children (46 boys), aged 10.9 (1.8) years was recruited from a child obesity clinic. Obesity was defined by body mass index percentile adjusted for age and sex. Metabolic biomarkers were measured by routine methods. Attachment strategies were assessed with self and parent-report questionnaires. Family functioning was assessed with parent-reported questionnaires (FACES-III). Multivariate linear regression analyses were performed. Type A, avoidant attachment strategies, had significant positive association with thyroid stimulating hormone levels and negative association with cortisol levels (R2 = 0.352). Type B, secure attachment strategies, had significant positive associations with both hypothyroidism and body mass index percentile (R2 = 0.541). 'Insecure attachment' (types A and C combined) strategies showed some evidence of positive association with thyroid stimulating hormone (R2 = 0.250). These findings suggest that there may be commonalities in the regulation of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. Processes involved in development of the type A attachment strategy appear to be associated with effects on the regulatory mechanisms of the hypothalamic-pituitary-adrenal axis. In obese children, different attachment strategies are associated with diverse metabolic profiles. How this may contribute to developing differentiated treatment approaches remains to be explored.


Policies to Improve Substance Use Disorder Treatment With Telehealth During the COVID-19 Pandemic and Beyond.
: The COVID-19 pandemic has created an urgent need to expand access to substance use disorder (SUD) treatment through telehealth. A more permanent adoption of tele-SUD treatment options could positively alter the future of SUD treatment. We identify four steps that will help to ensure a broader transition to telehealth will be successful in improving the health outcomes of patients with SUDs. These steps are: (1) investing in telehealth infrastructure to enable health care providers and patients to use telehealth; (2) training and equipping providers to provide SUD treatment through telehealth; (3) providing patients with the financial and social support, hardware, and training necessary to use telehealth; (4) making temporary changes to telehealth law and regulation permanent. We believe these 4 steps will be critical to initiating SUD treatment for many persons that have yet to receive it, and for preserving SUD treatment continuity for millions of other patients both during and after the pandemic.


Peri-implant tissue response following connective tissue and bone grafting in conjunction with immediate single-tooth replacement in the esthetic zone: a case series.
This case series evaluated the peri-implant tissue response following extraction and immediate placement and restoration of an implant in conjunction with subepithelial connective tissue grafting (SCTG) and bone grafting in the esthetic zone. Implant success rates and the peri-implant tissue response were also reported. Ten patients (four men, six women) with a mean age of 48 years (range, 35 to 70) underwent extraction and immediate tooth replacement with SCTG and were evaluated clinically and radiographically presurgically (T0), immediately after immediate tooth replacement and SCTG (T1), and at 3 months (T2), 6 months (T3), and 12 months (T4) after surgery. Data was analyzed using Friedman and Wilcoxon signed-ranks tests at the significance level of a = .05. At 1 year, all implants remained osseointegrated, with an overall mean marginal bone change of +0.10 mm and a mean facial gingival level change of -0.05 mm. Modified Plaque Index scores showed that patients were able to maintain a good level of hygiene throughout the study. Papilla Index scores indicated that at T4, more than 50% papilla fill was observed in 80% of all sites. The results of this case series suggest that, in addition to a favorable implant success rate and peri-implant tissue response, the facial gingival level around single immediately placed implants can also be maintained following connective tissue grafting when proper three-dimensional implant positioning is achieved and bone is grafted into the implant-socket gap.


oriP is essential for EBNA gene promoter activity in Epstein-Barr virus-immortalized lymphoblastoid cell lines.
During Epstein-Barr virus latent infection of B lymphocytes in vitro, six viral nuclear antigens (EBNAs) are expressed from one of two promoters, Cp or Wp, whose activities are mutually exclusive. Upon infection, Wp is initially active, followed by a switch to Cp for the duration of latency. In this study, the region upstream of Cp was analyzed for the presence of cis elements involved in regulating the activities of the EBNA gene promoters in established in vitro immortalized lymphoblastoid cell lines (LCLs). It was determined that oriP, the origin for episomal maintenance during latency, is essential for efficient transcription initiation from either Cp or Wp in LCLs, as well as in some Burkitt's lymphoma cell lines. Deletion of the EBNA2-dependent enhancer located upstream of Cp resulted in a ca. two- to fivefold reduction in Cp activity in the LCLs assayed. More extensive deletion of sequences upstream of Cp, including the EBNA2-dependent enhancer, resulted in nearly complete loss of Cp activity. This loss of activity was shown to correlate with deletion of two CCAAT boxes, a proximal CCAAT box located at bp -61 to -65 and a distal CCAAT box located at bp -253 to -257, upstream of Cp. Site-directed mutagenesis of these cis elements demonstrated that Cp activity is highly dependent on the presence of a properly positioned CCAAT box, with the dependence on the distal CCAAT box apparent only when the proximal CCAAT box was deleted or mutated. Deletion of the glucocorticoid response elements located at ca. bp -850 upstream of Cp did not result in a significant loss in activity. In general, deletions which diminished Cp activity resulted in induction of Wp activity, consistent with suppression of Wp activity by transcriptional interference from Cp. The identification of oriP and the EBNA2-dependent enhancer as the major positive cis elements involved in regulating Cp activity in LCL suggests that EBNA gene transcription is largely autoregulated by EBNA 1 and EBNA 2.


Physical properties of new ordered bimetallic phases M0.25Cd0.75PS3 (M = ZnII, NiII, CoII, MnII).
Four bimetallic phases of the thiophosphate family have been synthesized by the cationic exchange reaction using a freshly prepared K0.5Cd0.75PS3 precursor phase and methanolic solutions of nitrates of the divalent cations ZnII, NiII, CoII, and MnII. All the materials were characterized by FTIR, PXRD, SEM-EDXS and (in the case of the diamagnetic compounds) by solid state NMR. For the K0.5Cd0.75PS3 precursor, the X-ray powder diffraction data suggest a modification of the structure, while solid state NMR results confirm that this phase possesses an ordered arrangement of Cd vacancies. The cationic exchange reaction achieves a complete removal of potassium ions (no potassium detected by SEM-EDXS) and re-occupation of the vacancies by divalent cations. Therefore, the obtained compounds have an average composition of M0.25Cd0.75PS3 (M = ZnII, NiII, CoII, MnII) and possess an ordered distribution of the substituent cations. Even with the paramagnetic substitution level of 25%, antiferromagnetic behaviour is present in the phases with MnII, CoII and NiII, as evidenced by dc susceptibility and in the case of the MnII substituted phase by EPR. The cooperative magnetic interactions confirm the conclusion that the paramagnetic ions adopt an ordered arrangement. The analysis by broad band impedance spectroscopy allows to attribute the conductivity in these materials to charge movements in the layers due to the difference in electronegativity of the metal ions. Zn0.25Cd0.75PS3 is the phase that shows the highest conductivity values. Finally, the band gap energies of the bimetallic phases tend to be lower than those of the single-metal phases, probably due to an overlap of the band structures.


The Effect of Apneic Oxygenation on Reducing Hypoxemia During Rapid Sequence Induction and Intubation in the Acutely Ill or Injured.
Apneic oxygenation during intubation is the application of oxygen via a nasal cannula, which is left in place throughout laryngoscopy. The flow rate of oxygen is set to at least 15 L/min and theoretically reduces the risk of oxygen desaturation and hypoxemia during the procedure. Over the last 5 years, there have been several studies published on this topic with differing results. Despite conflicting results, use of apneic oxygenation is becoming more prevalent and is being implemented into standard operating procedures in some clinical settings. Because of the low risk of adding a nasal cannula during intubation and the potential benefit of reducing the incidence of hypoxemia and severe oxygen desaturation, it would be prudent to implement apneic oxygenation when available.


Excess-entropy scaling of dynamics for a confined fluid of dumbbell-shaped particles.
We use molecular simulation to study the ability of excess entropy scaling relationships to describe the kinetic properties of a confined molecular system. We examine a model for a confined fluid consisting of dumbbell-shaped molecules that interact with atomistically detailed pore walls via a Lennard-Jones potential. We obtain kinetic, thermodynamic, and structural properties of the system at three wall-fluid interaction strengths and over a temperature range that includes sub- and super-critical conditions. Four dynamic properties are considered: translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate scattering function. We carefully consider the reference state used to define the excess entropy of a confined fluid. Three ideal-gas reference states are considered, with the cases differentiated by the extent to which one-body spatial and orientational correlations are accounted for in the reference state. Our results indicate that a version of the excess entropy that includes information related to the one-body correlations in a confined fluid serves as the best scaling variable for dynamic properties. When adopting such a definition for the reference state, to a very good approximation, bulk and confined data for a specified dynamic property at a given temperature collapse onto a common curve when plotted against the excess entropy.


Delirium Incidence, Duration, and Severity in Critically Ill Patients With Coronavirus Disease 2019.
To determine delirium occurrence rate, duration, and severity in patients admitted to the ICU with coronavirus disease 2019. Retrospective data extraction study from March 1, 2020, to June 7, 2020. Delirium outcomes were assessed for up to the first 14 days in ICU. Two large, academic centers serving the state of Indiana. Consecutive patients admitted to the ICU with positive severe acute respiratory syndrome coronavirus 2 nasopharyngeal swab polymerase chain reaction test from March 1, 2020, to June 7, 2020, were included. Individuals younger than 18 years of age, without any delirium assessments, or without discharge disposition were excluded. Primary outcomes were delirium rates and duration, and the secondary outcome was delirium severity. Two-hundred sixty-eight consecutive patients were included in the analysis with a mean age of 58.4 years (sd, 15.6 yr), 40.3% were female, 44.4% African American, 20.7% Hispanic, and a median Acute Physiology and Chronic Health Evaluation II score of 18 (interquartile range, 13-25). Delirium without coma occurred in 29.1% of patients, delirium prior to coma in 27.9%, and delirium after coma in 23.1%. The first Confusion Assessment Method for the ICU assessment was positive for delirium in 61.9%. Hypoactive delirium was the most common subtype (87.4%). By day 14, the median number of delirium/coma-free were 5 days (interquartile range, 4-11 d), and median Confusion Assessment Method for the ICU-7 score was 6.5 (interquartile range, 5-7) indicating severe delirium. Benzodiazepines were ordered for 78.4% of patients in the cohort. Mechanical ventilation was associated with greater odds of developing delirium (odds ratio, 5.0; 95% CI, 1.1-22.2; p = 0.033) even after adjusting for sedative medications. There were no between-group differences in mortality. Delirium without coma occurred in 29.1% of patients admitted to the ICU. Delirium persisted for a median of 5 days and was severe. Mechanical ventilation was significantly associated with odds of delirium even after adjustment for sedatives. Clinical attention to manage delirium duration and severity, and deeper understanding of the virus' neurologic effects is needed for patients with coronavirus disease 2019.


Morbidity of left pancreatectomy when associated with multivisceral resection for abdominal mesenchymal neoplasms.
Resection of adjacent visceral organs is often required in surgery for abdominal mesenchymal tumors. To analyze the specific perioperative morbidity and mortality of a left pancreatectomy in multivisceral resections for mesenchymal tumors. This paper considered all patients treated at National Cancer Institute, Milan, Italy, from January 1997 to May 2009 for the resection of abdominal mesenchymal neoplasms requiring a concomitant left pancreatectomy. The extension of surgery, pathology of both the tumor and the pancreatic tissue, completeness of resection, administration of pre or postoperative treatments and postoperative outcome were analyzed. The overall survival of the entire population was also assessed. Fifty-seven patients affected by localized left retroperitoneal mesenchymal neoplasms or intra-abdominal gastrointestinal stromal tumors were identified. A macroscopically complete resection was achieved in all but 3 patients (5.3%) and the neoplastic involvement of pancreatic tissue was documented at pathology in 26 (45.6%) patients. Surgical postoperative complications occurred in 20 patients (35.1%); 7 patients (12.3%) developed a postoperative pancreatic fistula. With a median follow-up of the surviving patients of 32 months (interquartile range: 20-57 months), the overall survival at 5 years was 67.0%. Left pancreatic resection seemed to be a safe procedure, even when it is part of a multivisceral resection for abdominal mesenchymal neoplasms. When margins are crucial for cure, the left pancreas should then always be resected, independently of its direct infiltration.


Clostridioides difficile Infection in COVID-19 Hospitalized Patients: A Nationwide Analysis.
Clostridioides difficile infection (CDI) is a significant healthcare-associated infection with implications for patient morbidity, mortality, and healthcare costs. However, the connection between CDI and coronavirus disease 2019 (COVID-19) infection and its influence on patient outcomes remain uncertain. This study aimed to examine the association between CDI and COVID-19, specifically investigating whether CDI worsens outcomes in patients with COVID-19. By utilizing the extensive National Inpatient Sample (NIS) database and analyzing pertinent factors, this research endeavored to enhance our understanding of CDI within the context of COVID-19. The NIS database was searched for adult patients hospitalized with a primary diagnosis of COVID-19 infection in 2020. Patients with a secondary diagnosis of CDI were identified and separated into two groups based on CDI status. Baseline characteristics, Charlson Comorbidity Index (CCI), and outcomes were compared between the two groups using Chi-square and t-tests. Multivariate logistic and linear regressions were performed for the identification of independent predictors of CDI and mortality. A total of 1,045,125 COVID-19 hospitalizations were included, of which 4,920 had a secondary diagnosis of CDI. Patients with CDI and COVID-19 were older (mean age 69.9 vs. 64.2 years; P < 0.001), more likely to be female (54.1% vs. 47.1%; P < 0.001) and white (60% vs. 52.4%; P < 0.001). The CDI and COVID-19 group had a longer length of stay (14.1 vs. 7.42 days; P < 0.001), higher total hospital costs ($42,336 vs. $18,974; P < 0.001), and higher inpatient mortality (21.6% vs. 11%; P < 0.001) compared to the COVID-19 group without CDI. Patients in the CDI and COVID-19 group had a higher CCI score (51.7% with a score of 3 or more vs. 27.7%; P < 0.001), indicating a higher comorbidity burden. Multivariate logistic regression analysis revealed CDI was independently associated with increased mortality (odds ratio (OR) 1.37; P = 0.001) and showed that the female gender and several pre-existing comorbidities were associated with a higher likelihood of CDI. CDI is independently associated with increased mortality in patients admitted with COVID-19 infection. Female gender and several pre-existing comorbidities are independent predictors of CDI in COVID-19 patients.


[Malignant fibrous histiocytoma of the urinary bladder: a case report].
A case of malignant fibrous histiocytoma (MFH) of the urinary bladder was presented. A 59-year-old man visited our hospital with a chief complaint of gross hematuria with clots. Intravenous urography revealed a filling defect on the left side of the bladder. CT scan demonstrated that the tumor invaded the bladder wall deeply. The histology of the biopsy specimens obtained by TUR was suspected to be transitional cell carcinoma. Bleeding from the bladder was so severe that a lot of units of blood transfusion were required in order to compensate for anemia before total cystectomy was performed. The tumor was hemispheric, moderately demarcated, measuring 5.5 cm x 4.0 cm x 5.5 cm, and located at the posterior wall. The histological diagnosis was malignant fibrous histiocytoma, inflammatory type, with venous invasion of tumor cells. Postoperatively, the patient received 5 courses of combination chemotherapy of adriamycin (100 mg/body, day 1) and dacarbazine (400 mg/body, day 1-5). He is alive with no evidence of local and metastatic disease 24 months after operation, in spite of the poor prognosis predicted from the histological findings. MFH of the urinary bladder is very rare. We also made a brief review of prior reports on this disease.


[Gallbladder cancer in chronic calculous cholecystitis].
127 cases of gallbladder cancer are analysed. Among them there were 99(78%) women and 28(22%) men. The majority of the patients were at the age from 61 to 70 years; 19 (15%) patients were younger than 50 years. Mean average age of the patients was 61.7 years. Chronic calculous cholecystitis was detected in 116 (91.3%) patients. In 75 (59%) patients the duration of the disease exceeded 5 years. Women suffer more frequently than men because of higher rate of calculous cholecystitis in women. Radical surgery was possible only in 51 of 97 (52.7%) patients as a result of late diagnosis of the cancer. Cholecystectomy was performed in 32 patients, cholecystectomy in combination with liver resection in 9 patients, tumor removal in borderes of the healthy tissues in 10 patients. Palliative operations were performed in 46 (36.2%) patients. Long-term results of the surgery were followed up in 93 patients. 5 year survival after the radical surgery was 40%, 10 year survival--20%. Mean survival after the palliative surgery was 7 months. Gallbladder cancer is difficult for diagnosis and the results of its treatment are unsatisfactory. Timery surgery of chronic calculous cholecystitis is important in prevention of gallbladder cancer.


Chronic kidney disease progression and outcome according to serum phosphorus in mild-to-moderate kidney dysfunction.
Several factors might alter serum phosphate homeostasis and induce hyperhosphatemia in patients with chronic kidney disease (CKD) not requiring dialysis. However, whether and to what extent hyperphosphatemia is associated with a poor prognosis in different CKD patient groups remain to be elucidated. We utilized the "Prevenzione Insufficienza Renale Progressiva" (PIRP) database, a large project sponsored by the Emilia-Romagna Health Institute. PIRP is a collaborative network of nephrologists and general practitioners located in the Emilia-Romagna region, Italy, aimed at increasing awareness of CKD complications and optimizing CKD patient care. We identified 1716 patients who underwent a GFR and serum phosphorous assessment between 2004 and 2007. We tested whether phosphate levels ≥4.3 mg/dl are associated with the risk of CKD progression or all causes of death. Older age and male sex were associated with lower phosphate levels. Instead, higher phosphate levels were noted in patients with diabetes. Patients with phosphate levels ≥4.3 mg/dl were at an increased risk of starting dialysis or dying (hazard ratio 2.04; 95% confidence interval [1.44, 2.90]). Notably, subgroup analyses revealed that the magnitude of the risk associated with hyperphosphatemia varied depending on age, sex, diabetes, and different stages of CKD. These analyses lend support to the hypothesis that phosphorous abnormalities might have a negative effect on the residual renal function and prognosis in different groups of CKD patients. However, the risk associated with hyperphosphatemia might vary in specific CKD patient subgroups.


Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease.
IL-24 is a member of the IL-10 family of cytokines. In this study, we investigated IL-24 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-24 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-24 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-24 mRNA and protein expression was determined by real-time PCR and ELISA, respectively. AP-1 and C/EBP DNA-binding activity and IL-24 promoter activity were assessed by EMSA analysis and a reporter gene assay, respectively. IL-24 mRNA expression was significantly elevated in active lesions from patients who have ulcerative colitis and Crohn's disease. Colonic SEMFs were identified as a major source of IL-24 in the mucosa. IL-1beta, but not IL-17A, TNF-alpha, or IFN-gamma, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1beta-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-beta. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1beta. IL-24 induced JAK1/STAT-3 phosphorylation and SOCS3 expression in HT-29 colonic epithelial cells. IL-24 did not modulate the proliferation of HT-29 cells, but significantly increased the mRNA expression of membrane-bound mucins (MUC1, MUC3, and MUC4). IL-24 derived from colonic SEMFs acts on colonic epithelial cells to elicit JAK1/STAT-3 activation and the expression of SOCS3 and mucins, supporting their suppressive effects on mucosal inflammation in IBD.


Negative consequences of uncorrected hearing loss--a review.
Hearing loss gives rise to a number of disabilities. Problems in recognizing speech, especially in difficult environments, give rise to the largest number of complaints. Other kinds of disabilities may concern the reduced ability to detect, identify and localize sounds quickly and reliably. Such sounds may be warning or alarm signals, as well as music and birds singing. The communicative disability affects both hearing-impaired people and other people in their environment--family members, fellow workers, etc. Hearing-impaired people are not always aware of all the consequences of the impairment; they do not always know what they are missing. Several studies have shown that uncorrected hearing loss gives rise to poorer quality of life, related to isolation, reduced social activity, and a feeling of being excluded, leading to an increased prevalence of symptoms of depression. These findings indicate the importance of early identification of hearing loss and offers of rehabilitative support, where the fitting of hearing aids is usually an important component. Several studies also point to a significant correlation between hearing loss and loss of cognitive functions. Most of these studies show such a correlation without being able to show whether the hearing loss caused the reduction in cognitive performance or if both the hearing loss and the cognitive decline are parts of a common, general age-related degeneration. A couple of these studies, however, indicate that the uncorrected hearing loss may be the cause of cognitive decline. Whichever alternative is true, the correlation should be seen as a clear indication for early hearing aid fitting for those needing it. Monaural hearing aid fitting in subjects with bilateral hearing loss may give rise to a reduced ability to recognize speech presented to the unaided ear, the so-called late-onset auditory deprivation effect. This functional decline is reversible in some but not all subjects after fitting of a hearing aid also on the previously unaided ear.


Heavy metals in plants in constructed and natural wetlands: concentration, accumulation and seasonality.
The accumulation of heavy metals in plants is a function of uptake capacity and intracellular binding sites. The concentrations of heavy metals in plants growing in constructed wetlands vary considerably between species and systems but in general, the concentrations are within the range commonly found in natural stands. The highest concentrations are mostly found in roots, followed by rhizomes, leaves and stems. Unfortunately, concentration values are commonly used to evaluate the 'accumulation' of heavy metals, but this approach is not correct. In order to evaluate heavy metal accumulation, the biomass of particular plant parts must be taken into consideration. In addition, there are two other factors, which need to be taken into consideration when accumulation is evaluated, namely seasonality and distribution within the plant shoot. It has been found that the seasonal distribution of heavy metals in the biomass varies between heavy metals and mostly does not follow the pattern known for nutrients. In addition, the concentration and accumulation of heavy metals vary considerably within the shoot and this fact should be taken into consideration when analyses are carried out.


Classic Chromophobe Renal Cell Carcinoma Incur a Larger Number of Chromosomal Losses Than Seen in the Eosinophilic Subtype.
Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and prominent cell membranes (pale cells) are characteristic for classic chRCC. Classic and eosinophilic variants were defined in 42 Swiss chRCCs, 119 Japanese chRCCs and in whole-slide digital images of 66 chRCCs from the Cancer Genome Atlas (TCGA) kidney chromophobe (KICH) dataset. 32 of 42 (76.2%) Swiss chRCCs, 90 of 119 (75.6%) Japanese chRCCs and 53 of 66 (80.3%) TCGA-KICH were classic chRCCs. There was no survival difference between eosinophilic and classic chRCC in all three cohorts. To identify a genotype/phenotype correlation, we performed a genome-wide CNV analysis using Affymetrix OncoScan® CNV Assay (Affymetrix/Thermo Fisher Scientific, Waltham, MA, USA) in 33 Swiss chRCCs. TCGA-KICH subtypes were compared with TCGA CNV data. In the combined Swiss and TCGA-KICH cohorts, losses of chromosome 1, 2, 6, 10, 13, and 17 were significantly more frequent in classic chRCC (p < 0.05, each), suggesting that classic chRCC are characterized by higher chromosomal instability. This molecular difference justifies the definition of two chRCC variants. Absence of pale cells could be used as main histological criterion to define the eosinophilic variant of chRCC.


Stroke center designation can be achieved by small hospitals: the Massachusetts experience.
In January 2005, the Massachusetts Department of Public Health announced the designation of approved hospitals as Primary Stroke Services (PSS), based on verifiable demonstration of care pathways for acute ischemic stroke. We investigated the effect of hospital characteristics on participation in the PSS program.In 2003, the Massachusetts Department of Public Health surveyed 72 Massachusetts hospitals on their readiness for PSS designation. Survey results and PSS participation rates were compared among hospitals categorized by bed size (<150 vs. > or =150 beds), rural location, and major teaching hospital status. In answer to 2003 survey questions, smaller hospitals (n = 35) were less likely than larger hospitals to have acute stroke teams (P = 0.01), 24-hour rapid computed tomography scanning and interpretation (P = 0.0006), 24-hour neurosurgery coverage (P = 0.001), and a stroke registry (P = 0.007). Smaller hospitals were less likely to be interested in PSS application in 2003 (P = 0.008), and less likely to be designated PSS when ambulance rerouting to PSS hospitals began in July 2005 (P < 0.0001). Despite this, by December 2005 the majority of Massachusetts hospitals (66/71, 92%) had achieved PSS designation. Smaller hospitals were more likely to use telemedicine to access acute stroke teams (P = 0.003).Many smaller hospitals are able to acquire the resources needed for provision of acute stroke care, despite initial limitations. Innovative strategies, such as telemedicine consultation and transfer agreements, may successfully allow smaller hospitals to satisfy Brain Attack Coalition criteria for primary stroke centers.


A versatile micro-mechanical tester for actin stress fibers isolated from cells.
Conventional atomic force microscopy is one of the major techniques to evaluate mechanical properties of cells and subcellular components. The use of a cantilever probe for sample manipulation within the vertical plane often makes absolute positioning of the probe, subject to thermal drift, difficult. In addition, the vertical test is unable to observe changes in the sample structure responsible for mechanical behavior detected by the probe. In the present study, an alternative mechanical tester was developed that incorporated a pair of micro-needles to manipulate a sample in a project plane, allowing acquisition of the accurate probe position and entire sample image. Using a vision-based feedback control, a micro-needle driven by a piezo actuator is moved to give user-defined displacements or forces to sample. To show its usefulness and versatility, three types of viscoelastic measurements on actin stress fibers isolated from smooth muscle cells were demonstrated: strain rate-controlled tensile tests, relaxation tests and creep tests. Fluorescence imaging of the stress fibers using Qdots over the course of the measurements, obtained through multiple image detectors, was also carried out. The technique described here is useful for examining the quantitative relationship between mechanical behavior and related structural changes of biomaterials.