Brain oxidative stress and cognitive function in older adults with diabetes and pre-diabetes who are at risk for dementia.
Diabetes is an established risk factor for dementia. This study aimed to examine the relationship between various cognitive domains, brain oxidative stress and markers of diabetes in older adults at risk for dementia. Older adults at risk for dementia underwent comprehensive neuropsychological and medical assessment. At risk was defined as those with subjective and/or objective cognitive impairment. Pre-diabetes and type 2 diabetes were defined using American Diabetes Association definitions for fasting blood glucose and HbA1c. Brain oxidative stress as indicated by glutathione (GSH) was assessed via magnetic resonance spectroscopy in the anterior cingulate cortex. One-hundred and forty-seven older adults completed a neuropsychological assessment and fasting blood sample with 63 also undergoing magnetic resonance spectroscopy. Those with pre-diabetes/diabetes according to FBG had impaired memory retention, set-shifting and response inhibition, compared to those with normal blood glucose. In contrast, there were no significant differences in any cognitive outcome using the HbA1c definition. Increasing glucose and HbA1c levels were associated with reduced GSH concentration in the anterior cingulate. This study demonstrates that in older adults at risk for dementia, having pre-diabetes or diabetes is associated with impaired memory and executive dysfunction. It also highlights the potential role of oxidative stress as a pathophysiological mechanism that may underpin the link between diabetes and cognitive dysfunction.


The impact of survey nonresponse on estimates of healthcare employee burnout.
Accurate estimates of burnout prevalence are critical for workforce planning. We assessed survey nonresponse bias and its impact on burnout estimates by linking 27,226 primary care employees to administrative data, categorized by whether they responded to a 2016 workforce survey (19.2% response). We adjusted burnout prevalence by response propensity using mixed-effects logistic regression. Thirty-six percent of respondents screened positive for burnout. There were significant differences between respondents and non-respondents (e.g.,gender, tenure), but no difference between unadjusted (i.e., respondents only) and propensity-adjusted estimates of burnout among the workforce. This provides support that workforce surveys may yield valid burnout estimates despite low response.


Cotton Fever: A Condition Self-Diagnosed by IV Drug Users.
The presentation of fever in an intravenous drug user prompts diagnostic testing targeted at identifying infectious etiologies. However, an alternate diagnosis exists in "cotton fever." While few reports describe this phenomenon in the peer-reviewed literature, the diagnosis is well recognized among the intravenous drug user community. Although its etiology is not well understood, cotton fever seems to be a self-limited, febrile response to the intravenous administration of a drug filtered through cotton. Educating clinicians regarding cotton fever may limit unnecessary hospital admissions and improve our ability to care for this population.


Microbiological diagnosis of Eggerthella lenta blood culture isolates in a Swedish tertiary hospital: Rapid identification and antimicrobial susceptibility profile.
Eggerthella lenta is a Gram-positive anaerobic bacillus. Improved diagnostics and increased awareness of rare pathogens have revealed its potential to cause serious invasive infections. In this study, 18 clinical E. lenta isolates derived from positive blood cultures were included. Underlying problems of the patients were in the majority of cases related to the gastrointestinal tract. The performance of two MALDI-TOF MS systems, i.e. Bruker and Vitek MS, in identification of E. lenta was analyzed. In addition, the minimal inhibitory concentrations for clinically relevant antimicrobial agents were determined by routine procedures using E-test. 17 of the 18 E. lenta isolates investigated in this study were correctly identified to species level by the Bruker MS system, while the Vitek MS system identified all 18 isolates. Antimicrobial sensitivity towards the tested agents was in general good. However, high resistance rates were observed for penicillin G and piperacillin-tazobactam based on EUCAST breakpoints.


Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme.
To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with intravenous carboplatin for patients with previously untreated glioblastoma multiforme tumors. Between 1988 and 1992, 83 patients received 1.9-2.0 Gy radiation three times a day with 2-h infusions of 33 mg/m2 carboplatin for two 5-day cycles separated by 2 weeks; following radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until tumor progressed. Eighty-three patients were evaluable for analysis. Seventy-four of the 83 patients (89%) received one or more courses of PCV; their median survival was 55 weeks. Total resection was performed in 20% (15 of 74), subtotal resection in 69% (51 of 74), and biopsy in 11% (8 of 74); reoperation (total or subtotal resection) was performed in 28 patients (37%). Survival was worst for those > or = 61 year old (median 35 weeks). Fits of the Cox proportional hazards regression model showed covariates individually predictive of improved survival were younger age (p < 0.01), smaller log of radiation volume (p = 0.008), total or subtotal resection vs. biopsy (p = 0.056), and higher Karnofsky performance status (p = 0.055). A multivariate analysis showed that age (p = 0.013) and extent of initial surgery (p = 0.003) together were predictive of a better survival with no other variables providing additional significance. Only 8.4% (7 of 83) of patients had clinically documented therapy-associated neurotoxicity ("radiation necrosis"). When comparable selection criteria were applied, the survival in this study is similar to the results currently attainable with other chemoradiation approaches. The relative safety of accelerated fractionated radiotherapy, as used in this study with carboplatin, enables concomitant full-dose administration of chemotherapy or radiosensitizing agents in glioblastoma multiforme patients.


Reversal of a trimethyltin-induced learning deficit by desglycinamide-8-arginine vasopressin.
Trimethyltin (TMT) is an organometal neurotoxin which produces lesions primarily in the limbic system. Selectivity seems to depend upon the dose, but the hippocampus and related entorhinal cortical structures, of importance for learning and memory, are most often described as target sites. We have previously demonstrated that subjects treated with a moderate dose of TMT prior to acquisition sessions, are unable to learn a forward autoshaping task with a 6 sec delay of reinforcement, but are capable of acquiring the same task when no delay of reinforcement is used. These data suggested that the performance deficit is one of learning (i.e. consolidation) rather than of memory (i.e. storage), retrieval, or sensorimotor impairment. To more rigorously test this hypothesis, we determined if performance of a task already learned would be impaired by the neurotoxin. Adult male Long Evans rats were given 10 acquisition sessions of 24 trials, following which TMT (6.0 mg/kg, p.o.) was administered. One month later, these rats performed the lever-touching behavior as well as controls, despite the fact that the same dose of TMT interfered with learning if given one month prior to acquisition sessions, thus confirming our hypothesis. In a second experiment we determined if the peptide analog of vasopressin, desglycinamide-8-arginine vasopressin (DGAVP), could reverse a learning deficit in a population of non-learners. Rats were treated with TMT or water vehicle one month prior to autoshaping. TMT significantly retarded acquisition. After 10 sessions of 12 trials each, non-learners (i.e. rats treated with TMT that failed to associate the lever with delivery of a reinforcer) were administered saline or DGAVP (7.5 micrograms/kg, s.c.) 1 hr before sessions 11-13; treatment was discontinued prior to sessions 14 and 15. Peptide treated subjects showed evidence of acquisition and exhibited higher levels of lever-directed behavior than saline treated nonlearners. Performance was maintained after DGAVP treatment was discontinued, indicating that the learning-enhancing action of DGAVP was not transient or state-dependent.


Water adsorption isotherms of lipids.
Hydration of bilayer lipids is a fundamental property of biological membranes. The available database of lipid hydration isotherms is fitted over the entire range of water activities by using a statistical mechanical approach that is an extension of the common Brunauer-Emmett-Teller model, to include differential energies of association for water molecules beyond the first strongly bound layer. Three-parameter fits are obtained that can be used to represent the experimental isotherms to a good degree of accuracy over the complete range of water-binding activities. Fits are also made in terms of the hydration pressure and correlation length of water ordering, by using the polarization theory of lipid hydration. The relationship of the latter approach to measurements of hydration forces between lipid bilayers is discussed.


Asymmetrical dimethylarginine and severity of erectile dysfunction and their impact on cardiovascular events in patients with acute coronary syndrome.
Coronary artery disease (CAD) and vascular erectile dysfunction (ED) are related to endothelial dysfunction. Elevated asymmetrical dimethylarginine (ADMA) levels and ED are common in patients with increased cardiovascular risk. Our aim was to investigate whether ADMA has a predictive role for major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS). The secondary aim of this study was to investigate whether severity of ED predicts MACE in these patients. Follow-up data were available for severity of ED in 71 patients with ACS. Plasma ADMA levels were determined by ELISA in 57 patients. Erectile dysfunction was assessed by the International Index of Erectile Function-6 (IIEF-6) score. Major adverse cardiovascular events (reinfarction, all-cause hospitalisation, stroke and all-cause death) was evaluated after a median of 10 months. Severe ED had no significantly increased hazard ratio for cardiovascular events compared with mild, mild to moderate, and moderate ED (0.259 [95% CI 0.041-1.6], p = 0.147; 0.605 [95% CI 0.095-3.8], p = 0.594; 0.980 [95% CI 0.233-4.1], p = 0.978; and 0.473 [95% CI 0.052-1.3], p = 0.508). The patients who had ADMA levels ≥ 0.32 µmol/l had no significantly increased hazard ratio for cardiovascular events compared with patients who had ADMA levels < 0.32 µmol/l (2.018 [95% CI 0.615-6.6], p = 0.247). Severity of ED and ADMA did not increase the risk of cardiovascular events in follow-up patients with ACS in our study. Larger prospective studies are necessary to evaluate whether ADMA predicts cardiovascular events in patients with ACS.


Sequence of the precursor to rat bone gamma-carboxyglutamic acid protein that accumulates in warfarin-treated osteosarcoma cells.
A biosynthetic precursor to rat bone gamma-carboxyglutamic acid protein (BGP) was isolated from warfarin-treated ROS 17/2 osteosarcoma cells by antibody affinity chromatography followed by reverse phase high performance liquid chromatography. Thirty-two residues of its NH2-terminal sequence were determined by gas-phase protein sequence analysis. Comparison of this sequence with the known structure of rat BGP established that the intracellular precursor is a 76-residue molecule of Mr = 9120 that differs from 6000-Da bone BGP in having an NH2-terminal extension of 26 residues. This precursor appears to be generated from the primary translation product by cleavage of a hydrophobic signal peptide and is the probable substrate for gamma-carboxylation by virtue of its accumulation in the presence of warfarin. The putative targeting region for gamma-carboxylation previously identified in the leader sequences of vitamin K-dependent proteins is found in the propeptide portion of the precursor. Since the immunoreactive component secreted by warfarin-treated cells is identical in sequence to the 6000-Da BGP from bone, propeptide cleavage from the precursor is independent of gamma-carboxylation and precedes secretion of BGP from the cell.


Analysis of chlorophyll fluorescence spectra for the monitoring of Cd toxicity in a bio-energy crop (Jatropha curcas).
The vegetation of metal-contaminated soils using non-edible crops can be a safe and economical technique for Cd immobilization and the remediation of contaminated sites. Jatropha (Jatropha curcas L.) exhibits a relative tolerance to heavy metals and potential for biofuel production. The study was performed to monitor the Cd-induced alterations in jatropha plants by X-ray chlorophyll fluorescence. The Cd effects on photosynthetic pigments, the mineral composition of plants, defense enzyme activity and soluble proteins were also studied. Plants were grown for 20days in a nutrient solution with five Cd contents: 5, 10, 20, 30 and 40μmolL(-1); a control with no Cd addition was also monitored. The analysis of the chlorophyll fluorescence spectra allowed detecting alterations caused by Cd toxicity in the jatropha plants. The mineral composition of the plants was affected by the Cd doses; however, the Fe and Mg contents were not significantly reduced, which most likely improved the effects on the contents of the photosynthetic pigments. Because of its relative tolerance to Cd, Jatropha curcas may be a promising species to revegetate Cd-contaminated sites. Considering the long period needed to phytoremediate soils, the combination of remediation with bioenergy production could be an attractive option.


Benign and malignant lymphocytic skin infiltrates: immunological patterns recognized by immunohistochemical staining with monoclonal antibodies.
Skin biopsies from 150 patients with cutaneous lymphoma, premalignant or "pseudolymphomatous" conditions and benign dermatoses were examined by immunoenzymatic staining of frozen sections with a panel of monoclonal antibodies against lymphocytes, macrophages and accessory cells. Two patterns of infiltration were identified. In one of these T cells associated with Langerhans cells and HLA-DR-positive macrophages of dendritic morphology, were seen. In the other B cell follicles were present in addition to the above type of infiltrate. The latter pattern was restricted to patch tests biopsies, cutaneous lymphocytomas, and malignant lymphomas of B-cell origin. It is concluded that lymphocytic skin infiltrates are divisible into different patterns of immunological reactions similar to those seen in lymphoid organs.


miR-147b is an oncomiR acting synergistically with HIPK2 to promote pancreatic carcinogenesis.
MicroRNAs (miRs, miRNAs) are known players in the regulatory network of pancreatic tumorigenesis, but the downstream effectors remain poorly characterized. This study addressed this issue based on in silico prediction, in vitro experiments, and in vivo validation. The differentially expressed PCa-related miRNAs and bioinformatics tools predicted downstream regulators. The expression of miR-147b was examined in PCa cell lines. Putative targets of miR-147b were predicted by a publicly available database and confirmed by luciferase activity assay. Mimic/inhibitor, siRNA/overexpression plasmid, or pifithrin-α (p53 inhibitor) were delivered into PCa cells to assess the effect of miR-147b, HIPK2, and p53 on malignant phenotypes of PCa cells. AntagomiR-147b and shRNA targeting HIPK2 were introduced to xenograft-bearing nude mice for in vivo experiments. The expression of miR-147b was significantly increased in PCa cell lines. Ectopic expression of miR-147b promoted the malignant phenotypes of PCa cells and inhibited their apoptosis. HIPK2 was confirmed as a target gene of miR-147b. Inhibiting miR-147b could promote HIPK2 expression and potentially activate the p53 pathway, inhibiting PCa cell growth. In vivo experiments suggested that miR-147b inhibition suppressed the growth of xenograft tumors in nude mice, while HIPK2 knockdown counteracted its effect. Collectively, our work reveals a novel miR-147b-mediated carcinogenic regulatory network in PCa that may be a viable target for PCa treatment.


Percutaneous coronary intervention of a saphenous vein graft ostial stenosis in a patient with Bentall procedure.
Composite graft replacement of the aortic root and coronary reimplantation with or without coronary artery bypass surgery is the standard treatment for a variety of aortic root pathologies. Previously, percutaneous coronary intervention of either reimplanted coronary arteries or left/right coronary artery through cabrol graft has been described in post-Bentall patients. We describe percutaneous coronary intervention of a saphenous vein graft ostial stenosis in a patient with previous Bentall procedure and a vein graft to right coronary artery, which was complex and challenging.


Combination of percutaneous radiofrequency ablation and systemic chemotherapy are effective treatment modalities for metachronous liver metastases from gastric cancer.
This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. We enrolled a total of 44 patients who underwent percutaneous RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Systemic chemotherapy was combined with RFA in 40 patients; the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95% CI 18.4-23.4) and 9.8 months (95% CI 9.2-10.5), respectively. On multivariate analysis, the factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95% CI 3.7-42.9; p=0.001), no chemotherapy (HR 43.3, 95% CI 7.4-251.3; p=0.001), and tumor number≥2 (HR 2.6, 95% CI 1.2-5.9; p=0.015). The factors independently, negatively associated with RFS were extrahepatic metastatic lesions (HR 3.6, 95% CI 1.6-7.8; p=0.003) and bilobar intrahepatic distribution (HR 3.9, 95% CI 1.5-9.9; p=0.001). The efficacy of percutaneous RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of OS.


alpha-2-L-fucosyltransferase activity in sera of individuals with H-deficient red cells and normal H antigen in secretions.
alpha-2-L-fucosyltransferase activity was found in the sera of 4 H-deficient secretor individuals (Hz). This activity represented about 5-10% of the activity present in the serum of normal H phenotypes.


The Arrhenius plot behaviour of rat liver 5'-nucleotidase in different lipid environments.
The plasma membrane enzyme 5'-nucleotidase (EC 188.8.131.52) was prepared from rat liver as a complex with sphingomyelin or in detergent-solubilized forms. Each preparation exhibited a Km and Arrhenius break temperature indistinguishable from that of 5'-nucleotidase in plasma membranes. Measurement of fatty acid profiles, cholesterol and phospholipid content however showed a very wide variation between these preparations. We conclude that the biphasic nature of the Arrhenius plot of 5'-nucleotidase may be a property of the enzyme rather than its lipid environment.


Relationship of cell proliferation (Ki-67) to 99mTc-(V)DMSA uptake in breast cancer.
The aim of the present study was to identify the relationships between the uptake of radiotracers - namely pentavalent dimercaptosuccinic acid [(V)DMSA] and sestamibi (MIBI) - and the following parameters in primary breast cancer: steroid receptor concentrations (i.e. estrogen receptor [ER] and progesterone receptor [PR]), Ki-67 expression, tumor size, tumor grade, age, and levels of expression of p53 and c-erbB-2. In addition, by multivariate regression analysis, we further isolated those factors with independent associations with (V)DMSA and/or MIBI uptake in primary breast cancer. Thirty-four patients with histologically confirmed breast carcinoma underwent preoperative scintimammography with technetium-99m (99mTc)-(V)DMSA and/or 99mTc-MIBI in consecutive sessions 10 and 60 min after administration of 925-1110 MBq of each radiotracer. The tumor-to-background ratio was calculated and correlated with the presence of ER, PR, Ki-67, tumor size, tumor grade, p53, and c-erbB-2. ER, PR, p53, and c-erbB-2 were determined immunohistochemically. The analysis included tumor-to-background ratio of (V)DMSA and MIBI uptake as dependent and all of the other parameters as independent variables. Correlation was positive between Ki-67 and (V)DMSA (r = 0.37 at 10 min, P = 0.038; r = 0.42 at 60 min, P = 0.018) and inverse between PR and (V)DMSA uptake (r = -0.46 at 10 min, P = 0.010; r = -0.51 at 60 min, P = 0.003). Multivariate regression analysis demonstrated a positive correlation between Ki-67 and (V)DMSA at 60 min (P = 0.045). Ki-67 was not significantly correlated with MIBI uptake, whereas tumor size was positively correlated with MIBI uptake at 60 min both in univariate (r = 0.45, P = 0.027) and multivariate analysis (P = 0.024). Negative correlations were observed between (V)DMSA uptake and ER, as well as between ER/PR and MIBI uptake, but these were not significant. Ki-67 appears to represent the major independent factor affecting (V)DMSA uptake in breast cancer. Tumor size was the only independent parameter influencing MIBI uptake in breast cancer. (V)DMSA appears to have an advantage over MIBI in that it can be used to visualize tumors with intense proliferative activity, and thus it can identify those tumors that are more aggressive.


A high-precision and high-order error model for airborne distributed POS transfer alignment.
Distributed position and orientation systems (DPOSs) can provide abundant time-spatial information for interferometric synthetic aperture radar (InSAR) in airborne earth observation systems. However, some key error terms have not been taken into consideration in the traditional low-order error model, which suppresses the performance of the slave POS and further cannot meet the compensation precision of InSAR. To improve the compensation precision, a precise high-order error model with 45 dimensions was derived. Not only does it take into account the influence of scale factor errors and installation errors of the gyro and accelerometer, but it also makes use of random constants and a first-order Markov process model to describe the gyro drift and accelerometer bias. In addition, the flexure angle and its angular rate were added to the state variables of the transfer alignment model. Based on the model, a measurement equation for attitude errors that considers flexure was deduced. Then, a transfer alignment model based on the matching algorithm including position-velocity-attitude was designed. Finally, the proposed model was validated by simulated and real tests, and the experimental results show that its performance is obviously better than that of the traditional model.


An efficient edge/cloud medical system for rapid detection of level of consciousness in emergency medicine based on explainable machine learning models.
Emergency medicine (EM) is one of the attractive research fields in which researchers investigate their efforts to diagnose and treat unforeseen illnesses or injuries. There are many tests and observations are involved in EM. Detection of the level of consciousness is one of these observations, which can be detected using several methods. Among these methods, the automatic estimation of the Glasgow coma scale (GCS) is studied in this paper. The GCS is a medical score used to describe a patient's level of consciousness. This type of scoring system requires medical examination that may not be available with the shortage of the medical expert. Therefore, the automatic medical calculation for a patient's level of consciousness is highly needed. Artificial intelligence has been deployed in several applications and appears to have a high performance regarding providing automatic solutions. The main objective of this work is to introduce the edge/cloud system to improve the efficiency of the consciousness measurement through efficient local data processing. Moreover, an efficient machine learning (ML) model to predict the level of consciousness of a certain patient based on the patient's demographic, vital signs, and laboratory tests is proposed, as well as maintaining the explainability issue using Shapley additive explanations (SHAP) that provides natural language explanation in a form that helps the medical expert to understand the final prediction. The developed ML model is validated using vital signs and laboratory tests extracted from the MIMIC III dataset, and it achieves superior performance (mean absolute error (MAE) = 0.269, mean square error (MSE) = 0.625, R 2 score = 0.964). The resulting model is accurate, medically intuitive, and trustworthy.


Immune-antioxidant trait, Aeromonas veronii resistance, growth, intestinal architecture, and splenic cytokines expression of Cyprinus carpio fed Prunus armeniaca kernel-enriched diets.
Currently, the intervention of plant by-products in the fish diet has gained tremendous attention owing to the economic and high nutritious value. The current study is a pioneer attempt to incorporate the apricot, Prunus armeniaca kernel powder (PAKP) into the Common carp, Cyprinus carpio diets, and assess its efficacy on growth, digestion, intestinal morphology, immunity, antioxidant capacity, and splenic cytokines expression, besides the antibacterial role against Aeromonas veronii infection. Apparently healthy fish (N = 120) with an initial body weight of 24.76 ± 0.03g were allotted in 12 glass aquaria (60 L) and randomly distributed into four groups (triplicates, 10 fish/aquarium). The control group (PAKP0) was fed a basal diet without additives. The second, third, and fourth groups were provided PAKP diets with various concentrations (2.5 (PAKP2.5), 5 (PAKP5), and 10 g kg-1 (PAKP10)) respectively. After 60 days (feeding trial), sub-samples of the fish (12 fish/group) were intraperitoneally injected with 1 × 107 CFU mL-1 of A. veronii. Results revealed that body weight gain, feed conversion ratio, and specific growth rates were significantly augmented in the PAKP10 group in comparison to the other groups. The dietary inclusion of PAKP at all concentrations boosted the digestive capacity and maintained the intestinal morphology (average villus length, villus width, and goblet cells count) with a marked improvement in PAKP10. Moreover, fish fed on PAKP10 followed by PAKP5 then PAKP2.5 diets had noticeably elevated values of immunological biomarkers (IgM, antiprotease, and lysozyme activity) and antioxidant capabilities (the total antioxidant capacity, superoxide dismutase, and reduced glutathione) as well as significant up-regulation of immune and antioxidant-related genes (TGF-β2, TLR-2, TNF-α, IL-10, SOD, GPx, and GSS). Fourteen days post-infection with A. veronii, the highest relative percentage survival of fish was observed in PAKP10 (83.33%), followed by PAKP5 (66.67%), and PAKP2.5 (50%). Our results indicated that a dietary intervention with PAKP could promise growth, digestion, immunity, and protect C. carpio against A. veronii infection in a dose-dependent manner. This offers a framework for future application of such seeds as a growth promotor, immune-stimulant, and antioxidant, besides an alternative cheap therapeutic antibacterial agent for sustaining the aquaculture industry.


The effect of an adrenaline infusion on the splenic blood flow and intrasplenic platelet kinetics.
The effect of an adrenaline infusion on the venous platelet count, splenic blood flow and intrasplenic platelet kinetics was investigated in seven healthy male volunteers by using 111In-labelled platelets and dynamic gamma camera scintigraphy. The infusions were administered in two different doses, 0.2 microgram/kg/min and 0.1 microgram/kg/min, respectively. Regardless of the given dose, adrenaline was found to markedly decrease the splenic blood flow, decrease the exchangeable splenic platelet pool size and to prolong the intrasplenic platelet transit time. In response to the higher dose of adrenaline the splenic blood flow was 1.3 +/- 0.5 (SD) % of total blood volume per min and the intrasplenic platelet transit time 17.3 +/- 2.3 (SD) min. In contrast, after termination of infusion, the splenic blood flow was 7.0 +/- 2.1 (SD) % of total blood volume per min and the intrasplenic platelet transit time was 11.5 +/- 1.5 (SD) min. The present results firmly demonstrate that the splenic blood flow is the immediate variable governing the size of the exchangeable splenic platelet pool, and that the adrenaline-induced depletion of the splenic platelet pool is a consequence of the splenic blood flow reduction. Finally, the splenic perfusion appears to be a major determinant of the intrasplenic platelet transit time.


Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.
EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. Amgen, UK National Institute for Health Research Biomedical Research Centre.


Elastography of the thyroid.
Thyroid nodules are very common, while thyroid cancer is rare and has a very good prognosis. Thyroid nodule ultrasound characterization performed by experienced clinicians allows the selection of the tumours to be punctured and guiding fine needle aspiration (FNA). FNA provide cytology information able to differentiate benign tumours from cancer in approximately 80% of cases. However, it remains difficult to identify thyroid cancers with ultrasound imaging, as demonstrated by the very low rate of cancers detected in all of the carried out FNA (approximately 5%). As a majority of thyroid cancers are hard, the stiffness evaluation has become part of nodular characterization. Since 2005, elastography has been used for the evaluation of thyroid nodules; quasi-static elastography was the first technique available and used, at first, an external pressure induced by the probe, which was then replaced by carotid internal excitation allowing improvement in sensitivity. Semi-quantitative analysis allows comparison of tissue elasticities between tissue with elasticity anomalies and normal tissue and provides therefore useful analytic information. Shear wave elastography (SWE) provides a map of the elasticity in a region and allows stiffness quantification of lesions in kilopascals in order to reinforce the predictive value of malignancy. A tumour whose stiffness is greater than 65kPa or for which the stiffness ratio is greater than 3.7 compared to surrounding healthy tissue is highly suspicious. SWE may enable the detection of malignant follicular tumours that currently escape detection by the ultrasound-guided ultrasound/aspiration cytology couple. Lymph node metastasis of papillary thyroid cancer can also be detected by elastography due to its increased stiffness.


Oxidation of the Mycobacterium tuberculosis key virulence factor protein tyrosine phosphatase A (MptpA) reduces its phosphatase activity.
The Mycobacterium tuberculosis tyrosine-specific phosphatase MptpA and its cognate kinase PtkA are prospective targets for anti-tuberculosis drugs as they interact with the host defense response within the macrophages. Although both are structurally well-characterized, the functional mechanism regulating their activity remains poorly understood. Here, we investigate the effect of post-translational oxidation in regulating the function of MptpA. Treatment of MptpA with H2 O2 /NaHCO3 , mimicking cellular oxidative stress conditions, leads to oxidation of the catalytic cysteine (C11) and to a conformational rearrangement of the phosphorylation loop (D-loop) by repositioning the conserved tyrosine 128 (Y128) and generating a temporarily inactive preclosed state of the phosphatase. Thus, the catalytic cysteine in the P-loop acts as a redox switch and regulates the phosphatase activity of MptpA.


Efficient materially nonlinear [Formula: see text]FE solver for simulations of trabecular bone failure.
An efficient solver for large-scale linear [Formula: see text] simulations was extended for nonlinear material behavior. The material model included damage-based tissue degradation and fracture. The new framework was applied to 20 trabecular biopsies with a mesh resolution of [Formula: see text]. Suitable material parameters were identified based on two biopsies by comparison with axial tension and compression experiments. The good parallel performance and low memory footprint of the solver were preserved. Excellent correlation of the maximum apparent stress was found between simulations and experiments ([Formula: see text]). The development of local damage regions was observable due to the nonlinear nature of the simulations. A novel elasticity limit was proposed based on the local damage information. The elasticity limit was found to be lower than the 0.2% yield point. Systematic differences in the yield behavior of biopsies under apparent compression and tension loading were observed. This indicates that damage distributions could lead to more insight into the failure mechanisms of trabecular bone.


Anatomic Study of the Dorsalis Pedis Artery, First Metatarsal Artery, and Second Metatarsal Bone for Mandibular Reconstruction.
The purpose of this study was to clarify the anatomic variation of the dorsalis pedis and first metatarsal arteries and to define the trabecular-to-cortical bone ratio (TBR) of the second metatarsal bone to ascertain their suitability as implants. Fifty-two specimens were prepared for this study. Each specimen was dissected on the dorsal side of the foot to search for the dorsalis pedis artery. Three types of dorsalis pedis artery were found: in type A, which was the most common, the artery continuously formed the first metatarsal artery; in type C, which was the second most common, the artery coursed below the first dorsal interosseous muscle; and in type B, the artery coursed from the lateral side. Five variations of the first metatarsal artery were identified: the most common was type IIb, in which the artery coursed below the first dorsal interosseous muscle; followed by type Ib, in which the artery coursed obliquely through the muscle; type Ic, in which the artery coursed parallel to the muscle; type IIa, in which the artery coursed above and below the muscle; and type Ia, in which the artery coursed only above the muscle. The second metatarsal bone was divided into 5 regions. There was no trabecular bone in regions 1 and 5. The TBR appeared to be lower in region 3 than in regions 2 and 4 and highest in region 2. All regions of the second metatarsal bone appear to be suitable as implants, but when placing the implant in the proximal end, care should be taken not to overheat the bone and to be wary of perforation when placing it on the middle side.


Effects of in-utero exposure to oral hypoglycaemic drugs.
The observation that several Mexican-American women were taking oral hypoglycaemic agents while pregnant led to a study to confirm reports of associations between these agents and congenital abnormalities. 20 non-insulin-dependent (NIDDM) pregnant diabetic women with exposure to oral hypoglycaemic drugs during embryogenesis and 40 pregnant NIDDM women matched for age, race, parity, weight, and glycaemic control but not exposed to oral hypoglycaemic drugs were followed up. 10 infants (50%) in the exposed group had congenital malformations, compared with only 6 (15%) in the control group (p less than 0.002). 5 (25%) infants in the exposed group had ear malformations, anomalies not commonly described in diabetic embryopathy. Hyperbilirubinemia (p less than 0.04), polycythaemia, and hyperviscosity requiring partial exchange transfusions (p less than 0.03) were commoner among babies in the exposed than in the control group. 3 babies in the exposed group but none in the comparison group had severe prolonged neonatal hypoglycaemia lasting 2, 4, and 7 days; 2 of the 3 had been exposed for 22 and 28 weeks during gestation, whereas the third had been exposed throughout the first trimester. Although exposure to oral hypoglycaemic drugs during fetal life seems to be associated with congenital malformations and neonatal hypoglycaemia, a large, prospective study is needed to exclude the confounding effect of maternal metabolic derangement secondary to diabetes.


Arsenic and arsenic species in shellfish and finfish from the western Arabian Gulf and consumer health risk assessment.
This study reports the levels of total arsenic and arsenic species in marine biota such as clams (Meretrix meretrix; N=21) and pearl oyster (Pinctada radiata; N=5) collected from nine costal sites in Jan 2014, and cuttlefish (Sepia pharaonis; N=8), shrimp (Penaeus semisulcatus; N=1), and seven commercially important finfish species (N=23) collected during Apr-May 2013 from seven offshore sites in the western Arabian Gulf. Total As and As species such as dimethylarsinic acid (DMA), arsenobetaine (AB), trimethylarsine oxide (TMAO), arsenocholine (AC), tetramethylarsonium ion (Tetra), arsenosugar-glycerol (As-Gly) and inorganic As (iAs) were determined by using ICPMS and HPLC/ICPMS. In bivalves, the total As concentrations ranged from 16 to 118mg/kg dry mass; the toxic iAs fraction contributed on average less than 0.8% of the total As, while the nontoxic AB fraction formed around 58%. Total As concentrations for the remaining seafood (cuttlefish, shrimp and finfish) ranged from 11 to 134mg/kg dry mass and the iAs and AB fractions contributed on average 0.03% and 81% respectively of the total As. There was no significant relationship between the tissue concentrations of total As and iAs in the samples. There was also no significant relationship between As levels in seafood and geographical location or salinity of the waters from which samples were collected. Based on our results, we recommend introducing a maximum permissible level of arsenic in seafood from the Gulf based on iAs content rather than based on total As. Our analyses of cancer risks and non-cancer hazards identified non-negligible risks and the potential for hazards; the greatest risks were identified for expatriate consumers of bivalves and high-end consumers of seafood. Despite this, many uncertainties remain that would be best addressed by further analyses.


Bovine colostric transforming growth factor-beta-like peptide that induces growth inhibition and changes in morphology of human osteogenic sarcoma cells (MG-63).
TGF-beta like peptide, termed TGF(BC-1), was partially purified from defatted and decaseinated bovine colostrum by a sequence of DEAE-Sephacel chromatography and Sephadex G-50 gel filtration in 1M acetic acid. TGF(BC-1) was distinct from well-known 25K TGF-beta in chemical properties: TGF(BC-1) was sensitive to acid ethanol extraction (Roberts et al., 1980). Its apparent molecular weight ranged from 21k to 11k by gel filtration and it was composed of low MW peptides (15k, 13k, 10k and 7.3k but not 25k) as examined by SDS-PAGE under non-reducing conditions. However, TGF(BC-1) shares some biological properties with the prototype TGF-b. TGF(BC-1) remarkably suppressed growth of osteogenic sarcoma cells (MG-63), and this was intriguingly accompanied by a striking change in morphology.


Biosurfactant production from marine bacteria associated with sponge Callyspongia diffusa.
Marine-derived biosurfactants have gained significant attention due to their structural and functional diversity. Biosurfactant production was performed using bacteria associated with Callyspongia diffusa, a marine sponge inhabiting the southern coast of India. A total of 101 sponge-associated bacteria were isolated on different media, of which 29 isolates showed positive result for biosurfactant production. Among the 29 positive isolates, four were selected based on highest emusification activity and were identified based on 16S rDNA sequence analysis. These isolates were identified as Bacillus subtilis MB-7, Bacillus amyloliquefaciens MB-101, Halomonas sp. MB-30 and Alcaligenes sp. MB-I9. The 16S rDNA nucleotide sequences were deposited in GenBank with accession numbers KF493730, KJ540939, KJ414418 and KJ540940, respectively. Based on the highest oil displacement activity and effective surface tension reduction potential, the isolate B. amyloliquefaciens MB-101 was selected for further optimization and structural delineation. The production of biosurfactant by the isolate was significantly enhanced up to 6.76 g/l with optimal concentration values of 2.83 % for glycerol, 2.65 % for peptone, 20.11 mM for ferrous sulfate and 74 h of incubation by employing factorial design. The structural features of the purified biosurfactant from B. amyloliquefaciens MB-101 showed similarity with lipopeptide class of biosurfactant. In conclusion, the present study emphasizes the utilization of marine sponge-associated bacteria for the production of biosurfactant that may find various applications.


Deconstructing stemness.
Stem cells are unique in their capacity to self-renew and generate differentiated progeny to maintain tissues throughout life. A common molecular program for stem cells has remained elusive. We discuss what the molecular logic of stemness may be. We suggest that it may not be coupled to distinct cellular properties such as self-renewal or multipotency, but rather to the stable suspension at a specific developmental stage. In this view, the stem cell niche allows a cell to maintain a transcriptional accessibility enabling the generation of specific differentiated progeny.


Objective quality evaluation of fluorescence images to optimize automatic image acquisition.
Because different spectral sensitivities of human eye and image sensor lead to different perception of fluorescence signals, data generation is an important step in image analysis, because following work steps depend on it. We developed a method to determine image parameters allowing an objective appraisal of quality of image data as well as a separation of object and background. Calculated parameters can be used for an automated adjustment of camera parameters in image analysis systems. Our approach for objective adjusted data generation achieves an improvement of analysis quality.


Control of renal and extrarenal salt and water excretion by plasma angiotensin II in the kelp gull (Larus dominicanus).
The osmoregulatory effects of intravenously (i.v.) administered angiotensin II (AII) at dose rates of 5, 15 and 45 ng.kg-1.min-1 were examined in kelp gulls utilizing salt gland and/or kidneys as excretory organs. In birds given i.v. infusion of 1200 mOsmolal NaCl at 0.3 ml.min-1 and utilizing only the salt glands to excrete the load, infusion of AII for 30 min consistently inhibited salt gland function in a dose-dependent manner. In birds given i.v. infusion of 500 mOsmolal NaCl at 0.72 ml.min-1 and utilizing both salt glands and kidneys to excrete the load, each dose of AII given for 2 h inhibited salt gland function but stimulated the kidney, so that the overall outputs of salt and water were enhanced and showed significant (2P less than 0.01) positive correlations with plasma AII. In birds given i.v. infusion of 200 mOsmolal glucose at 0.5 ml.min-1 and utilizing only the kidneys to excrete the load, low doses of AII (5 and 15 ng.kg-1.min-1) caused renal salt and water retention, whereas a high dose (45 ng.kg-1.min-1) stimulated salt and water output. The actions of plasma AII in kelp gulls support the concept that this hormone plays a vital role in avian osmoregulation, having effects on both salt gland and kidney function. Elevation of plasma AII consistently inhibits actively secreting salt glands, but its effects upon renal excretion depend primarily on the osmotic status as well as on the plasma AII concentration. In conditions of salt and volume loading doses of AII stimulate sodium and water excretion. With salt and volume depletion, the action of AII is bi-phasic with low doses promoting renal sodium and water retention but high circulating levels causing natriuresis and diuresis.


Piezoelectric vibrator-stimulated potential and heart rate accelerations detected from the fetus.
The fetus is well known to have a substantial capacity for sound recognition in the uterine environment. The aim of this study was to develop a sound stimulus system equipped with a piezoelectric vibrator (PV), record the PV-stimulated potential (PVSP) of the fetus and monitor changes of the fetal heart rate (FHR) under PV stimulation. The relationship between the input voltage applied to a piezoelectric vibrator and the sound pressure generated in the uterus was calibrated based on a model of the maternal abdomen. Fourteen fetuses for the measurement of the PVSP and 22 fetuses for the measurement of the heart rate changes from low-risk pregnant women were recruited. The PVSP responses were obtained in 9 out of 14 fetuses. All the tested fetuses accelerated the FHR after the 2 kHz tone stimulation at 70 dB intensity generated by PV from 32 to 37 weeks gestational age. Using a newly developed sound stimulus system equipped with PV, the electric responses of a fetus recorded from electrodes placed on the mother's abdomen may be closely related to the auditory evoked response. Significant accelerations of FHR were objectively, accurately and readily obtained after the sound stimulation.


Trends and pitfalls with nomenclatures and classifications in medicine.
This paper reflects some of the main points in the history and the trends of classifications, nomenclatures and knowledge representation models in medicine. The relations with philosophical background are briefly related. The contributions in this field during the Medical Informatics Europe (MIE) conference in 1997 are presented. International collaborations in the field of lexico-semantic resources and inter-disciplinary partnership in natural language processing technologies are necessary steps to achieve definitive results that will lead to applications in the daily medical practice.


The management of insulinoma.
Insulinomas are rare tumours. Their clinical presentation, localization techniques and operative management were reviewed. An electronic search of the Medline, Embase and Cochrane databases was undertaken for articles published between January 1966 and June 2005 on the history, presentation, clinical evaluation, use of imaging techniques for tumour localization and operative management of insulinoma. Most insulinomas are intrapancreatic, benign and solitary. Biochemical diagnosis is obtained during a supervised 72-h fast. Non-invasive preoperative imaging techniques to localize lesions continue to evolve. Intraoperative ultrasonography can be combined with other preoperative imaging modalities to improve tumour detection. Surgical resection is the treatment of choice. In the absence of preoperative localization and intraoperative detection of an insulinoma, blind pancreatic resection is not recommended.


L-Arginine erythrocyte transport in normal pregnant and preeclamptic women.
Uptake of L-arginine by the cell via amino acid transporter systems is the first step for nitric oxide (NO) production. The current study aimed to assess the total L-arginine uptake in erythrocytes of normal pregnant and preeclamptic women. Twenty-one normal pregnant and 21 preeclamptic women were studied. To measure total L-arginine uptake in erythrocytes, carbon 14 was used as a marker and Michaelis-Menten kinetic parameters (V(max) and K(m)) were evaluated. In preeclamptic women, there was a significant increase (P<.004) in the mean maximal capacity of transport in erythrocytes (V(max)=982.69 micromol/L cells/h+/-433.51) in comparison with normal pregnant women (V(max)=584.73 micromol/L cells/h+/-422.33). No significant difference was detected in the half-saturation constant (P=0.978). The transport kinetics of the NO precursor, L-arginine, is altered in erythrocytes of preeclamptic women. It is possible that abnormal L-arginine uptake may contribute to the pathophysiologic mechanisms of preeclampsia syndrome.


Double Talk.
In this series of short essays, stories, poems, and personal observations, Robert A. Burton, neurologist and writer, uses both fiction and nonfiction to explore many paradoxes and contradictions inherent in scientific inquiry. A novelist as well as author of On Being Certain and A Skeptic's Guide to the Mind, Burton brings story to science and science to story.


Complex Foley Catheter Placement After Radical Prostatectomy.
To describe a method for replacement of a dislodged critical urethral foley catheter following a robotic- assisted laparoscopic radical prostatectomy. Following robotic-assisted laparoscopic radical prostatectomy (RALP), a bladder drainage via catheter is necessary to allow for proper healing of the urethrovesical anastomosis. In most cases, this is done using a transurethral foley catheter.1,2 Early traumatic loss of the urethral catheter following RALP is consider a urologic emergency and can lead to vesicourethral anastomotic urine leak, ileus, infection or abscess, and future anastomotic stenosis.3 Replacing the urethral catheter in this situation can be difficult even in experienced hands and often requires imaging assistance. A 53-year-old male with Grade Group 4 (Gleason 4 + 4) prostate cancer underwent an uncomplicated RALP. During his post-operative course, his urethral foley catheter fell out or was traumatically removed three times resulting in disruption of the posterior anastomosis. To replace the urethral catheter and prevent it from being dislodged again, a transabdominal approach under ultrasound and cystoscopic guidance was employed to replace the catheter into the bladder and secure it trans abdominally using a single G-tube safety Pexy T fastener. This case reports describes a technique used to replace and secure a urethral foley catheter in a patient who suffered from a posterior anastomotic disruption following repeated loss and traumatic removal of his urethral foley catheter during his RALP post-operative course. While replacement of a dislodged urethral foley catheter following a RALP can be challenging, the catheter can safely be placed and secured trans abdominally in these rare but serious situations where the conventional catheter secure devices and patient education alone are not sufficient to prevent removal.


A Study on Deep Neck Space Infections.
Deep neck space infections (DNSI) are serious diseases that involve several spaces in the neck. These are commonly seen in low socioeconomic group with poor oral hygiene, and nutritional disorders. These are bacterial infections originating from the upper aerodigestive tract. The incidence of this disease was relatively high before the advent of antibiotics. Treatment of DNSI includes antibiotic therapy, airway management and surgical intervention. Management of DNSI is traditionally based on prompt surgical drainage of the abscess followed by antibiotics or nonsurgical treatment using appropriate antibiotics in the case of cellulitis. This study was conducted to investigate the age and gender, clinical symptoms, site involved, etiology, co-morbidities, bacteriology, complications and outcomes in the patients of DNSI. A prospective study of deep neck space infections was conducted during the period July 2017 to July 2018 on the patients who attended the outpatient department and were admitted as inpatient in Safdarjung hospital, New Delhi. 40 Cases with DNSI all ages and both genders were included in the study. Patients who didn't require surgical intervention to drain pus were excluded. All parameters including age, gender, co-morbidities, presentation, site, bacteriology, complications, and investigations were studied. Due to advent of antibiotics, deep neck space infections are in decreasing trend. The common age group found to be affected is in 2nd and 3rd decade in our study. Out of all deep neck space infections, submandibular space infections were common (37.5%) followed by peritonsillar infections (12.5%). Infection of deep neck space remains fairly common and challenging disease for clinicians. Prompt recognition and treatment of DNSI are essential for an improved prognosis. Odontogenic and tonsillopharyngitis are the commonest cause. Key elements for improved results are the prompt recognition and early intervention. Special attention is required to high-risk groups such as diabetics, the elderly and patients with underlying systemic diseases as the condition may progress to life-threatening complications.


Improved methods of zearalenone and moniliformin preparation.
Modified procedures of zearalenone and moniliformin preparation, using solid substrate (rice or corn kernels) has been developed. Preliminary purification of toxins by 1iquid-liquid partition was applied, followed by column chromatography on silicagel and charcoal. Final yield was about lg from 1kg of dry cultures of crystalline zearalenone and liophylized moniliformin o high purity.


Screening forFusarium toxigenic isolates using larvae ofGalleria mellonella.
The toxicity of twenty-fourFusarium isolates was evaluated towards larvae ofGalleria mellonella by the antlfeedant activity of the autoclaved fungal culture incorporated into insect diet. Culturesof isolates belonging to F.sporotrichioldes, F. compactum andF. sambucinum, well known as capable to synthesize trichothecenes, showed high antifeedant activity (ca 60-70%); whereas controversial activity was showed byF. equiseti, F. proliferatum andF. solani cultures, and not significant activity was showed byF. oxysporum cultures. The G.mellonella larvae bioassay is suggested as a reliable sensitive Insectbioassay for screening fungal toxicity.


Development of a high-throughput RT-PCR based viral infectivity assay for monitoring the stability of a replicating recombinant Lymphocytic Choriomeningitis viral vector.
Traditional virus infectivity titration methods for lymphocytic choriomeningitis virus (LCMV) are laborious, time-consuming, and low-throughput (e.g., focus forming unit (FFA) assay). In this report, we developed a high-throughput reverse transcription quantitative PCR (RT-qPCR)-based virus infectivity assay for relative quantitation of a live, recombinant replicating LCMV -based viral vector (TT1). This in vitro infectivity assay demonstrated a 4-log linear range for TT1 titer quantitation. A high positive Pearson correlation coefficient value (≥ 0.80) was obtained between the RT-qPCR vs. the "gold-standard" FFU assay when comparing the stability profiles of stressed TT1 vector samples. In addition to the RT-qPCR infectivity assay, the stability of the TT1 vector upon freeze-thaw stress was investigated further with complementary viral particle characterization techniques (e.g., TEM, NTA, MFI). Correlations between viral infectivity and particle measurements during forced degradation studies were observed to be specific to the TT1 vector and its various formulations and such results facilitated the rank-ordering of formulation conditions. Overall, this infectivity RT-qPCR method showed increased sample throughput and improved assay flexibility compared to traditional viral infectivity assays. These results are discussed in the context of enabling future TT1 vector formulation development work, and potential utilization as an in-process monitoring tool during TT1 vector manufacturing.


The role of type 2 diabetes in neurodegeneration.
A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Aβ) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aβ may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.


Effects of piretanide in normal subjects.
Piretanide is a new loop diuretic similar to furosemide in pharmacologic properties and approximately six times as potent. We gave 3-, 6-, and 12-mg oral doses to 21 normal subjects and collected serial blood and urine samples for assessment of the drug's kinetics and dynamics. There was no evidence for dose-dependent elimination with the doses we used. Peak serum concentrations and urinary excretion rates appeared between 30 and 60 min. Elimination t1/2s were 60 to 90 min. Approximately 45% of a dose was recovered unchanged in the urine. Renal clearance rate was 90 to 100 ml/min and oral clearance was 200 ml/min. Examination of the relationship between urinary excretion rate of piretanide and sodium excretion allowed determination of potency at the tubular level. The piretanide dose that induced half-maximal response was 12.1 +/- 2.6 micrograms/min; it is 69.8 micrograms/min for furosemide and 1 micrograms/min for bumetanide. Piretanide kinetics, therefore, resemble those of furosemide and bumetanide, but piretanide is five or six times as potent as furosemide and one tenth as potent as bumetanide.


Does cardiology intervention improve mortality for post-operative troponin elevations after emergency orthopaedic-geriatric surgery? A randomised controlled study.
Troponin elevations are common after emergency orthopaedic surgery and confer a higher mortality at one year. The objective was to determine if comprehensive cardiology care after emergency orthopaedic surgery reduces mortality at one year in patients who sustain a post-operative troponin elevation versus standard care. A randomised controlled trial was conducted at a metropolitan teaching hospital in Melbourne, Australia. 187 consecutive patients were eligible with 70 patients randomised. Troponin I was tested peri-operatively and patients with a troponin elevation were randomised to cardiology care versus standard ward management. The main outcome measure was one year mortality. The incidence of a post-operative troponin elevation was 37.4% (70/187) and these 70 patients were randomised. In-hospital cardiac complications were similar between the randomised groups: standard care (7/35 or 20.0%) versus cardiology care (8/35 or 22.9%). There was no difference in 1 year mortality between the randomised groups (6/35 or 17.1% in each group). Multivariate predictors of 1 year mortality were post-operative troponin elevation OR 4.3 (95% CI, 1.1-16.4, p=0.035), age OR 1.1 (95% CI, 1.02-1.2, p=0.016) and number of comorbidities OR 2.1 (95% CI, 1.3-3.5, p=0.004). At 1 year 35/187 (18.7%) sustained a cardiac complication and 23/35 (65.7%) had a troponin elevation. There was no difference in mortality between patients with a post-operative troponin elevation randomised to cardiology care compared with standard care. Troponin elevation predicted one year mortality. Further research is needed to find an effective intervention to reduce mortality.


Cytostatic factor (CSF) activity in cytosols extracted from Xenopus laevis eggs.
Cytostatic factor (CSF), found in the cytoplasm of unfertilized eggs of amphibians, causes metaphase arrest when microinjected into cleaving blastomeres. Although CSF from Rana pipiens eggs has been extracted and characterized, little is known about CSF extracted from eggs of other species. We investigated the conditions required to preserve CSF activity in cytosols extracted from Xenopus laevis eggs and found that it was necessary to expose the eggs to CO2 prior to extraction and that the extraction buffer must contain sodium beta-glycerophosphate. CSF activity disappeared after 24 h of storage at 2 degrees C. Cytological examination showed that the arrested blastomeres injected with cytosols had been arrested at metaphase and contained a spindle lacking polar asters, in which highly condensed chromosomes were embedded.


Global trends and research hotspots on HACCP and modern quality management systems in the food industry.
HACCP (Hazard Analysis and Critical Control Points) and modern quality management systems have a significant impact on public health in the food industry. These systems ensure that food products are safe for consumption by identifying and managing potential hazards at every stage of the production process. To stimulate ongoing studies in both developing and underexplored areas of inquiry, this research synthesizes and organizes the contributions made in this field. It examines more than 40 years of studies from Scopus data base on HACCP and modern quality management systems in the food industry using the VOSviewer software version 1.6.18 (Leiden University, The Netherlands) and bibliometrix R-package. This represents, to the authors' knowledge, the first bibliometric analysis undergone in this direction. The graphical framework demonstrates the highest developments in research and the literature review investigates barriers and opportunities of implementing HACCP in food industry organizations. Findings indicate that until the beginning of the 1990s, there was not a large number of scientific production in the field of HACCP and modern quality management systems in the food industry. The USA were the most prolific affiliation terms of scientific production until 2012, when studies from Italy, the United Kingdom, China and Greece intensified. Currently, the most prolific country in terms of publications is Italy. In terms of global cooperation, the United Kingdom, The United States and The Netherlands represent most active nations on this topic Motor themes that reflect the main interest of the researchers include food diseases, quality control, hazards or food supply. The study also provides future research directions regarding food quality and safety management. These should be focused on improving the safety, quality, and sustainability of food products, while also adapting to changing consumer demands, emerging risks, and regulatory requirements.


The prognostic value of morphologic findings for lung squamous cell carcinoma patients.
Novel histopathological prognostic features for squamous cell carcinoma (SCC) of lung, such as tumor budding, mitotic rate, tumor stroma ratio, stroma type, stromal inflammation and necrosis, have been evaluated in the literature. In this study, the prognostic value of multiple morphological features is assessed in lung SCC. This study reports on seventy-six patients with lung SCC treated with complete surgical excision. Tumor size, tumor stage, lymph node status, lymphovascular invasion, histopathologic grade, mitotic count, necrosis, tumor budding, tumor stroma ratio, stroma type, stromal lymphoplasmacytic reaction and ratios of stromal plasma cells and their relationship with the prognosis were evaluated. Univariate and multivariate analyses were performed for histopathological markers for local disease free survival (LDFS), distant disease free survival (DDFS), overall disease free survival (ODFS) and overall survival (OS). The univariate prognostic analysis of the pathological factors revealed that the pathological stage (OS: p=0.001, DDFS: p=0.040), lymph node metastases (OS: p=0.013), mitotic index (OS: p=0.026), tumor necrosis (DDFS: p=0.013, ODFS: p=0.021) and tumor size (OS: p=0.002) had a prognostic significance. The multivariate analysis demonstrated that the pathological stage (OS: p=0.021), tumor size (OS: p=0.044), lymph node status (DDFS: p=0.019, ODFS; p=0.041) and necrosis (ODFS: p=0.048) were independent prognostic factors. Although many histopathological factors have recently been proposed as important prognostic markers, we only found significant results for mitotic index and tumor necrosis, as well as the well known parameters such as tumor stage and lymph node status. To the best of our knowledge, this is the first study evaluating such a wide range of morphological prognostic factors in lung SCC.


Chimera states among synchronous fireflies.
Systems of oscillators often converge to a state of synchrony when sufficiently interconnected. Twenty years ago, the mathematical analysis of models of coupled oscillators revealed the possibility for complex phases that exhibit a coexistence of synchronous and asynchronous clusters, known as "chimera states." Beyond their recurrence in theoretical models, chimeras have been observed under specifically designed experimental conditions, yet their emergence in nature has remained elusive. Here, we report evidence for the occurrence of chimeras in a celebrated realization of natural synchrony: fireflies. In video recordings of Photuris frontalis fireflies, we observe, within a single swarm, the spontaneous emergence of different groups flashing with the same periodicity but with a constant delay between them. From the three-dimensional reconstruction of the swarm, we demonstrate that these states are stable over time and spatially intertwined. We discuss the implications of these findings on the synergy between mathematical models and collective behavior.


Quality of life in patients with oculocutaneous albinism.
The social reality of the albino needs to be more studied in Brazil, as myths and social segregation regarding this illness are likely to be found in the country, with psychosocial and medical implications. As this subject has not been referenced in previous scientific articles in Brazil, this research intends to evaluate the quality of life of the albinos that treated at our medical institution. The quality of life was evaluated through the WHOQOL-BREF. Furthermore, two aspects of main relevance in the lives of the albinos were also objects of research, low vision and skin cancer. The sample consisted of forty oculocutaneous albinos and a control group of forty healthy individuals, matched by sex and age. Among the participants, 57.7% were between 18 and 40 years old, 28.2% were between 41 and 60, and 14.1% were over 60. 42.1% had skin cancer before the study, 18.4% had skin cancer during the study and 89.5% stated visual deficit. The results obtained in the questionnaires showed a statistically significant difference in the physical domain, with P < 0.001. Low vision combined with skin lesions and social stigma may contribute to disturbances in the quality of life of oculocutaneous albinos. The results presented in this study demonstrated the vulnerability of the affected individuals and the special care required by those patients, at the same time that the need for further research is highlighted in order to better elucidate the aspects related to albinism.


Infant Nutrition in Low- and Middle-Income Countries.
The burden of infant malnutrition is greatest in low- and middle-income countries (LMICs). Infant malnutrition is defined based on distinct subcategories, among them stunting (low-height-for-age) and wasting (low-weight-for-height). Some experts are shifting more toward understanding the interplay between these overlapping phenotypes and other confounding factors such as maternal nutrition and environmental hygiene. Current guidelines emphasize appropriate breastfeeding and nutrition within the 1000 days from conception to a child's second birthday to optimize early development. Future research directed toward better biomarkers of malnutrition before acute clinical symptoms develop will help direct targeted efforts toward at-risk populations.


Accounting for forest condition in Europe based on an international statistical standard.
Covering 35% of Europe's land area, forest ecosystems play a crucial role in safeguarding biodiversity and mitigating climate change. Yet, forest degradation continues to undermine key ecosystem services that forests deliver to society. Here we provide a spatially explicit assessment of the condition of forest ecosystems in Europe following a United Nations global statistical standard on ecosystem accounting, adopted in March 2021. We measure forest condition on a scale from 0 to 1, where 0 represents a degraded ecosystem and 1 represents a reference condition based on primary or protected forests. We show that the condition across 44 forest types averaged 0.566 in 2000 and increased to 0.585 in 2018. Forest productivity and connectivity are comparable to levels observed in undisturbed or least disturbed forests. One third of the forest area was subject to declining condition, signalled by a reduction in soil organic carbon, tree cover density and species richness of threatened birds. Our findings suggest that forest ecosystems will need further restoration, improvements in management and an extended period of recovery to approach natural conditions.


Herbivory by crabs and the control of algal epibionts on Caribbean host corals.
A short-term experiment was conducted to examine the relationships among the branching coral Porites porites, algal epibionts, and a facultative crab associate Mithrax sculptus in Belize, Central America. Initial field observations suggested that coral colonies supporting resident crabs generally had lower algal cover than colonies without crabs. The hypothesis was tested that Mithrax significantly depresses host coral algal cover and thereby indirectly affects host survivorship and growth. Crab accessibility to an array of coral colonies, similarly covered with algal epibionts, was manipulated in three treatments. Results strongly support the hypothesis, with significant differences in algal cover (primarily Dictyota spp.) noted among treatments after only one month. Caged heads with crabs included and uncaged natural controls allowing crabs free access averaged less than 10% cover, whereas mean algal cover exceeded 75% where crabs were excluded. The uncaged treatment, in which crabs were allowed free access to Porites heads was not significantly different from the crab inclusion treatment. Collectively, these results demonstrate that under natural conditions, crabs can have pronounced effects on host corals by reducing fouling algal epibionts. Furthermore, these facultative coral associates may have more important, albeit localized effects on Caribbean corals than has been suggested previously.


Evaluation of Leuconostoc mesenteroides YML003 as a probiotic against low-pathogenic avian influenza (H9N2) virus in chickens.
The aims of the study were to isolate anti-H9N2 bacteria from Korean Kimchi isolates and to evaluate its performance in cell line, egg and in specific pathogen-free (SPF) chickens. Using Madin-Darby canine kidney (MDCK) cell line, 220 bacterial isolates were screened and the isolate YML003 was selected having pronounced antiviral activity against H9N2 virus. This isolate was identified as Leuconostoc mesenteroides by 16S rRNA gene sequencing. Anti-H9N2 activity of the strain was also evaluated by hemagglutination assay. Leuconostoc mesenteroides YML003 was assessed for its survival in gastric juice and 5% bile acid and the antibiotic susceptibility. Both live and heat-killed cells were selected for in vivo chicken feeding experiment. Body weight, immune index, serobiochemical parameters and splenic IFN-γ production were assessed during selected intervals. Viral population in the trachea and cloacae were calculated by quantitative real-time reverse transcriptase PCR (qRT-PCR). Leuconostoc mesenteroides YML003 exhibited anti-H9N2 activity both in in vitro cell line as well as in vivo SPF chickens. This is a primary report on the anti-H9N2 activity by a Leuconostoc strain. Amid the increasing reports of avian influenza virus occurrence resulting in severe losses to the poultry industry, prophylactic administration of such probiotic strains are highly significant.


How ancient forest fragmentation and riparian connectivity generate high levels of genetic diversity in a microendemic Malagasy tree.
Understanding landscape changes is central to predicting evolutionary trajectories and defining conservation practices. While human-driven deforestation is intense throughout Madagascar, exceptions in areas such as the Loky-Manambato region (north) raise questions regarding the causes and age of forest fragmentation. The Loky-Manambato region also harbours a rich and endemic flora, whose evolutionary origin remains poorly understood. We assessed the genetic diversity of an endangered microendemic Malagasy olive species (Noronhia spinifolia Hong-Wa) to better understand the vegetation dynamics in the Loky-Manambato region and its influence on past evolutionary processes. We characterized 72 individuals sampled across eight forests through nuclear and mitochondrial restriction-associated DNA sequencing data and chloroplast microsatellites. Combined population and landscape genetics analyses indicate that N. spinifolia diversity is largely explained by the current forest cover, highlighting a long-standing habitat mosaic in the region. This sustains a major and long-term role of riparian corridors in maintaining connectivity across these antique mosaic habitats, calling for the study of organismal interactions that promote gene flow.


Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.
To determine dose-effect and concentration-effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together, we conducted a randomized, double-blind, 4 X 3 factorial, modified fixed-dose multicenter trial. Three hundred and eighty-four patients with essential hypertension (supine diastolic blood pressure, 95 to 110 mm Hg) were assigned to one of 12 groups that received all combinations of four doses of pinacidil (0, 12.5, 25, and 37.5 mg, b.i.d.) with three doses of hydrochlorothiazide (0, 12.5, and 25 mg, b.i.d.). Significant dose- and concentration-effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose- and concentration-effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near-maximal effects on blood pressure at both peak and trough. Edema occurred in 47% of those who received 37.5 mg pinacidil monotherapy (19% discontinued). The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety.


Childhood central nervous system vasculitis.
Inflammatory brain diseases in childhood are underrecognized and lead to devastating yet potentially reversible deficits. New-onset neurologic or psychiatric deficits in previously healthy children mandate an evaluation for an underlying inflammatory brain disease. Distinct disease entities, such as central nervous system (CNS) vasculitis, are now being increasingly reported in children. Clinical symptoms, initial laboratory test, and neuroimaging studies help to differentiate between different causes; however, more invasive tests, such as lumbar puncture, conventional angiography, and/or brain biopsy, are usually necessary before the start of treatment. This article focuses on childhood CNS vasculitis.


Correction to: Inhibition of the key metabolic pathways, glycolysis and lipogenesis, of oral cancer by bitter melon extract.
Following publication of the original article [1], it was reported that Fig. 1c was not entirely readable due to overlapping Fig. 1d. The publishers apologise for this error.


The indirect effects of multiplicity of infection on baculovirus expressed proteins in insect cells: secreted and non-secreted products.
The baculovirus expression vector system was employed to produce human apolipoprotein E and β-galactosidase in order to study the effect of multiplicity of infection on secreted and non-secreted recombinant protein production. Prior knowledge of the influence of other cell culture and infection parameters, such as the cell density at time of infection and the time of harvest, allowed determination of the direct and indirect influences of multiplicity of infection on recombinant protein synthesis and degradation in insect cells. Under non-limited, controlled conditions, the direct effect of multiplicity of infection (10(-1)-10 pfu/cell) on specific recombinant product yields of non-secreted β-galactosidase was found to be insignificant. Instead, the observed increased in accumulated product was directly correlated to the total number of infected cells during the production period and therefore ultimately dependent on an adequate supply of nutrients. Only the timing of recombinant virus and protein production was influenced by, and dependent on the multiplicity of infection. Evidence is presented in this study that indicates the extremely limited predictability of post-infection cell growth at very low multiplicities of infection of less than 0.1 pfu/cell. Due to the inaccuracy of the current virus quantification techniques, combined with the sensitivity of post-infection cell growth at low MOI, the possibility of excessive post-infection cell growth and subsequent nutrient limitation was found to be significantly increased. Finally, as an example, the degree of product stability and cellular and viral protein contamination at low multiplicity of infection is investigated for a secreted recombinant form of human apolipoprotein E. Comparison of human apolipoprotein E production and secretion at multiplicities of infection of 10(-4)-10 pfu/cell revealed increased product degradation and contamination with intracellular proteins at low multiplicities of infection.


NiSe2 Nanooctahedra as an Anode Material for High-Rate and Long-Life Sodium-Ion Battery.
In this article, we report NiSe2 nanooctahedra as a promising anode material for sodium-ion batteries (SIBs). They exhibit outstanding long-term cyclic stability (313 mAh/g after 4000 cycles at 5 A/g) and excellent high-rate capability (175 mAh/g at 20 A/g). Besides, the initial Coulombic efficiency of NiSe2 is also very impressive (over 90%). Such remarkable performances are attributed to good conductivity, structural stability, and the pseudocapacitive behavior of the NiSe2. Furthermore, the sodium ion storage mechanism of NiSe2 is first investigated by in situ XRD and ex situ XRD. These highlights give NiSe2 a competitive strength for rechargeable SIBs.


A concurrent neuro-fuzzy inference system for screening the ecological risk in rivers.
A conceptual model to assess water quality in river basins was developed here. The model was based on ecological risk assessment principles, and incorporated a novel ranking and scoring system, based on self-organizing maps, to account for the likely ecological hazards posed by the presence of chemical substances in freshwater. This approach was used to study the chemical pollution in the Ebro River basin (Spain), whose currently applied environmental indices must be revised in terms of scientific accuracy. Ecological hazard indexes for chemical substances were calculated by pattern recognition of persistence, bioaccumulation, and toxicity properties. A fuzzy inference system was proposed to compute ecological risk points (ERP), which are a combination of the ecological hazard to aquatic sensitive organisms and environmental concentrations. By aggregating ERP, changes in water quality over time were estimated. The proposed concurrent neuro-fuzzy model was applied to a comprehensive dataset of the network controlling the levels of dangerous substances, such as metals, pesticides, and polycyclic aromatic hydrocarbons, in the Ebro river basin. The approach was verified by comparison versus biological monitoring. The results showed that water quality in the Ebro river basin is affected by presence of micro-pollutants. The ERP approach is suitable to analyze overall trends of potential threats to freshwater ecosystems by anticipating the likely impacts from multiple substances, although it does not account for synergies among pollutants. Anyhow, the model produces a convenient indicator to search for pollutant levels of concern.


Radiomic features of cervical cancer on T2-and diffusion-weighted MRI: Prognostic value in low-volume tumors suitable for trachelectomy.
Textural features extracted from MRI potentially provide prognostic information additional to volume for influencing surgical management of cervical cancer. To identify textural features that differ between cervical tumors above and below the volume threshold of eligibility for trachelectomy and determine their value in predicting recurrence in patients with low-volume tumors. Of 378 patients with Stage1-2 cervical cancer imaged prospectively (3T, endovaginal coil), 125 had well-defined, histologically-confirmed squamous or adenocarcinomas with >100 voxels (>0.07 cm3) suitable for radiomic analysis. Regions-of-interest outlined the whole tumor on T2-W images and apparent diffusion coefficient (ADC) maps. Textural features based on grey-level co-occurrence matrices were compared (Mann-Whitney test with Bonferroni correction) between tumors greater (n = 46) or less (n = 79) than 4.19 cm3. Clustering eliminated correlated variables. Significantly different features were used to predict recurrence (regression modelling) in surgically-treated patients with low-volume tumors and compared with a model using clinico-pathological features. Textural features (Dissimilarity, Energy, ClusterProminence, ClusterShade, InverseVariance, Autocorrelation) in 6 of 10 clusters from T2-W and ADC data differed between high-volume (mean ± SD 15.3 ± 11.7 cm3) and low-volume (mean ± SD 1.3 ± 1.2 cm3) tumors. (p < 0.02). In low-volume tumors, predicting recurrence was indicated by: Dissimilarity, Energy (ADC-radiomics, AUC = 0.864); Dissimilarity, ClusterProminence, InverseVariance (T2-W-radiomics, AUC = 0.808); Volume, Depth of Invasion, LymphoVascular Space Invasion (clinico-pathological features, AUC = 0.794). Combining ADC-radiomic (but not T2-radiomic) and clinico-pathological features improved prediction of recurrence compared to the clinico-pathological model (AUC = 0.916, p = 0.006). Findings were supported by bootstrap re-sampling (n = 1000). Textural features from ADC maps and T2-W images differ between high- and low-volume tumors and potentially predict recurrence in low-volume tumors.


Preparation and characterization of electrospun rGO-poly(ester amide) conductive scaffolds.
Tissue engineering scaffolds should support tissue maturation through exposure to relevant stimuli and through successful cell infiltration. External electrical stimulation is particularly relevant for cardiac and neural applications, and requires conductive scaffolds to propagate electrical signals; cell infiltration is only possible with scaffolds that have sufficient porosity. The aim of this study was to impart conductivity and increased porosity of electrospun poly(ester amide) (PEA) scaffolds. Reduced graphene oxide (rGO) was incorporated into PEA and PEA-chitosan fibrous scaffolds, which increased scaffold conductivity and supported cardiac differentiation. The novel combination of ultrasonication and leaching of a sacrificial polymer was used to modify scaffold porosity, and resulted in an increase in pore area evaluated through image analysis. This approach aims to potentially promote tissue maturation with electrospun PEA scaffolds, by modifying both scaffold conductivity and porosity. This extends the relevance of electrospun PEA scaffolds to cardiac tissue engineering for the first time.


Anaphylaxis after intra-articular injection of orgotein. Detection of an IgE-mediated mechanism.
Orgotein, a recently introduced anti-inflammatory agent, is the generic name accepted in the U.S.A. for the drug version of copper-zinc superoxide dismutase. This metallo-enzyme is obtained from bovine liver and has a molecular weight of about 32,000. We report on a patient to whom an intra-articular injection of orgotein caused an anaphylactic reaction. An IgE-mediated mechanism was suggested by an immediate positive skin test to orgotein and by the finding of specific IgE against orgotein in the patient's serum.


X-Ray Structure of Rhodobacter Capsulatus Cytochrome bc (1): Comparison with its Mitochondrial and Chloroplast Counterparts.
Ubihydroquinone: cytochrome (cyt)c oxidoreductase, or cyt bc (1), is a widespread, membrane integral enzyme that plays a crucial role during photosynthesis and respiration. It is one of the major contributors of the electrochemical proton gradient, which is subsequently used for ATP synthesis. The simplest form of the cyt bc (1) is found in bacteria, and it contains only the three ubiquitously conserved catalytic subunits: the Fe-S protein, cyt b and cyt c (1). Here we present a preliminary X-ray structure of Rhodobacter capsulatus cyt bc (1) at 3.8 A and compare it to the available structures of its homologues from mitochondria and chloroplast. Using the bacterial enzyme structure, we highlight the structural similarities and differences that are found among the three catalytic subunits between the members of this family of enzymes. In addition, we discuss the locations of currently known critical mutations, and their implications in terms of the cyt bc (1) catalysis.


Secondary hemochromatosis due to prolonged iron ingestion.
Cases of secondary hemochromatosis caused by excessive iron ingestion are very rare. In most instances there are associated factors known to cause iron overload, such as anemia, alcoholism or the presence of the hemochromatosis allele. We report a patient who developed secondary hemochromatosis, apparently due only to excessive iron ingestion.


Structural requirements for the growth factor activity of the amino-terminal domain of urokinase.
High molecular weight urokinase-type plasminogen activator (uPA) in which proteolytic activity was inactivated (diisopropyl fluorophosphate (DFP)-uPA), its amino-terminal fragment (ATF, amino acids (aa) 1-143), and fucosylated and defucosylated growth factor domains (GFD, aa 4-43) were tested for growth-promoting effects and binding in human SaOS-2 osteosarcoma cells and U-937 lymphoma cells. DFP-uPA, ATF, and both the fucosylated and defucosylated GFD were capable of competing with 125I-ATF for binding to both SaOS-2 and U-937 cells. DFP-uPA, ATF, and fucosylated GFD were also mitogenic in SaOS-2 cells and increased cell numbers. However, defucosylated GFD was nonmitogenic in SaOS-2 cells and did not stimulate cell proliferation, even though it bound to these cells in a manner equivalent to the fucosylated GFD. A nonglycosylated high molecular weight uPA expressed and purified from Escherichia coli inhibited 125I-ATF binding to SaOS-2 cells but was also nonmitogenic. No mitogenic activity was observed in U-937 cells treated with the uPA forms capable of eliciting a mitogenic response in SaOS-2 cells. Proteolytically prepared kringle domain (aa 47-135) and low molecular weight uPA (aa 144-411) did not compete for 125I-ATF binding and did not elicit any mitogenic response in either of the cell lines tested. In addition, tissue plasminogen activator (tPA), which has been shown to be homologous to uPA in its growth factor domain and is also fucosylated, did not inhibit 125I-ATF binding nor elicit any mitogenic response. These results demonstrate that the GFD, implicated in binding to the uPA receptor, is also responsible for growth factor like activity in SaOS-2 cells and that the fucosylation at Thr18 within this domain may serve as a molecular trigger in eliciting this response.


What is "Value"? Results of a Survey of Cancer Patients and Providers.
We measured the importance patients with gastrointestinal cancer and health care providers place on treatment outcomes, quality of life, and costs. This cross-sectional survey study was conducted between June 1, 2020 and November 30, 2020. We identified surviving patients who had been treated or were anticipating treatment for pancreatic or gastric cancer at our single institution from January 1, 2000 through January 31, 2020. Surveys assessed the importance patients and providers placed on outcomes, well-being, costs, and experiences. Surveys measured how these values had changed over time. We compared the importance patients and providers place on each of the attributes of value. A total of 383 patients and 164 providers responded. Providers felt experience, emotional well-being, and costs were more important than patients themselves did (all p < 0.05). Patients more commonly reported that survival had become more important to them over time, while providers believed that emotional well-being, experience, and costs had become more important to patients (all p < 0.05). Postoperative patients ranked functional well-being as more important than preoperative patients did (p = 0.031). Patients of lower income and education levels more reported concerns of costs over the course of their care (both p < 0.05). Younger age was associated with concern for direct (r = -0.167, p = 0.004) and indirect costs (r = -0.318, p < 0.001). Although there are consistencies amongst the views of cancer patients and providers, there remain discordances in the perception of value. Patients' values differed across their treatment and survivorship course. These data demonstrate the importance of accounting for multistakeholder perspectives in assessments of value in health care.


Statistical approaches to pharmacodynamic modeling: motivations, methods, and misperceptions.
We have attempted to outline the fundamental statistical aspects of pharmacodynamic modeling. Unexpected yet substantial variability in effect in a group of similarly treated patients is the key motivation for pharmacodynamic investigations. Pharmacokinetic and/or pharmacodynamic factors may influence this variability. Residual variability in effect that persists after accounting for drug exposure indicates that further statistical modeling with pharmacodynamic factors is warranted. Factors that significantly predict interpatient variability in effect may then be employed to individualize the drug dose. In this paper we have emphasized the need to understand the properties of the effect measure and explanatory variables in terms of scale, distribution, and statistical relationship. The assumptions that underlie many types of statistical models have been discussed. The role of residual analysis has been stressed as a useful method to verify assumptions. We have described transformations and alternative regression methods that are employed when these assumptions are found to be in violation. Sequential selection procedures for the construction of multivariate models have been presented. The importance of assessing model performance has been underscored, most notably in terms of bias and precision. In summary, pharmacodynamic analyses are now commonly performed and reported in the oncologic literature. The content and format of these analyses has been variable. The goals of such analyses are to identify and describe pharmacodynamic relationships and, in many cases, to propose a statistical model. However, the appropriateness and performance of the proposed model are often difficult to judge. Table 1 displays suggestions (in a checklist format) for structuring the presentation of pharmacodynamic analyses, which reflect the topics reviewed in this paper.


Effect of Organic Selenium Supplementation on the Antioxidant Status, Immune Response, and the Relative Expression of IL-2 and IFN-γ Genes in Ewes During the Hot Season.
This study was conducted to evaluate the effects of different doses of selenium (Se) from Sel-Plex© (selenium-enriched Saccharomyces cerevisiae yeast) supplement on the antioxidant status, the antibody titers against the foot-and-mouth disease virus, and the expression of interleukin-2 (IL-2) and interferon-γ (IFN-γ) genes in ewes during the hot season. Six ewes were kept at 25 °C and received basal diet (the negative control group), and 24 ewes were kept at 38 °C for 5 h per day and received no supplement (the positive control), 0.15, 0.30, and 0.45 mg Se/kg. Ewes in the positive control had higher (P<0.001) liver enzyme activity, malondialdehyde (MDA), and cortisol levels, and lower antibody titer than the negative control. The liver enzymes' lowest (P<0.001) activities were observed in ewes receiving 0.30 and 0.45 mg Se/kg. Ewes receiving 0.30 and 0.45 mg Se/kg had lower MDA levels than other treatments. Ewes receiving 0.30 and 0.45 mg Se/kg had higher (P<0.001) total antioxidant capacity levels than those receiving 0.15 mg Se/kg and the positive control. Se-supplemented groups had lower (P<0.001) relative expression of IL-2 and higher (P<0.04) expression of IFN-γ than the positive control. The antibody titer was the same in the positive control and the group receiving 0.15 mg Se/kg. Ewes fed a diet with 0.30 and 0.45 mg Se/kg had higher (P<0.011) antibody titer than the positive control. The Se supplementation can reverse the decrease of antioxidant capacity and immune function caused by heat stress, and 0.3 mg Se/kg from Sel-Plex©is the best dose.


Construction, expression and functional analysis of anti-clenbuterol codon-optimized scFv recombinant antibody.
The construction, expression and functional analysis of codon-optimized single-chain variable fragment (coscFv) against clenbuterol (CBL) prepared from the Escherichia coli system is described. First, the ionic concentration for coscFv expression was optimized through single-factor experiments. Then, the extraction conditions of inclusion bodies were optimized, and coscFv was affinity-purified. Finally, the functional analysis of coscFv was elucidated by indirect competitive enzyme-linked immunosorbent assay (icELISA) and molecular docking. After optimizing the ionic concentration, the yield of coscFv increased from 21.69% to 23.26%. The molecular weight of coscFv was determined to be approximately 27 kDa according to the SDS-PAGE and Western blot assay. The percentage of coscFv was as high as 43.9% after the inclusion bodies were extracted, washed, and dissolved. Functional analysis indicated that the coscFv recognized CBL, and the 50% inhibition average concentration of CBL (IC50) was 4.22 ± 0.01 (n = 3) ng/mL. The binding site between coscFv and CBL consisted of Asp33H, Met34H, Ser50H, Arg52H, Tyr57H, Leu59H, Asp99H, and Tyr93L. Our study confirms that coscFv can bind with CBL through the key amino acid residues and can be used to sensitively detect CBL.