Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway.
Allergic asthma is a chronic inflammatory disease in which oxidative stress serves a pivotal role. In clinical practice, dexmedetomidine (DEX), an α‑2‑adrenergic receptor agonist, is used as a sedative. DEX exhibits antioxidative and organ‑protective properties. In a murine model of asthma, DEX has a therapeutic effect via the toll like receptor 4/NF‑кB signaling pathway; however, whether DEX can exert an antioxidative effect on asthma has yet to be elucidated. In the present study, a T helper (Th)2‑dominant murine asthma model was established. DEX treatment significantly reduced eosinophilic airway inflammation, mucus overproduction and airway hyperresponsiveness, as well as the concentrations of Th2 cytokines. The lung tissues of mice with asthma were characterized by redox imbalance (increased oxidative stress and impaired antioxidant capacity). DEX treatment alleviated this imbalance by decreasing the levels of malondialdehyde and reactive oxygen species, and increasing the levels of glutathione. Furthermore, the nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling pathway was inhibited in the lung tissues of asthmatic mice; these effects were noted in its downstream genes, heme oxygenase 1 and glutathione peroxidase 4. In mice with asthma, DEX treatment induced the expression of these antioxidant genes and the activation of Nrf2, whereas ML385 (an inhibitor of Nrf2) partially abrogated the antioxidative and therapeutic effects of DEX. To the best of our knowledge, the present study is the first to demonstrate the protective effect of DEX on Th2‑dominant asthma through the activation of the Nrf2 signaling pathway. The results suggested that the antioxidative properties of DEX could be beneficial in clinical application of DEX for the relief of asthmatic symptoms.


[Clinical case of the month. Twiddler's syndrome: report of a case].
The Twiddler's syndrome is characterized by the migration of pacemaker's leads due to rotation of the pulse generator. In our case, ventricular leads coiled in the upper side of the right atrium with stimulation of pectoralis major muscle during left decubitus lateralis position.


Performance-enhancing substances: is your adolescent patient using?
Small, but significant, numbers of adolescents use anabolic-androgenic steroids to improve their appearance or sports performance. Many more use creatine and other performance-enhancing substances with the hope of achieving these goals. This article assists primary care physicians in the office assessment of adolescents who may be using these substances, focusing on identifying adolescents at risk, asking the right questions, and helping adolescents feel comfortable discussing this sensitive topic. Providers must present themselves as credible sources of information on the topic to communicate effectively with adolescent athletes.


Frequency dependence of EPR signal intensity, 248 MHz to 1.4 GHz.
The electron paramagnetic resonance pulsed free induction decay (FID) of a degassed solution of a triaryl methyl radical, methyl tris(8-carboxy-2,2,6,6-tetramethyl(-d3)-benzo[1,2-d:4,5-d']bis(1,3)dithiol-4-yl) tripotassium salt, 0.2 mM in H2O, was measured at VHF (247.5 MHz) and L-band (1.40 GHz). The calculated and observed FID signal amplitudes (in millivolts) agreed within 1 and 6%, and the ratio of the normalized FID signals at the two frequencies agreed within 5%. The FID decay time constant was 2.7 micros at both frequencies.


Gender-Specific Independent and Combined Effects of the Progesterone and 17-Hydroxyprogesterone on Metabolic Syndrome: From the Henan Rural Cohort Study.
Although the concentrations of progesterone (P4) and 17-hydroxyprogesterone (17-OHP) have been correlated with some characteristics of metabolic syndrome (MetS), the relationships with MetS are inconclusive. Therefore, we investigated the relationship between P4 and 17-OHP with MetS. In all, the present study includes 4807 participants. Serum P4 and 17-OHP were measured through liquid chromatography-tandem mass spectrometry. Logistic regression and restricted cubic splines were used to assess the independent and combined effects of P4 and 17-OHP on MetS. After adjusting for multiple variables, the positive association of P4 with MetS was observed in postmenopausal women (Third tertiles vs First tertiles: OR = 1.49, 95% CI: 1.20-1.86) and the negative association of 17-OHP with MetS was observed in men (Third tertiles vs First tertiles: OR = 0.43, 95% CI: 0.32-0.58). Compared with the combination of low P4 and low 17-OHP, the combination of high P4 and high 17-OHP were significantly related to MetS in postmenopausal women (OR = 1.71, 95% CI: 1.18-2.48). Moreover, the combination of low P4 and high 17-OHP was negatively associated with MetS in men (OR = 0.41, 95% CI: 0.24-0.69). The association between P4 and MetS in postmenopausal women was positive, whereas 17-OHP was negatively associated with MetS in men. Additionally, their combination has a synergistic effect on MetS in postmenopausal women and an antagonistic effect on MetS in men.


Estimating outcome-specific effects in meta-analyses of multiple outcomes: A simulation study.
In meta-analysis, primary studies often include multiple, dependent effect sizes. Several methods address this dependency, such as the multivariate approach, three-level models, and the robust variance estimation (RVE) method. As for today, most simulation studies that explore the performance of these methods have focused on the estimation of the overall effect size. However, researchers are sometimes interested in obtaining separate effect size estimates for different types of outcomes. A recent simulation study (Park & Beretvas, 2019) has compared the performance of the three-level approach and the RVE method in estimating outcome-specific effects when several effect sizes are reported for different types of outcomes within studies. The goal of this paper is to extend that study by incorporating additional simulation conditions and by exploring the performance of additional models, such as the multivariate model, a three-level model that specifies different study-effects for each type of outcome, a three-level model that specifies a common study-effect for all outcomes, and separate three-level models for each type of outcome. Additionally, we also tested whether the a posteriori application of the RV correction improves the standard error estimates and the 95% confidence intervals. Results show that the application of separate three-level models for each type of outcome is the only approach that consistently gives adequate standard error estimates. Also, the a posteriori application of the RV correction results in correct 95% confidence intervals in all models, even if they are misspecified, meaning that Type I error rate is adequate when the RV correction is implemented.


Cloning, expression, purification, and characterization of Streptococcus pneumoniae IgA1 protease.
The IgA1 protease of Streptococcus pneumoniae is a Zn-metalloproteinase of 1964 amino acids that specifically cleaves the hinge region of IgA1, the predominant class of immunoglobulin present on mucosal membranes. This protease is associated to the bacterial cell surface via an N-terminal membrane anchor. Following proteolysis it is released in several forms of different molecular weight. Here, we describe the cloning, expression, and characterization of the enzymatic activity and immunogenicity of three fragments of IgA1 protease, including a large one lacking only the 103 N-terminal amino acids that constitute a typical prokaryotic signal sequence. Further, a proteolytically inactive mutant was generated by replacement of the glutamate residue with an alanine residue in the active site motif HExxH (1605-1609). This is the first report of recombinant active forms of S. pneumoniae IgA1 protease, which open the possibility of identifying specific inhibitors that could interfere with the mucosal colonization by pneumococcus. Moreover the inactive mutant could be considered as a candidate vaccine component.


Comparison of left ventricular function during interval versus steady-state exercise training in patients with chronic congestive heart failure.
This study sought to assess the safety of interval exercise training in patients with chronic congestive heart failure (CHF) with respect to left ventricular (LV) function. For effective rehabilitation in CHF, both aerobic capacity and muscle strength need to be improved. We have previously demonstrated in both coronary artery bypass surgery and patients with CHF that interval exercise training (IET) offers advantages over steady-state exercise training (SSET). However, because LV function during IET has not yet been studied, the safety of this method in CHF remains unclear. To assess LV function during IET and SSET, at the same average power output, 11 patients with stable CHF were compared with 9 stable coronary patients with minimal LV dysfunction (control group). Using first-pass radionuclide ventriculography, changes in LV function were assessed during work versus recovery phases, at temporally matched times between the fifth and sixteenth minute of IET and SSET. In CHF during IET, there were no significant variations in the parameters measured during work and/or recovery phases. During the course of both IET and SSET, there was a significant increase in LV ejection fraction (5 vs 4 U; p <0.05 each), accompanied by increased heart rate (6 vs 8 beats/min; p <0.05 each) and cardiac output (2.4 vs 1.8 L/min; p <0.01 and p <0.05). In CHF, the magnitude of change in LV ejection fraction during IET was similar to that seen in controls. Both LV ejection fraction and the clinical status in patients with CHF remained stable during IET. Because IET appears to be as safe as SSET with respect to LV function, IET can be recommended for exercise training in CHF to apply higher peripheral exercise stimuli and with no greater LV stress than during SSET.


Mechanically assisted crevice corrosion of the head-neck taper in a large head metal-on-metal total hip arthroplasty.
Taper corrosion of the head-neck junction is a potentially significant and devastating problem facing orthopedic surgeons. We present a case of a 53 year old male who presented for routine follow up for a left, large head, metal on metal total hip arthroplasty five years out. The patient was asymptomatic at the visit. X-rays at the time demonstrated a large amount of medial calcar osteolysis. Serum ion levels revealed a mildly increased cobalt and normal chromium level and hip aspiration revealed brownish fluid. At the time of revision surgery, corrosion of the head-neck taper was found with a normal appearing bearing surface leading to the diagnosis of mechanically assisted crevice corrosion of the head-neck taper with medial calcar osteolysis.


Marker-free transformation: increasing transformation frequency by the use of regeneration-promoting genes.
The generation of transgenic plants free of antibiotic resistance markers is a major challenge to plant biologists and plant breeders. Currently, there are two main strategies to achieve this goal: one approach is to excise or segregate marker genes from the host genome after regeneration of transgenic plants, and the second is based on so-called 'marker-free' transformation. Marker-free transformation has been successfully demonstrated by the use of several plant and non-plant genes that are capable of promoting explant regeneration. This approach appears not only to be effective for the generation of marker-free transgenic plants, but also has great potential to improve the transformation frequency of recalcitrant species.


Once-daily inhaled glucocorticosteroid administration in controlled asthma patients.
Inhaled glucocorticosteroids are usually administered in two equal daily doses. To simplify the method of treatment, once-daily administration has been used. However, little information regarding whether once-daily treatment can sufficiently control airway inflammation is available. We aimed to investigate whether once-daily administration of inhaled glucocorticosteroids can control airway inflammation. Twenty-four well-controlled asthma patients were enrolled in a randomized crossover trial to compare the efficacies of once-daily and twice-daily administration of inhaled glucocorticosteroids. Initially, the patients were randomly assigned to receive either once-daily or twice-daily administration for 16 weeks. After an 8-week washout period, patients who originally received twice-daily administration were assigned to once-daily administration for 16 weeks and vice versa. We assessed the changes in the forced expiratory volume in 1s, morning and evening peak expiratory flows, asthma symptoms, health-related quality of life and fractional exhaled nitric oxide levels. Patients with once-daily administration showed the same level of clinical control and lung functions as patients receiving twice-daily administration. There was no difference in the fractional exhaled nitric oxide levels between the beginning and end of the twice-daily treatment (35.69 and 33.23ppb, respectively). In contrast, the fractional exhaled nitric oxide level was significantly higher at the end of the once-daily treatment (33.87 and 39.38ppb, respectively, p< 0.001). Although once-daily administration is sufficient for clinical control of asthma, it might not control airway inflammation sufficiently.


Phase 2 Study of the PD-1 Inhibitor Serplulimab plus the Bevacizumab Biosimilar HLX04 in Patients with Previously Treated Advanced Hepatocellular Carcinoma.
Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively. Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.


Accumulation of copper in brown rice and effect of copper on rice growth and grain yield in different rice cultivars.
A pot experiment with 38 commonly cultured rice cultivars showed that the effect of Cu (100 mg kg(-1)) on rice growth, grain yield and accumulation of Cu in brown rice varied greatly with different cultivars. Although the average Cu concentration in brown rice of the 38 cultivars was significantly increased (P<0.01) compared with the control, in none of the cultivars did Cu concentration in brown rice exceed the maximum permissible limit of 10 mg Cu kg(-1). This suggests that rice grown in Cu-contaminated paddy soil (100 mg Cu kg(-1)) will not adversely affect human health through the food chain. Because of the significant negative correlation between grain weight and Cu concentration in brown rice with the soil Cu treatment, screening for cultivars with low Cu accumulation in brown rice and high grain yield for Cu-contaminated areas is feasible. The present research led to the recommendation of three such cultivars: Jiahua, Zhenxian 866, Zhe 733. The average grain yield under Cu treatment (100 mg Cu kg(-1) soil) was significantly (P<0.01) reduced compared with the control. The decreases or increases of grain yields mainly resulted from the combined effects of the panicles per pot, spikelets per panicle and filled spikelets per panicle under the soil Cu treatment. Furthermore, there were significant (r=0.869, P<0.01) positive correlations between the RC (relative changes) of spikelets per panicle and filled spikelets per panicle under the soil Cu treatment.


Investigations on metabolism of zearalenone in broilers.
Two experiments were carried out with male broilers to examine excretion kinetics of zearalenone (ZEA) and its metabolites (Exp. 1) and their occurrence in blood plasma and bile fluid (Exp.2) after a single oral dose of ZEA (approximately 6 µg/kg body weight) from naturally contaminated wheat. In addition, this ZEA bolus was administered either in absence or presence of a detoxifying agent (Mycofix® Plus, Biomin GmbH, Herzogenburg, Austria). Specimens were sampled at different times after ZEA bolus of up to 48 h. Excretion of ZEA and alpha-zearalenol as the only detectable metabolite of ZEA peaked at approximately 6.5 h after administration of the bolus. Cumulative excretion of both substances amounted approximately 58 % of ZEA intake after 48 h. Peak concentrations of ZEA and alpha-zearalenol in bile were detected in the time period of approximately 2 to 6 h after bolus whereas detection in plasma was not possible for each measurement point. Mycofix® Plus supplementation seemed to have only minor or no effects on the parameters examined.


The oxidation of some polysaccharides by the hydroxyl radical: an e.s.r. investigation.
E.s.r. Experiments employing a flow system in conjunction with the TiIII-H2O2 couple show that dextrans react with the hydroxyl radical (HO.) via indiscriminate attack (except that abstraction of hydrogen atoms from carbons which are both linked by glycosidic bonds and included in the pyranose ring may be inhibited, possibly for steric reasons). Acid- and base-catalysed transformations of first-formed radicals have been demonstrated; the suggestion that such reactions can lead to glycosidic cleavage is supported by viscosity studies which confirm the pH-dependence of radical-initiated degradation. For galacturonan and related compounds, e.s.r. results indicate that reaction with HO. proceeds preferentially via abstraction of the hydrogen on the carbon adjacent to the carboxyl group. The crucial step in the subsequent degradation pathway probably involves a pH-independent rearrangement.


Determination of the absolute configuration of the glucosinolate methyl sulfoxide group reveals a stereospecific biosynthesis of the side chain.
Glucosinolates are plant metabolites containing an anionic nitrogeneous thioglucosidic core structure and a structurally diverse amino acid-derived side chain, which after hydrolysis by thioglucohydrolases (myrosinases) afford biological active degradation products such as nitriles and isothiocyanates. Structural diversity in glucosinolates is partially due to enzymatic modifications occurring on the preformed core structure, like the recently described oxidation of sulfides to sulfoxides catalyzed by a flavin monooxygenase identified in Arabidopsis thaliana. The enzyme product, 4-methylsulfinylbutylglucosinolate, bears a chiral sulfoxide group in its side chain. We have analyzed the epimeric purity of 4-methylsulfinylbutylglucosinolate by NMR methods using a chiral lanthanide shift reagent. The absolute configuration of the sulfoxide group has been established by comparing the 1H NMR spectra of the two sulfoximine diastereomers of natural 4-methylsulfinylbutylglucosinolate. According to our data, 4-methylsulfinylbutylglucosinolate isolated from broccoli and A. thaliana is a pure epimer and its sulfoxide group has the RS configuration. The product of the A. thaliana flavin monooxygenase has these same properties demonstrating that the enzyme is stereospecific and supporting its involvement in glucosinolate side chain formation.


Microencapsulated mycelium-bound tannase from Aspergillus niger: an efficient catalyst for esterification of propyl gallate in organic solvents.
Microencapsulated Aspergillus niger with mycelium-bound tannase activity was employed to investigate the esterification of propyl gallate from gallic acid and propanol in organic solvents. The effects of various organic solvents (log P: -1.0 to 6.6) on the enzymatic reactions showed that benzene (log P: 2.0) was the suitable solvent, for which the conversion reached 26.8%. The optimum catalyst concentration and water concentration was found at 25 capsules in 10 mL of benzene and 0.04 g of water/capsule. The external mass transfer effect could be eliminated at stirring speeds of 180 rpm or higher. Both substrates 1-propanol and gallic acid had significant inhibition effects on the tannase activity. Maximum molar conversion (36.2%) was achieved with 9.1% (v/v) 1-propanol and 8 mM gallic acid and decreased with increasing amounts of substrates.


Perioperative management in microsurgery is a key element of success in reconstructive surgery. There are no uniform concepts for this in the German-speaking countries and individual schemes differ significantly from each other, as ascertained in an expert survey. In the course of the 41st Annual Conference of the German-speaking Working Group for Microsurgery (DAM) held in Munich in November 2019, concepts were evaluated and a survey was carried out and summarised as a position paper in due consideration of the scientific literature.


Sensory regulation of absence seizures in a mouse model of Gnb1 encephalopathy.
Absence seizures, manifested by spike-wave discharges (SWD) in the electroencephalogram, display synchronous reciprocal excitation between the neocortex and thalamus. Recent studies have revealed that inhibitory neurons in the reticular thalamic (RT) nucleus and excitatory thalamocortical (TC) neurons are two subcortical players in generating SWD. However, the signals that drive SWD-related activity remain elusive. Here, we show that SWD predominately occurs during wakefulness in several mouse models of absence epilepsy. In more focused studies of Gnb1 mutant mice, we found that sensory input regulates SWD. Using in vivo recording, we demonstrate that TC cells are activated prior to the onset of SWD and then inhibited during SWD. On the contrary, RT cells are slightly inhibited prior to SWD, but are strongly activated during SWD. Furthermore, chemogenetic activation of TC cells leads to the enhancement of SWD. Together, our results indicate that sensory input can regulate SWD by activating the thalamocortical pathway.


Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors.
Acute myelogenous leukaemia (AML) is an aggressive blood cancer characterized by the rapid proliferation of immature myeloid blast cells, resulting in a high mortality rate. The 5-year overall survival rate for AML patients is approximately 25%. Circa 35% of all patients carry a mutation in the FLT3 gene which have a poor prognosis. Targeting FLT3 receptor tyrosine kinase has become a treatment strategy in AML patients possessing FLT3 mutations. The most common mutations are internal tandem duplications (ITD) within exon 14 and a single nucleotide polymorphism (SNP) that leads to a point mutation in the D835 of the tyrosine kinase domain (TKD). Variations in the ITD sequence and the occurrence of other point mutations that lead to ligand-independent FLT3 receptor activation create difficulties in developing personalized therapeutic strategies to overcome observed mutation-driven drug resistance. Midostaurin and quizartinib are tyrosine kinase inhibitors (TKIs) with inhibitory efficacy against FLT3-ITD, but exhibit limited clinical impact. In this review, we focus on the structural aspects of the FLT3 receptor and correlate those mutations with receptor activation and the consequences for molecular and clinical responsiveness towards therapies targeting FLT3-ITD positive AML.


Lysine is catabolized to 2-aminoadipic acid in Penicillium chrysogenum by an omega-aminotransferase and to saccharopine by a lysine 2-ketoglutarate reductase. Characterization of the omega-aminotransferase.
The biosynthesis and catabolism of lysine in Penicillium chrysogenum is of great interest because these pathways provide 2-aminoadipic acid, a precursor of the tripeptide delta-L-2-aminoadipyl-L-cysteinyl-D-valine that is an intermediate in penicillin biosynthesis. In vivo conversion of labelled L-lysine into two different intermediates was demonstrated by HPLC analysis of the intracellular amino acid pool. L-lysine is catabolized to 2-aminoadipic acid by an omega-aminotransferase and to saccharopine by a lysine-2-ketoglutarate reductase. In lysine-containing medium both activities were expressed at high levels, but the omega-aminotransferase activity, in particular, decreased sharply when ammonium was used as the nitrogen source. The omega-aminotransferase was partially purified, and found to accept L-lysine, L-ornithine and, to a lesser extent, N-acetyl-L-lysine as amino-group donors. 2-Ketoglutarate, 2-ketoadipate and, to a lesser extent, pyruvate served as amino group acceptors. This pattern suggests that this enzyme, previously designated as a lysine-6-aminotransferase, is actually an omega-aminotransferase. When 2-ketoadipate is used as substrate, the reaction product is 2-aminoadipic acid, which contributes to the pool of this intermediate available for penicillin biosynthesis. The N-terminal end of the purified 45-kDa omega-aminotransferase was sequenced and was found to be similar to the corresponding segment of the OAT1 protein of Emericella (Aspergillus) nidulans. This information was used to clone the gene encoding this enzyme.


Changes in seizure severity and quality of life in patients with refractory partial epilepsy.
This 6-month observational, prospective, multicenter study assessed the influence of changes in seizure severity on quality of life in patients with refractory partial epilepsy. Patients (N = 262) diagnosed with partial epilepsy and receiving two antiepileptic drugs as determined by usual clinical practice were enrolled in this study. The primary endpoint was the mean seizure severity score obtained from the Seizure Severity Questionnaire. Reductions in seizure severity were detected from baseline to months 3 and 6 (P<0.0001). Improvements compared with baseline were found for several secondary measures: Hamilton Anxiety and Depression scales (P<0.0001), most Medical Outcomes Study-Sleep subscales (P<0.05), and seven subscales of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31; P<0.0005). Seizure severity correlated directly with anxiety (P<0.0001) and inversely with QOLIE-31 measures (P<0.0001). In conclusion, reducing seizure severity with appropriate medication may lead to improvement in the overall quality of life of patients with refractory partial epilepsy.


Differences in red cell behaviour between patients with Raynaud's phenomenon and systemic sclerosis and patients with Raynaud's disease.
The 'filterability' and electrophoretic mobility of erythrocytes from 42 patients with systemic sclerosis and Raynaud's phenomenon were studied and compared with the findings from 24 patients with Raynaud's disease and 26 normal controls. Red blood cells from patients with systemic sclerosis and Raynaud's phenomenon were less filterable (P less than 0.0001) and had decreased electrophoretic mobility (P less than 0.001) compared with erythrocytes from patients with Raynaud's disease and the controls. There was no significant difference between the values from the patients with Raynaud's disease and the controls. These results indicate that measurement of erythrocyte filterability and electrophoretic mobility may be useful in the differentiation of patients with Raynaud's disease who have no underlying collagen disease from those who have Raynaud's phenomenon in association with systemic sclerosis.


Identification of unobservable behavior in stochastic discrete event systems with a low number of sensors.
Dynamic discrete event systems (DDES) are systems that evolve from the asynchronous occurrence of discrete events. Their versatility has become a critical modeling tool in different applications. Finding models that define the behavior of DES is a topic that has been addressed from different approaches, depending on the type of system to be modeled and the model's objective. This article focuses on the identification of timed models for stochastic discrete event systems. The identified model includes both observable and unobservable behavior. The objective of the method is achieved through the following steps:•Identifying the sequences of events observed at different time instances during the closed-loop operation of the system (observed language),•Inferring the stochastic behavior of time between events and modeling the observable behavior as a stochastic timed Interpreted Petri Net (st-IPN),•and finally, inferring the non-observable behavior using the language projection operation between the observed language and the language generated by the st-IPN.This method has novel aspects because it uses timed events, can be applied to systems with a low number of sensors and can infer unobservable behavior for any sequence of events.


Heavy charged-particle induced lesions in rabbit cerebral cortex.
Fourteen male rabbits received single doses of 20, 40, and 80 Gy of neon irradiation with an extended Bragg peak. They were sacrificed at 1 day, 1 week, and 6 months post-irradiation. The tissue changes which showed a significant time-dose relationship were leakage of carbon particles from blood vessels, focal arachnoiditis, hemorrhage, cystic necrosis, and a total histopathologic score using a point system of grading. The focal nature of the lesions was clearly demonstrated with 2 mm thick macrotome sections. The transition zone between damaged brain and microscopically normal appearing brain was less than 1 mm and the tissue damage induced was morphologically similar to that of other radiation modalities. These findings may have important therapeutic implications for patients. The sharply demarcated boundaries of heavy charged-particle induced lesions suggest these beams will be useful for obliterating tissue in areas where it is critical that a transition from undamaged to severely damaged tissue must occur over a short distance, such as in the central nervous system.


Regulation of adrenomedullary preproenkephalin mRNA: effects of hypoglycemia during development.
To further evaluate whether transsynaptic mechanisms account for stress-induced changes in adrenomedullary preproenkephalin mRNA (ppEnk mRNA), neonatal rats were made hypoglycemic at a time when synapses are non-functional (less than 10 days postnatal age). While ppEnk mRNA in medullae from adult rats increased as much as 60-fold in this paradigm (insulin 10 U/kg), ppEnk mRNA levels in the newborn increased only 1.6-fold (insulin 20 U/kg). To evaluate whether postsynaptic cholinergic pathways of the neonatal adrenal medulla were functional, we treated 5-day-old pups with cholinergic agonists (nicotine [1 mg/kg, s.c., q 12 h] + carbachol [1.7 mumol/kg, s.c., q 12 h x 4 days]). Combined cholinergic agonist treatment augmented enkephalin prohormone and peptide levels up to 3-fold (P less than 0.05). To determine whether the blunted response to hypoglycemia in the newborn resulted from a deficiency in functional transsynaptic activity, synapses were matured using thyroid hormone pretreatment (postnatal days 2 and 3) before hypoglycemic stress. Hypoglycemia now caused a 40-fold increase in adrenomedullary ppEnk mRNA levels only in the T3/insulin treated group. To exclude other secondary effects of hypoglycemia (eg. hormonal, or insulin treatment-dependent), intracellular glycopenia was produced in the presence of secondary hyperglycemia by injecting adult rats or pups with 2-deoxyglucose (500 mg/kg). Similar to the insulin-hypoglycemia group, a large increase in adrenomedullary ppEnk mRNA resulted in the adult but not in the 5-day-old neonatal adrenal medullae. We conclude that enkephalin biosynthesis, like co-stored catecholamines, is induced by a transsynaptic process.(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-diabetic and anti-parasitic properties of a family of luminescent zinc coordination compounds based on the 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand.
We report on the formation of a triazolopyrimidine derivative ligand, 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (7-amtp), and a new family of coordination compounds based on this ligand and zinc as metal ion, synthesized by conventional routes. These materials possess different mononuclear structures, namely [ZnCl2(7-amtp)2] (1), [Zn(7-amtp)2(H2O)4](NO3)2·2(7-amtp)·6H2O (2) and [Zn(7-amtp)2(H2O)4](SO4)·1.5H2O (3) derived from the use of different zinc (II) salts, in such a way that the counterions govern the crystallization to a large extent. These compounds present and show variable luminescent properties based on ligand-centred charge transfers which have been deeply studied by Time Dependent Density Functional Theory (TD-DFT) calculations. When these compounds are transferred to solution, preserving complex entities as corroborated by NMR studies, they present interesting anti-diabetic and anti-parasitic capabilities, with a comparatively higher selectivity index than other previously reported triazolopyrimidine-based materials. The results derived from in vivo experiments conducted in mice also confirm their promising activity as anti-diabetic drug being capable of dropping glucose levels after oral administration. Therefore, these new materials may be considered as excellent candidates to be further investigated in the field of luminescent coordination compounds with biomedical applications.


Isolation and anticancer, anthelminthic, and antiviral (HIV) activity of acylphloroglucinols, and regioselective synthesis of empetrifranzinans from Hypericum roeperianum.
From the ethno-medicinally used leaves of Hypericum roeperianum we isolated a new tricyclic acylphloroglucinol (1), a new tetracyclic acylphloroglucinol (2), and a new prenylated bicyclic acylphloroglucinol (3) together with four known prenylated (4-7) and three known tetracyclic acylphloroglucinol derivatives (8-10). Structure elucidation was based on UV, IR, [α]D(25), 1D- and 2D-NMR experiments. Furthermore, empetrifranzinans A (8) and C (9) were synthesized regioselectively in only two steps. The isolated compounds were evaluated for their cytotoxicity against PC-3 and HT-29 cancer cell lines as well as antibacterial and anthelmintic activities. They were also tested in cell-based assays for cytotoxicity against MT-4 cells and for anti-HIV activity in infected MT-4 cells. Significant anthelmintic activity against Caenorhabditis elegans was exhibited by compound 7 (3-geranyl-1-(2'-methylbutanoyl)-phloroglucinol), which might provide a new lead.


Autoimmune hemolytic anemia and a further example of autoanti-Kpb.
A 65-year-old Caucasian man with myelodysplasia was admitted with autoimmune hemolytic anemia and a Hb of 5.6 g/dL. The patient's serum contained anti-K; the DAT on the patient's RBCs reacted 3+ with anti-IgG and 3+ with anti-C3d. K- RBC units were transfused, but there was no sustained increase in Hb level. The samples were referred to the reference laboratory of the National Blood Service. The DAT results remained the same, with anti-K detected only in the serum. An eluate prepared from the patient's DAT-positive RBCs revealed anti-Kp(b) specificity. This study reports an unusual case of autoanti-Kp(b), which is different from previously published cases in that no free anti-Kp(b) was detectable in the serum.


Assessment of surgical trainees' quality of knot-tying.
This study aimed to assess surgical trainees' knot tying technique and determine the type and security of knots created. Twenty-five participants were requested to tie 40 knots each, using Vicryl 2-0 and Prolene 2-0 sutures. With each suture material, the participants tied: in series 1, 4 knots as they would normally do during surgery; in series 2, 4 knots with 3 throws, 4 knots with 4 throws, 4 knots with 5 throws, and 4 knots with 6 throws. All knots were tested for tensile strength using a tensiometer. Knots with tensile strength of less than 5 N were considered dangerous. Of the 25 participants, 2 created square knots consistently, 2 created a mixture of square and slip knots, and 21 created only slip knots. Square knots accounted for only 12.8% of all the knots. The incidence of knot slipping under tension was significantly lower with square knots (p < 0.001). Square knots had significantly higher tensile strength than slip knots (p < 0.001). For Vicryl, 4-throw square knots were superior to 6-throw slip knots (p < 0.001). For Prolene, 3-throw square knots were superior to 6-throw slip knots (p = 0.035). Some 12.6% of Vicryl knots and 5.6% of Prolene knots were dangerous and all of these were slip knots with up to 6 throws. Three out of 12 participants who thought they had created square knots actually created square knots and the rest produced slip knots. The participants' surgical experience did not have any correlation with their knot security (r = -0.044, p = 0.833). Knot tying is often executed with technical errors resulting in slip knots with less than optimal security and high incidence of dangerous knots. Tensiometry testing could be used as an objective assessment tool for knot-tying competency for surgical trainees.


Practice Guidelines for Parkinson's disease.
'Practice Guidelines (PG) or treatment guidelines' are not infallible guidelines but tools with which to support a clinical decision, i.e. one factor when making a clinical decision. When making a clinical decision, medical practice is determined by taking into consideration PG, a patient's preferences, and a country's social and healthcare systems. Even if a PG provides a treatment method based on a high-level of evidence, the method simply represents a mean result obtained from past clinical studies, which are not always uniformly applicable to all patients. When consulting a PG, it is advisable to know in advance what group/society/organization prepared it, the purpose of its preparation, and the developmental method, including social equity, whether healthcare costs are assumed in the PG or whether the pharmaceutical industry had substantial involvement in its development. Thus, PGs need to be developed according to the actual conditions in a country or institution. As to the questions whose answers are not provided in a PG, these issues have to be defined and assessed through a literature search. This is the so-called implementation of Evidence-Based Medicine (EBM). The concepts of EBM further require the provision of better evidence. A PG is always fated to be out of date by the time it is published because new evidence is continually being published. It is therefore, always necessary to search for the most up to date evidence available.


New onset heart failure--Clinical characteristics and short-term mortality. A RICA (Spanish registry of acute heart failure) study.
Heart failure (HF) is a growing global epidemic. The main study aims is to evaluate the differences between new-onset and chronic-decompensated HF patients. Secondary objectives related only to new-onset HF patients include the role of left ventricular ejection fraction (LVEF) and mid-term mortality related risk factors We analyzed 2190 patients hospitalized for acute HF. We compare the 683 patients with a new-onset HF episode with the rest. Restricting the analysis to the new-onset HF patients, we also compare patients with preserved LVEF (EF>50%) with those with reduced LVEF, and analyze the factors associated with three-month mortality. A total of 683 (31.2%) patients fulfill the criteria for "new-onset HF". These patients are older, their HF is more often related to hypertension, show higher blood pressure and heart rate values upon admission, and present with less global and disease-specific comorbidity and better baseline overall functional status. New-onset HF is more often characterized by preserved LVEF, milder baseline NYHA class and lower plasma natriuretic peptide values. After 3 months; 33 (5.2%) new-onset HF patients had died (p<0.001). Cox multivariate analysis showed a correlation between mortality and older age (hazard ratio - HR - 1.08), higher global comorbidity (HR 1.20) and lesser prescription of beta-blockers at discharge (HR 0.34). LVEF was unrelated to mortality. New-onset HF patients show a clinical profile different to that of chronic-decompensated patients. For this subset of acute HF patients older age, higher comorbidity and beta-blocker nonprescription predict a higher risk of mid-term post-discharge mortality.


Improving emergency call detection of Out-of-Hospital Cardiac Arrests in the Greater Paris area: Efficiency of a global system with a new method of detection.
The detection of cardiac arrests by dispatchers allows telephone-assisted cardiopulmonary resuscitation (t-CPR) and improves Out-of-Hospital Cardiac Arrest (OHCA) survival. To enhance the OHCA detection rate, in 2012, the Paris Fire Brigade dispatch center created an original technique called "Hand On Belly" (HoB). The new algorithm that resulted has become a central point in a broader program for dispatch-assisted cardiac arrests. This is a repeated cross-sectional study with retrospective data of four 15-day call samples recorded from 2012 to 2018. We included all calls from OHCAs cared for by Basic Life Support (BLS) teams and excluded calls where the dispatcher was not in contact directly with a witness. The primary endpoint was the successful detection of an OHCA by the dispatcher; the secondary endpoints were successful t-CPR and measurements of the different time intervals related to the call. Logistic regressions were performed to assess parameters associated with detecting OHCAs and initiating t-CPR. From 2012 to 2018, among the detectable OCHAs, the proportion correctly identified increased from 54% to 93%; the rate of t-CPRs from 51% to 84%. OHCA detection and t-CPR initiation were both associated with HoB breathing assessments (adjustedOR: 89, 95%CI: 31-299, and adjustedOR: 11.2, 95%CI: 1.4-149, respectively). Over the study period, the times to answering calls and the time to sending BLS teams were shorter than those recommended by international guidelines; however, the times to OHCA recognition and starting t-CPR delivery were longer. The HoB effectively facilitated OHCA detection in our system, which has achieved very high performance levels.


Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat.
[125I]labeled NGF injected in very small quantities into the frontal or dorsal anterior occipital cortex of adult rats, was specifically taken up and transported retrogradely to large, presumably cholinergic neurons in the nucleus basalis region (lateral preoptic nucleus, anterior lateral hypothalamic nucleus, substantia innominata, ventral globus pallidus and internal capsule), as revealed by light microscopic autoradiography. Cells projecting to the injection site in the frontal cortex were localized ipsilaterally in the more caudal parts of the nucleus basalis region, whereas cells projecting to the dorsal anterior occipital cortex could be found throughout the entire extent of the nucleus basalis and also in the vertical and horizontal limb of the nucleus of the diagonal band of Broca. Other nuclei known to project to the cortex (locus coeruleus, substantia nigra, nucleus raphe, thalamus) were consistently found to be unlabeled. In contrast to [125I]NGF, injection of [125I]cytochrome C failed to label any cell bodies in the basal forebrain nuclei by retrograde transport. This high selectivity for uptake and retrograde transport of NGF indicates the presence of membrane receptors for NGF or a closely related molecule on these cholinergic neurons of the basal forebrain innervating the cerebral cortex.


Influence of temperature on slow flow in populations of regenerating axons with different elongation velocities.
The slow intra-axonal transport mechanisms may be subdivided into 4 elementary processes: (a) protein synthesis; (b) release of the slow material from the cell body; (c) transport of the molecules along the axon; and (d) deposition of the material from the moving phase into the immobile axonal constituents. These 4 components of the slow flow mechanisms are differently affected by temperature and react differently to axonal regeneration. They have been studied at temperatures ranging from 10 to 35 degrees C, in 3 different populations of regenerating C-fibers of the garfish olfactory nerve. These 3 classes of axons have very different elongation properties as determined by elongation rates ranging from a minimum of 0.3 mm/day at 14 degrees C to a maximum of 12.4 mm/day at 35 degrees C. From this study several properties of the slow intra-axonal transport mechanism can be underlined: (a) in regenerating nerves the rate of slow flow is multiplied by a factor of 3.3 as compared to the rate characteristic of an intact nerve. A similar increase was measured in every regenerating phase regardless of the specific elongation velocity of the growing axons. This accelerated rate of slow flow has been measured previously in degenerating axons detached from their perikarya: therefore the rate increase appears to be triggered by the injury rather than the needs of the neuron; (b) protein synthesis represents one of the main steps controlling axonal elongation. Neurons with the most active level of protein synthesis grow with the highest elongation velocity; (c) the somal releasing times decrease exponentially with temperature but are identical to the values measured in intact neurons; (d) finally the height of the slow flow peak decreases exponentially as a function of the distance, as seen previously in intact nerves, but a significantly larger amount of radioactivity reaches the end of the nerve. It can be concluded that slow flow is intimately linked with the regeneration process. The rate of slow flow and more specifically of Scb represents the upper limit that can be reached by the elongation velocities of regenerating fibers when all the growth conditions are maximal. When the regenerating conditions are not at their peak, the axonal elongation proceeds at velocities which can be very significantly slower than the rate of slow flow and might be determined by the level of protein synthesis in the perikarya. Axonal elongation, however, can never proceed at a rate faster than slow flow.


The neural underpinnings of cognitive flexibility and their disruption in psychotic illness.
Schizophrenia (SZ) has long been associated with a variety of cognitive deficits, including reduced cognitive flexibility. More recent findings, however, point to tremendous inter-individual variability among patients on measures of cognitive flexibility/set-shifting. With an eye toward shedding light on potential sources of variability in set-shifting abilities among SZ patients, I examine the neural substrates of underlying probabilistic reversal learning (PRL) - a paradigmatic measure of cognitive flexibility - as well as neuromodulatory influences upon these systems. Finally, I report on behavioral and neuroimaging studies of PRL in SZ patients, discussing the potentially influences of illness profile and antipsychotic medications on cognitive flexibility in SZ.


Mobile health technologies for the monitoring of menstrual cycle: A systematic review of online stores in Brazil.
To perform a systematic review of available mHealth apps for menstrual cycle monitoring in Brazil. A search for menstrual cycle mHealth apps from the Google Play Store and AppStore in Brazil was performed by two independent reviewers on October 2020, and the quality of eligible mHealth apps was assessed using the Mobile App Rating Scale (MARS). Our review identified 2400 potentially relevant mHealth apps, of which 56 were eligible for inclusion. The majority of the apps offered tools to track menstruation symptoms (63%) and educational content for users (32%). The mean ( ±SD) MARS app quality score for the 28 evaluated apps in Android was 3.5 ± 0.6 on a 0-5 scale. For the 28 evaluated apps in iOS, the mean app quality score was 3.8 ± 0.4. Most of the included apps, for both systems, scored average for credibility, user interface, and engagement. The majority of available tools in Brazil are of moderate quality and limited functionality for menstrual cycle monitoring. This study highlights the top three mHealth apps available on each online store for individuals seeking menstrual cycle monitoring options.


Whole Genome Sequencing of SARS-CoV-2: Adapting Illumina Protocols for Quick and Accurate Outbreak Investigation during a Pandemic.
The COVID-19 pandemic has spread very fast around the world. A few days after the first detected case in South Africa, an infection started in a large hospital outbreak in Durban, KwaZulu-Natal (KZN). Phylogenetic analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes can be used to trace the path of transmission within a hospital. It can also identify the source of the outbreak and provide lessons to improve infection prevention and control strategies. This manuscript outlines the obstacles encountered in order to genotype SARS-CoV-2 in near-real time during an urgent outbreak investigation. This included problems with the length of the original genotyping protocol, unavailability of reagents, and sample degradation and storage. Despite this, three different library preparation methods for Illumina sequencing were set up, and the hands-on library preparation time was decreased from twelve to three hours, which enabled the outbreak investigation to be completed in just a few weeks. Furthermore, the new protocols increased the success rate of sequencing whole viral genomes. A simple bioinformatics workflow for the assembly of high-quality genomes in near-real time was also fine-tuned. In order to allow other laboratories to learn from our experience, all of the library preparation and bioinformatics protocols are publicly available at protocols.io and distributed to other laboratories of the Network for Genomics Surveillance in South Africa (NGS-SA) consortium.


Clinical effect of cerebrovascular atherosclerosis on cognition in Alzheimer's disease.
The association between cerebrovascular atherosclerosis and Alzheimer's disease (AD) has been examined in many cross-sectional studies; however, there are few data regarding the role of cerebrovascular atherosclerosis on the longitudinal course of cognitive decline in AD. The aim of this study was to examine the progression of cognitive function in AD patients with cerebrovascular atherosclerosis compared to those without atherosclerosis over a two-year period. Forty-seven AD patients with cerebrovascular atherosclerosis and 81 AD patients without atherosclerosis were assessed for cognitive function at the time of diagnosis and again at follow-up after two years. The cognitive functions were evaluated by neuropsychological tests including mini-mental state examination (MMSE) and clinical dementia scale (CDR). Repeated-measures multivariate analyses showed that there was a significant group-by-time interactions for the temporal changes of the MMSE and CDR between the two groups. The group-by-time interactions remained significant when the atherosclerotic patients were sub-classified into either an extracranial stenosis (EC) group or an intracranial stenosis(IC) group. Comparing either the EC or IC group with the non-atherosclerosis group, there were no main effects by time or group alone, but there were significant group-by-time interactions for the MMSE and CDR. Cognitive function worsened more in terms of progressive impairment in AD patients with cerebrovascular atherosclerosis compared to AD patients without cerebrovascular atherosclerosis, regardless of whether the atherosclerosis was extracranial or intracranial.


Perceptions of cancer as a death sentence: Tracking trends in public perceptions from 2008 to 2017.
There has been steady progress in reducing cancer mortality in the United States; however, this progress hasn't been evenly distributed across regions. This paper assesses trends in cancer mortality salience (CMS), that is, agreeing that getting cancer is a death sentence, over time in the United States and examines correlates of CMS. Data from three administrations of the Health Information National Trends Survey (HINTS), gathered in 2008, 2013, and 2017, were merged, resulting in a total sample of 10,063 respondents. Trends in changes in CMS over time were examined as well as maps of the distribution of CMS in the United States. A logistic regression model was conducted, regressing CMS on a set of sociodemographic, psychological, health-related, and environmental predictors. The aggregated percentage of US adults who agreed with the CMS statement changed over time and was modified by age. Geographic distribution of agreement with CMS was inconsistent across the United States. In the adjusted logistic model, perceived health (worse health), cancer prevention, fatalism, and confusion, and cancer status (no cancer) were all significantly associated with CMS. There was also a significant interaction between survey year and age. Despite recent information that cancer mortality rates are decreasing, most US adults still see cancer as a death sentence and this is especially an issue in certain subgroups. These findings have ramifications for groups of people who may be at risk for developing cancer given their attitudes and beliefs that there isn't much they can do to prevent or control it.


Relationship between sleep duration and TV time with cardiometabolic risk in adolescents.
To verify the association between sleep duration and television time with cardiometabolic risk and the moderating role of age, gender, and skin color/ethnicity in this relationship among adolescents. Cross-sectional study with 1411 adolescents (800 girls) aged 10 to 17 years. Television time, sleep duration, age, gender, and skin color/ethnicity were obtained by self-reported questionnaire. Cardiometabolic risk was evaluated using the continuous metabolic risk score, by the sum of the standard z-score values for each risk factor: high-density lipoprotein cholesterol, triglycerides, glycemia, cardiorespiratory fitness, systolic blood pressure, and waist circumference. Generalized linear regression models were used. There was an association between television time and cardiometabolic risk (β, 0.002; 95% CI, 0.001; 0.003). Short sleep duration (β, 0.422; 95% CI, 0.012; 0.833) was positively associated with cardiometabolic risk. Additionally, age moderated the relationship between television time and cardiometabolic risk (β, - 0.009; 95% CI, - 0.002; - 0.001), suggesting that this relationship was stronger at ages 11 and 13 years (β, 0.004; 95% CI, 0.001; 0.006) compared to 13 to 15 years (β, 0.002; 95% CI, 0.001; 0.004). No association was found in older adolescents (β, 0.001; 95% CI, - 0.002; 0.002). Television time and sleep duration are associated with cardiometabolic risk; adolescents with short sleep have higher cardiometabolic risk. In addition, age plays a moderating role in the relationship between TV time and cardiometabolic risk, indicating that in younger adolescents the relationship is stronger compared to older ones.


Identification of nonlinear model of ankle joint dynamics during electrical stimulation of soleus.
The mechanical impedance of the ankle joint was estimated in two conditions: during submaximal surface electrical stimulation of the soleus muscle, and with no stimulation applied. Both neurologically intact (n = 5) and spinal cord injured subjects (n = 4) were used. The mechanical impedance was measured by applying angular step and constant velocity (13-100 degrees s-1) perturbations at 10 degrees to the ankle and measuring the resulting changes in torque. A five-element lumped model consisting of an inertial element, a parallel elastic element, and an elastic element in series with a viscous element and a pure tension generator produced a good fit for predicting the compliance characteristics of the ankle for both the relaxed and stimulated conditions. The elastic elements were piecewise linear with different values for the dorsiflexion and plantarflexion directions. The viscous element was velocity-dependent and it decreased in value as the velocity increased. The average torque error between the measured and model's response during soleus stimulation was 10.56% for the dorsiflexed and 11.93% for the plantarflexed perturbations. However, the average error was skewed by several subjects who had excessive error, due to volitional intervention or flexor withdrawal reflex. The average model error for the perturbations without stimulation was 7.12% for dorsiflexed and 5.58% for plantarflexed perturbations.


Accuracy between virtual surgical planning and actual outcomes in orthognathic surgery by iterative closest point algorithm and color maps: A retrospective cohort study.
To evaluate the accuracy between actual outcomes and virtual surgical planning (VSP) in orthognathic surgery regarding the use of three-dimensional (3D) surface models for registration using iterative closest point (ICP) algorithm and generated color maps. Construction of planning and postoperative 3D models in STL files format (M0 and M1, respectively) from CBCT of 25 subjects who had been submitted to bimaxillary orthognathic surgery was performed. M0 and M1 were sent to Geomagic software in semi-automatic alignment surface mesh order of M0 and M1 for registration using ICP algorithm to calculate mean deviation (MD, MD+, MD-, SD) and root mean square (RMS - 3D Error). Color maps were generated to assess qualitative congruence between M0 and M1. From deviation analysis, 3D Error was defined as accuracy measurement. To assess the reproducibility, the workflow was performed by two evaluators multiple times. t-tests were used to assess whether all means of MD, MD+, MD-, SD and 3D Error values would be ≤ - 2 mm and ≥ 2 mm. High intra and inter evaluators correlation were found, supporting the reproducibility of the workflow. t-tests proved that all MDs and 3D Error values were > - 2 mm and < 2 mm. 3D error mean was within the standards of clinical success lower than 2 mm. ICP algorithm provided a reproducible method of alignment between 3D models and generated color maps to evaluate 3D congruence but did not answer all methodological parameters regarding the assessment of accuracy in orthognathic surgery.


A comparison of serum albumin, age and the Sheffield prognostic index in the prediction of surgical complications.
The ability of the Sheffield prognostic index (S.P.I) to predict postoperative complications and death in patients undergoing gastrointestinal surgery has been compared with that of serum albumin alone, and with age. Both the S.P.I. and age were better at predicting complications than serum albumin. Serum albumin was the best predictor of death.


An increased prothrombin time-international normalized ratio in patients with acute type A aortic dissection: contributing factors and their influence on outcomes.
We investigated factors contributing to coagulopathy in patients with acute type A aortic dissection (ATAAD) and coagulopathy's influence on patient outcomes. We grouped 420 patients who underwent ATAAD repair-none under anticoagulation therapy or with liver disease-by the prothrombin time-international normalized ratio (PT-INR) at admission: < 1.2 (no coagulopathy, n = 371), 1.2-1.49 (mild coagulopathy, n = 33), or ≥ 1.5 (severe coagulopathy, n = 16). We then compared the clinical presentation, dissection morphology, and outcomes among the groups. We assessed the PT-INR in relation to the preoperative hemodynamics and searched for factors predictive of a PT-INR ≥ 1.2. The transfusion volume and operation time were increased among patients with coagulopathy (P < 0.05). The in-hospital mortality (15.2-37.5% vs. 5.1%, P < 0.001) and 5-year survival (61.1-74.4% vs. 87.6%) were relatively poor for these patients. The median PT-INR was 1.03 (0.97-1.1) for patients with stable hemodynamics (n = 318), 1.11 (1.02-1.21) for those in shock (blood pressure < 80 mmHg) not given cardiopulmonary resuscitation (CPR) (n = 81), and 1.1 (1.0-1.54) for those in shock given CPR (n = 21) (P < 0.001). A multivariable analysis identified shock (P < 0.001), a partially thrombosed false lumen (P = 0.006), and mesenteric malperfusion (P = 0.016) as predictive variables. Shock, a partially thrombosed false lumen, and mesenteric malperfusion appear to be predictive of dissection-related coagulopathy, which influences outcomes negatively.


Diagnosis and surgical outcomes of intraparotid facial nerve schwannoma showing normal facial nerve function.
The findings of intraparotid facial nerve schwannoma (FNS) using preoperative diagnostic tools, including ultrasonography (US)-guided fine needle aspiration biopsy, computed tomography (CT) scan, and magnetic resonance imaging (MRI), were analyzed to determine if there are any useful findings that might suggest the presence of a lesion. Treatment guidelines are suggested. The medical records of 15 patients who were diagnosed with an intraparotid FNS were retrospectively analyzed. US and CT scans provide clinicians with only limited information; gadolinium enhanced T1-weighted images from MRI provide more specific findings. Tumors could be removed successfully with surgical exploration, preserving facial nerve function at the same time. Gadolinium-enhanced T1-weighted MRI showed more characteristic findings for the diagnosis of intraparotid FNS. Intraparotid FNS without facial palsy can be diagnosed with MRI preoperatively, and surgical exploration is a suitable treatment modality which can remove the tumor and preserve facial nerve function.


Splinting Open Tray Impression Copings Using Long Shank Carbide Burs during Definitive Impression: A Dental Technique.
To splint implant impression copings using long shank carbide burs for definitive implant impressions. The accurate transfer of the orientation recorded by impression copings to a definitive cast is a challenging step in implant prosthodontics. For achieving a passive fit from the mouth to the cast may include some discrepancies. Traditional methods of splinting can be time-consuming and troublesome to handle. This article describes a technique by using long shank carbide burs for splinting implant impression copings. The favored implant splinting, evidence was inconclusive, and the data supporting splint pickup was the better performing technique, especially with an increased number of implants. This technique causes minimal discomfort and is straightforward when compared to other techniques.


Long-term ocular hypotensive effect of levobunolol: results of a one-year study.
Data for the first 12 months are reported for an ongoing, multicentre, clinical study comparing the long-term, ocular hypotensive efficacy and safety of topical levobunolol (0.5% and 1%) and timolol (0.5%). This study was a double-masked trial testing 88 patients with chronic open angle glaucoma or ocular hypertension. During the 12-month period drops were instilled twice daily into both eyes after a washout of prestudy ocular hypotensive medication. The effect of the three treatments in reducing intraocular pressure (IOP) was similar. Mean IOP reductions over the 12 months averaged 7.2 mmHg for the 0.5% levobunolol group, 6.2 mmHg for the 1% levobunolol group, and 6.0 mmHg for the timolol group. Decreases in mean heart rate of up to 5 beats per minute were observed in the 0.5% levobunolol group, up to 8 beats per minute in the 1% levobunolol group, and up to 4 beats per minute in the timolol group. Several patients were removed from the study owing to side effects possibly related to levobunolol treatment.


Analysis of parametric and non-parametric option pricing models.
In this paper, a closed-form analytical solution of option price under the Bi-Heston model is derived. Through empirical analysis, the advantages and disadvantages of the parametric pricing model are compared and analysed with those of the non-parametric model. The analysis shows that: (1) the parametric pricing model significantly outperforms the machine learning model in terms of in-sample pricing effects, while the Bi-Heston model slightly outperforms the Heston model. (2) In terms of out-of-sample pricing, the machine learning model is inferior to the parametric model for call options, while the Bi-Heston model is significantly better than the other two models for put options, and the other two models are similar. (3) In the robustness analysis of the three pricing models, the machine learning model shows strong instability, while the Bi-Heston model shows a more stable side.


Decomposed liver has a significantly adverse affect on the development rate of the blowfly Calliphora vicina.
The development rate of immature Calliphora vicina reared on decomposed liver was significantly slower, by as much as 30 h (55.4 % of total development time) for mid-sized larvae, and 71 h (35.0 %) and 58 h (14.6 %) if using times to the onset of pupariation and eclosion, respectively, than those of immatures that developed on fresh whole pig's liver. Development rates of larvae reared on decomposed liver were also slower than those of larvae reared on minced pig's liver and frozen/thawed pig's liver. These results suggest that any estimate of minimum post-mortem interval may result in an over estimate if the blowflies used were developing on an already decomposed body.


Modulation of oxidative neurometabolism in ischemia/reperfusion by nitrite.
Nitrite has been viewed essentially as an inert metabolic endpoint of nitric oxide (•NO). However, under certain conditions, nitrite can be a source of •NO. In the brain, this alternative source of •NO production independent of nitric oxide synthase activity may be particularly relevant in ischemia/reperfusion (I/R), where low oxygen availability limits enzymatic production of •NO. Notably, in vivo concentration of nitrite can be easily increased with diet, through the ingestion of nitrate-rich foods, opening the window for a therapeutic intervention based on diet. Considering the modulation of mitochondrial respiration by •NO, we have hypothesized that the protective action of nitrite in I/R may also result from modulation of mitochondrial function. We used high-resolution respirometry to evaluate the effects of nitrite in two in vitro models of I/R. In both cases, an increase in oxygen flux was observed following reoxygenation, a phenomenon that has been coined "oxidative burst". The amplitude of this "oxidative burst" was decreased by nitrite in a concentration-dependent manner. Additionally, a pilot in vivo study in which animals received a nitrate-rich diet as a strategy to increase circulating and tissue levels of nitrite also revealed that the "oxidative burst" was decreased in the nitrate-treated animals. These results may provide mechanistic support to the observation of a protective effect of nitrite in situations of brain ischemia.


Effectiveness of Decision Aid in Men with Localized Prostate Cancer: a Multicenter Randomized Controlled Trial at Tertiary Referral Hospitals in an Asia Pacific Country.
There are several treatment options for localized prostate cancer with very similar outcome but vary in terms of technique and side effect profiles and risks. Considering the potential difficulty in choosing the best treatment, a patient decision aid (PDA) is used to help patients in their decision-making process. However, the use and applicability of PDA in a country in Asia Pacific region like Malaysia is still unknown. This study aims to evaluate the effectiveness of a PDA modified to the local context in improving patients' knowledge, decisional conflict, and preparation for decision making among men with localized prostate cancer. Sixty patients with localized prostate cancer were randomly assigned to control and intervention groups. A self-administered questionnaire, which evaluate the knowledge on prostate cancer (23 items), decisional conflict (10 items) and preparation for decision-making (10 items), was given to all participants at pre- and post-intervention. Data were analyzed using independent T test and paired T test. The intervention group showed significant improvement in knowledge (p = 0.02) and decisional conflict (p = 0.01) from baseline. However, when compared between the control and intervention groups, there were no significant differences at baseline and post-intervention on knowledge, decisional conflict and preparation for decision-making. A PDA on treatment options of localized prostate cancer modified to the local context in an Asia Pacific country improved patients' knowledge and decisional conflict but did not have significant impact on the preparation for decision-making. The study was also registered under the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12614000668606 registered on 25/06/2014.


Changes in Hemostasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status.
Procoagulant status was modeled in outbred female mice by single injection of cisplatin in a maximum tolerated dose and hemostasis parameters monitored over 30 days by methods of coagulogram and low-frequency piezothromboelastography (global test). Monitoring revealed waveform changes in the hemostatic potential: the structural and chronometric hypercoagulation recorded starting from the first day and attaining its maximum on days 5-7 was followed by hypocoagulation and returned to normocoagulation on day 30. This pattern reflects prolonged effect of cisplatin: formation of severe dysfunction of the endothelium providing the main anticoagulant pool of hemostasis (day 1) aggravated by disturbances of the plastic functions of the liver (days 15-20), and recovery (days 20-30).


Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients.
We assessed the prevalence and clinical features of genital skin changes in men after allogeneic hematopoietic stem cell transplantation (HSCT) and evaluated the correlation between genital chronic graft-versus-host disease (cGVHD) and other manifestations of cGVHD as well as sexual issues. In a cross-sectional cohort study, 155 male recipients alive 1 year or more after HSCT were assessed during their annual follow-up evaluation. Correlation between genital skin changes and other cGVHD manifestations was evaluated, and post-transplantation sexual contentment and sexual functioning were assessed by 2 self-assessment questionnaires, including the 5-item version of the International Index of Erectile Function (IIEF-5) and the modified Brief Sexual Symptom Checklist (mBSSC). Median time between HSCT and genital examination was 5.9 years (range, 1 to 30.3 years). Thirty-one of 155 patients (20%) presented with genital skin changes. Twenty-one of those (13%) presented clinically inflammatory genital skin changes considered as genital cGVHD: 12 had inflammatory (noninfectious) balanoposthitis, 6 had lichen sclerosis-like lesions, 5 had phimosis, and 2 patients had more than 1 feature. Patients with inflammatory genital skin changes had a significantly higher coincidence of oral (P < .0001), ocular (P < .002), and/or cutaneous cGVHD (P < .026) when compared with patients without genital lesions. The rate of IIEF-5 questionnaire response was 59% (91 of 155). Among them, 67% reported erectile dysfunction. Erectile dysfunction was significantly more frequent in patients with genital cGVHD (P = .0075). Seventy-five of 155 patients (48%) answered the mBSSC questionnaire. Only 40% of them reported sexual contentment. Genital skin changes in male recipients after allogeneic HSCT are frequent and seem to be an under-reported relevant late effect. Inflammatory genital skin changes can be considered as a form of genital cGVHD often associated with manifestations of extragenital mucocutaneous cGVHD.


The Virus and the Atmosphere: Reviewing the Trajectory of Human History.
The article compares the COVID-19 pandemic and climate change in terms of natural characteristics of the crisis triggers as well as of socio-political responses.


Ischemic and Bleeding Events After First Major Bleeding Event in Patients Undergoing Coronary Stent Implantation.
There is a scarcity of data on ischemic and bleeding events in patients who experienced major bleeding after percutaneous coronary intervention (PCI). Moreover, there also is a shortage of data on comparative outcomes between patients with and without interruption of an antithrombotic drug after major bleeding. We evaluated the incidence and prognostic impacts of ischemic (myocardial infarction or ischemic stroke) and bleeding (Bleeding Academic Research Consortium type 3 or 5) events after major bleeding in 12,691 consecutive patients who underwent first PCI in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI registry cohort-3. In the entire cohort, incidence of the first ischemic event and bleeding event was 2.3 per 100 person-years and 3.8 per 100 person-years, respectively. Major bleeding (Bleeding Academic Research Consortium type 3) occurred in 2,142 patients during a median follow-up of 5.7 years. In patients with major bleeding, cumulative 30-day, 1-year, and 5-year incidence of an ischemic event was 2.6%, 4.8%, and 13.2% (3.2 per 100 person-years), respectively, whereas that of a bleeding event was 6.3%, 16.1%, and 29.2% (8.5 per 100 person-years), respectively. Ischemic and bleeding events were independently associated with mortality (hazard ratio 2.36, 95% confidence interval 1.87 to 2.96, p <0.001, and hazard ratio 2.85, 95% confidence interval 2.42 to 3.37, p <0.001). The cumulative 180-day incidence of ischemic and bleeding events was not significantly different between patients with and without interruption of an antithrombotic drug in patients with major bleeding. In conclusion, the incidence of an ischemic event after the first major bleeding was approximately 1/3 of that of recurrent major bleeding, and the rates of ischemic and bleeding events after the first major bleeding were higher than the rates of first events in the general PCI population. Both ischemic events and bleeding events were strongly associated with subsequent mortality. The incidence of ischemic and recurrent bleeding events was not different between patients with and without interruption of an antithrombotic drug.


Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.
Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.


Searching for an assessment instrument to determine temporomandibular disorder pain profiles for the purposes of primary health care.
The objective was to study the utility of the graded chronic pain (GCP) scale of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) for the purpose of recognizing TMD pain profiles in primary health care. The GCP scale was used to gather data from 93 consecutive TMD patients seeking treatment in a primary health care setting. The GCP data were compared with pain profiles assessed by scales similar to the more complicated multidimensional pain inventory (MPI). The scales used were able to produce the similar 'dysfunctional profiles' in the TMD patients as the original MPI scale in the sample of chronic pain patients. Also, the original MPI profiles of 'adaptive copers' and 'interpersonally distressed' were produced with distinctive features. The GCP grades distributed almost identically among the subgroups produced by the pain profiles. Most grade I patients were classified as adaptive copers (82--86%), most grade II patients were interpersonally distressed (59%) and all except one of the grade III patients were classified as dysfunctional (83%). The results seem to support the main assumption of our study that the GCP scale is a simple screening tool suitable for identifying primary care TMD patients with various types of pain profiles.


Indolent lymphomas other than follicular and marginal zone lymphomas.
This article addresses two of the less common entities among clinically indolent B-cell non-Hodgkin lymphomas: small lymphocytic lymphoma and lymphoplasmacytic lymphoma, also known as "Waldenstrom's macroglobulinemia." Differential diagnoses and prognostic factors are discussed for each as well as new treatment options and stem cell transplantation.


Activation of cardiac renin-angiotensin system and plasminogen activator inhibitor-1 gene expressions in oral contraceptive-induced cardiometabolic disorder.
Clinical studies have shown that combined oral contraceptive (COC) use is associated with cardiometabolic disturbances. Elevated renin-angiotensin system (RAS) and plasminogen activator inhibitor-1 (PAI-1) have also been implicated in the development of cardiometabolic events. To determine the effect of COC treatment on cardiac RAS and PAI-1 gene expressions, and whether the effect is circulating aldosterone or corticosterone dependent. Female rats were treated (p.o.) with olive oil (vehicle) or COC (1.0 µg ethinylestradiol and 10.0 µg norgestrel) daily for six weeks. COC treatment led to increases in blood pressure, HOMA-IR, Ace1 mRNA, Atr1 mRNA, Pai1 mRNA, cardiac PAI-1, plasma PAI-1, C-reactive protein, uric acid, insulin and corticosterone. COC treatment also led to dyslipidemia, decreased glucose tolerance and plasma 17β-estradiol. These results demonstrates that hypertension and insulin resistance induced by COC is associated with increased cardiac RAS and PAI-1 gene expression, which is likely to be through corticosterone-dependent but not aldosterone-dependent mechanism.


How important is coronary artery disease when considering lung transplant candidates?
Coronary artery disease (CAD) remains a relative contraindication for lung transplantation, but should it be if amenable to effective palliation? From January 2005 to July 2010, 356 adults undergoing primary lung transplantation had no significant (<50%) coronary arterial stenosis and 70 had significant (≥50%) CAD requiring prior or concomitant revascularization. Propensity matching on 38 pre-transplant patient characteristics identified 61 well-matched pairs (87% of possible matches) and 295 no-CAD unmatched patients to compare post-operative morbidity, graft function, and time-related pulmonary function and survival. Compared with no-CAD patients, those with CAD intervention were older, more likely to be male, had more comorbidities, and were more likely to have idiopathic pulmonary fibrosis. Among propensity-matched patients, 5 died in-hospital in the CAD intervention group and 6 in the no-CAD group (p = 0.7). Intensive care unit stay (5 vs 7 days), post-operative stay (14 vs 15 days), tracheostomy requirement (12 vs 11 patients), primary graft dysfunction scores (p >0.8), and early longitudinal post-transplant pulmonary function (p = 0.2) were similar, as was time-related mortality (20% vs 22% and 51% vs 52% at 1 and 4 years, respectively; p = 0.6). Unmatched no-CAD patients had fewer comorbidities and lower mortality than matched patients (15% and 39% at 1 and 4 years, respectively; p = 0.01). CAD is an important risk factor in lung transplant candidates, but its influence can be minimized in experienced centers by effective palliation. Surprisingly, however, CAD is a marker for an unfavorable patient phenotype with worse than typical post-transplant survival, irrespective of whether CAD is present.


Two levels of cooperativeness in the binding of TodT to the tod operon promoter.
The TodS/TodT two-component system controls the expression of tod genes for toluene degradation in Pseudomonas putida. TodT binds to two pseudopalindromes at -106 (Box-1) and -85 (Box-2), as well as to a half-palindrome (Box-3), with respect to the main transcription initiation site in the PtodX promoter. TodT recognizes each half-palindrome in Boxes-1 and -2, but affinities for these sequences are lower than those for the pseudopalindromes, pointing towards positive cooperativeness in intrabox recognition. TodT's affinity for DNA fragments containing two vicinal boxes (either Boxes-1 and -2 or Boxes-2 and -3) is higher than its affinity for individual boxes, suggesting interbox cooperativeness. Similar patterns of cooperativeness were observed for the recombinant TodT DNA-binding domain [C-terminal TodT fragment (aa 154-206) (C-TodT)], suggesting important cooperativeness determinants in this domain. Occupation of PtodX by TodT is initiated at Box-1, and optimization of its palindromic order increases affinity in vitro; however, this does not result in enhanced in vivo gene expression. Mutations at either half of the Box-1 palindrome have no significant effects on transcriptional activity, whereas mutations in the entire Box-1 cause a 12-fold reduction. Using atomic force microscopy, we show that TodT induces a DNA hairpin bend at PtodX between Boxes-2 and -3, as supported by footprint studies showing a hyperreactive nucleotide at G -68. The N-terminal part of TodT seems to play a central role in hairpin formation, since C-TodT neither induces a bend nor causes G -68 hyperreactivity in footprints. This hairpin seems important for transcriptional activation, since C-TodT binding to PtodX does not stimulate transcription.


Road traffic injuries: a major global public health crisis.
Evidence suggests that the present and projected global burden of road traffic injuries is borne disproportionately by countries that can least afford to meet the health service, economic and societal challenges. Although the evidence base on which these estimates are made remains somewhat precarious in view of the limited data systems in most low- and middle-income countries, these projections highlight the essential need to address road traffic injuries as a public health priority. Most well-evaluated effective interventions do not focus directly on efforts to protect vulnerable road users, such as motorcyclists and pedestrians. However, these groups comprise the majority of road traffic victims in low- and middle-income countries, and consequently the majority of road traffic victims globally. Responding appropriately to the disparities in available evidence and prevention efforts is necessary in order to address this global public health crisis comprehensively.


Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis (OA). Clinical, prospective, randomized, single-blinded study. Exercise physiology laboratory. Elderly subjects with knee OA (N=32) were divided into 3 groups: (1) squat exercises on a vibratory platform (platform group, n=11); (2) squat exercises without vibration (squat group, n=10); and (3) the control group (n=11). The structured program of squat exercises in the platform and squat groups was conducted 3 times per week, on alternate days, for 12 weeks. Plasma soluble tumor necrosis factor-α receptors 1 (sTNFR1) and 2 (sTNFR2) were measured using immunoassays (the enzyme-linked immunosorbent assay method). The Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used to evaluate self-reported physical function, pain, and stiffness. The 6-minute walk test, the Berg Balance Scale, and gait speed were used to evaluate physical function. In the platform group, there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 (P<.001 and P<.05, respectively) and self-reported pain (P<.05) compared with the control group, and there was an increase in balance (P<.05) and speed and distance walked (P<.05 and P<.001, respectively). In addition, the platform group walked faster than the squat group (P<.01). The results suggest that whole-body vibration training improves self-perception of pain, balance, gait quality, and inflammatory markers in elderly subjects with knee OA.


Single- versus double-bundle suture button reconstruction of the forearm interosseous membrane for the chronic Essex-Lopresti lesion.
Reconstruction of the ruptured interosseous membrane (IOM) is critical to restore forearm stability for the chronic Essex-Lopresti injury. Positive outcomes have been reported following IOM reconstruction with a single-bundle suture button (Mini-Tightrope) construct, although recent work suggests that double-bundle Mini-TightRope® IOM reconstruction is biomechanically superior. The purpose of this study was to determine whether double-bundle Mini-TightRope® reconstruction of the forearm IOM results in superior clinical outcomes to the single-bundle technique. Five patients with chronic Essex-Lopresti injuries treated with double-bundle Mini-TightRope® IOM reconstruction were matched to five patients treated with single-bundle Mini-TightRope® reconstruction. Improvement in clinical examination measures and patient-reported outcomes was compared between the groups. Results were good to excellent in all 10 patients. At final follow-up, forearm rotation was significantly better in the single-bundle group, while maintenance of ulnar variance was better in the double-bundle group. No significant differences were noted between the two groups for any other numerical outcomes, and no complications occurred. These findings suggest that while IOM reconstruction with a double-bundle Mini-TightRope® construct results in greater resistance to proximal migration of the radius in the intermediate term, there is a modest concomitant loss of forearm rotation when compared to single-bundle reconstruction. Therapeutic Level IV.


Combining TMEM Doorway Score and MenaCalc Score Improves the Prediction of Distant Recurrence Risk in HR+/HER2- Breast Cancer Patients.
to develop several digital pathology-based machine vision algorithms for combining TMEM and MenaCalc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and MenaCalc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and MenaCalc. Different ways of combining TMEM doorway and MenaCalc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71-8.37), compared to 3.56 years (95% CI: 0.95-6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25-5.87) for the associated standalone MenaCalc analysis. combining TMEM doorway and MenaCalc scores as a new biomarker improves prognostication over that observed with TMEM doorway or MenaCalc Score alone in this cohort of 86 patients.


Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice.
Obesity is associated with chronic diseases such as fatty liver, type 2 diabetes, cardiovascular disease, and severe metabolic syndrome. Obesity causes metabolic impairment including excessive lipid accumulation and fibrosis in the hepatic tissue as well as the increase in oxidative stress. In order to investigate the effect of mulberry leaf (Morus alba L.) extract (MLE) on obesity-induced oxidative stress, lipogenesis, and fibrosis in liver, MLE has been gavaged for 12 weeks in high-fat diet (HFD)-induced obese mice. MLE treatment significantly ameliorated LXRα-mediated lipogenesis and hepatic fibrosis markers such as α-smooth muscle actin, while MLE up-regulated lipolysis-associated markers such as lipoprotein lipase in the HFD-fed mice. Moreover, MLE normalized the activities of antioxidant enzymes including heme oxygenase-1 and glutathione peroxidase in accordance with protein levels of 4-hydroxynonenal in the HFD-fed mice. MLE has beneficial effects on obesity-related fatty liver disease by regulation of hepatic lipid metabolism, fibrosis, and antioxidant defense system. MLE supplementation might be a potential therapeutic approach for obesity-related disease including non-alcoholic fatty liver disease.


The Role of Vaccination Interventions to Promote HPV Vaccine Uptake Rates in a College-Aged Population: a Systematic Review.
This systematic review provided synthesized evidence regarding the effectiveness of the interventions promoting the human papillomavirus (HPV) vaccination in college-aged population. The HPV infection is the most prevailing sexually transmitted disease. Despite the availability and effectiveness of the 9-Valent HPV vaccine, the vaccine coverage among young adults remained low. In witness to the increasing burden of HPV-related infections and cancers, research focused on the vaccination interventions should be conducted to determine the effectiveness of the vaccination strategy and address the gap. The search was conducted through PubMed, Cochrane, and CINAL. Studies were included if they (1) included vaccination programs, (2) target population was young adults aged 17-26, (3) examined factors associated with the intervention effectiveness, (4) were published in English, and (5) were published between February 2010 and February 2020. HPV-related knowledge and intentions toward HPV vaccination were all reported increased after the intervention. Increased HPV vaccination intentions were found associated with the increased vaccine initiation and completion. Among bisexual or homosexual individuals, females were found more likely to complete the HPV dose 2 and 3. The review findings suggested using vaccination interventions incorporated with educational components to promote vaccine uptake among young adults. Supportive interventions tailored to different populations and settings are crucial to address the suboptimal HPV-related knowledge and vaccination status among the young beneficiaries.


Peaks of Fine Particulate Matter May Modulate the Spreading and Virulence of COVID-19.
A probe of a patient, seeking help in an emergency ward of a French hospital in late December 2019 because of Influenza like symptoms, was retrospectively tested positive to COVID-19. Despite the early appearance of the virus in Europe, the prevalence and virulence appeared to be low for several weeks, before the spread and severity of symptoms increased exponentially, yet with marked spatial and temporal differences. Here, we compare the possible linkages between peaks of fine particulate matter (PM2.5) and the sudden, explosive increase of hospitalizations and mortality rates in the Swiss Canton of Ticino, and the Greater Paris and London regions. We argue that these peaks of fine particulate matter are primarily occurring during thermal inversion of the boundary layer of the atmosphere. We also discuss the influence of Saharan dust intrusions on the COVID-19 outbreak observed in early 2020 on the Canary Islands. We deem it both reasonable and plausible that high PM2.5 concentrations-favored by air temperature inversions or Saharan dust intrusions-are not only modulating but even more so boosting severe outbreaks of COVID-19. Moreover, desert dust events-besides enhancing PM2.5 concentrations-can be a vector for fungal diseases, thereby exacerbating COVID-19 morbidity and mortality. We conclude that the overburdening of the health services and hospitals as well as the high over-mortality observed in various regions of Europe in spring 2020 may be linked to peaks of PM2.5 and likely particular weather situations that have favored the spread and enhanced the virulence of the virus. In the future, we recommended to monitor not only the prevalence of the virus, but also to consider the occurrence of weather situations that can lead to sudden, very explosive COVID-19 outbreaks.


Orthodontic pain: c-Fos expression in rat brain nuclei after rapid maxillary expansion.
The aim of this in vivo study was to quantitatively evaluate pain after rapid maxillary expansion (RME) in young rats by analyzing the activation of nociception-related structures, that is, the caudalis, interpolaris, and oralis subnuclei, according to the Fos expression. A total of 65 Wistar rats were assigned to three groups: control group (n = 15) with no treatment, positive control group (n = 25), and experimental group (n = 25) with RME. The experimental animals were euthanized at 6, 12, 24, 48, and 72 hours after RME, and the brain was later carefully collected. Coronal sections through the spinal trigeminal caudalis, spinal trigeminal interpolaris, and spinal trigeminal oralis were cut (thickness of 40 µm) on a cryostat and processed for Fos immunohistochemistry. Images from the sections were captured under light microscopy, and ImageJ software was used to count Fos-like immunoreactive neurons. The Analysis of variance (ANOVA) and Tukey test were used for statistical analysis, and the significance level was set at 5%. RME induced incisor distalization and opening of the midpalatal suture, as well as neuronal activation of the spinal trigeminal nucleus. The experimental group demonstrated significantly more Fos-positive neurons in subnuclei caudalis and subnuclei interpolaris 6 hours after the maxillary expansion. The Fos immunoreactivity significantly decreased at 12 hours and increased again at 24 and 48 hours (P < 0.001). The RME increases the neural activation of brain regions involved in the nociception region, as determined by the Fos expression. The most intense Fos-like immunoreactive expression was detected in the brain 6 hours after the start of the palatal expansion.


The quantitative nuclear cystogram: an aid in determining the spontaneous resolution of vesicoureteral reflux.
The quantitative data derived from serial nuclear cystograms during a 5-year period in 39 children were compared to the clinical course. A direct correlation (93 per cent) between an increasing bladder volume at which reflux occurs was observed in the clinically stable group. In the clinically unstable group there was a 77 per cent correlation of an unchanged or decreasing bladder volume at which reflux occurs. The quantitative nuclear cystogram provides an objective as opposed to subjective data base for management of patients with vesicoureteral reflux.


A THIN-LAYER LIF THERMOLUMINESCENCE DOSEMETER SYSTEM WITH FAST READOUT FOR THE USE IN PERSONAL DOSIMETRY SERVICES.
A newly developed thermoluminescence dosemeter system is presented that is suitable for application in fields where personal monitoring of a large number of users is required. The system presented here is intended to be used as the upcoming main dosemeter for whole body dosimetry at the dosimetry service of the MPA NRW (Germany) with ∼110,000 evaluations per month.


P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain.
Activation of P2X(3) and P2X(2/3) receptors (P2X(3)R/P2X(2/3)R), ionotropic ATP receptor subtypes, in primary sensory neurons is involved in neuropathic pain, a debilitating chronic pain that occurs after peripheral nerve injury. However, the underlying mechanisms remain unknown. We investigated the role of cytosolic phospholipase A(2) (cPLA(2)) as a downstream molecule that mediates the P2X(3)R/P2X(2/3)R-dependent neuropathic pain. We found that applying ATP to cultured dorsal root ganglion (DRG) neurons increased the level of Ser505-phosphorylated cPLA(2) and caused translocation of Ser505-phosphorylated cPLA(2) to the plasma membrane. The ATP-induced cPLA(2) activation was inhibited by a selective antagonist of P2X(3)R/P2X(2/3)R and by a selective inhibitor of cPLA(2). In the DRG in vivo, the number of cPLA(2)-activated neurons was strikingly increased after peripheral nerve injury but not after peripheral inflammation produced by complete Freund's adjuvant. Pharmacological blockade of P2X(3)R/P2X(2/3)R reversed the nerve injury-induced cPLA(2) activation in DRG neurons. Moreover, administering the cPLA(2) inhibitor near the DRG suppressed nerve injury-induced tactile allodynia, a hallmark of neuropathic pain. Our results suggest that P2X(3)R/P2X(2/3)R-dependent cPLA(2) activity in primary sensory neurons is a key event in neuropathic pain and that cPLA(2) might be a potential target for treating neuropathic pain.


A difficult-to-diagnose case of Borrmann type IV gastric cancer with marked transverse colon stenosis.
We report a difficult-to-diagnose case of Borrmann type IV gastric cancer with poor typical findings and marked colonic stenosis in a 47-year-old man and present a literature review.