Analysis of Anxiety, Depression and Aggression in Patients Attending Pain Clinics.
The aim of the study was to measure the frequency of such emotional disturbances as anxiety, depression and aggression among patients treated in a pain clinic, as well as assess the factors contributing to such disorders. Research was conducted from January 2014 to April 2018 and involved patients treated in two pain clinics in the city of Warsaw, Poland. The study used the Hospital Anxiety and Depression Scale-Modified Version (HADS-M) and the Numerical Rating Scale (NSR). 1025 patients were recruited. The main reasons for their attending the pain clinic were osteoarticular pain (43.61%) and neuropathic pain (41.56%). Emotional disturbances in the form of anxiety were diagnosed in 32.39% of all the patients, depression in 17.85%, and aggression in 46.15%. The factors determining the level of anxiety in the study group were: sex, age, pain intensity and the lack of pharmacological treatment. Depression was determined by sex, pain intensity and the time of treatment in the clinic, while aggression by age and pain intensity.


Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia.
Background: Whether to continue renin−angiotensin−aldosterone system inhibitor (RAASi) therapy in patients with hyperkalemia remains a clinical challenge, particularly in patients with heart failure (HF), where RAASis remain the cornerstone of treatment. We investigated the incidence of dose reduction or the cessation of RAASis and evaluated the threshold of serum potassium at which cessation alters the risk−benefit balance. Methods: This retrospective analysis of a Japanese nationwide claims database investigated treatment patterns of RAASis over 12 months after the initial hyperkalemic episode. The incidences of the clinical outcomes of patients with RAASi (all ACEi/ARB/MRA) or MRA-only cessation (vs. non-cessation) were compared via propensity score-matched patients. A cubic spline regression analysis assessed the hazard of death resulting from treatment cessation vs. no cessation at each potassium level. Results: A total of 5059 hyperkalemic HF patients were identified; most received low to moderate doses of ACEis and ARBs (86.9% and 71.5%, respectively) and low doses of MRAs (76.2%). The RAASi and MRA cessation rates were 34.7% and 52.8% at 1 year post-diagnosis, while the dose reduction rates were 8.4% and 6.5%, respectively. During the mean follow-up of 2.8 years, patients who ceased RAASi or MRA therapies were at higher risk for adverse outcomes; cubic spline analysis found that serum potassium levels of <5.9 and <5.7 mmol/L conferred an increased mortality risk for RAASi and MRA cessation, respectively. Conclusions: Treatment cessation/dose reduction of RAASis are common among HF patients. The risks of RAASi/MRA cessation may outweigh the benefits in patients with mild to moderate hyperkalemia.


The Consistency Factor and the Viscosity Exponent of Soybean-Protein-Isolate/Wheat-Gluten/Corn-Starch Blends by Using a Capillary Rheometry.
Blends with different proportions of protein or starch show different rheological behaviors, which may be related to the fibrous structure formation of extruded textured plant proteins. The consistency factor K and the viscosity exponent n of soybean-protein-isolate (SPI)/wheat-gluten (WG)/corn-starch (CS) blends were investigated through capillary rheometry. All blends exhibited shear-thinning behavior at 80 °C and 50% moisture. The CS content in SPI/CS blends or WG content in SPI/WG blends showed a positive relation to the viscosity exponent n and a negative relation to the consistency factor K. However, there was no correlation between the CS content in WG/CS blends and n or K. The coefficient of determination of the linear relationship between K and mass fraction in SPI/CS, SPI/WG/CS, SPI/WG and WG/CS decreased from 0.872 to 0.073. SPI was more likely to form a non-interactive structure, while wheat-gluten was more likely to form a highly interactive structure. It turned out that the materials with globular morphology, such as soybean-protein-isolate and corn-starch, are likely to form a non-interactive structure.


Biliary tract complications in human orthotopic liver transplantation.
The results of 393 consecutive orthotopic liver transplants in 313 patients were reviewed to determine the incidence of primary biliary tract complications. There were 52 biliary tract complications in 393 grafts (13.2%), and 5 directly related deaths. Choledochojejunostomy over an internal stent to a Roux-en-Y limb of proximal jejunum (RYCJ-S) was the most frequently used technique (175 cases) and the most successful with only 9 technical failures (5.2%). Choledochocholedochostomy over a T tube (CC-T) was used in 159 cases and was successful in all but 20 cases (12.6%). Other methods of reconstruction were associated with high failure rates or technical complexity that do not justify their use. Biliary leak and obstruction were the most common complications. Leakage after CC-T at the T tube exit site was usually directly repaired, but anastomotic leakage required conversion to RYCJ-S. Obstruction may be relieved by percutaneous balloon dilatation but definitive treatment also usually required conversion to RYCJ-S. The most common complication after RYCJ-S is functional obstruction by a retained stent, which has a low morbidity but may necessitate surgical removal. Anastomotic leaks, which occurred in 2 cases, were successfully managed by revision of the choledochojejunostomy.


Microalgal biomass production pathways: evaluation of life cycle environmental impacts.
Microalgae are touted as an attractive alternative to traditional forms of biomass for biofuel production, due to high productivity, ability to be cultivated on marginal lands, and potential to utilize carbon dioxide (CO2) from industrial flue gas. This work examines the fossil energy return on investment (EROIfossil), greenhouse gas (GHG) emissions, and direct Water Demands (WD) of producing dried algal biomass through the cultivation of microalgae in Open Raceway Ponds (ORP) for 21 geographic locations in the contiguous United States (U.S.). For each location, comprehensive life cycle assessment (LCA) is performed for multiple microalgal biomass production pathways, consisting of a combination of cultivation and harvesting options. Results indicate that the EROIfossil for microalgae biomass vary from 0.38 to 1.08 with life cycle GHG emissions of -46.2 to 48.9 (g CO2 eq/MJ-biomass) and direct WDs of 20.8 to 38.8 (Liters/MJ-biomass) over the range of scenarios analyzed. Further anaylsis reveals that the EROIfossil for production pathways is relatively location invariant, and that algae's life cycle energy balance and GHG impacts are highly dependent on cultivation and harvesting parameters. Contrarily, algae's direct water demands were found to be highly sensitive to geographic location, and thus may be a constraining factor in sustainable algal-derived biofuel production. Additionally, scenarios with promising EROIfossil and GHG emissions profiles are plagued with high technological uncertainty. Given the high variability in microalgae's energy and environmental performance, careful evaluation of the algae-to-fuel supply chain is necessary to ensure the long-term sustainability of emerging algal biofuel systems. Alternative production scenarios and technologies may have the potential to reduce the critical demands of biomass production, and should be considered to make algae a viable and more efficient biofuel alternative.


Abnormal cognitive effort allocation and its association with amotivation in first-episode psychosis.
Abnormal effort-based decision-making represents a potential mechanism underlying motivational deficits (amotivation) in psychotic disorders. Previous research identified effort allocation impairment in chronic schizophrenia and focused mostly on physical effort modality. No study has investigated cognitive effort allocation in first-episode psychosis (FEP). Cognitive effort allocation was examined in 40 FEP patients and 44 demographically-matched healthy controls, using Cognitive Effort-Discounting (COGED) paradigm which quantified participants' willingness to expend cognitive effort in terms of explicit, continuous discounting of monetary rewards based on parametrically-varied cognitive demands (levels N of N-back task). Relationship between reward-discounting and amotivation was investigated. Group differences in reward-magnitude and effort-cost sensitivity, and differential associations of these sensitivity indices with amotivation were explored. Patients displayed significantly greater reward-discounting than controls. In particular, such discounting was most pronounced in patients with high levels of amotivation even when N-back performance and reward base amount were taken into consideration. Moreover, patients exhibited reduced reward-benefit sensitivity and effort-cost sensitivity relative to controls, and that decreased sensitivity to reward-benefit but not effort-cost was correlated with diminished motivation. Reward-discounting and sensitivity indices were generally unrelated to other symptom dimensions, antipsychotic dose and cognitive deficits. This study provides the first evidence of cognitive effort-based decision-making impairment in FEP, and indicates that decreased effort expenditure is associated with amotivation. Our findings further suggest that abnormal effort allocation and amotivation might primarily be related to blunted reward valuation. Prospective research is required to clarify the utility of effort-based measures in predicting amotivation and functional outcome in FEP.


Seizure and Sudden Unexpected Death in Epilepsy (SUDEP) characteristics in an urban UK intellectual disability service.
This study identifies epilepsy-related characteristics and SUDEP risk factors in people with epilepsy (PWE) attending an urban community ID service in the UK where managing epilepsy is not part of the service remit, to understand the care provided to this vulnerable population. An electronic database search in a north London community ID service (catchment population approx. 290,000) identified relevant ID/epilepsy characteristics in PWE to compare those with mild ID to moderate-profound ID. The SUDEP and Seizure Safety Checklist ("Checklist"), was administered to patients and families/carers. Risk management data was compared to similar data from Cornwall UK where PWE are supported within the ID service and the Checklist is used annually. One fifth (137/697) of people attending the service had epilepsy. Over 3/4 had moderate-profound ID. Neurodevelopmental disorders were coexistent in 2/3, psychiatric conditions in 1/3 (1/4 of which was psychosis). The mean number of anti-seizure drugs was 1.45 ± 0.98, and 1/4 were taking psychotropic medications. Over a third did not have an epilepsy care plan. None contacted (n = 103) had SUDEP awareness. The median number of Checklist risk factors was seven (IQR 4.5-9). A third had experienced seizures lasting >5 min or status epilepticus. In comparison to the Cornish ID data significant differences were evident in four of seven modifiable risk factors. This real world study highlights the complexity and risks among PWE and ID. The lack of a "joined up" approach can undermine the safety of this vulnerable population. Person-centred risk communication and care plans are easily achievable and essential.


Aging and Oral Care: An Observational Study of Characteristics and Prevalence of Oral Diseases in an Italian Cohort.
Background: Poor oral health is a common condition in patients suffering from dementia. Several aspects of this systemic pathology contribute to causing oral problems: cognitive impairment, behavior disorders, communication and, motor skills deterioration, low levels of cooperation and medical-nursing staff incompetency in the dental field. Objectives: The objectives of this study were to evaluate the prevalence and the characteristics of oral pathology in a demented elderly population, as well as to check the association between the different degree of dementia and the oral health condition of each patient. Materials and Methods: In this observational study (with cross-sectional design) two groups of elderly patients suffering from dementia, living in two different residential care institutions were recruited. The diagnosis of dementia of each included patient was performed using the Clinical Dementia Rating Scale. In order to evaluate the oral health condition of the included subjects, each patient underwent a physical examination of the oral cavity, during which different clinical parameters were analyzed (number of remaining teeth, oral mucosa, periodontal tissues, bone crests). To each parameter, a score was assigned. Spearman's Rho test was used. Results: Regarding the prevalence of oral pathology in elderly suffering from dementia, it emerged that 20.58% of the included patients had mucosal lesions and/or new mucosal formations (in most cases undiagnosed and therefore untreated). The prevalence of periodontal disease was equal to 82.35% and a marked clinically detectable reabsorption of bone crests was found in almost all patients (88.23%). 24.13% of patients, who underwent the oral examination, had totally edentulous maxillae and/or with retained roots, without prosthetic rehabilitations. The correlation index r showed the presence of a linear correlation (inverse relationship) between the degree of dementia and the state of health of the oral cavity of each patient. Conclusions: Several factors contribute to poor oral health in the elderly suffering from dementia: cognitive functions deterioration, behavioral disorders and inadequate medical-staff nursing training on oral hygiene. This study also demonstrated that the lower the dementia degree is, the lower tends to be the oral health status. In order to guarantee a complete assistance to these patients, residential care institutions should include in their healthcare program specific dental protocols.


Isolation and characterization of the mycobacterial phagosome: segregation from the endosomal/lysosomal pathway.
Mycobacteria have the ability to persist within host phagocytes, and their success as intracellular pathogens is thought to be related to the ability to modify their intracellular environment. After entry into phagocytes, mycobacteria-containing phagosomes acquire markers for the endosomal pathway, but do not fuse with lysosomes. The molecular machinery that is involved in the entry and survival of mycobacteria in host cells is poorly characterized. Here we describe the use of organelle electrophoresis to study the uptake of Mycobacterium bovis bacille Calmette Guerin (BCG) into murine macrophages. We demonstrate that live, but not dead, mycobacteria occupy a phagosome that can be physically separated from endosomal/lysosomal compartments. Biochemical analysis of purified mycobacterial phagosomes revealed the absence of endosomal/lysosomal markers LAMP-1 and beta-hexosaminidase. Combining subcellular fractionation with two-dimensional gel electrophoresis, we found that a set of host proteins was present in phagosomes that were absent from endosomal/lysosomal compartments. The residence of mycobacteria in compartments outside the endosomal/lysosomal system may explain their persistence inside host cells and their sequestration from immune recognition. Furthermore, the approach described here may contribute to an improved understanding of the molecular mechanisms that determine the intracellular fate of mycobacteria during infection.


Evaluation of skin regeneration after burns in vivo and rescue of cells after thermal stress in vitro following treatment with a keratin biomaterial.
Thermal burns typically display an injury pattern dictated by the transfer of the thermal energy into the skin and underlying tissues and creation of three zones of injury represented by a necrotic zone of disrupted cells and tissue, an intermediate zone of injured and dying cells, and a distant zone of stressed cells that will recover with proper treatment. The wound healing capabilities of a keratin biomaterial hydrogel were studied in two pilot studies, one using a chemical burn model in mice and the other a thermal burn model in swine. In both studies, keratin was shown to prevent enlargement of the initial wound area and promote faster wound closure. Interestingly, treating thermally stressed dermal fibroblast in culture demonstrated that soluble keratin was able to maintain cell viability and promote proliferation. Separation of so-called alpha and gamma fractions of the keratin biomaterial had differential effects, with the gamma fraction producing more pronounced cell survival and recovery. These results suggest that the gamma fraction, composed essentially of degraded alpha keratin proteins, may facilitate cell rescue after thermal injury. Treatment of burns with gamma keratin may therefore represent a potential therapy for wounds with an intermediate zone of damaged tissue that has the potential to contribute to spontaneous healing.


The rotunda2 mutants identify a role for the LEUNIG gene in vegetative leaf morphogenesis.
Leaf development in Arabidopsis thaliana is considered to be a two-step process. In the first step, a leaf primordium is formed that involves a switch from indeterminate to leaf developmental fate in the shoot apical meristem cells. The second step, known as leaf morphogenesis, consists of post-initiation developmental events such as patterned cell proliferation, cell expansion, and cell differentiation. The results are presented of the molecular and genetic analyses of the rotunda2 (ron2) mutants of Arabidopsis, which were isolated based on their wide and serrated vegetative leaf lamina. The RON2 gene was positionally cloned and was identical to LEUNIG (LUG); it encodes a transcriptional co-repressor that has been described to affect flower development. Morphological and histological analyses of expanded leaves indicated that RON2 (LUG) acts at later stages of leaf development by restricting cell expansion during leaf growth. Real-time reverse-transcription polymerase chain reaction was used to quantify the expression of KNOX, WUSCHEL, YABBY3, LEAFY, ASYMMETRIC LEAVES, and GIBBERELLIN OXIDASE genes in expanding and fully expanded rosette leaf laminas of the wild type and ron2 and lug mutants. SHOOTMERISTEMLESS was expressed in wild-type leaves and down-regulated in the mutants. The results indicate that RON2 (LUG) has a function in later stages of leaf development.


New doxorubicin nanocarriers based on cyclodextrins.
Polymeric nanoparticles and fibrin gels (FBGs) are attractive biomaterials for local delivery of a variety of biotherapeutic agents, from drugs to proteins. We combined these different drug delivery approaches by preparing nanoparticle-loaded FBGs characterized by their intrinsic features of drug delivery rate and antiproliferative/apoptotic activities. Inclusion complexes of doxorubicin (DOXO) with oligomeric β-cyclodextrins (oCyD) functionalized with different functional groups were studied. These nanocarriers were able to interact with FBGs as shown by a decreased release rate of DOXO. One of these complexes, oCyDNH2/DOXO, demonstrated good antiproliferative and apoptotic activity in vitro, reflecting a higher drug uptake by cells. As hypothesized, the nanocarrier/FBG complexes showed a lower drug release rate than similar FBGs loaded with the corresponding non-functionalized oCyD/DOXO. Taken together, our results provide experimental evidence that oCyDNH2/DOXO complexes may be useful components in enhanced FBGs and further build support for the great promise these complex molecules hold for clinical use in localized anticancer therapy of inoperable or surgically removable tumors of different histological origin.


Diagnostic utility of nasogastric tube aspiration and the ratio of blood urea nitrogen to creatinine for distinguishing upper and lower gastrointestinal tract bleeding.
The American College of Gastroenterology's 2016 clinical guidelines for treating lower gastrointestinal (GI) tract bleeding recommends evaluating of nasogastric tube aspiration and the ratio of blood urea nitrogen (BUN) to creatinine to differentiate upper from lower GI bleeds. However, the evidence base to support recommending these 2 diagnostic variables is low. This study aimed to evaluate the diagnostic utility of nasogastric tube aspiration and the BUN-to-creatinine ratio for distinguishing between upper and lower GI bleeding. We conducted a systematic review of the literature to find studies reporting the diagnostic precision of the BUN-to-creatinine ratio and nasogastric aspiration in patients with GI bleeding without hematemesis. The sensitivity of both methods is low for detecting upper GI bleeding. Both blood in the aspirate and an elevated BUN-to-creatinine ratio significantly increase the probability of finding an upper GI source. The positive likelihood ratio varies from positive 2 to 11. However, the sensitivity of both tests for a diagnosis of upper GI bleeding is very low (negative likelihood ratio of 0.6). A negative result on either of the 2 diagnostic tests provides little useful information and does not firmly rule out an upper GI bleed. Nasogastric tube aspiration cannot be recommended for distinguishing between upper and lower GI bleeding. If the diagnosis is in doubt, endoscopic exploration of the upper GI tract is necessary.


Update on Ultrasound Diagnostic Criteria and New Ultrasound Severity and Activity Scorings of Hidradenitis Suppurativa: Modified SOS-HS and US-HSA.
Hidradenitis suppurativa (HS) is a devasting autoimmune cutaneous disease that affects the hair follicles and can clinically present palpable nodules, abscesses, and tunnels (fistulas), usually in the intertriginous regions. It has been widely reported that color Doppler ultrasound can detect subclinical abnormalities and stage the severity of the disease more accurately. Nevertheless, the ultrasound diagnostic criteria were reported with 15 MHz 10 years ago, and now it is possible to detect early anatomical abnormalities in HS using 70 MHz. Thus, an update of the ultrasonographic diagnostic criteria is needed. The most widely used sonographic staging of severity of HS (SOS-HS) includes the number of affected regions, besides counting the number of key lesions like pseudocysts, fluid collections, and tunnels; however, the total number of affected regions may fit better in an activity scoring. Furthermore, a high number of tunnels or communicated tunnels can complicate the management and may indicate an even more urgent treatment, which should be considered in the severity classification. To date, no hidradenitis scoring of activity has been reported in the literature, making it difficult to track the degree of inflammation under treatment objectively. Therefore, two new scorings are proposed. The first is an updated sonographic scoring of severity called modified SOS-HS (mSOS-HS), and the second is an activity ultrasound scoring of HS called US-HSA. Both staging systems can provide better anatomical information for discriminating the categories and, therefore, selecting more appropriate treatments and supporting research and clinical trials by giving more objective anatomical tools in real-world settings.


[Effect of plague "murine" toxin on activity of antioxidant system in cells of experimental animals].
To study nature of changes in components of glutathione disulfide system of experimental animals influenced by plague "murine" toxin. Total glutathione level as well as levels of oxidated (G-SS-G) and reduced (GSH) forms of glutathione, activity of glutathione reductase and glutathione peroxidase in erythrocytes of Mongolian gerbils (Meriones unguiculatus), mice and guinea pigs were studied. Sharp decrease of reduced glutathione level as well as increase of oxidated glutathione level were observed in all experimental animal species after intraperitoneal administration of plague "murine" toxin. Changes in levels of GSH and G-SS-G were followed with decrease of total glutathione level. Activity of glutathione peroxidase was decreased in mice and Mongolian gerbils. There was increase of activity of this enzyme in guinea pigs. Level of glutathione reductase was decreased in all studied animals. Performed studies allow to hypothesize that oxidation of thiolic functional groups in organisms of animals as a result of H2O2 generation has important role during plague intoxication (administration of sublethal doses of plague "murine" toxin).


Quantitative metabolic profiling based on gas chromatography.
The quantitative metabolic profiles of volatilizable components of human biological fluids, particularly urinary organic acids, is reviewed, with emphasis on the use of gas-chromatography/mass spectrometer/computer systems. Various definitions of metabolic profiling are considered and techniques for obtaining such profiles are discussed. The role of computer processing of such data is examined, and statistical techniques for treating quantitative metabolic profiles are suggested.


[Spontaneous rupture of the spleen during chronic pancreatitis. A report on two new cases (author's transl)].
Spontaneous spleen rupture during chronic pancreatitis is scarcely seen. About 2 personal cases, the authors study 15 published cases. The spleen break can occur in patients with a known chronic pancreatitis, or with pancreatic signs, or without any symptomatology. Diagnosis is hard: spontaneous spleen break often looks like an acute pancreatitis. The high frequency of associated left pleural effusion is significant. Arteriography is helpful when it is done. Splenectomy, often too late, is the right treatment.


Epithelial structure revealed by chemical dissection and unembedded electron microscopy.
Cytoskeletal structures obtained after extraction of Madin-Darby canine kidney epithelial cell monolayers with Triton X-100 were examined in transmission electron micrographs of cell whole mounts and unembedded thick sections. The cytoskeleton, an ordered structure consisting of a peripheral plasma lamina, a complex network of filaments, and chromatin-containing nuclei, was revealed after extraction of intact cells with a nearly physiological buffer containing Triton X-100. The cytoskeleton was further fractionated by extraction with (NH4)2SO4, which left a structure enriched in intermediate filaments and desmosomes around the nuclei. A further digestion with nuclease and elution with (NH4)2SO4 removed the chromatin. The stable structure that remained after this procedure retained much of the epithelial morphology and contained essentially all of the cytokeratin filaments and desmosomes and the chromatin-depleted nuclear matrices. This structural network may serve as a scaffold for epithelial organization. The cytoskeleton and the underlying nuclear matrix intermediate filament scaffold, when examined in both conventional embedded thin sections and in unembedded whole mounts and thick sections, showed the retention of many of the detailed morphological aspects of the intact cells, which suggests a structural continuum linking the nuclear matrix, the intermediate filament network, and the intercellular desmosomal junctions. Most importantly, the protein composition of each of the four fractions obtained by this sequential procedure was essentially unique. Thus, the proteins constituting the soluble fraction, the cytoskeleton, the chromatin fraction, and the underlying nuclear matrix-intermediate filament scaffold are biochemically distinct.


Mechanistic Explanation of the pH Dependence and Onset Potentials for Hydrocarbon Products from Electrochemical Reduction of CO on Cu (111).
Energy and environmental concerns demand development of more efficient and selective electrodes for electrochemical reduction of CO2 to form fuels and chemicals. Since Cu is the only pure metal exhibiting reduction to form hydrocarbon chemicals, we focus here on the Cu (111) electrode. We present a methodology for density functional theory calculations to obtain accurate onset electrochemical potentials with explicit constant electrochemical potential and pH effects using implicit solvation. We predict the atomistic mechanisms underlying electrochemical reduction of CO, finding that (1) at acidic pH, the C1 pathway proceeds through COH to CHOH to form CH4 while C2 (C3) pathways are kinetically blocked; (2) at neutral pH, the C1 and C2 (C3) pathways share the COH common intermediate, where the branch to C-C coupling is realized by a novel CO-COH pathway; and (3) at high pH, early C-C coupling through adsorbed CO dimerization dominates, suppressing the C1 pathways by kinetics, thereby boosting selectivity for multi-carbon products.


A fluorescent-switch-based computing platform in defending information risk.
A molecular computing platform to defend against illegal information theft and invasion is obtained by the rational control of chemical reaction sequences in a newly prepared multiswitchable fluorophore 2-(4-aminophenylethylyl)-5-methoxy-2-(2-pyridyl)thiazole. Some of the fluorescent states with distinct recognition features are only activated through input-sequence-sensitive conversions. Chemically encoded user identity information can then be transmitted from a sequential logic unit to a combinational logic circuit, and hence, result in user-specific digital functionalities. The user's password entry is authorized prior to each computing step to check not only the user's identity, but also to reconfigure the molecular platform from the standby state to the corresponding operational state. Illegal accesses to the molecular computing platform are unable to activate the operation of the trusted users due to the incorrect activation processes, thereby ensuring the information is secured against information invasions.


What is the potential measurement error in occupational exposure studies?
This paper demonstrates statistical methods that estimate measurement error from available industrial hygiene data. Errors in measuring a continuous exposure variable may arise when all individuals in a work area are assigned the same exposure. An example is when the mean of exposure measurements obtained on a sample of individuals is assigned to all workers with similar jobs. This may lead to inaccurate point and interval estimates in exposure-response modeling. A method of simulating the distribution of true (i.e., unobserved) individual exposures is described in order to estimate the mean and variance of measurement error. The minimum variance unbiased estimator approximates the mean of lognormally distributed exposure measurements. The distribution of true individual exposures is approximated by the distribution of simulated estimates of mean exposure. The methodology is illustrated by exposure data from work areas manufacturing refractory ceramic fiber (RCF) and RCF products. Results show that exposure is slightly underestimated in work areas with between 25 and 113 exposure measurements; measurement error variance averages about 1.3% of the total variance.


Variations in the relationship between the diaphysis and the epiphyses of the tibia.
In all 56 tibiae from Lapps and 56 tibiae from Norwegians have been studied. These ethnic groups represent different weight bearing situations. Variables expressing adaptation to non-axial loading are dealt with. The bone is mainly studied in the AP and the ML planes, as well as in the three dimensional space. The material is analyzed statistically. The distribution form is examined and the deviations from normality are found to be moderate. Mainly positive skewness occurs. Platykurtosis is found as often as leptokurtosis. The deviations from a standard normal distribution are not supposed to affect the results significantly. There is a non-systematic pattern of distribution. The variability is generally lower in Lapps than in Norwegians. The standard deviation shows highest numerical values in indices, lowest in linear variables. Systematic group differences, especially in similar variables, are supposed to be of greater importance than isolated differences. The variables giving deviations from the reference planes or the diaphyseal axis, show the largest and the consistent left-right differences. In linear variables Lapps and females show lower mean values than males and Norwegians, respecitvely. In linear variables giving deviations from the reference planes, in angular variables and in indices, Lapps usually show the highest mean values. Lapps tend to show larger sex differences in variables giving deviations from the reference planes or the diaphyseal axis. However, the sex differences within the Lapps are small. The variations of the tibia are supposed to be the results of mechanical factors in bone remodelling. The epiphyseal-metaphyseal parts tend to have a constant shape, the adaptations to non-axial loading predominantly appearing in the diaphysis. The relation between the weight bearing line and the diaphyseal axis is discussed, particularly regarding the ML stability mechanism of the knee joint. The occurrence of torsion and its influence upon the AP and ML projected values regarding the relationship between the epiphyses and the diaphysis are discussed.


Physician reimbursement in Medicare risk contracting.
The Medicare population remains largely unmanaged despite its increasing cost burden. With a few notable exceptions, health maintenance organizations (HMOs) have historically avoided serving this expensive segment. In many cases, the inability to control costs results from failing to understand the importance of specialist reimbursement mechanisms. This article examines the importance of these mechanisms and describes how to successfully capitate specialty physicians in a Medicare risk program. The article also includes a case study on a successful capitation agreement between an HMO and a specialty group.


Emergent groin hernia repair at a County Hospital in Guatemala: patient-related issues vs. health care system limitations.
The rate of emergent groin hernia repair in developing countries is poorly understood. A retrospective analysis of groin hernia repairs performed at a county hospital in Guatemala [Hospital Nacional de San Benito (HSNB)] was undertaken and compared to a literature review in developed countries. Patients with incarcerated hernias were interviewed to determine factors related to late presentation. Twenty-five percent of patients with groin hernias in this analysis presented at HNSB emergently (vs. 2.5-7.7% in developed countries). Most patients were male in their fifth decade of life. Ten percent of hernias were femoral. There was no delay in scheduling patients for surgery presenting for elective repair. Most patients lived within 20 miles of the hospital, but only 50% of patients returned for their follow-up appointment. Most patients with an incarcerated inguinal hernia (56%) did not seek medical attention because of family obligations, but when they did, this decision was influence by their children (66%). None of the patients presenting with an incarcerated hernia had education past secondary school. In fact, most (56%) did not have any form formal education. Nearly 90% of patients who had an incarcerated hernia repaired thought that the hospital provided good-to-excellent care. A high number of patients present emergently for groin hernia repair at a county hospital in Guatemala compared to developed countries. Our data suggest that emergent hernias are likely the result of patient-related issues rather than health care system limitations.


Case-area targeted preventive interventions to interrupt cholera transmission: Current implementation practices and lessons learned.
Cholera is a major cause of mortality and morbidity in low-resource and humanitarian settings. It is transmitted by fecal-oral route, and the infection risk is higher to those living in and near cholera cases. Rapid identification of cholera cases and implementation of measures to prevent subsequent transmission around cases may be an efficient strategy to reduce the size and scale of cholera outbreaks. We investigated implementation of cholera case-area targeted interventions (CATIs) using systematic reviews and case studies. We identified 11 peer-reviewed and eight grey literature articles documenting CATIs and completed 30 key informant interviews in case studies in Democratic Republic of Congo, Haiti, Yemen, and Zimbabwe. We documented 15 outbreaks in 12 countries where CATIs were used. The team composition and the interventions varied, with water, sanitation, and hygiene interventions implemented more commonly than those of health. Alert systems triggering interventions were diverse ranging from suspected cholera cases to culture confirmed cases. Selection of high-risk households around the case household was inconsistent and ranged from only one case to approximately 100 surrounding households with different methods of selecting them. Coordination among actors and integration between sectors were consistently reported as challenging. Delays in sharing case information impeded rapid implementation of this approach, while evaluation of the effectiveness of interventions varied. CATIs appear effective in reducing cholera outbreaks, but there is limited and context specific evidence of their effectiveness in reducing the incidence of cholera cases and lack of guidance for their consistent implementation. We propose to 1) use uniform cholera case definitions considering a local capacity to trigger alert; 2) evaluate the effectiveness of individual or sets of interventions to interrupt cholera, and establish a set of evidence-based interventions; 3) establish criteria to select high-risk households; and 4) improve coordination and data sharing amongst actors and facilitate integration among sectors to strengthen CATI approaches in cholera outbreaks.


Catalysis by cobalt(II)-substituted carbonic anhydrase II of the exchange of oxygen-18 between CO2 and H2O.
We have measured the catalysis by Co(II)-substituted bovine carbonic anhydrase II from red cells of the exchange of 18O between CO2 and H2O using membrane-inlet mass spectrometry. We chose Co(II)-substituted carbonic anhydrase II because the apparent equilibrium dissociation constant of HCO3- and enzyme at pH 7.4, KHCO3-eff approximately equal to 55 mM, was within a practicable range of substrate concentrations for the 18O method. For the native, zinc-containing enzyme KHCO3-eff is close to 500 mM at this pH. The rate constant for the release from the active site of water bearing substrate oxygen kH2O was dependent on the fraction of enzyme that was free, not bound by substrate HCO3- or anions. The pH dependence of kH2O in the pH range 6.0-9.0 can be explained entirely by a rate-limiting, intramolecular proton transfer between cobalt-bound hydroxide and a nearby group, probably His-64. The rate constant for this proton transfer was found to be 7 X 10(5) S-1 for the Co(II)-substituted enzyme and 2 X 10(6) S-1 for the native enzyme. These results are applied to models derived from proton-relaxation enhancement of water exchanging from the inner coordination shell of the cobalt in carbonic anhydrase. The anions iodide, cyanate, and thiocyanate inhibited catalysis of 18O exchange by Co(II)-substituted carbonic anhydrase II in a manner competitive with total substrate (CO2 and HCO3-) at chemical equilibrium and pH 7.4. These results are discussed in terms of observed steady-state inhibition patterns and suggest that there is no significant contribution of a ternary complex between substrate, inhibitor, and enzyme.


The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD.
During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated in vivo models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.


Short bowel syndrome: highlights of patient management, quality of life, and survival.
Short bowel syndrome (SBS) occurs as a result of intestinal resection, and in many patients is associated with complications, such as diarrhea, dehydration, weight loss, and nutrition deficiencies. Many individuals with SBS develop intestinal failure and require parenteral nutrition (PN) and/or intravenous (IV) fluids (PN/IV). Although PN is essential for survival, some patients with SBS who require long-term PN experience significant complications that contribute to morbidity and mortality. Consequently, therapies that decrease reliance on PN are of considerable importance. Intestinal adaptation, which results in morphologic and functional changes that increase performance of the remnant bowel, occurs spontaneously after intestinal resection. These effects can be enhanced with nutrition and pharmaceutical approaches. For example, oral or tube-fed nutrients stimulate growth and adaptation of intestinal tissues. In addition, prebiotics support growth of beneficial intestinal microbiota that produce short-chain fatty acids, which have been shown in preclinical studies to enhance intestinal structure and function. Finally, glucagon-like peptide 2 (GLP-2) is an endogenous peptide that promotes intestinal rehabilitation and improves intestinal absorption. Teduglutide, a recombinant human GLP-2 analog, has recently been approved in the United States for the treatment of adults with SBS who are dependent on PN. In pharmacodynamic and clinical studies, teduglutide has been shown to promote changes in intestinal structure, such as increases in villus height and crypt depth, and to improve intestinal absorption, as indicated by reduced PN/IV dependence. This article presents a brief overview of SBS, including effects on survival and quality of life and current treatment options.


Postoperative Discharge to Acute Rehabilitation or Skilled Nursing Facility Compared to Home Does Not Reduce Hospital Readmissions, Return to Surgery or Improve Outcomes Following Adult Spine Deformity Surgery.
Retrospective review of a prospective multi-center adult spinal deformity (ASD) study. Evaluate 30-day readmissions, 90-day return to surgery, postoperative complications, and patient reported outcomes (PROs) for matched ASD patients receiving nonhome discharge (NON), including acute rehabilitation (REHAB) and skilled nursing facility (SNF), or home (HOME) discharge following ASD surgery. Postoperative disposition following ASD surgery frequently involves nonhome discharge. Little data exists for longer term outcomes for ASD patients receiving nonhome discharge versus patients discharged to home. Surgically treated ASD patients prospectively enrolled into a multicenter study were assessed for NON or HOME disposition following hospital discharge. NON was further divided into REHAB or SNF. Propensity score matching (PSM) was used to match for patient age, frailty, spine deformity, levels fused and osteotomies performed at surgery. Thirty-day hospital readmissions, 90-day return to surgery, postoperative complications, 1-year and minimum 2-year postoperative PROs were evaluated. 241 of 374 patients were eligible for study. NON patients were identified and matched to HOME patients. Following matching, 158 patients remained for evaluation; NON and HOME had similar preoperative age, frailty, spine deformity magnitude, surgery performed, and duration of hospital stay (P>0.05). Thirty-day readmissions, 90-day return to surgery, and postoperative complications were similar for NON versus HOME, and similar for REHAB (N=64) versus SNF (N=42) versus HOME (P>0.05). At 1-year and minimum 2-year follow up, HOME demonstrated similar to better PRO scores including ODI, SF-36 MCS and PCS, and SRS scores versus NON, REHAB and SNF (P<0.05). Acute needs must be considered following ASD surgery, however matched analysis comparing 30-day hospital readmissions, 90-day return to surgery, postoperative complications and PROs demonstrated minimal benefit for NON, REHAB or SNF versus HOME at 1-year and 2-year follow up, questioning the risk and cost/benefits of routine use of nonhome discharge. I-IV: Level III; prognostic.


Investigating the Immune Basis of Green Tea Extract Induced Liver Injury in Healthy Donors Expressing HLA-B*35:01.
Epigallocatechin-3-O-gallate (EGCG) is the major component of green tea extract, commonly found in dietary supplements, and has been associated with immune-mediated liver injury. The purpose of this study was to investigate the immunogenicity of EGCG in healthy donors expressing HLA-B*35:01, and characterize EGCG responsive T-cell clones. We have shown that EGCG can prime peripheral blood mononuclear cells and T-cells from donors with and without the HLA-B*35:01 allele. T-cell clones were CD4+ve and capable of secreting Th1, Th2, and cytolytic molecules. These data demonstrate that EGCG can activate T-cells in vitro, suggesting a significant role in the pathogenesis of green tea extract induced liver injury.


Positive effects of some gyrase inhibitors on survival and development of Pimpla turionellae (Hymenoptera: Ichneumonidae) larvae reared on an artificial diet.
Effects of novobiocin, nalidixic, and oxolinic acids on the survival and development of the hymenopterous endoparasitoid Pimpla turionellae L. were investigated alone and in various combinations by rearing larvae aseptically on chemically defined synthetic diets. Effects varied with the levels and kinds of the antibiotics in the tested combinations. Among the tested antibiotics alone, only the lowest level of novobiocin enhanced the postlarval survival. Most of the combinations significantly increased the number of survivors in the postlarval developmental stages. Novobiocin in combination with nalidixic acid (6.0:2.0 mg) in the artificial diet produced a yield of 80.8% pupae and 69.4% adults, respectively. This combination also shortened the developmental time to adult emergence. Similarly, on most of the diets with combinations of the antibiotics, the development of the larvae up to adult stage was noticeably faster than those on the control diets. An approximately equals 50% reduction in the percentages of pupae and adults was recorded by 6.0 mg of novobiocin in combination with 0.75 mg of oxolinic acid compared with the control diet. Although this combination prolonged the complete development of the insect according to other novobiocin and oxolinic acid combinations, developmental time was significantly shorter than that with control diet.


Awareness of Migraine Among Primary Care Physicians in Turkey: A Regional Study.
Migraine is a primary headache that involves genetic and environmental factors. In studies conducted in different countries, migraine was shown to be underdiagnosed, treated insufficiently, and highly related to disability. The primary aim of this study was to identify the competence in making a diagnosis of migraine by primary care physicians who provide basic health care to patients. Primary care physicians (266 individuals) working in the primary health service centers located within the borders of Kayseri province were included in our study. The research was conducted by using techniques such as face-to-face meetings with the primary care physicians and by participants filling in questionnaires. A neurologist evaluated the questionnaire form. The information provided by the participants was evaluated according to the migraine without aura diagnostic criteria prepared by the International Headache Society (ICHD-3 Beta). Only 10.5% participants were able to give the complete diagnostic criteria of migraine without aura. The most well-known properties were unilateral (53.4%) and pulsating headaches (47%). This study showed that educational programs are required regarding migraines for primary care physicians, supported by complete educational material.


Does performance of hang power clean differentiate performance of jumping, sprinting, and changing of direction?
The primary purpose of this study was to investigate whether the athlete who has high performance in hang power clean, a common weightlifting exercise, has high performances in sprinting, jumping, and changing of direction (COD). As the secondary purpose, relationships between hang power clean performance, maximum strength, power and performance of jumping, sprinting, and COD also were investigated. Twenty-nine semiprofessional Australian Rules football players (age, height, and body mass [mean +/- SD]: 21.3 +/- 2.7 years, 1.8 +/- 0.1 m, and 83.6 +/- 8.2 kg) were tested for one repetition maximum (1RM) hang power clean, 1RM front squat, power output during countermovement jump with 40-kg barbell and without external load (CMJ), height of CMJ, 20-m sprint time, and 5-5 COD time. The subjects were divided into top and bottom half groups (n = 14 for each group) based on their 1RM hang power clean score relative to body mass, then measures from all other tests were compared with one-way analyses of variance. In addition, Pearson's product moment correlations between measurements were calculated among all subjects (n = 29). The top half group possessed higher maximum strength (P < 0.01), power (P < 0.01), performance of jumping (P < 0.05), and sprinting (P < 0.01). However, there was no significant difference between groups in 5-5 COD time, possibly because of important contributing factors other than strength and power. There were significant correlations between most of, but not all, combinations of performances of hang power clean, jumping, sprinting, COD, maximum strength, and power. Therefore, it seems likely there are underlying strength qualities that are common to the hang power clean, jumping, and sprinting.


Genotoxicological investigation of hospital nurses occupationally exposed to ethylene-oxide: I. Chromosome aberrations, sister-chromatid exchanges, cell cycle kinetics, and UV-induced DNA synthesis in peripheral blood lymphocytes.
Structural, and numeric chromosome aberrations (CA), sister-chromatid exchange (SCE), phytohemagglutinin stimulation (LI), proliferative rate index (PRI), and UV light-induced unscheduled DNA-synthesis (UDS) were investigated in peripheral blood lymphocytes (PBL) of 48 historical controls ("Controls"); of 14 hospital controls in Budapest, Hungary ("Budapest controls"); of 9 nurses occupationally exposed to low-dose ethylene-oxide in Budapest ("Budapest exposed"); of 10 hospital controls in Eger, Hungary ("Eger controls"); and of 27 high dose ETO-exposed nurses in Eger ("Eger exposed"), where neoplasias, mainly breast cancers, were observed. ETO concentrations in the ambient air samples varied from 5 to 20 mg/m3 in Budapest; and from 5 to 100 mg/m3 in Eger. Bothe LI and PRI were depressed in Budapest exposed, indicating ETO-induced cytotoxicity and, however, normal in Eger exposed. SCE was slightly elevated in Budapest exposed, but significantly increased in Eger exposed. The yields of cells with high frequency SCE (HFC) were only increased in Eger exposed. The expected low CA frequencies were found in Controls and in Budapest controls. ETO exposures significantly increased the CA frequencies in Budapest and Eger exposed. In Budapest exposed, as expected, we found deletions; in a lesser extent chromatid exchanges and dicentrics; but no rings were detected. These results are in a good accordance to the published data of other investigations carried out on ETO-exposed human populations. However, in Eger exposed, beside the increased yields of deletions, the frequencies of dicentrics and rings showed a significant excess compared to the reviewed data. An unexpected, significant increase of dicentric and ring frequencies was also detected among the hospital controls in Eger controls without known clastogenic exposure. The role of confounding factors (age, smoking and drinking habit, total leukocyte count and hematocrit) was investigated by an analysis of variance on CA and SCE frequencies in Controls and in Eger exposed. Leukocyte count and mean age showed only significant effects on CA in Eger exposed and on SCE in Controls, respectively. A possible active confounding factor could be the temporary natural radioactivity of the local tap water. UDS in Budapest exposed and in Eger control were significantly higher then in the Controls and in Budapest controls. In Eger exposed UDS was significantly decreased compared to the Budapest exposed and Eger control groups. The explanation of the present results is difficult on the basis of the reviewed data on ETO-induced CA frequencies in exposed human populations, and it raises an issue of an independent genotoxic effect in Eger, which is common both in Eger controls and in Eger exposed, such as natural radioactivity.


Mendelian Randomization using Public Data from Genetic Consortia.
Mendelian randomization (MR) is a technique that seeks to establish causation between an exposure and an outcome using observational data. It is an instrumental variable analysis in which genetic variants are used as the instruments. Many consortia have meta-analysed genome-wide associations between variants and specific traits and made their results publicly available. Using such data, it is possible to derive genetic risk scores for one trait and to deduce the association of that same risk score with a second trait. The properties of this approach are investigated by simulation and by evaluating the potentially causal effect of birth weight on adult glucose level. In such analyses, it is important to decide whether one is interested in the risk score based on a set of estimated regression coefficients or the score based on the true underlying coefficients. MR is primarily concerned with the latter. Methods designed for the former question will under-estimate the variance if used for MR. This variance can be corrected but it needs to be done with care to avoid introducing bias. MR based on public data sources is useful and easy to perform, but care must be taken to avoid false precision or bias.


Interdisciplinary Therapy Improves the Mediators of Inflammation and Cardiovascular Risk in Adolescents with Obesity.
Obesity is associated with inflammation and an increased risk of cardiovascular disease and premature mortality, as well as a range of other conditions. Obesity is a growing global problem, not only in adults, but also in children and adolescents. Therefore, the present study aimed to assess the effects of a one-year interdisciplinary intervention on the cardiometabolic and inflammatory profiles of adolescents with obesity. Twenty-two adolescents completed the intervention, which included clinical, nutritional, psychological and physical exercise counselling. Body composition, and metabolic, inflammatory, and cardiovascular risk biomarkers were analyzed before and after one year of intervention. Visceral and subcutaneous fat were determined ultrasonographically. The homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) equation were used to estimate insulin resistance and insulin sensitivity, respectively. A reduction in body mass, adiposity, glucose, and insulin and an improved lipid profile were observed after the therapy. Hyperleptinemia was reduced from 77.3% to 36.4%. Plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule 1 (ICAM-1), leptin, the leptin/adiponectin ratio, and the adiponectin/leptin ratio were also significantly improved. Metabolic changes were associated with a reduction in visceral fat and waist circumference, and adiponectin and the leptin/adiponectin ratio were associated with HOMA-IR. The interdisciplinary therapy promoted improvements in hyperleptinemia and metabolic, inflammatory, and cardiovascular biomarkers.


Comparative Review of Dopamine Receptor Agonists in Parkinson's Disease.
Limitations of long term levodopa therapy for Parkinson's disease represent a major problem in the management of many patients. Dopamine receptor agonists provide antiparkinsonian effects and their use is most clearly defined in the context of complications from levodopa therapy. As such, dopamine receptor agonists are useful adjunctive agents to levodopa. Because typical adverse effects of dopamine receptor agonists may differ from those of levodopa, combination therapy is often effective and well tolerated.A variety of dopamine receptor agonists, both ergot and non-ergot derivatives, are useful in the treatment of Parkinson's disease. Five dopamine receptor agonists are currently available for use throughout much of the world, and many more are in developmental phases. Varying pharmacodynamic and pharmacokinetic profiles allow selection of appropriate dopamine receptor agonists for specific clinical scenarios. Recently reported comparative studies also suggest certain prescribing recommendations.


Long-term trial of disodium cromoglycate and isoprenaline in children with asthma.
A year-long double-blind trial was carried out in 53 asthmatic children with severe perennial symptoms who were not receiving corticosteroids or corticotrophin. The treatment group were given disodium cromoglycate with isoprenaline (Intal Co.) while the placebo group were given lactose with isoprenaline four times daily. The groups were closely matched for clinical, physiological, and immunological features. Evaluation was based on the use of a diary and clinical and physiological investigations, including exercise tests.After one year 71% of the treatment group were still well controlled while 76% of the placebo group had dropped out because of inadequate control of symptoms. There was no rise in the rate of failure towards the end of the trial period and there were no seasonal variations in the failure rate. No important toxic effects were noted. It was impossible to predict the outcome of the trial in any given patient from his clinical, physiological, or immunological status at the beginning. However, the prevention of exercise-induced asthma by premedication with disodium cromoglycate in a laboratory exercise test did correlate well with the satisfactory clinical response to the drug.


Species prioritization for monitoring and management in regional multiple species conservation plans.
Successful conservation plans are not solely achieved by acquiring optimally designed reserves. Ongoing monitoring and management of the biodiversity in those reserves is an equally important, but often neglected or poorly executed, part of the conservation process. In this paper we address one of the first and most important steps in designing a monitoring program - deciding what to monitor. We present a strategy for prioritizing species for monitoring and management in multispecies conservation plans. We use existing assessments of threatened status, and the degree and spatial and temporal extent of known threats to link the prioritization of species to the overarching goals and objectives of the conservation plan. We consider both broad and localized spatial scales to capture the regional conservation context and the practicalities of local management and monitoring constraints. Spatial scales that are commensurate with available data are selected. We demonstrate the utility of this strategy through application to a set of 85 plants and animals in an established multispecies conservation plan in San Diego County, California, USA. We use the prioritization to identify the most prominent risk factors and the habitats associated with the most threats to species. The protocol highlighted priorities that had not previously been identified and were not necessarily intuitive without systematic application of the criteria; many high-priority species have received no monitoring attention to date, and lower-priority species have. We recommend that in the absence of clear focal species, monitoring threats in highly impacted habitats may be a way to circumvent the need to monitor all the targeted species.


How many people would benefit from a smart wheelchair?
Independent mobility is important, but some wheelchair users find operating existing manual or powered wheelchairs difficult or impossible. Challenges to safe, independent wheelchair use can result from various overlapping physical, perceptual, or cognitive symptoms of diagnoses such as spinal cord injury, cerebrovascular accident, multiple sclerosis, amyotrophic lateral sclerosis, and cerebral palsy. Persons with different symptom combinations can benefit from different types of assistance from a smart wheelchair and different wheelchair form factors. The sizes of these user populations have been estimated based on published estimates of the number of individuals with each of several diseases who (1) also need a wheeled mobility device and (2) have specific symptoms that could interfere with mobility device use.


Activation of macrophages for enhanced release of superoxide anion and greater killing of Candida albicans by injection of muramyl dipeptide.
The adjuvant muramyl dipeptide (MDP) has been shown to affect a number of macrophage functions in vitro. We studied the effect of subcutaneous injection of MDP into mice. Cultured peritoneal macrophages from treated mice displayed increased spreading, total cell protein, and specific activity of beta-glucosaminidase a constituent of macrophage lysosomes, and of lactate dehydrogenase. Generation of superoxide anion (O2-) by MDP-treated macrophages stimulated by contact with phorbol myristate acetate was enhanced by over fivefold to levels achieved by macrophages from bacillus Calmette-Guérin-infected mice. The enhancement in stimulated O2- release was noted by 1 h after injection of MDP, peaked by 3 h, and remained high for at least 48 h. Priming for enhancement of O2- release by MDP was similar in athymic nude mice and in normal littermates, suggesting that mature T lymphocytes are not involved in this MDP effect. Priming for enhanced stimulated O2- release, and morphologic and enzymic changes, were not achieved by injection of the D-D stereoisomer of MDP. Phagocytosis of Candida albicans was only slightly greater by macrophages from mice give MDP, but MDP-stimulated cells killed two times more C. albicans in vitro than did cells from untreated animals. When MDP was given 18 h before, simultaneously with, or 24 h after lethal infectious challenge with C. albicans, treated mice were protected compared with controls. These results suggest that injection of MDP effectively and rapidly activates macrophages in the recipient animal. This agent should serve as an important probe of macrophage physiology and, perhaps ultimately, as a means of enhancing host defense in humans.


Percutaneous Transhepatic Cholangioscopy in Bilioenteric Anastomosis Stricture.
Bilioenteric anastomosis strictures are a serious complication of biliary surgery, and often result in recurrent cholangitis, choledocholithiasis, biliary cirrhosis, and hepatic failure. Bilioenteric reconstructive surgery is the standard treatment of choice for such complications. However, percutaneous transhepatic cholangioscopy (PTCS), also known as per-oral endoscopic-guided intervention, is a less invasive procedure that is becoming an increasingly popular alternative. This review describes the PTCS procedure (including the preparation process), as well as the diagnostic and therapeutic role of PTCS in bilioenteric anastomosis strictures.


[The role of cytokines in the development and clinical course of cardiac insufficiency].
The review is focused on the main premises of the theory of progressive cardiac insufficiency based on the notion of immune activation and systemic inflammation as markers of adverse prognosis and high risk of cardiovascular complications. The relationship between blood cytokine level/composition and severity of cardiac insufficiency is illustrated. Classification of cytokines is considered along with possible causes of their increased concentration and involvement in the development and clinical course of this condition. Special attention is given to the studies of methods for the correction of enhanced cytokine levels. The importance of further studies on the influence of cytokines on the clinical course of cardiac insufficiency is emphasized.


The effect of ginseng (genus Panax) on blood pressure: a systematic review and meta-analysis of randomized controlled clinical trials.
Pre-clinical evidence indicates the potential for ginseng to reduce cardiovascular disease risk and acutely aid in blood pressure (BP) control. Clinical evidence evaluating repeated ginseng exposure, however, is controversial, triggering consumer and clinician concern. A systematic review and meta-analysis were conducted to assess whether ginseng has an effect on BP. MEDLINE, EMBASE, Cochrane and CINAHL were searched for relevant randomized controlled trials ⩾4 weeks that compared the effect of ginseng on systolic (SBP), diastolic (DBP) and/or mean arterial (MAP) BPs to control. Two independent reviewers extracted data and assessed methodological quality and risk of bias. Data were pooled using random-effects models and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed and quantified. Seventeen studies satisfied eligibility criteria (n=1381). No significant effect of ginseng on SBP, DBP and MAP was found. Stratified analysis, although not significant, appears to favour systolic BP improvement in diabetes, metabolic syndrome and obesity (MD=-2.76 mm Hg (95% CI=-6.40, 0.87); P=0.14). A priori subgroup analyses revealed significant association between body mass index and treatment differences (β=-0.95 mm Hg (95% CI=-1.56, -0.34); P=0.007). Ginseng appears to have neutral vascular affects; therefore, should not be discouraged for concern of increased BP. More high-quality, randomized, controlled trials assessing BP as a primary end point, and use of standardized ginseng root or extracts are warranted to limit evidence of heterogeneity in ginseng research and to better understand its cardiovascular health potential.


Doped Graphene for DNA Analysis: the Electrochemical Signal is Strongly Influenced by the Kind of Dopant and the Nucleobase Structure.
Doping graphene with heteroatoms can alter the electronic and electrochemical properties of the starting material. Contrasting properties should be expected when the doping is carried out with electron donating species (n-type dopants) or with electron withdrawing species (p-type dopants). This in turn can have a profound influence on the electroanalytical performance of the doped material being used for the detection of specific probes. Here we investigate the electrochemical oxidation of DNA bases adenine, guanine, thymine and cytosine on two heteroatom-doped graphene platforms namely boron-doped graphene (p-type dopant) and nitrogen-doped graphene (n-type dopant). We found that overall, boron-doped graphene provided the best response in terms of electrochemical signal sensitivity for all bases. This is due to the electron deficiency of boron-doped graphene, which can promote the oxidation of DNA bases, as opposed to nitrogen-doped graphene which possesses an excess of electrons. Moreover, also the structure of the nucleobase was found to have significant influence on the obtained signal. Our study may open new frontiers in the electrochemical detection of DNA bases which is the first step for label-free DNA analysis.


Transcriptomic modifications of the thyroid gland upon exposure to phytosanitary-grade fipronil: Evidence for the activation of compensatory pathways.
Fipronil is a phenylpyrazole insecticide used for the control of a variety of pest for domestic, veterinary and agricultural uses. Fipronil exposure is associated to thyroid disruption in the rat. It increases thyroid hormone (TH) hepatic clearance. The effect on thyroxine (T4) clearance is about four fold higher than the effect on T4 plasma concentrations suggesting that the thyroid gland might develop compensatory mechanisms. The aim of this study was to document the potential effects of fipronil treatment on the thyroid transcriptome together with its effects on TSH and TH blood levels under well characterized internal exposure to fipronil and its main metabolite fipronil sulfone. Fipronil (3 mg/kg/d by gavage for 14 days) clearance increased while its half-life decreased (about 10 fold) throughout treatment. Fipronil treatment in adult female rats significantly decreased total T4 and free triiodothyronine (T3) concentrations. Key genes related to thyroid hormone synthesis and/or cellular dynamic were modulated by fipronil exposure. RT-PCR confirmed that thyroglobulin gene expression was upregulated. A trend toward higher Na/I symporter expression was also noted, while sulfotransferase 1a1 gene expression was down-regulated. The expression of genes potentially involved in thyroid cell dynamic were upregulated (e.g. prostaglandin synthase 1, amphiregulin and Rhoa). Our results indicate that both pathways of TH synthesis and thyroid cell dynamics are transcriptional targets of fipronil and/or its main sulfone metabolite. The underlying mechanisms remain to be elucidated.


[Quantitative analysis of diffusion-weighted magnetic resonance images during chemoradiation therapy for cancer of the cervix uteri: Prognostic role of pretreatment diffusion coefficient values].
to carry out a quantitative analysis of diffusion-weighted magnetic resonance images (DWI) in cancer of the cervix uteri (CCU) and to estimate the possibility of using pretreatment measured diffusion coefficient (MDC) to predict chemoradiation therapy (CRT). The investigation prospectively enrolled 46 women with morphologically verified Stages IB-IVB CCU. All the women underwent diffusion-weighted magnetic resonance imaging of pelvic organs before and after treatment. A semiautomatic method was used to determine tumor signal intensity (SI) on DWI at b 1000 s/mm2 (SI b1000) and tumor MDC. The reproducibility of MDC measurements was assessed in 16 randomly selected women. The investigators compared the pretreatment quantitative DWI measures in complete and incomplete regression (CR and IR) groups and the presence and absence of tumor progression during a follow-up. An association of MDC with progression-free and overall survivals (PFS and OS) was determined in the patients. A semiautomatic tumor segmentation framework could determine the pretreatment quantitative DMI measures with minimal time spent and high reproducibility. The mean tumor MDC was 0.82 +/- 0.14 x 10(-3) mm2/s. CR and IR were established in 28 and 18 women, respectively. The MDC < or = 0.83 x 10(-3) mm2/s predicted CR with a sensitivity of 64.3% and a specificity of 77.8% (p=0.007). The median follow-up was 47 months (range, 3-82 months). With the MDC < or = 0.86 x 10(-3) mm2/s, 5-year PFS was 74.1% versus 42.1% with a higher MDC (p=0.023) and 5-year OS was 70.4 and 40.6%, respectively (p=0.021). The survival difference was insignificant in relation to the degree of tumor regression. The pretreatment IS at b1000 was of no prognostic value. The pretreatment tumor MDC may serve as a biomarker for predicting the efficiency of CRT for CCU.


[Bactericidal effect of soybean peroxidase-hydrogen peroxide-potassium iodide system].
To study the bactericidal effect and the possible mechanisms of the three components system [soybean peroxidases (SBP)-hydrogen peroxide (H2O2)-potassium iodide (KI), SBP-H2O2-KI]. The inhibition and bactericidal effect of SBP-H2O2-KI system to bacteria was detected by OD600 and the number of live bacteria (CFU). The sensitivity was tested by comparing the minimum inhibitory concentration (MIC) of bacterial cultures before and after cultured under sub-lethal dose of SBP-H2O2-KI system. Oxidizing activity groups were detected with physical and chemical methods in order to explain the bactericidal mechanisms of SBP-H2O2-KI system. SBP-H2O2-KI ternary system had rapid and high efficient bactericidal effect to a variety of bacterial strains in just several minutes. The MICs had no significant changes when bacterial cultures continuously cultured in sub-lethal dose of SBP-H2O2-KI system, and no resistance/tolerance mutant strains could be isolated from them. Both physical and chemical test results showed that no hydroxyl radical produced in SBP- H2O2-KI reaction system, chemical test results showed that no superoxide anion but a singlet oxygen and iodine produced in SBP-H2O2-KI reaction system. These results suggested that singlet oxygen and iodine or the iodine intermediate state may possible be the main sterilization factors for SBP-H2O2-KI system, and hydroxyl radical and superoxide anion not. In addition, the both characteristics of SBP-H2O2-KI system: rapid and high efficient bactericidal effect, and bacteria difficultly resisting to it, indicated it would have a good potential application in medical and plant protection area.


Analysis of the Relative Age Effect in Elite Youth Judo Athletes.
The purpose of this investigation was to evaluate relative age effects (RAEs) in elite youth judo athletes from different chronological age groups, between sexes, and across weight categories. Data from 1542 place winners of the cadet (under 17 y, 2009-2013) and junior judo world championships (under 20/21 y, 1990-2013) were separated by birth month into quarters (Q1, Q2, Q3, and Q4). The observed values were compared with expected annual age distributions using χ2 analyses, and odd ratios (OR) were used to evaluate effect sizes between quarters. The observed frequency of place winners was significantly different from the expected frequency for the age-group and sex comparisons and all body-mass groups (P < .05) with the exception of the extra-light categories (P = .572). When comparing Q1 with Q4 (OR, 95% confidence interval), small effect sizes were observed for cadets (1.72, 1.12-2.66), juniors (1.54, 1.23-1.94), males (1.75, 1.32-2.33), females (1.39, 1.03-1.87), and the light- (1.79, 1.21-2.64) and middle-weight (1.80, 1.20-2.70) categories. RAEs are apparent in cadet and junior judo athletes. Thus, coaches and administrators should consider the potential for physical and/or competitive advantages while adopting strategies that encourage long-term participation in youth judo athletes.


Breast cancer risk assessment in women aged 70 and older.
Although the benefit of screening mammography for women over 69 has not been established, it is generally agreed that screening recommendations for older women should be individualized based on health status and breast cancer risk. However, statistical models to assess breast cancer risk have not been previously evaluated in this age group. In this study, the original Gail model and three more recent models that include mammographic breast density as a risk factor were applied to a cohort of 19,779 Vermont women aged 70 and older. Women were followed for an average of 7.1 years and 821 developed breast cancer. The predictive accuracy of each risk model was measured by its c-statistic and associations between individual risk factors and breast cancer risk were assessed by Cox regression. C-statistics were 0.54 (95% CI = 0.52-0.56) for the Gail model, 0.54 (95% CI = 0.51-0.56) for the Tice modification of the Gail model, 0.55 (95% CI = 0.53-0.58) for a model developed by Barlow and 0.55 (95% CI = 0.53-0.58) for a Vermont model. These results indicate that the models are not useful for assessing risk in women aged 70 and older. Several risk factors in the models were not significantly associated with outcome in the cohort, while others were significantly related to outcome but had smaller relative risks than estimated by the models. Age-related attenuation of the effects of some risk factors makes the prediction of breast cancer in older women particularly difficult.


Immunocytochemical demonstration of the expression and induction of manganese-superoxide dismutase in the adenohypophysis.
Immunocytochemistry for manganese-superoxide dismutase (Mn-SOD) was studied in 12 normal adenohypophyses and 38 various pituitary lesions. The proportions of cells with granular immunoreactivity for Mn-SOD in normal adenohypophysis ranged from 9.8% to 29.6% (mean +/- SD; 18.4+/-6.2%). Some positive cells tended to accumulate in clusters, distribution of which corresponded well with those immunopositive for mitochondrial protein and cytochrome oxidase. The number of Mn-SOD-positive cells increased in adjacent residual adenohypophysis in eight of nine recent infarcts, in two of five old infarcts, in all four cases of lymphocytic hypophysitis, in two of four abscess cases and in one of three metastatic tumour cases, whereas the immunoreactivities of mitochondrial protein- and cytochrome oxidase-positive cells either did not vary or decreased. The intensity of the histological inflammatory reactions showed a positive correlation with reactivity for Mn-SOD in these lesions. Of eight adenomas, the surrounding area of compressed adenohypophysis showed increased numbers of Mn-SOD- and mitochondrial protein-/cytochrome oxidase-positive cells in four and six cases respectively. It is suggested that positivity for Mn-SOD may be related to some functional activity of mitochondria. It is further suggested that adenohypophysial cells have a high potential to induce Mn-SOD by inflammatory and ischaemic stress and, in addition, by enhanced mitochondrial activity.


Atrial fibrillation in myocardial infarction patients: Impact on health care utilization.
Atrial fibrillation (AF) often complicates myocardial infarction (MI). While AF adversely impacts survival in MI patients, the impact of AF on health care utilization has not been studied. The risk of hospitalizations, emergency department (ED) visits, and outpatient visits associated with prior, new-onset (<30 days post-MI), and late-onset (≥30 days post-MI) AF was assessed among incident MI patients from the Olmsted County, Minnesota, community. Of 1,502 MI patients, 237 had prior AF, 163 developed new-onset AF, 113 developed late-onset AF, and 989 had no AF. Over a mean follow-up of 3.9 years, 3,661 hospitalizations, 5,559 ED visits, and 80,240 outpatient visits occurred. After adjustment, compared with patients without AF, those with prior and new-onset AF exhibited a 1.6-fold and 1.3-fold increased risk of hospitalization, respectively. In contrast, late-onset AF carried a 2.2-fold increased risk of hospitalization. The hazard ratios were 1.4, 1.2, and 1.8 for ED visits and 1.4, 1.2, and 1.7 for outpatient visits for prior, new-onset, and late-onset AF. Additional adjustment for time-dependent recurrent MI and heart failure attenuated the results slightly for hospitalizations and ED visits; however, patients with late-onset AF still exhibited a >50% increased risk for both utilization measures. In MI patients, the risk of hospitalizations, ED visits, and outpatient visits differed by the timing of AF onset, with the greatest risk conferred by late-onset AF. Atrial fibrillation imparts an adverse prognosis after MI, underscoring the importance of its management in MI patients.


Utilising a dual human transporter MDCKII-MDR1-BCRP cell line to assess efflux at the Blood Brain Barrier (BBB).
To facilitate the design of drugs readily able to cross the blood brain barrier (BBB) a MDCK cell line was established that over expresses both P‑glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP) the main human efflux transporters of the BBB. Proteomics analyses indicate BCRP is expressed at a higher level than Pgp in this cell line. This cell line shows good activity for both transporters (BCRP substrate dantrolene efflux ratio (ER) 16.3 {plus minus} 0.9, Pgp substrate quinidine ER 27.5 {plus minus} 1.2) and use of selective transport inhibitors enables an assessment of the relative contributions to overall ERs. The MDCKII-MDR1-BCRP ER negatively correlates with rat unbound brain/unbound plasma ratio, Kpuu Highly brain penetrant compounds with rat Kpuu {greater than or equal to} 0.3 show ERs {less than or equal to} 2 in the MDCKII-MDR1-BCRP assay whilst compounds predominantly excluded from the brain, Kpuu {less than or equal to} 0.05, demonstrate ERs {greater than or equal to} 20. A subset of compounds with MDCKII-MDR1-BCRP ER <2 and rat Kpuu < 0.3 were shown to be substrates of rat Pgp using a rat transfected cell line, MDCKII-rMdr1a. These compounds also showed ERs >2 in the human NIH MDCKI-MDR1 (high Pgp expression) cell line which suggests that they are weak human Pgp substrates. Characterisation of 37 drugs targeting the central nervous system (CNS) in the MDCKII-MDR1-BCRP efflux assay show 36 have ERs < 2. In drug discovery, use of the MDCKII-MDR1-BCRP in parallel with the NIH MDCKI-MDR1 cell line is useful for identification of compounds with high brain penetration. Significance Statement A single cell line, that includes both the major human efflux transporters of the BBB, (MDCKII-MDR1-BCRP) has been established facilitating the rapid identification of efflux substrates and enabling the design of brain penetrant molecules. Efflux ratios using this cell line demonstrate a clear relationship with brain penetration as defined by rat brain Kpuu.


A comparison of all-ceramic restorative systems: Part 2.
Overall, any of these systems can provide well-fitting, natural looking restorations as long as care is taken during the preparation and fabrication procedures. A key to successful use of all-ceramic materials is proper selection based on the clinical conditions involved in specific restorative procedures (see table). All systems have limitations on their use and when we try to stretch those limits, success rates may fall drastically. High stress areas should shift selection to high strength, clinically documented materials. Low stress areas requiring high translucency may be restored successfully using the lower strength castable glasses. Intermediate areas may shift selection to higher strength yet still translucent materials such as In-Ceram Spinell or Empress 2. Posterior regions might best be addressed with the use of In-Ceram Alumina or Procera. The case of posterior bridges would lock the selection into In-Ceram Zirconia. Finally, it is important for each of us to continually educate ourselves and to examine the evidence in order to make an informed decision and maximize clinical success.


Toxicological screening of lyophilized extract of some Nigerian wild mushrooms in mice.
Mushrooms are macrofungi widely consumed as food. However, many mushrooms rot away in the wild because of fear of toxicity. Therefore, lyophilized aqueous extracts of 6 mushroom species collected from Zaria, Nigeria and taxonomically identified as Chlorophyllum molybdites, Panaeolus subalteatus, Macrolepiota procera, Leucopaxillus albissmus, Hygrophoropsis aurantiacus and Pholiota aurea were screened for toxicity in mice. Lyophilized aqueous extract of each of these mushrooms was administered to three groups of 3 mice intraperitoneally (i.p.) at doses of 100, 1000 and 10, 000 mg kg(-1), respectively. Another group of three mice given distilled water served as control. The mice were examined for clinical signs of toxicity over a period of 72 h and pathological examinations conducted on dead animals. The severity of clinical signs, onset of death and pathological lesions were dose dependent. Death occurred within 10 min in all the mice dosed at 10,000 mg kg(-1) with the lyophilized extracts of all the mushrooms screened, with the exception of that of H. aurantiacus, which produced death 21-23 h post administration. This result showed that all the screened mushrooms, including the popular edible M. procera were found toxic. Therefore, since all the mushrooms screened were found toxic, it is recommended that extreme caution should be exercised in their consumption. Furthermore, in view of the regional differences in the toxicity of mushrooms, there is the need to screen more wild mushrooms found in Nigeria for toxicity. This will boost mushroom mycophagy, reduce poisoning incidence and reduce wastage of edible mushrooms in the wild.


Involvement of LEU13 in interferon-induced refractoriness of human RSa cells to cell killing by X rays.
Culture of human cells with human interferon alpha and beta (IFNA and IFNB) results in increased resistance of the cells to cell killing by X rays. To identify candidate genes responsible for the IFN-induced X-ray resistance, we searched for genes whose expression levels are increased in human RSa cells treated with IFNA, using an mRNA differential display method and Northern blotting analysis. RSa cells, which showed increased survival (assayed by colony formation) after X irradiation when they were treated with IFNA prior to irradiation, showed increased expression levels of LEU13 (IFITM1) mRNA after IFNA treatment alone. In contrast, IF(r) and F-IF(r) cells, both of which are derived from RSa cells, showed increased X-ray resistance and high constitutive LEU13 mRNA expression levels compared to the parental RSa cells. Furthermore, the IFNA-induced resistance of RSa cells to killing by X rays was suppressed by antisense oligonucleotides for LEU13 mRNA. LEU13, a leukocyte surface protein, was previously reported to mediate the actions of IFN such as inhibition of cell proliferation. The present results suggest a novel role of LEU13 different from that in the inhibition of cell proliferation, involved in IFNA-induced refractoriness of RSa cells to X rays.


Role of cyclic GMP in cholinergic activation of Na-K pump in duck salt gland.
Na-K-ATPase will hydrolyze an alternate substrate, p-nitrophenylphosphate (pNPP). The hydrolysis is ouabain sensitive and occurs at an external site on the cell membrane, thereby allowing measurement of Na-K-ATPase activity in the intact cell. pNPP hydrolysis was monitored in salt gland slices incubated in a bicarbonate-buffered Ringer solution. Methacholine-stimulated pNPP hydrolysis was inhibited by either atropine or ouabain. The hydrolysis was also dependent on the presence of calcium and sodium in the Ringer solution. cGMP stimulated ouabain-sensitive pNPP hydrolysis at concentrations from 10(-8) M to 10(-4) M with an optimum at 10(-5) M. cAMP did not produce a significant activation of pNPP hydrolysis. The effect of cGMP ws not dependent on either sodium or calcium in the Ringer solution and was not inhibited by atropine. Hydrolysis of pNPP promoted by either methacholine or cGMP occurred under conditions where no net influx of Na+ into the cells could occur. Sodium-pump activation during cholinergic stimulation, therefore, does not depend on an elevation of cell sodium but must occur by another mechanism. cGMP appears to play a direct role in that mechanism.


Localization of discoidin domain receptors in rat kidney.
The discoidin domain receptors (DDRs) DDR1 and DDR2 are cardinal members of a receptor tyrosine kinase subfamily, activated by collagens. They are candidate effectors in tissue injury and fibrosis. We investigated the DDR expression in normal and remnant rat kidneys. The DDR expression in kidney and other tissues was examined by indirect immunofluorescence, immunoblotting, and ribonuclease protection assays. The expression patterns in remnant and control kidneys were compared at 2-, 4-, and 8-week time points, following induction of injury. DDR1 is expressed in basolateral membranes of select nephron segments, from the connecting tubule to the renal papilla. DDR2 is expressed in apical membranes of select nephron segments, from the loop of Henle to the macula densa. The DDR1 protein expression is upregulated within the glomeruli of remnant kidneys. The distribution of DDR2 in remnant kidneys is similar to that in controls. The DDR mRNA levels in remnant and control kidneys were not significantly different, at any time point. The DDR1 localization in the rat kidney is consistent with roles in cell-matrix interactions. Upregulation within glomeruli of remnant kidneys suggests the possibility of additional roles in kidney injury. The DDR2 localization in adult rat kidneys is inconsistent with roles in cell-matrix interactions.


Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19.
Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.


Nonisotopic detection methods for strand displacement assays of nucleic acids.
Using the enzymes terminal deoxyribonucleotidyltransferase (EC 220.127.116.11) and polynucleotide phosphorylase (EC 188.8.131.52), we constructed polyriboadenylic acid tracts, approximately 8000 AMP residues long, attached to the 3'-terminus of a synthetic deoxynucleotide. The polyadenylated DNA, termed the "signal strand", was used in a displacement-type nucleic acid probe assay (see pp 1631-6, this issue). A probe-signal strand complex was made by hybridizing the signal strand to a deoxycytidylate-terminal probe DNA. The probe-signal strand complex was immobilized on an oligo (dG)-cellulose support and subsequently displaced from the immobilized hybrid complex with various amounts of analyte DNA. After the displacement procedure, the polyadenylate tracts were converted to ATP by the combined action of polynucleotide phosphorylase and pyruvate kinase. ATP was quantified by a bioluminescence assay with luciferase from Photinus pyralis. Displacement events were also quantified with biotinylated signal strand bound to avidin-conjugated horseradish peroxidase. Such enzyme-amplified assays offer considerable versatility: they may be coupled to a variety of detection systems including colorimetry, fluorimetry, and luminometry.


Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.


[Differential cell mutability during oogenesis and exposure to ethyleneimine and ethylmethane sulfonate in different Drosophila melanogaster lines].
The rate of recessive sex-linked lethal mutations (RLM) was estimated by brood pattern method at different stages of oogenesis, initially, in the wild-type R-86 strain of Drosophila melanogaster after treatment with EI and EMS. The former which is known to induce dominant lethals in mature oocytes of the 14th stage with a high frequency was equally effective in inducing RLM in oocytes of different age and in oogonia. EMS which does not induce dominant lethals when used as vapour was shown to increase RLM frequency in mature fraction of oocytes (the 14A stage only). Similar type of different mutability was found in mutagen-sensitive strain mus-201G1 and in the control 3-4 strain having the same genetical background as mus mutation. Female germ cells of mus-201G1 strain appeared to have a higher mutability in the case of EI, though no differences in mutability between these strains after EMS treatment were registered. The data are discussed in view of the specificity of primer damages occurring as a result of comparable mutagens action and participation of different repair systems in elimination of these damages.


Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models.
Metastasis is a major cause of mortality for cancer patients and remains as the greatest challenge in cancer therapy. Driven by multiple factors, metastasis may not be controlled by the inhibition of single target. This study was aimed at assessing the hypothesis that drugs could be rationally combined to co-target critical DNA, RNA and protein molecules to achieve "saturation attack" against metastasis. Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination. Consequently, triple-drug treatment showed a strong synergism in suppressing 143B cell proliferation and the greatest effects in reducing cell invasion. Compared to single- and dual-drug treatment, triple-drug therapy suppressed pulmonary metastases and orthotopic osteosarcoma progression to significantly greater degrees in orthotopic osteosarcoma xenograft/spontaneous metastases mouse models, while none showed significant toxicity. In addition, triple-drug therapy improved the overall survival to the greatest extent in experimental metastases mouse models. These findings demonstrate co-targeting of DNA, RNA and protein molecules as a novel therapeutic strategy for the treatment of metastasis.


Influence of dentin primer application methods on dentin bond strength.
This study was carried out to determine the influence of dentin primer application methods on bond strength to human dentin. Two dentin bonding restorative systems, Imperva Bond/Lite-Fil II A (Shofu) and Scotchbond Multi-Purpose/Z-100 (3M) were employed. Human molars were mounted in self-cured resin and the buccal surfaces were prepared with #600-grit SiC paper. These surfaces were then conditioned according to each manufacturer's instructions. Two experiments were designed: (1) effect of the primer application procedures (inactive and active application), and (2) effect of the air drying time (0, 1, 5, 10, 20, and 30 seconds). The adhesives were applied and resin composites were bonded to the teeth. Ten samples per test group were stored in 37 degrees C deionized water for 24 hours, and shear tested with a circular knife edge at a crosshead speed of 1.0 mm/minute. A one-way ANOVA followed by the Newman-Keuls multiple comparison at P < 0.05 was done. For both restorative systems, the bond strengths for active application were higher than those for inactive application, but there was no significant difference between the two mean values. According to the air drying time, there appeared to be an optimal range of drying times, longer for Imperva Bond (10-30 seconds) than for Scotchbond MP (1-5 seconds). The data suggest that the bond strengths of employed dentin bonding systems were greatly influenced by the methods of the dentin primer application.