Metabolism of small antimicrobial β(2,2)-amino acid derivatives by murine liver microsomes.
We have investigated the in vitro metabolism of three small antimicrobial β(2,2)-amino acid derivatives (M (w) < 500) that are highly potent against methicillin resistant Staphylococcus aureus, and are among the first compounds designed from small cationic antimicrobial peptides with potential for oral administration. The β(2,2)-amino acid derivatives are virtually completely resistant against degradation by proteases, and to further explore their drug potential, we have investigated the hepatic Phase I metabolism of this class of antimicrobial compounds. The β(2,2)-amino acid derivatives were incubated with murine liver microsomes and the metabolites analyzed semi-quantitatively by HPLC-MS and qualitatively by ultra performance liquid chromatography coupled to a tandem mass spectrometer which enabled identification of the metabolites by careful interpretation of the collision activated dissociation spectra. The study shows that sterically hindered β(2,2)-amino acid derivatives that otherwise are stable against proteolytic degradation underwent Phase I metabolism and were oxidized to a number of different metabolites depending on the structure of the β(2,2)-amino acid side-chains.


Geographic distribution of selected elements in the livers of polar bears from Greenland, Canada and the United States.
To assess geographic distributions of elements in the Arctic we compared essential and non-essential elements in the livers of polar bears (Ursus maritimus) collected from five regions within Canada in 2002, in Alaska between 1994 and 1999 and from the northwest and east coasts of Greenland between 1988 and 2000. As, Hg, Pb and Se varied with age, and Co and Zn with gender, which limited spatial comparisons across all populations to Cd, which was highest in Greenland bears. Collectively, geographic relationships appeared similar to past studies with little change in concentration over time in Canada and Greenland for most elements; Hg and Se were higher in some Canadian populations in 2002 as compared to 1982 and 1984. Concentrations of most elements in the polar bears did not exceed toxicity thresholds, although Cd and Hg exceeded levels correlated with the formation of hepatic lesions in laboratory animals.


Fundamental insights into the interaction between telomerase/TERT and intracellular signaling pathways.
Telomerase activity is critical for cancer cells to provide unrestricted proliferation and cellular immortality through maintaining telomeres. Telomerase enzymatic activity is regulatable at the level of DNA, mRNA, post translational modifications, cellular transport and enzyme assembly. More recent studies confirm the interaction of the telomerase with various intracellular signaling pathways including PI3K/AKT/mTOR, NF-κB and Wnt/β-catenin which mainly participating in inflammation, epithelial to mesenchymal transition (EMT) and tumor cell invasion and metastasis. Furthermore, hTERT protein has been detected in non-nuclear sites such as the mitochondria and cytoplasm in cells. Mitochondrial TERT indicates various non-telomere-related functions such as decreasing reactive oxygen species (ROS) generation, boosting the respiration rate, protecting mtDNA by direct binding, interacting with mitochondrial tRNAs and increasing mitochondrial membrane potential which can lead to higher chemoresistance rate in cancer cells during therapies. Understanding the molecular mechanisms of the TERT function and depended interactions in tumor cells can suggest novel therapeutic approaches. Hence, in this review we will explain the telomerase activity regulation in translational and post translational levels besides the established correlations with various cell signaling pathways with possible pathways for therapeutic targeting.


Development and evaluation of a dual-pump microcomputer-based closed-loop arterial pressure control system.
Hypertension after cardiac surgery is common and is associated with increased morbidity. It is usually managed by the infusion of short acting vasodilators. The use of a closed-loop computer system to control the infusion of a vasodilator has been shown to compare favourably with manual control. We have developed a closed-loop system for the ATARI 1040ST microcomputer to control arterial pressure by the simultaneous infusion of two vasodilators. The control program is based on a proportional-integral-derivative algorithm which has been adapted to allow control of two IMED 929 infusion pumps from one RS-232 port. All communication between the user and computer is carried out with a 'mouse', thus increasing acceptability of the system to ward staff. Cardiovascular data are collected on-line from the patient monitor via a custom-built analogue to digital convertor. This system was used to study glyceryl trinitrate and sodium nitroprusside in 24 patients requiring vasodilators after cardiopulmonary bypass. The study showed that in 14 of the patients hypertension was controlled by GTN alone and 10 required supplementary SNP. We have demonstrated that this dual-pump automatic arterial pressure control system is a satisfactory and safe method of administering two vasodilators simultaneously. It is suitable for both routine clinical and research uses.


Exploring specific primers targeted against different genes for a multiplex PCR for detection of Listeria monocytogenes.
The efficacy of six different sets of primers targeted against 16S rRNA and virulence genes such as 'iap', 'hly' and 'prf' was evaluated in separate PCR assays. The primer pairs targeted against 16S rRNA resulted into amplification of 1.2 kb PCR product. However, sets of primers targeted against different regions of 'iap' produced 371 and 660 bp PCR products, respectively. The primer pair targeted against 'prf' gene could produce 508 bp product. Three primer pairs targeted against different regions of 'hly', i.e., 'hly', 'hly A' and 'hly K9' were able to amplify 713, 276 and 384 bp products, respectively. The PCR conditions were also optimized in respect of two internal sets of primers falling within 'iap' and 'hly' genes that amplified 119 and 188 bp products to verify the PCR results obtained with respective external sets of primers. Three different combinations involving four sets of primers based on 16S rRNA, 'iap', 'hly' and 'prf' were explored in respective multiplex PCR assays in order to select a suitable combination. Combination 1 and 3 worked successfully as revealed by amplification of all the four bands of expected sizes on agarose gel. However, while optimizing the different parameters for developing a functional multiplex PCR, it was observed that in both these combinations, only two of the amplified products, i.e., 1.2 kb and 713 bp could be invariably detected. Hence, these two primers were combined in the multiplex PCR and the conditions were optimized for application in dairy foods for detection of Listeria monocytogenes.


Spontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep.
The purpose of this study was to examine the hypothesis that fetuses from multiple pregnancies who exhibited spontaneous, stable hypoxia would show more rapid development of metabolic acidosis and hypotension during short repeated episodes of umbilical cord occlusion than normoxic singleton or twin fetuses and, if this proved to be true, to determine whether this deterioration could be identified by changes in T/QRS height or ST waveform shape. Chronically instrumented near-term sheep fetuses (124 +/- 1 day) were subjected to 1-minute umbilical cord occlusions every 5 minutes (normoxic group, 8 fetuses; hypoxic group, 10 fetuses) for a total of 4 hours or until mean arterial blood pressure fell below 20 mm Hg for 2 successive occlusions. The spontaneous hypoxic, but not normoxic, fetuses had progressive compromise during repeated umbilical cord occlusions, with severe, progressive metabolic acidosis (pH, 7.07 +/- 0.14; base deficit,13 +/- 1.5 mmol/L vs 7.34 +/- 0.07 mmol/L; base deficit after the final occlusion, 1.1 +/- 1.4 mmol/L; P < .001), and hypotension (24 +/- 2 mm Hg vs 45.5 +/- 3 mm Hg; P < .0001); 4 hypoxic fetuses were unable to complete the 4-hour series of occlusions. The hypoxic group showed a much greater increase in T/QRS ratio during (P < .001) and between occlusions. Biphasic ST segment waveforms were not seen in either group either during or between occlusions. Exaggerated elevation of the T/QRS ratio during decelerations in early labor may be a useful marker of greater myocardial anaerobic stress (eg, because of pre-existing spontaneous hypoxia), but not of the development of fetal acidemia or hypotension.


Coronary Artery Calcification Score and the Progression of Chronic Kidney Disease.
An elevated coronary artery calcification score (CACS) is associated with increased cardiovascular disease risk in patients with CKD. However, the relationship between CACS and CKD progression has not been elucidated. We studied 1936 participants with CKD (stages G1-G5 without kidney replacement therapy) enrolled in the KoreaN Cohort Study for Outcome in Patients With CKD. The main predictor was Agatston CACS categories at baseline (0 AU, 1-100 AU, and >100 AU). The primary outcome was CKD progression, defined as a ≥50% decline in eGFR or the onset of kidney failure with replacement therapy. During 8130 person-years of follow-up, the primary outcome occurred in 584 (30.2%) patients. In the adjusted cause-specific hazard model, CACS of 1-100 AU (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.04 to 1.61) and CACS >100 AU (HR, 1.42; 95% CI, 1.10 to 1.82) were associated with a significantly higher risk of the primary outcome. The HR associated with per 1-SD log of CACS was 1.13 (95% CI, 1.03 to 1.24). When nonfatal cardiovascular events were treated as a time-varying covariate, CACS of 1-100 AU (HR, 1.31; 95% CI, 1.07 to 1.60) and CACS >100 AU (HR, 1.46; 95% CI, 1.16 to 1.85) were also associated with a higher risk of CKD progression. The association was stronger in older patients, in those with type 2 diabetes, and in those not using antiplatelet drugs. Furthermore, patients with higher CACS had a significantly larger eGFR decline rate. Our findings suggest that a high CACS is associated with significantly increased risk of adverse kidney outcomes and CKD progression.


Orthogonal excitations of lanthanide nanoparticle up/down conversion emissions via switching NIR lights for in-vivo theranostics.
With multiple emissions ranging from NIR-IIb to visible lights, near-infrared light-excited lanthanide nanoparticle (LnNP) is an ideal in-vivo theranostic platform to achieve imaging guided phototherapy. However, current reported LnNPs typically demonstrate simultaneous up and downconversion emissions with fixed single excitation light, which impairs therapeutic efficiency and generates side effect during navigation. Here we develop a lanthanide-based conversion switching nanoparticle (CSNP) with independent activation of 1550 nm NIR-IIb downconversion emission under 808 nm excitation and 345/450 nm upconversion emission under 980 nm excitation. CSNP is modified with Cy-GSH to quench NIR-IIb emission and photosensitizer hypocrellin A. In vivo delivery of CSNP is traced via 808 nm irradiation, and Cy-GSH changes structure in response to glutathione to activate NIR-IIb imaging. This indicates the tumor position and timing to switch for 980 nm irradiation to activate hypocrellin A for photodynamic therapy. Orthogonal activation of CSNP up/down conversion emissions demonstrates high tumor-to-normal tissue ratio in vivo and good therapeutic result, would have promising potential as a theranostics platform.


Distribution of natural radionuclides in the production and use of phosphate fertilizers in Brazil.
The Brazilian phosphate fertilizer is obtained by wet reaction of igneous phosphate rock with concentrated sulphuric acid, giving as final product, phosphoric acid and dehydrated calcium sulphate (phosphogypsum) as by-products. Phosphoric acid is the starting material for triple superphosphate (TSP), single superphosphate (SSP), monoammonium phosphate (MAP) and diammonium phosphate (DAP). The phosphate rock used as raw material presents in its composition radionuclides of the U and Th natural series. Taking this into account, the main aim of this paper is to evaluate the fluxes of natural radionuclides and radioactive disequilibria involved in the Brazilian industrial process of phosphoric acid production; to determine the content of radioactivity in several commercial fertilizers produced by this industry; to estimate their radiological impact in crop soils and the long term exposure due to their application. Radiological characterization of phosphate rock, phosphogypsum and phosphate fertilizers was performed by alpha and gamma spectrometry. The fertilizer samples, which are derived directly from phosphoric acid, MAP and DAP, presented in their composition low activity concentrations for 226Ra, 228Ra and 210Pb. As for U and Th, the concentrations found in MAP and DAP are more significant, up to 822 and 850Bqkg(-1), respectively. SSP and TSP, which are obtained by mixing phosphoric acid with different amounts of phosphate rock, presented higher concentrations of radionuclides, up to 1158Bqkg(-1) for (238)U, 1167Bqkg(-1) for (234)U, 1169Bqkg(-1) for 230Th, 879Bqkg(-1) for 226Ra, 1255Bqkg(-1) for 210Pb, 521Bqkg(-1) for 232Th, 246Bqkg(-1) for 228Ra and 302Bqkg(-1) for 228Th. Long term exposure due to successive fertilizer applications was evaluated. Internal doses due to the application of phosphate fertilizer for 10, 50 and 100 years were below 1mSvy(-1), showing that the radiological impact of such practice is negligible.


Occurrence and temperature dependence of atmospheric gas-phase organophosphate esters in high-mountain areas (Pyrenees).
The air concentrations of organophosphate esters (OPEs) were studied in a network of six remote high-mountain areas of the Pyrenees located along an altitudinal profile between 1619 m and 2453 m above sea level on a restricted planar surface to assess their vertical distribution based on long-range atmospheric transport and temperature gradients. Polyurethane foam passive samplers were used in five periods spanning over three years (September 2017-October 2020). The sum of concentrations of five OPEs were between 5.3 and 100 pg m-3, averaging 16-53 pg m-3 across campaigns at the different locations. These concentrations were much lower than those observed in areas under anthropogenic influence but also than those found in low altitude remote continental sites. A significant progressive change in predominant compounds was observed along the altitudinal gradient, with prevalence of tris(1-chloro-2-propyl) phosphate (TCIPP) or tris(2-chloroethyl) phosphate (TCEP) below or above 2300 m above sea level, respectively. This trend was consistent with the higher volatility of TCEP, which was retained at greater extent at lower environmental temperatures (higher altitude). A significant temperature dependence of the gas phase concentrations was observed for TCEP, TCIPP and triphenyl phosphate (TPHP), which could be explained by retention in the cold periods, predominantly adsorbed in snow, and their release to the atmosphere during snowmelt. This mechanism was consistent with the good agreement found between the vaporization enthalpies measured under laboratory conditions and the experimental values obtained from the slopes of the significant linear regressions when representing the vertical gradients.


A critical re-evaluation of Mohs micrographic surgery for a facial basal cell carcinoma in older adults: Should we waive this treatment in certain patients?
Skin cancer incidences are increasing. Treatment for basal cell carcinomas (BCCs) can be questioned in certain patients. Treatment options are various, but Mohs micrographic surgery (MMS) has the highest cure rate. It is, however, time-consuming and results in high logistical burden and treatment costs for both patients and society. This study critically re-evaluates MMS for facial BCCs in older adults. The main objective is to examine all clinical, tumour and patient characteristics in relation to safety and survival to detect a subgroup in which MMS was not the best choice. The overall aim is to identify characteristics that support clinical decision-making in daily practice. Patients that received MMS between November 1998 and December 2012 were included. Only patients >75 years with a facial BCC were withheld for analysis. This is a retrospective cohort study, since evaluating the outcome of MMS in accordance with life expectancy is the main objective. Patient charts were evaluated towards comorbidities, complications and survival. This cohort comprises 207 patients. Median survival was 7.85 years. The age-adjusted Charlson comorbidity index (aCCI) was divided into low/medium scores (aCCI < 6) and high scores (aCCI ≥ 6). Median survival was 11.58 years in the low aCCI group and 3.60 years in the high aCCI group (p < 0.001). There was a very strong association between high aCCI and survival (HR, 6.25; 95% CI, 3.83-10.21). Other characteristics were not associated with survival. Clinicians should assess the aCCI in older patients presenting with a facial BCC before deciding if MMS is an eligible treatment option. High aCCI has shown to be an indicator for low median survival, even in MMS patients with usually high functional status. MMS should be waived as treatment in older patients with high aCCI scores in favour of other, less intensive and less expensive treatment options.


Subsequent Receipt of Interventions for Glaucoma Among a Nationwide Sample of Patients Who Underwent Laser Peripheral Iridotomy.
To evaluate use of medical, laser, or incisional surgical interventions for glaucoma after laser peripheral iridotomy (LPI). Retrospective longitudinal cohort study. All enrollees aged ≥21 years in a US managed-care network who underwent bilateral LPIs in 2001-2011 were identified. The mean numbers of pre- and post-LPI glaucoma medication classes prescribed and the proportion of enrollees requiring cataract or glaucoma surgery within 2 years after the LPIs were determined. Multivariable logistic regression assessed factors associated with enrollees' prescription of ≥1 glaucoma medication class after bilateral LPIs. Of the 1660 patients undergoing bilateral LPIs, 1280 (77.1%) had no pre- or post-LPI prescriptions for any glaucoma medication class. Of the remaining patients, 251 (66.1%) required more glaucoma medication classes after than before the procedures, whereas 44 (11.6%) used fewer after the procedures; 85 (22.4%) were prescribed the same number before and after the LPIs. A total of 167 patients (10.1%) underwent cataract surgery and 79 (4.8%) received glaucoma surgery over the 2-year follow-up. Black patients had a 130% increased odds for glaucoma medication-class prescriptions after bilateral LPIs, compared with white patients (P = .02). The odds of post-LPI glaucoma medication use increased by 21% for every additional 5 years of age (P < .0001). Most patients undergoing bilateral LPIs received no pre- or post-LPI glaucoma medication-class prescriptions and had no cataract or additional glaucoma surgery within 2 years after LPIs. Clinicians should alert black or older patients and those already taking glaucoma medications before the procedure of their higher odds of requiring medications afterward.


Managing the value Co-creation of peer service providers in the sharing economy: The perspective of customer incivility.
Previous studies have discussed the preconditions for peer service providers participation in value co-creation from the perspective of the platforms or the peer service providers themselves. However, little attention has been paid to the influence of customers. In the sharing economy, however, customers interact closely with peer service providers, and they have a major influence on the attitudes and behaviours of peer service providers. Based on resource conservation theory, this study uses three waves of tracking surveys and two experiments to investigate the impact of customer unfriendliness on the shared value creation of peer service providers. The results suggest that rude customers in the sharing economy reduce the value creation behaviour of peer service providers by increasing emotional exhaustion. Furthermore, self-efficacy in regulating negative emotions is found to buffer the mechanism by which customer incivility increases the likelihood of emotional exhaustion. Peer service providers with higher self-efficacy in negative emotion regulation have weaker such relationships. This research fills the gap of how customers influence the value creation behaviour of peer service providers in the sharing economy, identifies the potential negative impacts of customer incivility and increases the overall added value of the sharing economy.


Factors That Influence Mortality in Critically Ill Patients with SARS-CoV-2 Infection: A Multicenter Study in the Kingdom of Saudi Arabia.
SARS-CoV-2 infection has a high mortality rate and continues to be a global threat, which warrants the identification of all mortality risk factors in critically ill patients. This is a retrospective multicenter cohort study conducted in five hospitals in the Kingdom of Saudi Arabia (KSA). We enrolled patients with confirmed SARS-COV-2 infection admitted to any of the intensive care units from the five hospitals between March 2020 and July 2020, corresponding to the peak of recorded COVID-19 cases in the KSA. In total, 229 critically ill patients with confirmed SARS-CoV-2 infection were included in the study. The presenting symptoms and signs of patients who died during hospitalization were not significantly different from those observed among patients who survived. The baseline comorbidities that were significantly associated with in-hospital mortality were diabetes (62% vs. 48% among patients who died and survived (p = 0.046)), underlying cardiac disease (38% vs. 19% (p = 0.001)), and underlying kidney disease (32% vs. 12% (p < 0.001)). In our cohort, the baseline comorbidities that were significantly associated with in-hospital mortality were diabetes, underlying cardiac disease, and underlying kidney disease. Additionally, the factors that independently influenced mortality among critically ill COVID-19 patients were high Activated Partial Thromboplastin Time (aPTT )and international normalization ratio (INR), acidosis, and high ferritin.


Transplacental transfer of total immunoglobulin G and antibodies to Plasmodium falciparum antigens between the 24th week of gestation and term.
Full-term newborns have antibody (Ab) repertoires and levels similar to their mothers to help protect them from environmental pathogens. Unfortunately, preterm babies, especially those born < 34 weeks, have reduced levels of protective antibodies. In Africa, antibodies to Plasmodium falciparum are important in protection from malaria. This study investigated the transfer of total IgG and antibodies to 9 P. falciparum antigens and tetanus toxoid between 24 weeks and term. Paired maternal and cord samples from 166 preterm (24-37 weeks) and 154 term deliveries were used. Transfer efficiency was expressed as the ratio of Ab levels in cord to maternal plasma (CMR). At 24-25 weeks, CMR ranged from 0.31 to 0.94 for the different antigens; the rate of transfer was similar for all antigens between 24 and 40 weeks; resulting in median CMR of 0.49-0.95 at term. Babies of mothers with hypergammaglobulinemia and normal IgG levels had similar amounts of IgG, supporting data that saturation of the neonatal Fc-receptor occurs at ~ 16 mg IgG/ml. Thus, babies born prior to 34-35 weeks in Africa are likely to have reduced Ab levels to some, but not all antigens. Since IgG transfer is Fc-mediated, why differences exist in CMR among the antigens warrants further investigation.


Effects of Lon protease down-regulation on the mitochondrial function and proteome.
The Lon protease is an ATP-dependent protease of the mitochondrial matrix that contributes to the degradation of abnormal and oxidized proteins in this compartment. It is also involved in the stability and regulation of the mitochondrial genome. The effects of a depletion of this protease on the mitochondrial function and the identification of oxidized target proteins of Lon have been performed using as cellular model HeLa cells in which Lon level expression can be down-regulated. The expression level of proteins playing a role in the stress response was first determined. The amount of ClpP, another protease in charge of protein degradation of the mitochondrial matrix, and the amount of several chaperones have been evaluated. The expression level of respiratory chain subunits was also measured with or without Lon depletion. The mitochondrial compartment morphology was monitored in different stress conditions, and measured using a parameter devoted to the evaluation of the mitochondrial dynamics. None of these investigations showed a significant phenotype resulting from Lon down-regulation A possible impact of Lon depletion on oxidized mitochondrial proteins level was then sought. 1D gel electrophoresis after the derivatization of protein carbonyl groups with 2,4-dinitrophenyl hydrazine (DNPH) revealed an increase in carbonylated proteins more important in mitochondrial extracts than in total cellular extracts. 2D difference gel electrophoresis (DIGE) experiments provide results consistent with these observations with some enlightenments. Performed with fluorescent dyes labelling either proteins or their carbonyl groups, these experiments indicated proteome modifications in cells with Lon down-regulation both at the level of protein expression and at the level of protein oxidation. These variations are noted in proteins acting in different cellular activities, i.e. metabolism, protein quality control and cytoskeleton organization.


Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model.
Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as synergistic or antagonistic, depending on the deviation of the observed combination response from the expected effect calculated based on a reference model of non-interaction. The existing reference models were proposed originally for low-throughput drug combination experiments, which make the model assumptions often incompatible with the complex drug interaction patterns across various dose pairs that are typically observed in large-scale dose-response matrix experiments. To address these limitations, we proposed a novel reference model, named zero interaction potency (ZIP), which captures the drug interaction relationships by comparing the change in the potency of the dose-response curves between individual drugs and their combinations. We utilized a delta score to quantify the deviation from the expectation of zero interaction, and proved that a delta score value of zero implies both probabilistic independence and dose additivity. Using data from a large-scale anticancer drug combination experiment, we demonstrated empirically how the ZIP scoring approach captures the experimentally confirmed drug synergy while keeping the false positive rate at a low level. Further, rather than relying on a single parameter to assess drug interaction, we proposed the use of an interaction landscape over the full dose-response matrix to identify and quantify synergistic and antagonistic dose regions. The interaction landscape offers an increased power to differentiate between various classes of drug combinations, and may therefore provide an improved means for understanding their mechanisms of action toward clinical translation.


A novel electrochemical sensing platform for anions based on conducting polymer film modified electrodes integrated on paper-based chips.
In this paper, conducting polymer film modified electrodes were applied to fabricate paper-based chips (PCs), and different concentrations of chloride ions (Cl(-)) in water can be selectively detected based on the potential response towards Cl(-). The three-electrode system was screen-printed on paper and the polypyrrole (PPy) film doped with Cl(-) was electrochemically polymerized on working electrodes through cyclic voltammetry in aqueous solution. Open circuit potential-time method was used to measure the potential response. Based on such PCs, Cl(-) can be selectively detected in the range of 10(-7)-10(-2)M. Moreover, such PCs were utilized for Cl(-) analysis in real water samples and resulted in good results with recoveries between 113% and 124%. Besides, following the strategy we also employed this method to detect F(-) in water to demonstrate its general applicability. In view of its novelty, simplicity, sensitivity and low price, such PCs will potentially be utilized for the monitoring of anions in the environment, and our method made a start for the application of CMEs to PCs to design electrochemical sensors.


Postmortem tissue and plasma concentrations of digoxin in newborns and infants.
Postmortem tissue and plasma concentrations of digoxin were studied in 13 premature newborns, 6 mature newborns, and 5 older infants (age 1 to 14 months). The pertinent results of our study are as follows: The tissue digoxin concentrations tend to be higher in premature and mature newborns than in infants. This difference is statisitcally significant with respect to the concentration in myocardium and skeletal muscle. The renal digoxin concentration of premature newborns is significantly lower than that of mature newborns, the tissue concentrations in the other organs examined being essentially equal. In all age groups examined, skeletal muscle contains the greatest portion of digoxin, followed by the liver. The relation of myocardial to plasma digoxin concentration shows no significant difference between the various age groups. Within the groups, the variation is relatively large.


Comparison of results of voriconazole disk diffusion testing for Candida species with results from a central reference laboratory in the ARTEMIS global antifungal surveillance program.
The accuracy of antifungal susceptibility testing is important for reliable resistance surveillance and for the clinical management of patients with serious infections. Our primary objective was to compare the results of voriconazole disk diffusion testing of Candida spp. performed by centers participating in the ARTEMIS program with disk diffusion and MIC results obtained by the central reference laboratory. A total of 2,934 isolates of Candida spp. were tested by CLSI disk diffusion and reference broth microdilution methods in the central reference laboratory. These results were compared to the results of disk diffusion testing performed in the 54 participating centers. All tests were performed and interpreted following CLSI recommendations, as follows: susceptible (S), MIC of <or=1 microg/ml (>or=17 mm); susceptible dose dependent (SDD), MIC of 2 microg/ml (14 to 16 mm); and resistant (R), MIC of >or=4 microg/ml (<or=13 mm). The overall categorical agreement between participant disk diffusion test results and reference laboratory MIC results was 94.1%, with 0.1% very major errors (VME) and 3.4% major errors (ME). The categorical agreement between disk diffusion test results obtained in the reference laboratory and the MIC test results was 99.0%. Likewise, good agreement was observed between participant disk diffusion test results and reference laboratory disk diffusion test results, with an agreement of 93.8%, 0.2% VME, and 3.4% ME. The disk diffusion test was reliable for detecting those isolates of Candida spp. that were characterized as resistant (MIC of >or=4 microg/ml) by MIC testing. External quality assurance data obtained by surveillance programs such as the ARTEMIS Global Antifungal Surveillance Program ensure the generation of useful surveillance data and result in the continued improvement of antifungal susceptibility testing practices.


Neural correlates of clinical improvement in response to N-acetylcysteine in adolescents with non-suicidal self-injury.
Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect.


Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: 11-year Demographic Clinical and Prognostic Characteristics.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening, severe drug reactions. Randomized studies on these diseases are difficult to perform. The purpose of this study was to summarize the demographic and clinical characteristics of patients with SJS and TEN in a tertiary hospital in Turkey. We evaluated the records of 33 patients with SJS and TEN who were followed in our clinic or examined between January 2008 and June 2019, retrospectively. Age, sex, time of admission to hospital, causative drug, presence of concomitant disease, skin findings, mucosal involvement, the severity-of-illness score for TEN, the medication used, antibiotic use, transfer to intensive care, development of complications, and death or discharge status were noted. Of the 33 patients, 11 (33.3%) had SJS, 3 (9.1%) had SJS/TEN overlap, and 19 (57.6%) had TEN. The majority (60.6%) of the patients were female. Nineteen (57.6%) patients had one, and 13 (39.4%) had more than one suspected drug exposure in their history. The most commonly suspected drugs were antibiotics. Twelve (36.4%) patients had intensive care unit hospitalization. Ten (30.3%) patients died. The demographic data of our study were consistent with the literature. Similar to the literature, antibiotics were the most common reaction-causing drugs. However, antiepileptic drugs, which were more frequently reported in other studies, were identified as suspicious in only one patient. We believe that our study will contribute to the determination of characteristics of this rare disease with real-life data.


Functional identification of the SecB homologue in Methanococcus jannaschii and direct interaction of SecB with trigger factor.
In this study Mj0357 protein, a hypothetical protein from Methanococcus jannaschii which shows an 18% sequence identity with SecB from E. coli, has been identified as a functional homologue of SecB in M. jannaschii through a number of biochemical and biophysical examinations. It is composed mostly of beta-strands and exists as a homotetramer in solution. Mj0357 protein exhibits in vitro chaperone-like activity, suppressing thermal aggregation of citrate synthase and binding to partially folded maltose-binding protein. Upon binding to a peptide ligand, the protein undergoes a conformational change to expose a hydrophobic patch on the protein surface. All these physicochemical properties are highly similar to those of E. coli SecB. In addition, E. coli trigger factor (TF) has been shown here for the first time to bind E. coli SecB and Mj0357 protein with low micromolar affinities, indicating that the TF could interact directly along the SecB-dependent translocation pathway. These results indicate that the translocation pathway is conserved and functionally homologous in at least one of the archaeal organisms.


Alcoholization of Intercostal Nerves for Incident Pain Due to Rib Metastases.
Rib metastases may cause incident pain on coughing, deep respiration, or on specific thoracic wall movement. Proper titration of opioid doses relieves the background pain adequately, but does not allow a good pain control for incident pain. A patient with rib metastases presented incident pain due to minimal chest wall movement, limiting breathing. Alcoholization of intercostal nerves at T6,T7, T8, and T9, at level of ribs angle, RESULTS: Intercostal blocks were highly effective in relieving incident pain due to rib metastases. A simple and safe procedure may produce effective analgesia preventing incident pain due to rib metastases. Differently from other sites of bone metastases, ribs are easily localized and the neurolytic block results to be effective and safe.


Physiological response to prone positioning in intubated adults with COVID-19 acute respiratory distress syndrome: a retrospective study.
COVID-19 related acute respiratory distress syndrome (ARDS) has specific characteristics compared to ARDS in other populations. Proning is recommended by analogy with other forms of ARDS, but few data are available regarding its physiological effects in this population. This study aimed to assess the effects of proning on oxygenation parameters (PaO2/FiO2 and alveolo-arterial gradient (Aa-gradient)), blood gas analysis, ventilatory ratio (VR), respiratory system compliance (CRS) and estimated dead space fraction (VD/VT HB). We also looked for variables associated with treatment failure. Retrospective monocentric study of intubated COVID-19 ARDS patients managed with an early intubation, low to moderate positive end-expiratory pressure and early proning strategy hospitalized from March 6 to April 30 2020. Blood gas analysis, PaO2/FiO2, Aa-gradient, VR, CRS and VD/VT HB were compared before and at the end of each proning session with paired t-tests or Wilcoxon tests (p < 0.05 considered as significant). Proportions were assessed using Fischer exact test or Chi square test. Forty-two patients were included for a total of 191 proning sessions, median duration of 16 (5-36) hours. Considering all sessions, PaO2/FiO2 increased (180 [148-210] vs 107 [90-129] mmHg, p < 0.001) and Aa-gradient decreased (127 [92-176] vs 275 [211-334] mmHg, p < 0.001) with proning. CRS (36.2 [30.0-41.8] vs 32.2 [27.5-40.9] ml/cmH2O, p = 0.003), VR (2.4 [2.0-2.9] vs 2.3 [1.9-2.8], p = 0.028) and VD/VT HB (0.72 [0.67-0.76] vs 0.71 [0.65-0.76], p = 0.022) slightly increased. Considering the first proning session, PaO2/FiO2 increased (186 [165-215] vs 104 [94-126] mmHg, p < 0.001) and Aa-gradient decreased (121 [89-160] vs 276 [238-321] mmHg, p < 0.001), while CRS, VR and VD/VT HB were unchanged. Similar variations were observed during the subsequent proning sessions. Among the patients who experienced treatment failure (defined as ICU death or need for extracorporeal membrane oxygenation), fewer expressed a positive response in terms of oxygenation (defined as increase of more than 20% in PaO2/FiO2) to the first proning (67 vs 97%, p = 0.020). Proning in COVID-19 ARDS intubated patients led to an increase in PaO2/FiO2 and a decrease in Aa-gradient if we consider all the sessions together, the first one or the 4 subsequent sessions independently. When considering all sessions, CRS increased and VR and VD/VT HB only slightly increased.


Long noncoding RNA LTCONS6801 up-regulates TBK1 mediated antiviral innate immunity in miiuy croaker, Miichttys miiuy.
The development of sequencing technology has further accelerated the research of noncoding RNA (ncRNA). A large number of studies have shown that long noncoding RNA (lncRNA) in ncRNA can regulate gene expression in various ways and then affect various physiological and biochemical processes of the host. In this study, we found a novel lncRNA in Miichthys miiuy, named LTCONS6801, which is beneficial to TANK-binding kinase 1 (TBK1) and its mediated pathway to promote the host immune function. First, we found that lncRNA LTCONS6801 can enhance cell activity through cell viability detection and cell proliferation detection. Besides, after poly (I: C) stimulation, overexpression of lncRNA LTCONS6801 promoted the expression of antiviral gene and TBK1. We found that lncRNA LTCONS6801 further affects NF-κB and IRF3 signaling pathways by regulating the expression of TBK1. In short, lncRNA LTCONS6801 is an lncRNA that can positively regulate the host innate immune response by regulating the expression of TBK1. Our study enriches the theory and insight of lncRNA regulating antiviral immune pathway and clarifies the important role of lncRNA in antiviral immunity of teleost fish.


The determinants of the duration of postpartum sexual abstinence in West Africa: a multilevel analysis.
The question of how postpartum sexual abstinence responds to social change in West Africa is important because declines in the practice could increase fertility levels and worsen child and maternal health. This study uses data from the late 1970s in Cote d'Ivoire, Ghana, and Cameroon to examine effects of modernization and women's status on the length of abstinence. The results show that modernization and female status should be associated with declines in abstinence, which could lead to an increase in fertility and deterioration in maternal and child health.


Mouse natural killer (NK) cell activity against human cell lines is not influenced by superinfection of the target cell with xenotropic murine C-type virus.
Mouse natural killer (NK) cells can lyse a variety of syngeneic, allogeneic and xenogeneic target cells in short-term 51Cr release assays. The target specificity of NK cells is not known, but endogenous C-type viral antigens have been suggested as possible target structures. To test this hypothesis, human lymphoid lines were superinfected with xenotropic mouse C-type virus either by repeated dosage through nude mice or by in vitro superinfection with the supernatants of nude-mouse-passaged lines. The appearance of surface-associated MuLV antigens after superinfection was confirmed in a complement-dependent cytotoxicity test. Subsequently, the NK sensitivity of each infected line was compared with its non-infected counterpart in direct cytolytic and competition assays. None of these two assay systems showed a consistent difference in NK sensitivity of infected and non-infected cell lines. These findings do not lend support to the concept tht murine C-type viral antigens are responsible for NK sensitivity.


Inhibition of 11beta-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?
The metabolic syndrome (syndrome X) is a cluster of risk factors and a common cause of cardiovascular disease in humans. Although the underlying mechanism for metabolic syndrome is still poorly understood, recent clinical data and studies with transgenic animals implicate elevated intracellular glucocorticoid tone in the etiology of metabolic syndrome. Development of selective inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 and their use in rodent animal disease models encompassing several aspects of metabolic syndrome indicate the possibility of therapeutic intervention. This review will focus on recent advances in our understanding of the role of 11beta-HSD1 in metabolic disorders and other disease processes.


Motivation for rhinoplasty: changes in 5970 cases, in three groups, 1964 to 1997.
The motivational factors were divided into three categories: (1) independent decision, (2) observation of previous patients, and (3) external influences. The results of the percentage breakdown of the patients in our present study are compared with previous results are presented in 1983 in this journal. Once again, the independent decision of the patient was the most important factor in deciding to have cosmetic rhinoplasty, followed by their observation of results in other patients. These two factors have been the motivation in approximately 80% of all the patients in all three studies. The age breakdown of cosmetic rhinoplasty patients shows that after the age of 21, as patients get older, a smaller and smaller percentage of patients was motivated for surgery by independent decision alone. These older patients need external influences to motivate them to have surgery. In most cases, the desire for surgery had smoldered in them since adolescence, and they needed an external "OK" to have it done.


Longitudinal impact of a collaborative care model on employment outcomes in bipolar disorder.
Few treatments are available to directly address employment or work functioning among individuals with bipolar disorder (BD) and currently available treatment models have not been evaluated to examine their impact employment outcomes. We examined impact of affective symptoms and health-related quality of life (HRQoL) on longitudinal employment outcomes in a community-based sample of individuals with bipolar disorder who completed the Life Goals-Collaborative Care (LG-CC) intervention. Participants (N=178) were assessed based on HRQoL, employment status, affective symptoms (depressive/manic), and work hours at baseline, 6-, 12- and 24-months after initiation of LG-CC. Frequency of LG-CC sessions and number of care-manager contacts also were ascertained. At baseline, 21% were employed, 29.5% were unemployed, and 49.6% were on disability. Improvement in affective symptoms was seen over the 24-month period, but not in HRQoL. Lower depression symptoms, but not mania, at baseline predicted greater likelihood of employment status in 24-months. Degree of LG-CC participation was associated with a reduced likelihood of becoming disabled/unemployed and increased number of hours worked in 24-months. The study was originally designed to compare implementation strategies and not the effectiveness of LG-CC on employment outcomes. Further, it was unclear whether improvement in work functioning were personal goals of the participants of this study. Fewer depressive symptoms were associated with positive employment outcomes over time. Collaborative Care Models that are already implemented by existing providers that focus on management of affective symptoms show promise in positively impacting employment outcomes.


[Toxicity of lead nitrate to the carp (Cyprinus carpio L.). Effect on respiratory metabolism and histological structure of gill lamellae (author's transl)].
Oxygen uptake of gills was estimated after lead poisoning of the Carp. Histological structure of gill lamellae was also examined. Oxygen uptake quickly decreased after two weeks then increased again in long term poisoning without total recovery. On the other hand, desquamation of the gill epithelium was observed as well as proliferation of mast cells probably loaded with lead. The return to clean water for eleven weeks, allowed the lamellar epithelium recovery but not the mast cells elimination.


Strategies for Optimization of the Clustered Regularly Interspaced Short Palindromic Repeat-Based Genome Editing System for Enhanced Editing Specificity.
The clustered regularly interspaced short palindromic repeats (CRISPR) system is inarguably the most valuable gene editing tool ever discovered. Currently, three classes of CRISPR-based genome editing systems have been developed for gene editing, including CRISPR/CRISPR associate system (Cas) nucleases, base editors, and prime editors. Ever-evolving CRISPR technology plays an important role in medicine; however, the biggest obstacle to its use in clinical practice is the induction of off-target effects (OTEs) during targeted editing. Therefore, continuous improvement and optimization of the CRISPR system for reduction of OTEs is a major focus in the field of CRISPR research. This review aims to provide a comprehensive guide for optimization of the CRISPR-based genome editing system.


[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].
A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.


Interleukin-2 protects against endothelial dysfunction induced by high glucose levels in rats.
Interleukin-2 (IL-2) can modulate cardiovascular functions, but the effect of IL-2 on vascular endothelial function in diabetes is not known. We hypothesized that IL-2 may attenuate endothelial dysfunction induced by high glucose or diabetes. So the aim of this study was to investigate the effect of IL-2 on endothelium-response of aortas incubated with high glucose or from diabetic rats and its underlying mechanism. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EIR), superoxide dismutase (SOD) and nitric oxide synthase (NOS) were measured in aortas isolated from non-diabetic rats and exposed to a high glucose concentration and from streptozotocin-induced diabetic rats. Incubation of aortic rings with high glucose (44 mM) for 4 h resulted in a significant inhibition of EDR, but had no effects on EIR. Co-incubation with IL-2 for 40 min prevented the inhibition of EDR caused by high glucose in a concentration-dependent manner. Similarly, high glucose decreased SOD and NOS activity in aortic tissue. IL-2 (1000 U/ml) significantly attenuated the decrease of SOD and NOS activity caused by high glucose. In addition, EDR declined along with the decrease of serum NO level in aortas from STZ-induced diabetic rats. Injection of IL-2 (5000 and 50,000 U kg(-1) d(-1), s.c.) for 5 weeks prevented the inhibition of EDR and the decrease of serum NO levels caused by diabetes. IL-2 significantly ameliorated the endothelial dysfunction induced by hyperglycemia, in which the activation of the NO pathway and SOD may be involved.


Isolation of rotavirus from foals with diarrhoea.
A rotavirus, morphologically similar to other known rotaviruses, was demonstrated in the faeces of 5 foals with diarrhoea on two properties. Four of these 5 samples produced specific intracytoplasmic fluorescence in cell culture when reacted with calf rotavirus antiserum conjugate. Sixteen affected foals from both properties were depressed, did not suckle and became recumbent. Most had a watery diarrhoea which lasted for 3 days and resulted in some dehydration and loss of body condition. Sick foals were separated from their mothers following the onset of diarrhoea and given fluid therapy and antibiotics, but despite these measures 4 of 12 affected foals on one property died. Acute and convalescent sera were collected from 6 foals, and in each case a rise in the titres of complement fixing and neutralising antibodies was demonstrated. Faecal filtrates containing foal rotaviruses were fed to gnotobiotic piglets and the effects compared with those of other rotaviruses. Viral isolates from both properties produced an asymptomatic infection in piglets. This contrasts with the other rotaviruses isolated in Australia that have been shown to cause diarrhoea in gnotobiotic piglets.


Diastasis recti abdominis in adult women based on abdominal computed tomography imaging: Prevalence, risk factors and its impact on life.
This study aimed to obtain the incidence of diastasis recti abdominis (DRA) and analyse possible risk factors in adult females. Moreover, the relationships between DRA and lower back pain, pelvic floor function and quality of life were also analysed. Diastasis recti abdominis is a separation of the abdominal muscles at the linea alba. Currently, studies on the prevalence rates, risk factors and consequences of DRA are varied. In particular, reports on DRA among adult women are lacking. A one-sample questionnaire study design is used following the STROBE checklist. The inter-rectus distance was measured by computed tomography in 644 women. Custom questionnaires, the Oswestry Disability Index, The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were used to investigate personal information, the subjects' back pain, pelvic floor function and quality of life, respectively. The incidence of DRA was 28.4%. Age, the number of pregnancies, BMI and diabetes were influencing factors for DRA. After age stratification, pregnancy and diabetes were found to be risk factors for DRA in young women, and obesity and diabetes were risk factors for DRA in older women. This study showed that the association between DRA and low back pain was highly significant. Diastasis recti abdominis is common in adult women. Avoiding multiple pregnancies, preventing diabetes and controlling weight may prevent DRA, which may be beneficial for decreasing low back pain in women. The findings have important implications for the health of adult women which can provide the basis for appropriate nursing implementation for DRA patients. The application of specific prevention and intervention measures for the risk factors may reduce the severity of low back pain.


Unmet needs and health-related quality of life of dementia family caregivers transitioning from home to long-term care: A scoping review.
This scoping review is to identify experiences, unmet needs, and health-related quality of life (HRQoL) of family caregivers transitioning their care recipients with dementia into long-term care (LTC). The methodological framework of Arksey and O'Malley guided the review. Themes from nineteen selected studies were organized around three categories. First, caregiver experiences during LTC placement featured challenges around placement decision-making and distress and changes in relationships and responsibilities. Second, unmet needs of caregivers were desired emotional support and information about transitions. Finally, caregivers' HRQoL varies around transition. Family caregivers experience unique challenges and can have unmet needs during the LTC placement of their care recipients with dementia. Findings suggest the need for interventions that teach skills, care planning, assistance with conflict resolution, communication training, and guidance finding services and resources.


Intravenous lidocaine to prevent endothelial dysfunction after major abdominal surgery: a randomized controlled pilot trial.
Major abdominal surgery is associated with endothelial glycocalyx disruption. The anti-inflammatory effects of lidocaine were recently associated with endothelial barrier protection. This was a single-centre, parallel group, randomized, controlled, double blind, pilot trial. Forty adult patients scheduled for major abdominal surgery were included between December 2016 and March 2017 in the setting of a University Hospital in Brussels (Belgium); reasons for non-inclusion were planned liver resection and conditions associated to increased risk of local anesthetics systemic toxicity. Patients were randomized to receive either lidocaine by continuous intravenous administration or an equivalent volume of 0.9% saline. The primary endpoint was the postoperative syndecan-1 concentration (difference between groups). Near-infrared spectroscopy of the thenar eminence in association with the vascular occlusion test, and contemporary analysis of flow-mediated dilation of the brachial artery were the secondary outcomes, along with haemodynamic data. Blood samples and data were collected before surgery (T0), and at 1-3 h (T1) and 24 h (T2) post-surgery. Syndecan-1 concentration increased significantly post-surgery (P < 0.001), but without any difference between groups. The near-infrared spectroscopy-derived and flow-mediated dilation-derived variables showed minor changes unrelated to group assignment. Compared with the placebo group, the intervention group had a significantly lower peri-operative mean arterial pressure and cardiac index, despite equally conducted goal-directed haemodynamic management. Postoperative lactate concentrations were similar between groups. Lidocaine failed to have any effect on endothelial function. Since in comparisons to other types of clinical situations, syndecan-1 was only slightly upregulated, endothelial dysfunction after major abdominal surgery might be overestimated. « ISRCTN Registry » identifier: ISRCTN63417725. Date: 15/06/2020. Retrospectively registered.


RECOVERING A TREE FROM THE LENGTHS OF SUBTREES SPANNED BY A RANDOMLY CHOSEN SEQUENCE OF LEAVES.
Given an edge-weighted tree T with n leaves, sample the leaves uniformly at random without replacement and let Wk , 2 ≤ k ≤ n, be the length of the subtree spanned by the first k leaves. We consider the question, "Can T be identified (up to isomorphism) by the joint probability distribution of the random vector (W2, …, Wn )?" We show that if T is known a priori to belong to one of various families of edge-weighted trees, then the answer is, "Yes." These families include the edge-weighted trees with edge-weights in general position, the ultrametric edge-weighted trees, and certain families with equal weights on all edges such as (k + 1)-valent and rooted k-ary trees for k ≥ 2 and caterpillars.


Statistical modeling of methylene blue degradation by yeast-bacteria consortium; optimization via agro-industrial waste, immobilization and application in real effluents.
The progress in industrialization everyday life has led to the continuous entry of several anthropogenic compounds, including dyes, into surrounding ecosystem causing arduous concerns for human health and biosphere. Therefore, microbial degradation of dyes is considered an eco-efficient and cost-competitive alternative to physicochemical approaches. These degradative biosystems mainly depend on the utilization of nutritive co-substrates such as yeast extract peptone in conjunction with glucose. Herein, a synergestic interaction between strains of mixed-culture consortium consisting of Rhodotorula sp., Raoultella planticola; and Staphylococcus xylosus was recruited in methylene blue (MB) degradation using agro-industrial waste as an economic and nutritive co-substrate. Via statistical means such as Plackett-Burman design and central composite design, the impact of significant nutritional parameters on MB degradation was screened and optimized. Predictive modeling denoted that complete degradation of MB was achieved within 72 h at MB (200 mg/L), NaNO3 (0.525 gm/L), molasses (385 μL/L), pH (7.5) and inoculum size (18%). Assessment of degradative enzymes revealed that intracellular NADH-reductase and DCIP-reductase were key enzymes controlling degradation process by 104.52 ± 1.75 and 274.04 ± 3.37 IU/min/mg protein after 72 h of incubation. In addition, azoreductase, tyrosinase, laccase, nitrate reductase, MnP and LiP also contributed significantly to MB degradation process. Physicochemical monitoring analysis, namely UV-Visible spectrophotometry and FTIR of MB before treatment and degradation byproducts indicated deterioration of azo bond and demethylation. Moreover, the non-toxic nature of degradation byproducts was confirmed by phytotoxicity and cytotoxicity assays. Chlorella vulgaris retained its photosynthetic capability (˃ 85%) as estimated from Chlorophyll-a/b contents compared to ˃ 30% of MB-solution. However, the viability of Wi-38 and Vero cells was estimated to be 90.67% and 99.67%, respectively, upon exposure to MB-metabolites. Furthermore, an eminent employment of consortium either freely-suspended or immobilized in plain distilled water and optimized slurry in a bioaugmentation process was implemented to treat MB in artificially-contaminated municipal wastewater and industrial effluent. The results showed a corporative interaction between the consortium examined and co-existing microbiota; reflecting its compatibility and adaptability with different microbial niches in different effluents with various physicochemical contents.


Investigation of myocardial metabolism for the study of the pathophysiology of cardiac disease.
Many variables, including food ingestion, circulating hormone, and the cardiac work load, affect myocardial metabolism. Important changes in myocardial metabolism are associated with myocardial ischemia. The study of myocardial metabolism by means of different invasive and noninvasive techniques allows a better understanding of both cardiac physiology and pathophysiology in humans.


Amino acid restriction increases β-cell death under challenging conditions.
Malnutrition programs metabolism, favor dysfunction of β cells. We aimed to establish an in vitro protocol of malnutrition, assessing the effect of amino acid restriction upon the β cells. Insulin-producing cells INS-1E and pancreatic islets were maintained in RPMI 1640 medium containing 1× (Ctl) or 0.25× (AaR) of amino acids. We evaluated several markers of β-cell function and viability. AaR Insulin secretion was reduced, whereas cell viability was unaltered. Calcium oscillations in response to glucose increased in AaR. AaR showed lower Ins1 RNAm, snap 25, and PKC (protein kinase C) protein content, whereas phospho-eIF2α was increased. AaR cells exposed to nutrient or chemical challenges displayed higher apoptosis rates. We showed that amino acid restriction programmed β cell and induced functional changes. This model might be useful for the study of molecular mechanisms involved with β-cell programming helping to establish novel therapeutic targets to prevent harmful outcomes of malnutrition.


Mesenteric venous thrombosis in a patient with prothrombin 20210A mutation and antithrombin III deficiency: challenges to conventional anticoagulation--a case report.
Mesenteric venous thrombosis presents as vague abdominal pain in patients with a medical or family history suggestive of a hypercoagulable state. Classic computed tomography findings will often confirm the diagnosis, and the presence of persistent abdominal pain or tenderness will determine the need for surgical intervention. Expeditious anticoagulation is the treatment of choice. This case demonstrates the CT findings for mesenteric venous thrombosis and discusses the challenges of anticoagulation in a patient with 2 hypercoagulable disorders.


Kinetics of nuclear translocation and turnover of the vitamin D receptor in human HL60 leukemia cells and peripheral blood lymphocytes--coincident rise of DNA-relaxing activity in nuclear extracts.
High affinity receptors (VDR) for 1,25-dihydroxycholecalciferol (calcitriol) are expressed in HL60 human leukemia cells and in low numbers in peripheral blood lymphocytes (PBL). HL60 cells, expressing some characteristics of promyelocytes, can be induced to monocytoid differentiation by calcitriol. Specific nuclear translocation of [3H]calcitriol/VDR was examined after exposure of whole cells to 10(-9) M/l calcitriol in the presence and absence of a 500-fold excess of unlabeled ligand and subsequent isolation of nuclei. Specific nuclear translocation of [3H]calcitriol/VDR was found to be time dependent reaching a maximum of approximately 2100 binding sites/nucleus after 3 h of incubation in HL60 cells, whereas a maximum of approximately 310 binding sites/nucleus was found after 3 h in PBL. Pulse exposure of HL60 to radiolabeled hormone for 3 h followed by culture in medium without serum and calcitriol lead to nuclear retention of approximately 1600 radiolabeled VDR by 8 h and approximately 1000 VDR by 24 h. Radiolabeled VDR disappeared from the nuclear compartment with a halflife of approximately 30 min if cells were cultured with identical concentrations of unlabeled hormone after the pulse (pulse/chase-experiments). No difference of VDR retention in pulse and pulse/chase-experiments was seen in PBL, where VDR halflife was approximately 30 min. No specific translocation into the nuclear compartment was seen when isolated nuclei were incubated in [3H]calcitriol. Radiolabeled hormone/receptor complexes of nuclei isolated from cells exposed for 3 h to radiolabeled hormone--in contrast to identical experiments with intact cells--did not disappear from the nuclear compartment upon incubation of nuclei with identical concentrations of the unlabeled compound. The activity of DNA relaxing enzymes (e.g. topoisomerases I and II) in nuclear extracts was measured using a PBR 322-relaxation-assay. Enhanced overall enzyme activity was found in nuclear extracts by 1 h after incubation with calcitriol (final ethanol concentration 0.0001% v/v) in HL60 and PBL. The enhanced activity disappeared after 2 h in PBL, whereas it was still enhanced by 4 h in HL60. No effect was seen in ethanol treated controls. We conclude that a specific nuclear translocation mechanism exists for calcitriol in both cell types examined, most likely due to translocation of receptor proteins after hormone binding. Translocated hormone/receptor complexes compete for a limited number of specific nuclear binding sites. Enhanced activity of topoisomerases in nuclear extracts upon translocation of VDR might reflect interaction of both within the nuclear compartment, thus initiating DNA-unwinding, a prerequisite of transcription initiation.


A facile C-C bond cleavage in the epoxides and its use for the synthesis of oxygenated heterocycles by a ring expansion strategy.
The bicyclic epoxy alcohols when treated with DAST gave a new class of rearranged organofluorine compounds, by a ring expansion via C-C bond cleavage of the oxirane ring. The outcome of this reaction with respect to ring size and stereochemical relation between the functionalities is presented here.


Access to mental health supports in England: crisis resolution teams and day services.
Access to health care is a complex issue with multiple supply and demand side facets. Here just two issues are explored; the potential for access through availability and the actual access made as indicated by utilisation rates. These perspectives are explored for two mental health services, crisis resolution teams and day hospitals, both of which are recommended components for a comprehensive local mental health care service in England. The geographical spread of these services is considered alongside the level of provision and the extent of their use. Associations between availability and needs, and between use and needs are tested. Tracking resources from funding allocations to provision is also complex and issues around resource allocation are discussed.


Muscle fiber capillarization is associated with various indices of skeletal muscle mass in healthy, older men.
Muscle fiber capillarization plays a fundamental role in the regulation of skeletal muscle mass maintenance. However, it remains unclear to what extent capillarization is related to various other skeletal muscle characteristics. In this study we determined whether muscle fiber capillarization is independently associated with measures of skeletal muscle mass, both on a whole-body and cellular level, and post-absorptive muscle protein synthesis rates in healthy older men. Forty-six healthy older (70 ± 4 y) men participated in a trial during which basal muscle protein synthesis rates were assessed using stable isotope tracer methodology. Blood and muscle biopsy samples were collected to assess post-absorptive muscle protein synthesis rates over a 3-hour period. Immunohistochemistry was performed to determine various indices of muscle fiber capillarization, size, type distribution, and myonuclear content/domain size. Dual energy x-ray absorptiometry scans were performed to determine whole-body and appendicular lean tissue mass. Capillary-to-fiber ratio (C/Fi) and perimeter exchange (CFPE) index correlated with whole-body lean tissue mass (r = 0.43, P < 0.01 and r = 0.25, P < 0.10, respectively), appendicular lean tissue mass (r = 0.52, P < 0.001 and r = 0.37, P < 0.05, respectively) as well as appendicular lean tissue mass divided by body mass index (r = 0.65, P < 0.001 and r = 0.62, P < 0.001, respectively). Muscle fiber size correlated with C/Fi (r = 0.45, P < 0.01), but not with CFPE index. No associations were observed between different indices of muscle fiber capillarization and post-absorptive muscle protein synthesis rates in healthy, older men. The present study provides further evidence that muscle fiber capillarization may be a critical factor in the regulation of skeletal muscle maintenance in healthy older men.


Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread.
Bladder plasmacytoid carcinoma is an invasive urothelial carcinoma subtype that is emphasized for its morphological overlap with plasma cells and metastatic carcinoma. Our experience suggests frequent intraperitoneal spread that is not typical of conventional urothelial carcinoma. We identified cases of plasmacytoid urothelial carcinoma diagnosed on radical cystectomy. Patient age, gender, American Joint Committee on Cancer (7th edition) stage, metastatic spread/recurrence sites and clinical disease status at last followup were recorded. A total of 10 male and 5 female patients 42 to 81 years old were identified. One tumor was pT2, 11 pT3 and 3 pT4. Six of 15 patients (40%) presented with lymph node metastasis and 5 (33%) had intraperitoneal metastasis at cystectomy. These initial sites of metastatic spread included the prerectal space, ovary and vagina, ovary and fallopian tube, bowel serosa, and omentum and bowel serosa in 1 case each. Three patients had subsequent metastasis involving the prerectal space, pleural fluid and small bowel serosa, and bowel serosa in 1 each. Eight patients had followup information available, including 3 who died of disease, 3 with disease and 2 with no evidence of disease. Of the patients 33% with the plasmacytoid variant of urothelial carcinoma presented with intraperitoneal disease spread and 20% had subsequent metastasis involving serosal surfaces. The possibility of noncontiguous intraperitoneal spread involving serosal surfaces should be recognized to ensure proper intraoperative staging and clinical followup for patients with plasmacytoid carcinoma.


Weakly supervised bilayer convolutional network in segmentation of HER2 related cells to guide HER2 targeted therapies.
Overexpression of human epidermal growth factor receptor 2 (HER2/ERBB2) is identified as a prognostic marker in metastatic breast cancer and a predictor to determine the effects of ERBB2-targeted drugs. Accurate ERBB2 testing is essential in determining the optimal treatment for metastatic breast cancer patients. Brightfield dual in situ hybridization (DISH) was recently authorized by the United States Food and Drug Administration for the assessment of ERRB2 overexpression, which however is a challenging task due to a variety of reasons. Firstly, the presence of touching clustered and overlapping cells render it difficult for segmentation of individual HER2 related cells, which must contain both ERBB2 and CEN17 signals. Secondly, the fuzzy cell boundaries make the localization of each HER2 related cell challenging. Thirdly, variation in the appearance of HER2 related cells is large. Fourthly, as manual annotations are usually made on targets with high confidence, causing sparsely labeled data with some unlabeled HER2 related cells defined as background, this will seriously confuse fully supervised AI learning and cause poor model outcomes. To deal with all issues mentioned above, we propose a two-stage weakly supervised deep learning framework for accurate and robust assessment of ERBB2 overexpression. The effectiveness and robustness of the proposed deep learning framework is evaluated on two DISH datasets acquired at two different magnifications. The experimental results demonstrate that the proposed deep learning framework achieves an accuracy of 96.78 ± 1.25, precision of 97.77 ± 3.09, recall of 84.86 ± 5.83 and Dice Index of 90.77 ± 4.1 and an accuracy of 96.43 ± 2.67, precision of 97.82 ± 3.99, recall of 87.14 ± 10.17 and Dice Index of 91.87 ± 6.51 for segmentation of ERBB2 overexpression on the two experimental datasets, respectively. Furthermore, the proposed deep learning framework outperforms 15 state-of-the-art benchmarked methods by a significant margin (P<0.05) with respect to IoU on both datasets.


[Clinical evaluation of DHEA-S plasma levels and possible therapeutic value of the hormone in the third trimester].
Three groups of women were studied. The first included women without obstetric or systemic pathology; in these, plasma concentrations of progesterone, E, and DHEA-S were assayed at 30-40 weeks of pregnancy. The second group comprised women after physiological first delivery at term, and in these the plasma levels of the same hormones were assessed. In the third group, comprising women at 38 weeks of pregnancy with unripened cervix and DHEA-S plasma levels that were by 1-2 weeks below those of women with ripened cervix of the same gestational age, the effect of repeated perfusion with DHEA-S was examined.


Outpatient anesthesia at the Ambulatory Surgery Center, Tucson Medical Center.
The safety, economy and acceptability of the concept of the ambulatory surgical facility have been proved; its future depends upon the support it receives from us as physicians. The role of the anesthesiologist in the short-stay surgical facility is also well established.


p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates.
Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4CRBN and p97 pathways.


Metabolic engineering of Bacillus subtilis for production of D-lactic acid.
Poly lactic acid (PLA) based plastics is renewable, bio-based, and biodegradable. Although present day PLA is composed of mainly L-LA, an L- and D- LA copolymer is expected to improve the quality of PLA and expand its use. To increase the number of thermotolerant microbial biocatalysts that produce D-LA, a derivative of Bacillus subtilis strain 168 that grows at 50°C was metabolically engineered. Since B. subtilis lacks a gene encoding D-lactate dehydrogenase (ldhA), five heterologous ldhA genes (B. coagulans ldhA and gldA101, and ldhA from three Lactobacillus delbrueckii) were evaluated. Corresponding D-LDHs were purified and biochemically characterized. Among these, D-LDH from L. delbrueckii subspecies bulgaricus supported the highest D-LA titer (about 1M) and productivity (2 g h-1 g cells-1 ) at 37°C (B. subtilis strain DA12). The D-LA titer at 48°C was about 0.6 M at a yield of 0.99 (g D-LA g-1 glucose consumed). Strain DA12 also fermented glucose at 48°C in mineral salts medium to lactate at a yield of 0.89 g g-1 glucose and the D-lactate titer was 180 ± 4.5 mM. These results demonstrate the potential of B. subtilis as a platform organism for metabolic engineering for production of chemicals at 48°C that could minimize process cost.


Bioavailability of xanthorrhizol following oral administration of a supercritical extract of Java turmeric.
Although xanthorrhizol, a sesquiterpenoid oil obtained from the rhizome of Curcuma xanthorrhiza Roxb., known as Java turmeric, has many pharmacological effects, its pharmacokinetics remain unclear. Therefore, we investigated the pharmacokinetics of xanthorrhizol in mice and rats. Xanthorrhizol was administered intravenously and orally to mice, while xanthorrhizol and a Java turmeric supercritical extract were administered orally to rats. The terminal half-life (t1/2), clearance, and absolute bioavailability (BA) of xanthorrhizol in mice were almost 8 h, 6.5 L/h/kg, and 10.2%, respectively. In comparison, the clearance of xanthorrhizol was 3-fold higher in rats than mice. The absolute BAs of xanthorrhizol in rats were 12.9% and 13.4% after oral administration of xanthorrhizol and a supercritical extract, respectively. Our results regarding the pharmacokinetics of xanthorrhizol could guide the conversion of intravenous and oral doses, and help identify the optimal maintenance doses of xanthorrhizol and the extract for desirable pharmacodynamic effects.


Preoperative Patient-Reported Outcome Measure Thresholds Should Not be Used for Indicating Total Knee Arthroplasty.
While Medicare requires patient-reported outcome measures (PROMs) for many quality programs, some commercial insurers are requiring preoperative PROMs when determining eligibility for total knee arthroplasty (TKA). Concerns exist that these data may be used to deny TKA to patients above a specific PROM score, but the optimal threshold is unknown. We aimed to evaluate TKA outcomes based on theoretical PROM thresholds. We retrospectively analyzed 25,246 consecutive primary TKA patients from 2016 to 2019. Hypothesized preoperative knee injury and osteoarthritis outcome score for joint replacement cutoffs of 40, 50, 60, and 70 points were used. Preoperative scores below each threshold were considered "approved" surgery. Preoperative scores above each threshold were considered "denied" surgery. In-hospital complications, 90-day readmissions, and discharge disposition were evaluated. One-year minimum clinically important difference (MCID) achievement was calculated using previously validated anchor-based methods. For "denied" patients below thresholds 40, 50, 60, and 70 points, 1-year MCID achievement was 88.3%, 85.9%, 79.6%, and 77%, respectively. In-hospital complication rates for approved patients were 2.2%, 2.3%, 2.1%, and 2.1%, while 90-day readmission rates were 4.6%, 4.5%, 4.3%, and 4.3%, respectively. Approved patients had higher MCID achievement rates (P < .001) for all thresholds but higher nonhome discharge rates than denied patients for thresholds 40 (P < .001), 50 (P = .002), and 60 (P = .024). Approved and denied patients had similar in-hospital complication and 90-day readmission rates. Most patients achieved MCID at all theoretical PROMs thresholds with low complication and readmission rates. Setting preoperative PROM thresholds for TKA eligibility can help optimize patient improvement, but such a policy can create access to care barriers for some patients who would otherwise benefit from a TKA.


Rice cropping density and intensity lessened in southeast China during the twenty-first century.
Accurate and updated time series maps of paddy rice distribution and planting intensity will greatly improve our knowledge. Unfortunately, spatiotemporal explicit information on rice fields is relatively limited, and considerable uncertainties still exist as regards to its inter-annual variations in China. In this study, an improved rice mapping methodology was proposed through combined consideration of vegetation phenology and surface moisture variations from different seasonal rice. This method was applied to southeast China based on 500 m 8 day composite Moderate Resolution Imaging Spectroradiometer (MODIS) Enhance Vegetation Indices with two bands (EVI2) during the period 2001-2013. Its efficiency was validated with 763 ground survey sites, with an overall accuracy of 95.02 % and the kappa index of 0.9217. Spatiotemporal analysis indicated that rice cropping density and intensity lessened in southeast China during the period 2001-2013. Particularly, the paddy rice-planted areas reduced by 30.09 %, changing from 231,005 to 161,484 km(2). Among them, the planted areas of double rice decreased by 49.34 %, changing from 34,215 to 17,335 km(2). Therefore, averaged rice cropping intensity in southeast China decreased from 1.148 to 1.107. The primary dynamic patterns were from single rice or a rotation of rice plus other crops to non-rice (93,386 km(2)) and double rice to non-double rice (24,132 km(2)). When analyzed at provincial and altitudinal gradient levels, it was obvious that areas with greater rice cropping density or intensity were associated with more remarkable reductions. Graphical abstract The left graph shows that the rice cropping density lessened in Hubei, Hunan, Guangdong, Jiangxi, Anhui, Jiangsu, Henan provinces and other three provincial-level administrative units (Zhejiang, Fujian and Shanghai) from 2001 to 2013. The middle graph indicates the movement of gravity center as well as the variations in the total planted areas of single rice, rice plus others and double rice. The right graph denotes that the rice cropping intensity decreased in each provincial-level administrative unit from 2001 to 2013.


NMR-based metabolomics: a probe to utilize biodiversity.
Metabolomics is a comprehensive profiling tool used to identify qualitatively and quantitatively all the metabolites present in a biological system. As the number of metabolites in a living being is assumed to be around 30,000, it is necessary to use an adequate extraction procedure and a good analytical technique to perform metabolomic analyses. Each analytical platform used in metabolomics has both advantages and disadvantages in terms of the sensitivity and resolution for metabolites to be detected. Of the methods, nuclear magnetic resonance (NMR) spectroscopy has been proved to have several advantages over other MS-based methods. NMR provides an efficient, robust, and nondestructive metabolomics analysis of crude extracts or samples as well as easy quantitation without calibration curves for each metabolite, although it shows relatively low sensitivity than MS-based methods. Thus, NMR-based metabolomics have been often used for the first step to capture the insight of the metabolome of organisms. This chapter presents general steps of NMR-based metabolomic analysis involved in the study of biodiversity.


Soluble eggshell membrane: A natural protein to improve the properties of biomaterials used for tissue engineering applications.
Extracellular matrix (ECM) acts as an instructing template for the cells contained in tissues. It plays a vital role in regulating cellular behavior by holding and interacting with various growth factors and signaling molecules. The ECM materials are either directly derived from a natural origin, or synthesized mimicking the natural ECM. In this review, we have addressed the ECM derived from eggshell membrane (ESM). The development of porous structures from natural biopolymers, such as ESM holds a number of advantages for tissue engineering applications. By using ESM in tissue engineering application, the cells attach and function to make a required tissue. Thereafter, the scaffold provides mechanical support as well as a platform for cellular interaction, hence, forming a fully functional tissue. The present review summarizes the structure-function relationship of ESM and advancement in its processing methods; the contribution of its soluble form (soluble eggshell membrane protein, SEP) in the development of promising hybrid biomaterials; and the recent advancement of their applications. In addition, this comprehensive review highlights the use of ESM for guided tissue regeneration; promising future applications of SEP in tissue engineering and regenerative medicine.


An acculturization curriculum: orienting international medical graduates to an internal medicine residency program.
The number of International Medical Graduate (IMG) applicants to residency programs has increased steadily over the past decade. Despite high motivation and significant medical knowledge, differences in training and cultural expectations can create knowledge gaps and influence how IMGs relate to patients and staff. This contributes to increased opportunities for medical errors, patient dissatisfaction, and frustration among colleagues. To improve this transition we introduced a required, 2-week precourse for IMGs entering our program. The curriculum focused around the Accreditation Council for Graduate Medical Education core competencies. Participants reported knowledge gains and rated favorably didactic sessions and small-group activities. Program directors and other key stakeholders reported positive experiences with the precourse, especially the reduction in transition stress and missed work time in July. An intensive precourse for IMGs can attenuate transition stress and increase knowledge of core medical skills and competencies.


Disturbances in T-cell subpopulations in B-cell chronic lymphocytic leukaemia.
The relative proportions of immunoregulatory T-cell subpopulations defined by OKT monoclonal antibodies are disturbed in chronic lymphocytic leukaemia (CLL) patients (even early mild cases) compared with normal subjects in the same age range. The mean ratio OKT4+:OKT8+ (helper:suppressor/cytotoxic) is reversed from the normal 1.6:1 to 1:1.9. The absolute concentration of each OKT population in the circulation is slightly higher than normal, the increase in OKT8+ being the most significant. The E-rosette-forming cells did not always correlate with OKT+ cells and, in four cases, the discrepancy between the size of the OKT3+ population and the sum of OKT4+ and OKT8+ suggested the presence of T cells with an immature (thymic) phenotype in peripheral blood. These abnormalities may account for the depressed immune function of CLL patients.


Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: a case-control study.
Giant cell tumor (GCT) of bone is a benign but locally aggressive tumor that is characterized by the presence of mononuclear stromal cells and multinucleated giant cells. Although topical adjuvants have been used in the past, local recurrence following intralesional excision of GCT of bone continues to remain a problem. The use of bisphosphonates as an anti-osteoclastic agent in the management of osteolytic bone metastases is well accepted. Furthermore in vitro studies have shown that bisphosphonates also induce apoptosis in GCT stromal cells. Therefore our clinical study aims to investigate whether the administration of bisphosphonate as an adjuvant can further decrease local recurrence following the surgical treatment of GCT of bone. A retrospective case-control study was performed between 1988 and 2004. Forty-four patients with histological diagnosed appendicular GCT were included. Intralesional curettage or wide excision of the lesions was followed with cementation or biological reconstruction. Additional intravenous and oral bisphosphonates were given peri-operatively to 24 patients who were treated between 1998 and 2004. The average follow-up of the control group was 115 months while that of the treatment group was 48 months. In the bisphosphonate treated group, 1 of 24 patients (4.2%) developed local recurrence. In the control group, 6 of 20 patients (30%) developed local recurrence. The difference in the recurrence rate was statistically significant between the bisphosphonate treatment group and the control group (Log Rank test p=0.056). The effect of reduction of local recurrence was significant in patients with stage III diseases. Patients treated with bisphosphonate did not report any untoward effects. Clinical use of bisphosphonates as an adjuvant therapy for giant cell tumor of bone demonstrated a lower local recurrence rate. The clinical response seems to be more promising in stage III diseases.


An evaluation of insulin-like growth factor-1 as an indicator of nutritional status.
This study evaluated the usefulness of insulin-like growth factor-1 (IGF-1) as a marker of nutritional status in 185 hospitalised patients compared with conventional biochemical (albumin) and anthropometric parameters. C-reactive protein (CRP) was used as a biochemical marker of underlying illness. 77 (42%) patients were normally nourished or overweight and 108 (58%) were nutritionally depleted. IGF-1 and albumin were significantly lower in the malnourished patients as a group. However, in the malnourished patients with normal CRP, there was no correlation between albumin or anthropometric measurements and IFG-1. In malnourished patients with a raised CRP, there was no relationship between malnutrition determined by body mass index and anthropometry and either albumin of IGF-1 concentrations. In normally nourished patients with a raised CRP, there was a relationship between albumin and CRP; and IGF-1 and CRP and between albumin and IGF-1. IGF-1 was related to age in all groups of patients. We conclude that neither albumin nor IGF-1 can be reliably used to assess nutritional status.


Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity.
Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers. Six healthy volunteers received a 60-mg oral dose of [14C]-tolebrutinib, and metabolite profiling of 14C-labeled metabolites was performed using a combination of liquid chromatography, mass spectrometry, and radioactivity assay methods. Tolebrutinib was rapidly and completely absorbed from the gastrointestinal tract, followed by rapid and extensive metabolism. Excretion via feces was the major elimination pathway of the administered radioactivity (78%). Tolebrutinib was highly metabolized, with 19 metabolites identified in human plasma. Phase 1 biotransformations were primarily responsible for the circulating metabolites in plasma. Seven metabolites that achieved exposure in plasma similar to or higher than the parent compound were characterized biochemically for inhibition of Bruton's tyrosine kinase activity. Metabolite M8 exceeded the exposure threshold of 10% (18%) of the total radioactivity but had little if any pharmacological activity. Metabolite M2 (4% of circulating radioactivity) retained the ability to irreversibly and potently inhibit Bruton's tyrosine kinase in vitro, similar to the parent compound. Tolebrutinib and metabolite M2 had short (3.5-h) half-lives but durable pharmacodynamic effects as expected for an irreversible antagonist. Tolebrutinib was extensively metabolized to multiple metabolites. The hydroxylated metabolite M2 demonstrated similar inhibitory potency toward Bruton's tyrosine kinase as the parent compound. Both tolebrutinib and metabolite M2 likely contributed to pharmacological activity in vivo.


Risk factors associated with senile dementia of the Alzheimer's type.
Significant cognitive impairment affects approximately 15 percent of the U.S. population over age 65. The most prevalent form of irreversible dementia is senile dementia of the Alzheimer's type (SDAT), which accounts for at least 50 percent of nursing home admissions and roughly 10 billion dollars a year in health care costs. In spite of the social, economic, and medical impact of the disease, epidemiological data are scarce concerning risk factors associated with the disease. Until recently, most of the population-based studies of senile dementia in the elderly were carried out in Northern European countries. The methodological problems that arise in performing epidemiologic studies on SDAT may in part explain the lack of sufficient data pertaining to certain risk factors. This paper provides a review of the literature and research on risk factors in dementia in the elderly and discusses directions for future research. The epidemiological issues associated with certain key studies are also discussed. Although the major studies that have attempted to look at risk factors in mental illness in the elderly are beginning to fill in some of the gaps in the understanding of the etiology and epidemiology of the disease, further epidemiologic studies on both institutionalized and community-based elderly populations are needed. These should assess a wide range of possible factors (demographic, psychological, environmental, health practice, and medical) in terms of their association with SDAT. By developing a comprehensive epidemiologic profile of SDAT, possible preventive measures and therapeutic approaches to treating the disease may be identified and hypotheses for future epidemiological and laboratory investigations developed.


Effect of chlorphentermine pretreatment on 5-hydroxytryptamine disposition in the isolated perfused rat lung.
Chlorphentermine (CP) is known to be highly accumulated by the lung, to cause pulmonary phospholipidosis and has been suspect in causing pulmonary hypertension possibly by inhibiting the clearance of 5-hydroxytryptamine (5-HT). It was of interest to determine if subacute CP treatment might inhibit 5-HT clearance by the lung. Animals were treated with CP (50 mg/kg/day po in saline) for 7 days while controls received the vehicle only. Artificially ventilated isolated rat lungs were perfused with a constituted medium. In recirculation perfusion experiments, lungs from CP treated animals exhibited both decreased uptake and metabolism of 14C-5-HT (0.02 microM). In order to distinguish between CP-induced morphological effects and the effect of CP itself, CP was added at an initial perfusate concentration of 0.5 or 5 mumol to the perfusate of lung from untreated animals. A dose-dependent inhibition of 5-HT uptake and metabolism was observed, such that lungs receiving 5 mumol of CP inhibited 5-HT metabolism similarly to that observed in treated lungs. In order to distinguish the effect of CP on 5-HT uptake from its effect on metabolism, pulmonary disposition of 5-HT was studied in the presence of pargyline, a monoamine oxidase (MAO) inhibitor known to block the metabolism of 5-HT. In the presence of 1 mM pargyline, CP (5 mumol) significantly decreased 5-HT uptake by the lung. CP was also noted to inhibit the metabolism of 14C-5-HT by in vitro incubations of 700 g lung supernatent fractions. In conclusion, subacute treatment with CP results in obtunded clearance of 5-HT by the rat lung, supporting the proposal that CP-induced pulmonary hypertension may be mediated by decreased pulmonary clearance of 5-HT.


Understanding factors that influence unintentional insider threat: a framework to counteract unintentional risks.
The exploitation of so-called insiders is increasingly recognised as a common vector for cyberattacks. Emerging work in this area has considered the phenomenon from various perspectives including the technological, the psychological and the sociotechnical. We extend this work by specifically examining unintentional forms of insider threat and report the outcomes of a series of detailed Critical Decision Method (CDM) led interviews with those who have experienced various forms of unwitting cybersecurity breaches. We also articulate factors likely to contribute firmly in the context of everyday work-as-done. CDM's probing questions were used to elicit expert knowledge around how decision making occurred prior, during and post an unintentional cyber breach whilst participants were engaged in the delivery of cognitive tasks. Through the application of grounded theory to data, emerging results included themes of decision making, task factors, accidents and organisational factors. These results are utilised to inform an Epidemiological Triangle to represent the dynamic relationship between three vectors of exploit, user and the work environment that can in turn affect the resilience of cyber defences. We conclude by presenting a simple framework, which for the purposes of this work is a set of recommendations applicable in specific scenarios to reduce negative impact for understanding unintentional insider threats. We also suggest practical means to counteract such threats rooted in the lived experience of those who have fallen prey to them.


Increased postural sway in control subjects with poor orthostatic tolerance.
This study sought to evaluate postural sway in control subjects with good and poor orthostatic tolerance (OT). Some asymptomatic volunteers, when subjected to a progressive orthostatic stress test, show early presyncope. We hypothesized that normal subjects with poor OT do not usually faint because they adopt a strategy of increased lower limb movement, which helps maintain venous return. In 12 asymptomatic subjects with good OT and 11 with poor OT, assessed by the combined orthostatic stress of head-up tilting and lower body suction, we determined postural sway using a force platform after 1, 5, and 10 min of motionless standing. The subjects with poor tolerance had greater distances and velocities of sway in the anteroposterior direction but not the mediolateral direction. There was a significant negative correlation between postural sway and orthostatic tolerance. We have shown that in normal subjects with poor OT during a passive orthostatic stress test, their leg movements tend to be greater when standing. These movements are likely to enhance venous return and may at least partly explain why, despite their poor test results, they do not normally faint.