Logistic risk model for the unique effects of inherent aerobic capacity on +Gz tolerance before and after simulated weightlessness.
Small sample size (n less than 10) and inappropriate analysis of multivariate data have hindered previous attempts to describe which physiologic and demographic variables are most important in determining how long humans can tolerate acceleration. Data from previous centrifuge studies conducted at NASA/Ames Research Center, utilizing a 7-14 d bed rest protocol to simulate weightlessness, were included in the current investigation. After review, data on 25 women and 22 men were available for analysis. Study variables included gender, age, weight, height, percent body fat, resting heart rate, mean arterial pressure, VO2max, and plasma volume. Since the dependent variable was time to greyout (failure), two contemporary biostatistical modeling procedures (proportional hazard and logistic discriminant function) were used to estimate risk, given a particular subject's profile. After adjusting for pre-bed-rest tolerance time, none of the profile variables remained in the risk equation for post-bed-rest tolerance greyout. However, prior to bed rest, risk of greyout could be predicted with 91% accuracy. All of the profile variables except weight, MAP, and those related to inherent aerobic capacity (VO2max, percent body fat, resting heart rate) entered the risk equation for pre-bed-rest greyout. A cross-validation using 24 new subjects indicated a very stable model for risk prediction, accurate within 5% of the original equation. The result for the inherent fitness variables is significant in that a consensus as to whether an increased aerobic capacity is beneficial or detrimental has not been satisfactorily established. We conclude that tolerance to +Gz acceleration before and after simulated weightlessness is independent of inherent aerobic fitness.


Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders.
Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion. We examined the correlation of adipose Nrg4 expression with obesity in a cohort of diet-induced obese mice and investigated the upstream signals that regulate Nrg4 expression. We performed metabolic cage and hyperinsulinemic-euglycemic clamp studies in Nrg4 transgenic mice to dissect the metabolic pathways regulated by Nrg4. We investigated how Nrg4 regulates hepatic lipid metabolism in the fasting state and explored the effects of Nrg4 on adipose tissue gene expression, particularly those encoding secreted factors. Adipose Nrg4 expression is inversely correlated with adiposity and regulated by pro-inflammatory and anti-inflammatory signaling. Transgenic expression of Nrg4 increases energy expenditure and augments whole body glucose metabolism. Nrg4 protects mice from diet-induced hepatic steatosis in part through activation of hepatic fatty acid oxidation and ketogenesis. Finally, Nrg4 promotes a healthy adipokine profile during obesity. Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in patients.


Application of nicardipine prolonged-release implants: analysis of 97 consecutive patients with acute subarachnoid hemorrhage.
Since October 1999, nicardipine prolonged-release implants (NPRIs) have been used to prevent vasospasm in patients with subarachnoid hemorrhage. This study was conducted to examine the incidence of cerebral vasospasm and outcome after the application of NPRIs. Ninety-seven consecutive patients among 125 patients with subarachnoid hemorrhage who were surgically treated within 72 hours were analyzed. NPRIs were applied principally to patients with thick clots (Fisher Group 3) through a frontotemporal or frontal craniotomy. Sixty-nine patients, including five in Fisher Group 2, were treated with NPRIs, and 28 were not. NPRIs were placed in the cisterns of thick clots where vasospasm was highly probable. Four (6%) of the 69 patients treated with NPRIs and 3 (11%) of the 28 patients not treated with NPRIs developed delayed ischemic neurological deficits (DINDs). Of these patients, clinical deterioration with infarction occurred in two patients (3%). Current smoking (P = 0.0088) and intraventricular hemorrhage on admission computed tomographic (CT) scans (P = 0.0077) were correlated with DIND. CT groupings on admission and postoperatively were not correlated, nor were World Federation of Neurosurgical Societies grades. Hypertension was inversely correlated with DIND (P = 0.0233). Eighty-six patients (89%) had an independent status at 3 months. Logistic regression analysis demonstrated that age (odds ratio [OR], 6.836; P = 0.034), World Federation of Neurosurgical Societies grade (OR, 23.317; P = 0.001), intraventricular hemorrhage on admission CT scans (OR, 6.332; P = 0.024), and surgical complications (OR, 32.861; P = 0.003) were independent risk factors influencing an unfavorable outcome. CT grouping on admission and DIND were not. Our findings suggest that the incidence of DIND may decrease and, therefore, an unfavorable outcome may improve if NPRIs are applied for patients with thick clots (Fisher Group 3) during surgery.


Development and validation of an algorithm to assess risk of first-time falling among home care clients.
The falls literature focuses on individuals with previous falls, so little is known about individuals who have not experienced a fall in the past. Predicting falls in those without a prior event is critical for primary prevention of injuries. Identifying and intervening before the first fall may be an effective strategy for reducing the high personal and economic costs of falls among older adults. The purpose of this study was to derive and validate a prediction algorithm for first-time falls (1stFall) among home care clients who had not fallen in the past 90 days. Decision tree analysis was used to develop a prediction algorithm for the occurrence of a first fall from a cohort of home care clients who had not fallen in the last 90 days, and who were prospectively followed over 6 months. Ontario home care clients who were assessed with the Resident Assessment Instrument-Home Care (RAI-HC) between 2002 and 2014 (n = 88,690) were included in the analysis. The dependent variable was falls in the past 90 days in follow-up assessments. The independent variables were taken from the RAI-HC. The validity of the 1stFall algorithm was tested among home care clients in 4 Canadian provinces: Ontario (n = 38,013), Manitoba (n = 2738), Alberta (n = 1226) and British Columbia (n = 9566). The 1stFall algorithm includes the utilization of assistive devices, unsteady gait, age, cognition, pain and incontinence to identify 6 categories from low to high risk. In the validation samples, fall rates and odds ratios increased with risk levels in the algorithm in all provinces examined. The 1stFall algorithm predicts future falls in persons who had not fallen in the past 90 days. Six distinct risk categories demonstrated predictive validity in 4 independent samples.


Prevention of murine norovirus infection in neonatal mice by fostering.
Murine norovirus (MNV) causes subclinical chronic infections in adult immunocompetent mice and is endemic in many mouse colonies. The susceptibility of neonatal mice to MNV infection was investigated. Intestinal homogenates from Swiss Webster (SW) mice inoculated orally with MNV-L on postpartum days (ppd) 1 to 3 were negative for MNV by RT-PCR at postinoculation days (pid) 3 and 7. In contrast, 69% of intestinal homogenates prepared on pid 3 and 7 from mice inoculated orally at ppd 5 to 8 were MNV-positive by RT-PCR. Because only mice 10 d of age or older were infected by contact with infected dams, a study was performed to determine whether fostering of neonatal mice from MNV-infected to MNV-naïve dams could be effective at preventing infection of neonatal mice. Four litters each of 1-, 2-, 4-, or 6 d-old mice from MNV-L- infected dams were transferred to naïve dams with similar-aged litters and vice versa. On ppd 21, feces from all MNV-infected dams and litters transferred to them were MNV-positive. In contrast on ppd 21, feces from all MNV-naïve dams and litters transferred to them were MNV-negative. Fostering of 2-d-old mice from 5 of 5 MNV-C-, 5 of 6 MNV-D-, and 7 of 8 MNV-G- infected dams onto MNV-naïve dams prevented MNV infection of the foster mice. In the 2 litters where MNV was detected, dams were infected within 7 d of transfer, suggesting that the neonatal mice had served as fomites. In summary, fostering was effective at preventing MNV infection in 33 of 35 litters of neonatal mice. Precautions to prevent transmission of virus on the surface of neonatal mice to foster dams could increase the efficiency of the fostering process.


Near-field imaging of perfectly conducting grating surfaces.
A novel approach is presented to solving the inverse diffractive grating problem in near-field optical imaging, which is to reconstruct perfectly conducting grating surfaces with resolution beyond the diffraction limit. The grating surface is assumed to be a small and smooth deformation of a plane surface. An analytical solution of the direct grating problems is derived by using the method of transformed field expansion. Based on the analytic solution, an explicit reconstruction formula is deduced for the inverse grating problem. The method requires only a single incident field and is realized efficiently by using the fast Fourier transform. Numerical results show that the method is simple, stable, and effective in reconstructing grating surfaces with super-resolved resolution.


Laparoscopic bilateral nephroureterectomy and bladder cuff excision for native renal pelvic and ureteral transitional cell carcinoma after renal transplantation.
A 37-years-old female who was suffering from end-stage renal disease for about 6 years received allograft renal transplantation 4 years ago. She has been receiving 50mg of Cyclosporin A orally daily for immuno-suppression since then. Gross haematuria was noted and computerised tomography showed native left renal pelvic and ureteral multi-focal transitional cell carcinoma with severe hydronephrosis. Laparoscopic bilateral nephroureterectomy and bladder cuff excision were performed. In the past, history of previous operation was considered a relative contraindication for laparoscopic surgery. To our knowledge, we present the first case of laparoscopic treatment for native renal pelvic and ureteral transitional cell carcinoma after renal allograft transplantation without a hand-assisted device. This case shows the feasibility of laparoscopic bilateral nephroureterectomy in patients with transplanted kidneys.


Left atrial appendage occlusion with the Amplatzer Cardiac Plug could improve survival and prevent thrombo-embolic and major bleeding events in atrial fibrillation patients with increased bleeding risk.
Literature suggests a beneficial effect of percutaneous left atrial appendage occlusion (LAAO) to prevent thrombo-embolic events in patients with non-rheumatic atrial fibrillation (AF). We compared outcome of LAAO versus 'suboptimal standard' treatment in AF patients with high bleeding risk. Patients with sufficient follow-up data (n = 125) who underwent LAAO with the Amplatzer Cardiac Plug (ACP) were selected from the Belgian ACP database. AF patients who survived intracranial haemorrhage were recruited from the Leuven Neurosurgical Registry (LNR, n = 113). After propensity score adjustment, the outcome of both groups was compared for the combined end point (death, stroke, transient ischaemic attack, systemic emboli, and major bleeding event). The LAAO group did not differ from the LNR group for mean age and gender (74 ± 7 versus 75 ± 10 years, P = 0.29; female 39% versus 48%, P = 0.18). However, the CHA2DS2-VASc and HAS-BLED scores were both higher in the LAAO group (4.8 ± 1.7 versus 3.9 ± 1.7, P = 0.0001; 3.5 ± 1.4 versus 3.2 ± 1.4, P = 0.036). After propensity score adjustment, the risk for the primary end point was significantly higher for the LNR group (HR 2.012, 95% CI 1.113-3.638). LAAO with ACP seems to improve the combination of survival and the prevention of thrombo-embolic and major bleeding events in patients with atrial fibrillation and increased bleeding risk.


[Variability of glycemia and ventricular rhythm disturbances in patients with chronic heart failure and type 2 diabetes mellitus].
Aim of this observational study was assessment of effect of variability of glycemia on ventricular ectopic activity in patients with chronic heart failure (CHF) and type 2 diabetes mellitus (n=80). According to study protocol 24-hour Holter ECG monitoring was carried out at baseline, and after 3 and 6 months. Measurements of blood glucose level were made at 8 points during ECG monitoring - before and in 2 hours after main meals, before bedtime and at 3 o'clock in the morning. In 20 patients continuous combined monitoring of ECG and of blood glucose level was carried out. During monitoring of ECG high grade ventricular arrhythmias were found in 42 patients (53%). Pronounced variations of blood glucose level (mean amplitude of glycemic excursion >5 mmol/L) were associated with 2.3 fold increase risk of ventricular arrhythmias (p=0.04). A conclusion was made that pronounced 24-hour variations of glucose level in blood was associated with elevation of ventricular ectopic activity. High 24-hour variability of glycemia appeared to be proarrhythmogenic factor in patients with CHF and concomitant diabetes.


Evolving beyond the vicious triad: Differential mediation of traumatic coagulopathy by injury, shock, and resuscitation.
A subset of trauma patients with critical injury present with coagulopathy, portending markedly worse outcomes. Clinical practice is evolving to treat the classical risk factors of hypothermia, hemodilution, and acidosis; however, coagulopathy persists even in the absence of these factors. We sought to determine the relative importance of injury- and shock-specific factors compared with resuscitation-associated factors in coagulopathy after trauma. Comprehensive demographic data, laboratory data, and outcomes data were prospectively collected from seven trauma centers over 8 years (November 2003 to August 2011) as part of the Inflammation and the Host Response to Injury Large-Scale Collaborative Program. A total of 1,537 critically injured patients with blunt trauma and hemorrhagic shock were analyzed to evaluate predictors of admission coagulopathy (international normalized ratio [INR] ≥ 1.3), multiorgan failure, and mortality. Of 1,537 patients, 578 (37.6%) had admission INR of 1.3 or greater. Coagulopathic patients had more severe injury, more severe base deficit and lactate levels, as well as lower admission temperature, lower pH, and higher prehospital crystalloid volume (all p < 0.001). Coagulopathic patients required more blood products and mechanical ventilation and had higher rates of nosocomial infection, multiorgan failure, and mortality (all p < 0.02). Injury severity, temperature, and acidosis (all p < 0.02) independently predicted coagulopathy in multivariate analysis, with a significant interaction between lactate and prehospital crystalloid. In Cox regression models, however, coagulopathy itself remained an independent predictor of both multiorgan failure and mortality (p < 0.02) even when adjusted for injury severity, shock, and elements of the vicious triad. Most patients with coagulopathy after trauma have mixed risk factors; however, coagulopathy has deleterious effects independent of injury severity, shock, and the vicious triad. Better understanding of the biochemical mechanisms of acute traumatic coagulopathy may facilitate biochemically targeted resuscitation strategies and improve outcomes. Prognostic and epidemiologic study, level II.


[Manifestation of polylysogeny in Pseudomonas vignae].
Ultraviolet irradiation and treatment with mitomycin C demonstrated that a culture of Ps. vignae, strain 1025, was polylysogenic, as electron microscopic preparations of phagolysates revealed two types of virus particles: "large" with a hexagonal head of 700 A in diameter, and "small" with a round head of 500 A in diameter. Subcultivation of the test and indicator cultures showed in both cases formation of particles of these phages, the content of "small" virions increasing with the number of passages of negative colonies. Attempts to separate these viruses biological methods were not successfull. The phenomenon of polylysogeny is unusual in that moderate phage adsorbed repeatedly on host bacteria culture and lysed it. The causes of the discovered phenomenon are discussed.


Ultrasound-guided Percutaneous Lavage in the Treatment of Calcific Tendinopathy of Elbow Extensor Tendons: A Case Report.
We report the efficacy of the ultrasound-guided percutaneous treatment in the management of elbow extensor tendons calcific tendinopathy. The ultrasound-guided percutaneous treatment is broadly used with positive results in patients suffering from rotator cuff calcific tendinopathy. However, this interventional method has been reported only in one patient in the medical literature. A 34 years-old female who complained pain, swelling and severe functional limitation of the right elbow was referred to our unit. Elbow radiographs and ultrasound examination showed a soft-fluid calcification above the origin of the extensor tendons. Ultrasound-guided percutaneous treatment was therefore performed. After one year, the patient reported no pain and regained complete range of elbow motion. This method, in well trained hands, is an alternative treatment in the management of the uncommon elbow calcific deposit.


Effect of phytosterols on rumen fermentation in vitro.
We investigated the effect of phytosterols on rumen fermentation in vitro using gas syringes as incubators. Phytosterols were dissolved in ethyl acetate (8.3%) and added at various concentrations to the common diet in rumen fluid. In vitro gas production (GP) was recorded after 3, 6, 12, 18, and 24 h incubation. Incubation was stopped at 6, 12, and 24 h and the inoculants were then tested for pH, dry matter digestibility (DMD), microbial protein yield (MCP), lactic acid, NH3-N, and volatile fatty acids (VFAs). GP was consistently higher than the control; particularly, treatments at 12, 18, and 24 h reached extremely significant levels (P < 0.01). Compared to the control group, the pH of ruminal fluid was slightly lower after incubation, and DMD and MCP increased with increasing phytosterol level except for the content of MCP at 6 h, which changed only minimally. Lactate was significantly lower after treatment compared to the control at 12 h (P < 0.01) and 24 h (P < 0.05), while NH3-N at 12 h (P < 0.05) and 24 h (P < 0.01) after treatment decreased significantly. Acetate, propionate, butyrate, and total VFA for all treatments were higher than those of the control, particularly for butyrate at 6 h (P < 0.01). These results suggest that phytosterols modify rumen fermentation by inhibiting released harmful products and promoting the release of beneficial product, which may be useful for improving nutrient utilization and animal health.


A SVM-based quantitative fMRI method for resting-state functional network detection.
Resting-state functional magnetic resonance imaging (fMRI) aims to measure baseline neuronal connectivity independent of specific functional tasks and to capture changes in the connectivity due to neurological diseases. Most existing network detection methods rely on a fixed threshold to identify functionally connected voxels under the resting state. Due to fMRI non-stationarity, the threshold cannot adapt to variation of data characteristics across sessions and subjects, and generates unreliable mapping results. In this study, a new method is presented for resting-state fMRI data analysis. Specifically, the resting-state network mapping is formulated as an outlier detection process that is implemented using one-class support vector machine (SVM). The results are refined by using a spatial-feature domain prototype selection method and two-class SVM reclassification. The final decision on each voxel is made by comparing its probabilities of functionally connected and unconnected instead of a threshold. Multiple features for resting-state analysis were extracted and examined using an SVM-based feature selection method, and the most representative features were identified. The proposed method was evaluated using synthetic and experimental fMRI data. A comparison study was also performed with independent component analysis (ICA) and correlation analysis. The experimental results show that the proposed method can provide comparable or better network detection performance than ICA and correlation analysis. The method is potentially applicable to various resting-state quantitative fMRI studies.


A method for estimating the parameters of electrodynamic drivers in thermoacoustic coolers.
The electroacoustic efficiency of high-power actuators used in thermoacoustic coolers may be estimated using a linear model involving a combination of six parameters. A method to identify these equivalent driver parameters from measured total electrical impedance and velocity-voltage transfer function data was developed. A commercially available, moving-magnet driver coupled to a functional thermoacoustic cooler was used to demonstrate the procedure experimentally. The method, based on linear electrical circuit theory, allowed for the possible frequency and amplitude dependence of the driver parameters to be estimated. The results demonstrated that driver parameters measured in vacuo using this method can be used to predict the driver efficiency and performance for operating conditions which may be encountered under load.


Comparison of the bactericidal activities of ofloxacin and ciprofloxacin alone and in combination with ceftazidime and piperacillin against clinical strains of Pseudomonas aeruginosa.
On the basis of MIC data, ciprofloxacin exhibits superior activity against Pseudomonas aeruginosa than the other currently available fluoroquinolones do. Despite the antipseudomonal advantage noted for ciprofloxacin monotherapy, it is unknown whether this advantage is maintained when the fluoroquinolones are used in combination with antipseudomonal beta-lactams such as ceftazidime and piperacillin. Twelve healthy volunteers were enrolled in this open-label, randomized, steady-state, six-way cross-over, comparative trial. All subjects received the following regimens: (i) 400 mg of ofloxacin given intravenously (i.v.) every 12 h (q12h), (ii) 400 mg of ciprofloxacin given i.v. q12h, (iii) 400 mg of ofloxacin given i.v. q12h plus 1 g of ceftazidime given i.v. every 8 h (q8h), (iv) 400 mg of ciprofloxacin given i.v. q12h plus 1 g of ceftazidime given i.v. q8h, (v) 400 mg of ofloxacin given i.v. q12h plus 4 g of piperacillin given i.v. q8h, and (vi) 400 mg of ciprofloxacin given i.v. q12h plus 4 g of piperacillin given i.v. q8h. Serum bactericidal titers with subsequent calculation of the area under the bactericidal curve were determined against three clinical isolates of P. aeruginosa. As monotherapy, ciprofloxacin demonstrated superior antipseudomonal activity than ofloxacin did; however, combination of these agents with ceftazidime yielded remarkably similar and statistically comparable activity profiles. In contrast, ciprofloxacin-piperacillin retained a bactericidal advantage over ofloxacin-piperacillin. Although ciprofloxacin exhibits superior antipseudomonal activity when used as monotherapy, combination of ofloxacin or ciprofloxacin with ceftazidime yielded equivalent activity profiles against susceptible strains of P. aeruginosa.


Diurnal variation in autonomic regulation among patients with genotyped Rett syndrome.
Rett syndrome is a severe neurological disorder with a range of disabling autonomic and respiratory symptoms and resulting predominantly from variants in the methyl-CpG binding protein 2 gene on the long arm of the X-chromosome. As basic research begins to suggest potential treatments, sensitive measures of the dynamic phenotype are needed to evaluate the results of these research efforts. Here we test the hypothesis that the physiological fingerprint of Rett syndrome in a naturalistic environment differs from that of controls, and differs among genotypes within Rett syndrome. A comprehensive array of heart rate variability, cardiorespiratory coupling and cardiac repolarisation measures were evaluated from an existing database of overnight and daytime inhome ambulatory recordings in 47 cases and matched controls. Differences between girls with Rett syndrome and matched controls were apparent in a range of autonomic measures, and suggest a shift towards sympathetic activation and/or parasympathetic inactivation. Daily temporal trends analysed in the context of circadian rhythms reveal alterations in amplitude and phase of diurnal patterns of autonomic balance. Further analysis by genotype class confirms a graded presentation of the Rett syndrome phenotype such that patients with early truncating mutations were most different from controls, while late truncating and missense mutations were least different from controls. Comprehensive autonomic measures from extensive inhome physiological measurements can detect subtle variations in the phenotype of girls with Rett syndrome, suggesting these techniques are suitable for guiding novel therapies.


Production of TRPM4 knockout cell line using rat cardiomyocyte H9c2.
The method presented in this article are related to the research article entitled as "Role of the TRPM4 channel in mitochondrial function, calcium release, and ROS generation in oxidative stress" [1]. TRPM4, a non-selective monovalent cation channel, is not only involved in the generation of the action potential in cardiomyocytes, but also thought to be a key molecule in the development of the ischemia-reperfusion injury of the brain and the heart [2], [3], [4], [5]. However, existing pharmacological inhibitors for the TRPM4 channel have problems of non-specificity [6]. This article describes methods used for targeted genomic deletion in the rat cardiomyocyte H9c2 using the CRISPR-Cas9 genome editing system in order to suppress TRPM4 protein expression. Confocal microscopy, flow cytometry, Sanger sequencing, and western blotting are performed to confirm vector transfection and the subsequent knockout of the TRPM4 protein.•These data provide information on the comprehensive analyses for knocking out the rat TRPM4 channel using CRISPR/Cas9. The analyses include confocal microscopy, flow cytometry, Sanger sequencing, and western blotting.•This dataset will benefit biological and medical researchers studying the function of TRPM4-expressing cells including neurons, cardiomyocytes, and vascular endothelial cells. It is also useful to study the involvement of the TRPM4 channel in pathological processes such as cardiac arrhythmia and ischemia-reperfusion injury.•The dataset can be used to guide the experiment of knocking out the TRPM4 gene and its subsequent application to the study of disease process caused by the gene.


Compartmentalization of cyclic AMP during phagocytosis by human neutrophilic granulocytes.
Immunocytochemistry shows that early during phagocytosis of zymosan, adenosine 3',5'-monophosphate (cyclic AMP) appears on the cell surface before the phagosome is internalized. The appearance of cyclic AMP on the cell surface is coincident with that of granule products and regulatory subunit of type I cyclic AMP-dependent protein kinase. Guanosine 3',5'-monophosphate is not associated with the initiation site of phagocytosis, but is observed throughout the granular cytoplasmic region. This sharply localized accumulation of cyclic AMP may serve as a signal for the initiation of phagocytosis.


Magnetic Chirality Controlled by the Interlayer Exchange Interaction.
Chiral magnetism, wherein there is a preferred sense of rotation of the magnetization, determines the chiral nature of magnetic textures such as skyrmions, domain walls, or spin spirals. Current research focuses on identifying and controlling the interactions that define the magnetic chirality in thin film multilayers. The influence of the interfacial Dzyaloshinskii-Moriya interaction (IDMI) and, recently, the dipolar interactions have been reported. Here, we experimentally demonstrate that an indirect interlayer exchange interaction can be used as an additional tool to effectively manipulate the magnetic chirality. We image the chirality of magnetic domain walls in a coupled bilayer system using scanning electron microscopy with polarization analysis. Upon increasing the interlayer exchange coupling, we induce a transition of the magnetic chirality from clockwise rotating Néel walls to degenerate Bloch-Néel domain walls and we confirm our findings with micromagnetic simulations. In multilayered systems relevant for skyrmion research, a uniform magnetic chirality across the magnetic layers is often desired. Additional simulations show that this can be achieved for reduced IDMI values (up to 30%) when exploiting the interlayer exchange interaction. This work opens up new ways to control and tailor the magnetic chirality by the interlayer exchange interaction.


The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane.
The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor.


The evolutionarily conserved repetitive sequence d(TG.AC)n promotes reciprocal exchange and generates unusual recombinant tetrads during yeast meiosis.
We have studied the genetic behavior of the alternating copolymer d(TG.AC)n inserted into a defined position in the genome of the yeast Saccharomyces cerevisiae. When d(TG.AC)n sequences were present at the HIS3 locus on homologous chromosomes, diploid cells undergoing meiosis generated an excess of tetrads containing reciprocally recombined products with crossover points close to the repetitive DNA insert. Most of these tetrads exhibited gene conversion of a d(TG.AC)n insert. However, the insertion of d(TG.AC)n sequences had no effect on the frequency of gene conversion of closely linked marker genes. Surprisingly, when d(TG.AC)n sequences were present on only one homolog at the HIS3 locus, one-half of the tetrads exhibiting nonparental segregation for marker genes that flanked the repetitive DNA insert were very unusual and appeared to have arisen by multiple recombination events in the vicinity of the d(TG.AC)n insert. Similar multiply recombinant tetrads were seen in crosses in which d(TG.AC)n sequences were present on both homologs. Combined, the data strongly suggest that d(TG.AC)n sequences significantly enhance reciprocal meiotic recombination and may be important in causing multiple recombination events to occur within a relatively small region of the yeast chromosome. Molecular evidence is presented that clearly documents the postmeiotic segregation of an 80-base stretch of d(TG.AC)n.


Hospice Referral in Advanced Cancer in New Jersey.
The need for hospice care is increasing in the United States, but insufficient lengths of stay and disparity in access to care continue. Few studies have examined the relationship between the presence of symptoms and hospice referral. The study measured the association between hospice referral and demographic characteristics and the presence of pain and depression in a cohort of people hospitalized with metastatic cancer in New Jersey in 2018. This study was secondary analysis of the 2018 New Jersey State Inpatient Database. The sample was limited to adult patients with metastatic cancer. Descriptive statistics evaluated the composition of the sample. Generalized linear modeling estimated the effect of pain and depression on incidence of hospice referral in a racially and economically diverse population. Absence of pain resulted in lower odds of receiving a referral to hospice upon discharge (adjusted odds ratio [AOR], 0.44; 95% confidence interval [CI], 0.40-0.49; P = .00). Likewise, an absence of depression also resulted in decreased odds of a hospice referral (AOR, 0.85; 95% CI, 0.76-0.96; P = .008). Compared with Whites, Blacks (AOR, 0.86; 95% CI, 0.76-0.97; P = .00) and Hispanics had significantly lower odds of receiving a hospice referral (AOR, 0.84; 95% CI, 0.72-0.96; P = .01). Patients with a primary language other than English, there were significantly lower odds of receiving a hospice referral (AOR, 0.85; 95% CI, 0.73-0.99; P = .03). Patients with pain and depression had increased hospice referrals. Disparities persist in hospice referral, particularly in Black and Hispanic cases and those without a primary language of English.


[Use of immunomodulators in the therapy of chronic hepatitis C: improving standard approach].
Results of a comparative study of the standard and an improved (triple) antiviral therapy in a group of 86 patients with chronic viral hepatitis C (1b genotype) with a period of infection up to five years are presented. The standard therapy consisted in the administration of concentrated alpha-interferon (Interal, Russia) and synthetic nucleozide ribavirin, while the improved (triple) therapy additionally included the administration of the interferon inducer cycloferon. The effectiveness of treatment using the improved scheme increased by 8.8%, the number of adverse drug reactions decreased more than three times, and morphological improvement was observed in 69.4-87.8% of patients. Modification of the standard treatment of hepatitis C improves the quality of life of hepatitis C patients.


[Glycolytic enzyme defects and neurodegeneration].
This study was devoted to the continued search for an explanation of the neurodegeneration found in a severely TPI deficient Hungarian patient whose brother with genomically completely identical TPI defect was completely free of neurological disorders. The changes found in the molecular species composition of the major PL subclasses and the decrease in PE plasmalogens explain the earlier round increase in membrane fluidity interfering thereby with the physiological function of membrane enzymes, receptors, signal transduction, protein-protein interactions and vesicle fusion. Plasmalogens have also the capacity to protect against oxidative stress, that is deemed to contribute to neurodegenerative processes. The presence of chronic oxidative stress was well reflected in the decreased levels of GSH and alpha-tocopherol in the affected brothers. Decrease in plasmalogens have been described recently in Zellweger's syndrome, in other peroxisomal neurodegenerative disorders, in demyelinating processes and in Alzheimer's disease. The brain in normal individuals is highly enriched in plasmalogens. The pathological decrease found in TPI deficient lymphocytes will presumably be more pronounced in excitatory tissues. The recently described role of expanding nucleotide triplets in the development of neurodegeneration is suggested to result through the selective binding via their polyglutamine repeats to GAPDH. The role of GAPDH in TPI deficiency may be of crucial help in the elucidation of the development of neurodegeneration, since the enzymatic defect of TPI can be partially bypassed by means of the HMP shunt which generates GAP via GAPDH without the participation of TPI. Considering the results found in TPI deficiency in comparison to the new literary findings in different neurodegenerative diseases the following pathomechanism may be proposed. The protein products of the defective genes due to their abnormal steric structure bind GAPDH in a different manner or in differing quantity than their normal counterparts. The PL composition and the resulting differences in the biophysical properties of the cell membranes have crucial impact on these protein-protein interactions and on the activity of enzymes and membrane transport functions. The plasmalogen decrease impairs the protection against oxidative stress with consecutive worsening of the neurodegenerative process. The final common pathway to neuronal death leads through destabilization of intracellular Ca2+ homeostasis via elevation of intracellular Ca2+ to apoptosis. The most important conclusion is that lipids are not an inert environment of membrane proteins. Unravelling of the pathogenesis of neurodegeneration needs more concerted investigation of the interactions between genetic changes with biophysical and biochemical cell membrane lipid alterations.


Weed target detection at seedling stage in paddy fields based on YOLOX.
Weeds are one of the greatest threats to the growth of rice, and the loss of crops is greater in the early stage of rice growth. Traditional large-area spraying cannot selectively spray weeds and can easily cause herbicide waste and environmental pollution. To realize the transformation from large-area spraying to precision spraying in rice fields, it is necessary to quickly and efficiently detect the distribution of weeds. Benefiting from the rapid development of vision technology and deep learning, this study applies a computer vision method based on deep-learning-driven rice field weed target detection. To address the need to identify small dense targets at the rice seedling stage in paddy fields, this study propose a method for weed target detection based on YOLOX, which is composed of a CSPDarknet backbone network, a feature pyramid network (FPN) enhanced feature extraction network and a YOLO Head detector. The CSPDarknet backbone network extracts feature layers with dimensions of 80 pixels ⊆ 80 pixels, 40 pixels ⊆ 40 pixels and 20 pixels ⊆ 20 pixels. The FPN fuses the features from these three scales, and YOLO Head realizes the regression of the object classification and prediction boxes. In performance comparisons of different models, including YOLOv3, YOLOv4-tiny, YOLOv5-s, SSD and several models of the YOLOX series, namely, YOLOX-s, YOLOX-m, YOLOX-nano, and YOLOX-tiny, the results show that the YOLOX-tiny model performs best. The mAP, F1, and recall values from the YOLOX-tiny model are 0.980, 0.95, and 0.983, respectively. Meanwhile, the intermediate variable memory generated during the model calculation of YOLOX-tiny is only 259.62 MB, making it suitable for deployment in intelligent agricultural devices. However, although the YOLOX-tiny model is the best on the dataset in this paper, this is not true in general. The experimental results suggest that the method proposed in this paper can improve the model performance for the small target detection of sheltered weeds and dense weeds at the rice seedling stage in paddy fields. A weed target detection model suitable for embedded computing platforms is obtained by comparing different single-stage target detection models, thereby laying a foundation for the realization of unmanned targeted herbicide spraying performed by agricultural robots.


A novel augmented deep transfer learning for classification of COVID-19 and other thoracic diseases from X-rays.
Deep learning has provided numerous breakthroughs in natural imaging tasks. However, its successful application to medical images is severely handicapped with the limited amount of annotated training data. Transfer learning is commonly adopted for the medical imaging tasks. However, a large covariant shift between the source domain of natural images and target domain of medical images results in poor transfer learning. Moreover, scarcity of annotated data for the medical imaging tasks causes further problems for effective transfer learning. To address these problems, we develop an augmented ensemble transfer learning technique that leads to significant performance gain over the conventional transfer learning. Our technique uses an ensemble of deep learning models, where the architecture of each network is modified with extra layers to account for dimensionality change between the images of source and target data domains. Moreover, the model is hierarchically tuned to the target domain with augmented training data. Along with the network ensemble, we also utilize an ensemble of dictionaries that are based on features extracted from the augmented models. The dictionary ensemble provides an additional performance boost to our method. We first establish the effectiveness of our technique with the challenging ChestXray-14 radiography data set. Our experimental results show more than 50% reduction in the error rate with our method as compared to the baseline transfer learning technique. We then apply our technique to a recent COVID-19 data set for binary and multi-class classification tasks. Our technique achieves 99.49% accuracy for the binary classification, and 99.24% for multi-class classification.


Gap junction-mediated intercellular communication in a long-term primary mouse hepatocyte culture system.
Gap junction-mediated intercellular communication (GJIC) is critical for maintaining integral cellular processes including differentiation and growth control. The disruption of GJIC has been correlated with aberrant function in many cell types, including hepatocytes in vivo; therefore it is imperative that cellular model systems support intercellular communication to simulate normal cellular functions. Functional GJIC has been shown in long-term primary rat hepatocyte cultures, which have been implemented widely to study various aspects of hepatocellular function; however, the onset of transgenic technology in murine species has necessitated the development of a primary mouse hepatocyte system. In this report, we analyze GJIC in a dimethylsulfoxide (DMSO)-containing long-term primary mouse hepatocyte culture system. The cells retain morphologic and biochemical characteristics of differentiated hepatocytes through day 30 post plating, including liver-specific gene expression. We further show that connexin32 and connexin26 expression and gap junction plaque formation increase over time in culture concomitant with an increase in GJIC between adjoining primary mouse hepatocytes. In conclusion, the findings described in this study make it possible to maintain differentiated primary mouse hepatocytes that also show GJIC in long-term culture for 30 days. In addition, this system has the potential to be extended to study primary mouse hepatocytes isolated from genetically engineered mice.


Novel Spiro-Core Dopant-Free Hole Transporting Material for Planar Inverted Perovskite Solar Cells.
Hole-transporting materials (HTMs) have demonstrated their crucial role in promoting charge extraction, interface recombination, and device stability in perovskite solar cells (PSCs). Herein, we present the synthesis of a novel dopant-free spiro-type fluorine core-based HTM with four ethoxytriisopropylsilane groups (Syl-SC) for inverted planar perovskite solar cells (iPSCs). The thickness of the Syl-SC influences the performance of iPSCs. The best-performing iPSC is achieved with a 0.8 mg/mL Syl-SC solution (ca. 15 nm thick) and exhibits a power conversion efficiency (PCE) of 15.77%, with Jsc = 20.00 mA/cm2, Voc = 1.006 V, and FF = 80.10%. As compared to devices based on PEDOT:PSS, the iPSCs based on Syl-SC exhibit a higher Voc, leading to a higher PCE. Additionally, it has been found that Syl-SC can more effectively suppress charge interfacial recombination in comparison to PEDOT:PSS, which results in an improvement in fill factor. Therefore, Syl-SC, a facilely processed and efficient hole-transporting material, presents a promising cost-effective alternative for inverted perovskite solar cells.


Urea-Hydroxyapatite Nanohybrids for Slow Release of Nitrogen.
While slow release of chemicals has been widely applied for drug delivery, little work has been done on using this general nanotechnology-based principle for delivering nutrients to crops. In developing countries, the cost of fertilizers can be significant and is often the limiting factor for food supply. Thus, it is important to develop technologies that minimize the cost of fertilizers through efficient and targeted delivery. Urea is a rich source of nitrogen and therefore a commonly used fertilizer. We focus our work on the synthesis of environmentally benign nanoparticles carrying urea as the crop nutrient that can be released in a programmed manner for use as a nanofertilizer. In this study, the high solubility of urea molecules has been reduced by incorporating it into a matrix of hydroxyapatite nanoparticles. Hydroxyapatite nanoparticles have been selected due to their excellent biocompatibility while acting as a rich phosphorus source. In addition, the high surface area offered by nanoparticles allows binding of a large amount of urea molecules. The method reported here is simple and scalable, allowing the synthesis of a urea-modified hydroxyapatite nanohybrid as fertilizer having a ratio of urea to hydroxyapatite of 6:1 by weight. Specifically, a nanohybrid suspension was synthesized by in situ coating of hydroxyapatite with urea at the nanoscale. In addition to the stabilization imparted due to the high surface area to volume ratio of the nanoparticles, supplementary stabilization leading to high loading of urea was provided by flash drying the suspension to obtain a solid nanohybrid. This nanohybrid with a nitrogen weight of 40% provides a platform for its slow release. Its potential application in agriculture to maintain yield and reduce the amount of urea used is demonstrated.


Differences in the serum levels of acetaldehyde and cytotoxic acetaldehyde-albumin complexes after the consumption of red and white wine: in vitro effects of flavonoids, vitamin E, and other dietary antioxidants on cytotoxic complexes.
After the consumption of ethanol, acetaldehyde levels increase in the serum, and the serum develops a nondialyzable cytotoxic activity caused by the formation of unstable acetaldehyde-albumin complexes. The concentration of acetaldehyde in the serum and the cytotoxic activity in serum albumin 8.5 hr after six healthy volunteers began to drink 94 g of ethanol were significantly less when the ethanol was consumed as red wine than as white wine. The serum acetaldehyde was measured by a fluorigenic HPLC assay, and the cytotoxic activity in albumin was determined using two different assays based on dissimilar endpoints: (1) detachment of adherent A9 cells and (2) impairment of the ability of A9 cells to reduce tetrazolium. When serum obtained from five other healthy volunteers after the consumption of white wine was incubated at 37 degrees C for 3 hr with a number of dietary antioxidants at a concentration of 100 mumol/liter, the cytotoxicity of the albumin was markedly reduced. The antioxidants studied consisted of six flavonoids (kaempherol, fisetin, quercetin catechin, taxifolin, and coumarin) and three nonflavonoids (salicylic acid, tannic acid, and alpha-tocopherol). In the cases of alpha-tocopherol, a statistically significant reduction of cytotoxicity was observed at a concentration of 10 mumol/liter. In addition, the cytotoxicity of artificially prepared acetaldehyde-albumin complexes was significantly reduced when such complexes were incubated with 50 to 100 mumol/liter of kaempherol, fisetin, quercetin, coumarin or salicylic acid, or 10 mumol/liter of alpha-tocopherol at 37 degrees C for 3 hr. Evidently, in vitro, flavonoid and nonflavonoid dietary constituents reduce the amount of unstable acetaldehyde-albumin complexes found in both postalcohol serum and in artificially produced acetaldehyde-albumin complexes. The difference in the amount of unstable acetaldehyde-albumin complexes found in serum after the consumption of red and white wine may therefore be caused by the higher concentration of antioxidants, including flavonoids, in red wine than in white wine. Because acetaldehyde and acetaldehyde-albumin complexes have been implicated in the pathogenesis of alcohol-mediated tissue damage, these data suggest that dietary antioxidants may influence the biological consequences of excess alcohol consumption.


The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes.
Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B) on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be achieved in humans supplemented with orally administered milk thistle extracts due to the poor bioavailability of flavonolignans documented with most commercially available formulations.


Effect of cyclic nucleotide analogs on intrachain site I of protein kinase isozymes.
The effects of numerous cAMP analogs present in the [3H]cAMP binding reaction on subsequent dissociation of [3H]cAMP from the regulatory subunit of cAMP-dependent protein kinase I and II were analyzed. Certain analogs with modification at either C-8 or C-2 showed relative selectivity for one (site 1) of two intrachain cAMP binding sites of both isozymes. Modification at C-6 caused selectivity for the second site (site 2). The combination of a site-1-directed and site-2-directed analog inhibited [3H]cAMP binding much more than did either analog alone. In general, there was a correlation between the site 1 selectivity and the ability of the analog to stimulate the binding of [3H]cIMP, which selects site 2. The site-1-directed analogs stimulated the initial rate of [3H]cIMP binding. The stimulatory effect was enhanced in the presence of a polycationic protein such as histone and was inhibited by high ionic strength. The type I and II isozymes exhibited large differences in analog specificity for this effect. For type I, of the analogs tested the most efficacious for stimulating [3H]cIMP binding were those containing a nitrogen atom attached to C-8, 8-aminobutylamino-cAMP being the most effective. Type II responded best to analogs containing a sulfur atom attached to C-8, 8-SH-cAMP being the most effective of those tested. The stimulatory effect was accentuated in the presence of MgATP when using type I, but this nucleotide had no effect when using type II. It is proposed that in intact tissues cAMP binding to site 1 of either isozyme stimulates the binding to site 2.


Trade-offs in the evolution of virulence in an indirectly transmitted macroparasite.
The adaptive trade-off theory for the evolution and maintenance of parasite virulence requires that virulence be genetically correlated with other fitness characteristics of the parasite. Many theoretical models rely on a positive correlation between virulence and transmissibility. They assume that high parasite replication rates are associated with a high probability of transmission (and, hence, increased parasite fitness), but also with high levels of damage to the host (high virulence). Schistosomes are macroparasites with an indirect life cycle involving a mammalian and a molluscan host. Here we demonstrate, through the development of five substrains, a genetic basis for schistosome virulence. We used these substrains further in order to investigate the presence of parasite fitness traits that were genetically correlated with virulence. High virulence in the (mouse) definitive host was, as predicted, positively correlated with parasite replication. In contrast, in the (snail) intermediate host high virulence was associated with low parasite replication rates. Variation in infectivity to and parasite replication in the definitive host was suggested as a compensating mechanism for the maintenance of virulence in the snail host. This is the first report of a trade-off in parasite reproductive success across hosts in an indirectly transmitted macroparasite.


[Treatment approaches for bronchopulmonary infection in myasthenia gravis patients].
Nineteen patients with bronchopulmonary infection and myasthenia gravis were enrolled in the study. The microbiological analysis of the specimens of phlegm and bronchial secretion revealed both grampositive and gramnegative bacteria. All the isolates were susceptible to the antibiotic used (cefoperazone/sulbactam). Intravenous immunoglobulins (IvIgs) were used to increase the treatment efficacy, to opsonize the infection foci and to decrease the hospitalization terms. The antibiotic therapy and simultaneous use of intravenous immunoglobulins provided higher clinical efficacy in 16 out of 19 patients (84.2%).


Polytetrafluoroethylene sponge syringosubarachnoid shunt.
Syringomyelia is condition in which a cyst or cavity forms inside the spinal cavity. Its management always remains a difficult. A variety of surgical techniques have been used in management of syringomyelia. Syringosubarachnoid shunt remains an effective method in management of syringomyelia. Shunt tube obstruction remains an important complication of shunt procedure. We describe a novel technique of use of polytetrafluoroethylene sponge shunt for syringosubarachnoid shunt in patient with large syrinx and Chiari 1 malformation. Polytetrafluoroethylene sponge is a non irritant material with multiple porosities that is less susceptible to blockages or kinking. It could provide a good alternative technique in syringosubarachnoid shunting.


Membrane traffic in animal cells: cellular glycoproteins return to the site of Golgi mannosidase I.
The recycling of cellular glycoproteins to the site of Golgi mannosidase I, an enzyme of asparagine-linked oligosaccharide synthesis, was studied in K562 human erythroleukemia cells. Cells were metabolically labeled in the presence of deoxymannojirimycin, a reversible inhibitor of Golgi mannosidase I. This generates glycoproteins with immature oligosaccharides in their normal locations. Transport to the mannosidase I compartment was then assessed by testing for the conversion of oligosaccharides into mature forms during reculture without deoxymannojirimycin. Transferrin receptor (TfR) was acted on by mannosidase I during reculture, suggesting that it returned to the region of the Golgi complex where this enzyme resides. The slow rate of this transport (t1/2 greater than 6 h) implies that it is probably different than TfR movement during transferrin internalization (t1/2 = 10-20 min) and TfR transport to the sialyltransferase compartment in the Golgi complex (t1/2 = 2-3 h) (Snider, M. D., and O. C. Rogers, 1985, J. Cell Biol., 100:826-834). The total cell glycoprotein pool was also transported to the mannosidase I compartment with a half-time of 4 h. Because this transport is 5-10 times faster than the rate of de novo glycoprotein synthesis in these cells, it is likely that most of the glycoprotein traffic through the Golgi complex is composed of recycling molecules.


Heat shock protein 90 (Hsp90) inhibitor STA-9090 (Ganetespib) ameliorates inflammation in a mouse model of atopic dermatitis.
Molecular chaperones belonging to the heat shock protein 90 (Hsp90) family are implicated in inflammatory processes and described as potential novel therapeutic targets in autoimmune/inflammatory skin diseases. While the pathological role of circulating Hsp90 has been recently proposed in patients with atopic dermatitis (AD), a chronic inflammatory skin disease characterized by intense itching and recurrent skin lesions, studies aimed at investigating the role of Hsp90 as a potential target of AD therapy have not yet been conducted. Here, the effects of the Hsp90 blocker STA-9090 (Ganetespib) applied systemically or topically were determined in an experimental mouse model of dinitrochlorobenzene (DNCB)-induced AD. Intraperitoneal administration of STA-9090 ameliorated clinical disease severity, histological epidermal thickness, and dermal leukocyte infiltration in AD mice which was associated with reducing the scratching behavior in DNCB-treated animals. Additionally, topically applied STA-9090 led to lowered disease activity in AD mice, reduced serum levels of IgE, and up-regulated filaggrin expression in lesional skin samples. Our observations suggest that Hsp90 may be a promising therapeutic target in atopic dermatitis and potentially other inflammatory or autoimmune dermatoses.


Coating thickness and coverage effects on the forces between silica nanoparticles in water.
The structure and interactions of coated silica nanoparticles have been studied in water using molecular dynamics simulations. For 5 nm diameter amorphous silica nanoparticles, we studied the effects of varying the chain length and grafting density of polyethylene oxide on the nanoparticle coating's shape and on nanoparticle-nanoparticle effective forces. For short ligands of length n = 6 and n = 20 repeat units, the coatings are radially symmetric while for longer chains (n = 100) the coatings are highly anisotropic. This anisotropy appears to be governed primarily by chain length, with coverage playing a secondary role. For the largest chain lengths considered, the strongly anisotropic shape makes fitting to a simple radial force model impossible. For shorter ligands, where the coatings are isotropic, we found that the force between pairs of nanoparticles is purely repulsive and can be fit to the form (R/2r(core) - 1)(-b) where R is the separation between the center of the nanoparticles, r(core) is the radius of the silica core, and b is measured to be between 2.3 and 4.1.


Factors associated with suicide in patients with genitourinary malignancies.
Approximately 70% of all suicides in patients aged >60 years are attributed to physical illness, with higher rates noted in patients with cancer. The purpose of the current study was to characterize suicide rates among patients with genitourinary cancers and identify factors associated with suicide in this specific cohort. Patients with prostate, bladder, kidney, testis, and penile cancer were identified in the Surveillance, Epidemiology, and End Results database (1988-2010). Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for each anatomic site. Multivariable logistic regression models generated odds ratios (ORs) for the identification of factors associated with suicide for each malignancy. There were 2268 suicides identified among 1,239,522 individuals with genitourinary malignancies observed for 7,307,377 person-years. The SMRs for patients with cancer were 1.37 for prostate cancer (95% CI, 0.99-1.86), 2.71 for bladder cancer (95% CI, 2.02-3.62), 1.86 for kidney cancer (95% CI, 1.32-2.62), 1.23 for testis cancer (95% CI, 0.88-1.73), and 0.95 for penile cancer (95% CI, 0.65-1.35). On multivariable analysis, male sex was found to be associated with odds of suicide among patients with bladder cancer (OR, 6.63) and kidney cancer (OR, 4.98). Increasing age was associated with suicide for patients with prostate, bladder, and testis cancer (OR range, 1.03-1.06). Distant disease was associated with suicide in patients with prostate, bladder, and kidney cancer (OR range, 2.82-5.43). Among patients with prostate, bladder, and kidney cancer, African American patients were less likely to commit suicide compared with white individuals (OR range, 0.26-0.46). Suicide in patients with genitourinary malignancies poses a public health dilemma, especially among men, the elderly, and those with aggressive disease. Clinicians should be aware of risk factors for suicide in these patients.


Metabolic fuel selection: the importance of being flexible.
Studies in genetically engineered mice have shown the importance of cross-talk between organs in the regulation of energy metabolism. In this issue, a careful metabolic characterization of mice with genetic deficiency of the GLUT4 glucose transporter in adipocytes and muscle is reported. These mice compensate for decreased peripheral glucose disposal by increasing hepatic glucose uptake and lipid synthesis as well as by increasing lipid utilization in peripheral tissues. These findings are relevant to humans with type 2 diabetes, in whom a key feature is diminished peripheral glucose disposal.


Ingestible Sensors.
Ingestible sensing capsules are fast emerging as a critical technology that has the ability to greatly impact health, nutrition, and clinical areas. These ingestible devices are noninvasive and hence are very attractive for customers. With widespread access to smart phones connected to the Internet, the data produced by this technology can be readily seen and reviewed online, and accessed by both users and physicians. The outputs provide invaluable information to reveal the state of gut health and disorders as well as the impact of food, medical supplements, and environmental changes on the gastrointestinal tract. One unique feature of such ingestible sensors is that their passage through the gut lumen gives them access to each individual organ of the gastrointestinal tract. Therefore, ingestible sensors offer the ability to gather images and monitor luminal fluid and the contents of each gut segment including electrolytes, enzymes, metabolites, hormones, and the microbial communities. As such, an incredible wealth of knowledge regarding the functionality and state of health of individuals through key gut biomarkers can be obtained. This Review presents an overview of the gut structure and discusses current and emerging digestible technologies. The text is an effort to provide a comprehensive overview of ingestible sensing capsules, from both a body physiology point of view as well as a technological view, and to detail the potential information that they can generate.


Electrophysiological correlates of diurnal feeding rhythm disruption in rats.
Electrical activity was recorded simultaneously from Ventromedial (VMH) and Lateral Hypothalamus (LH) in chronically prepared rats before and during one hour gustation tests as also during and after food intake in Group I (ad lib feeding) and Group II (3-hour food schedule) animals. The VMH/LH activity designated as Response Ratio (RR) was calculated and gave a better index of the food related behaviour. The basal RR was higher in Group I as compared to Group II rats but the response to glucose and saccharin ingestion showed a differential pattern of decrease after glucose intake in Group I and an increase in Group II. By contrast, on saccharin intake, Group I showed an increase. RRs after food intake did not show a significant change in both Group I and II rats.


G-6-PD and haemoglobin variants among twelve endogamous Dhangar castes of Maharashtra, India.
Incidence of haemoglobin variants and G-6-PD deficiency among 1385 males belonging to 12 endogamous Dhangar castes of Maharashtra, India, have been reported. Of the 12 castes studied 11 lacked the allele for G-6-PD deficiency; 2.7% of the Thellaris were found to be deficient. Haemoglobin Hb-D trait is found in 2 of the 12 castes; the incidence among Ahirs and Hatkars being 0.82% and 1.91%, respectively. One case of Hb-J among the Ahirs, and 2 examples of thalassaemia trait, one each among Ahirs and Gadharis, have been detected. The low incidence of observed G-6-PD deficiency and the detection of Hb-D and J traits, as well as thalassaemia have been discussed in the light of the nomadic way of life of some of the Dhangar castes and prevalence of malaria in the region they occupy. The data strongly suggest that the Dhangars arrived in Maharashtra in the recent past from northwest.


Functional differences and interactions between the Escherichia coli type III secretion system effectors NleH1 and NleH2.
The human pathogens enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC), as well as the related mouse pathogen Citrobacter rodentium, utilize a type III secretion system (T3SS) to inject multiple effector proteins into host cells. The E. coli O157:H7 strain EDL933 carries two copies of non-locus of enterocyte effacement (LEE)-encoded protein H, designated NleH1 and NleH2, both of which bind to the human ribosomal protein S3 (RPS3), a subunit of NF-κB transcriptional complexes. In this study, we describe significant functional differences between NleH1 and NleH2 in their ability to regulate the host NF-κB pathway. We show that the EHEC and EPEC NleH effectors are functionally equivalent in their ability to affect RPS3 nuclear translocation. NleH1, but not NleH2, inhibited NF-κB activity without altering the kinetics of IκBα phosphorylation/degradation. We also determined that the class I PSD-95/Disc Large/ZO-1 (PDZ)-binding domain of NleH was important for its activity in the NF-κB pathway. In addition to binding RPS3, we found that NleH1 and NleH2 are able to bind to each other in vitro and in vivo, suggesting an additional mechanism by which the E. coli NleH effectors may regulate the extent and duration of NF-κB activation after their T3SS-dependent translocation. We also performed mouse infection experiments and established that mouse mortality and Citrobacter colonization were reduced in mice infected with ΔnleH. Complementing ΔnleH with NleH1 restored Citrobacter virulence and colonization to wild-type levels, whereas complementing with NleH2 reduced them. Taken together, our data show that NleH1 and NleH2 have pronounced functional differences in their ability to alter host transcriptional responses to bacterial infection.


The development of visual object recognition in school-age children.
This study documents the age-dependent development of visual object recognition abilities in 115 children aged 6 to 11 years, using a battery of neuropsychological tests based on Marrs model (Efron test, Warringtons Figure-Ground Test, Street Completion Test, Poppelreuter-Ghent Test, a selection of stimuli from the Birmingham Object Recognition Battery, a series of color photographs of objects presented from unusual perspectives or illuminated in unusual ways). The results suggest a maturation of complex visual perceptual abilities, possibly related to the development of the cerebral processes involved in object recognition, and could be the starting point for future investigations of these skills in impaired populations.


COBL7 is required for stomatal formation via regulation of cellulose deposition in Arabidopsis.
As a key regulator of plant photosynthesis, water use efficiency and immunity, stomata are specialized cellular structures that adopt defined shapes. However, our knowledge about the genetic players of stomatal pore formation and stomatal morphogenesis remains limited. Forward genetic screening, positional cloning, confocal and electron microscopy, physiological and pharmacological assays were employed for isolation and characterization of mutants and genes. We identified a mutant, dsm1, with impaired cytokinesis and deformed stomata. DSM1 is highly expressed in guard mother cells and guard cells, and encodes COBRA-LIKE 7 (COBL7), a plant-specific glycosylphosphatidylinositol (GPI)-anchored protein. COBRA-LIKE 7 and its closest homologue, COBL8, are first enriched on the forming cell plates during cytokinesis, and then their subcellular distribution and abundance change are correlated with the progressive stages of stomatal pore formation. Both COBL7 and COBL8 possess an ability to bind cellulose. Perturbing the expression of COBL7 and COBL8 leads to a decrease in cellulose content and inhibition of stomatal pore development. Moreover, we found that COBL7, COBL8 and CSLD5 have synergistic effects on stomatal development and plant growth. Our findings reveal that COBL7 plays a predominant and functionally redundant role with COBL8 in stomatal formation through regulating cellulose deposition and ventral wall modification in Arabidopsis.


The Scribble polarity protein stabilizes E-cadherin/p120-catenin binding and blocks retrieval of E-cadherin to the Golgi.
Several polarity proteins, including Scribble (Scrb) have been implicated in control of vesicle traffic, and in particular the endocytosis of E-cadherin, but through unknown mechanisms. We now show that depletion of Scrb enhances endocytosis of E-cadherin by weakening the E-cadherin-p120catenin interaction. Unexpectedly, however, the internalized E-cadherin is not degraded but accumulates in the Golgi apparatus. Silencing p120-catenin causes degradation of E-cadherin in lysosomes, but degradation is blocked by the co-depletion of Scrb, which diverts the internalized E-cadherin to the Golgi. Loss of Scrb also enhances E-cadherin binding to retromer components, and retromer is required for Golgi accumulation of Scrb, and E-cadherin stability. These data identify a novel and unanticipated function for Scrb in blocking retromer-mediated diversion of E-cadherin to the Golgi. They provide evidence that polarity proteins can modify the intracellular itinerary for endocytosed membrane proteins.


Feeding grape seed extract to horses: effects on health, intake and digestion.
A feeding trial involving four Thoroughbred race horses was undertaken to establish whether inclusion of grape seed extract (GSE) in the diet of horses undergoing mild exercise had any effects on their general health, intake and digestion. Supplementation with GSE had no effect on either feed or water intake of the horses and the supplement was readily palatable to the horses at all levels of inclusion. Feeding GSE caused no adverse effects in terms of animal health (temperature, pulse and respirations rates), and there were some positive effects related to a presumed alteration in fermentation in the hindgut. Feeding GSE increased faecal pH, changing from acid faeces (pH 6.6) when no GSE was fed to neutral faeces (pH 7.0) when 150 mg GSE/kg body weight (BW) was fed. In addition, blood glucose concentrations were significantly (P < 0.05) decreased when GSE was fed at 100 and 150 mg/kg BW (5.50 ± 0.26 and 5.32 ± 0.72 mmol/l, respectively) compared with the control diet (5.77 ± 0.31 mmol/l). The actual mechanisms causing these alterations are yet to be elucidated, but could have important implications for the prevention of acidosis.


Activity and stability of α-chymotrypsin in biocompatible ionic liquids: enzyme refolding by triethyl ammonium acetate.
In view the of wide scope of structural information of biomolecules in biocompatible ionic liquids (ILs) in various applications including chemical and biochemical, it is essential to study the productive preferential interactions between biological macromolecules and biocompatible ILs. We have therefore explored the stability and activity of α-chymotrypsin (CT) in the presence of five ILs from different families, such as triethyl ammonium acetate (TEAA), triethyl ammonium phosphate (TEAP) from ammonium salts, 1-benzyl-3-methylimidazolium chloride ([Bzmim][Cl]), 1-benzyl-3-methylimidazolium tetrafluoroborate ([Bzmim][BF(4)]) from imidazolium salts and tetra-butyl phosphonium bromide (TBPBr) from phosphonium families. Circular dichroism (CD) and UV-vis spectrophotometer experiments were used to study CT stabilization by ILs, related to the associated structural changes and enzyme activity studies, respectively. We observed that all ILs have a dominant contribution to the stabilization of CT. The stability and activity of CT depends on the structural arrangement of the ions of ILs. Our experimental results explicitly elucidate that more hydrophobic imidazolium and phosphonium cations carrying longer alkyl chains of ILs ([Bzmim][Cl], [Bzmim][BF(4)] and TBPBr) were weak stabilizers for CT, while small alkyl chain molecules of triethyl ammonium salts (TEAA and TEAP) are strong stabilizers and therefore more biocompatible for CT stability. Our CD and NMR measurements reveal that TEAA is a refolding additive for CT from a quenched thermal unfolded enzyme structure.


Betaglycan knock-down causes embryonic angiogenesis defects in zebrafish.
Angiogenesis is an essential requirement for embryonic development and adult homeostasis. Its deregulation is a key feature of numerous pathologies and many studies have shown that members of the transforming growth factor beta (TGF-β) family of proteins play important roles in angiogenesis during development and disease. Betaglycan (BG), also known as TGF-β receptor type III, is a TGF-β coreceptor essential for mice embryonic development but its role in angiogenesis has not been described. We have cloned the cDNA encoding zebrafish BG, a TGF-β-binding membrane proteoglycan that showed a dynamic expression pattern in zebrafish embryos, including the notochord and cells adjacent to developing vessels. Injection of antisense morpholinos decreased BG protein levels and morphant embryos exhibited impaired angiogenesis that was rescued by coinjection with rat BG mRNA. In vivo time-lapse microscopy revealed that BG deficiency differentially affected arterial and venous angiogenesis: morphants showed impaired pathfinding of intersegmental vessels migrating from dorsal aorta, while endothelial cells originating from the caudal vein displayed sprouting and migration defects. Our results reveal a new role for BG during embryonic angiogenesis in zebrafish, which has not been described in mammals and pose interesting questions about the molecular machinery regulating angiogenesis in different vertebrates. genesis 53:583-603, 2015. © 2015 Wiley Periodicals, Inc.


Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer.
Silymarin is a complex extract isolated from the plant Silybum marianum, widely known for its prominent antioxidant and hepatoprotective effects, although increasing evidences have reported extraordinary antiproliferative and apoptotic abilities. As a result, several signaling pathways involved in cell cycle control, cell proliferation, and cell death have been deconvoluted as critical mechanisms. In this regard, cyclin and cyclin-dependent pathways have been the most studied ones. Following that, apoptotic pathways, such as p53, Akt, STAT-3, Ras, and caspases pathways, have been extensively studied, although other mechanisms involved in inflammation and angiogenesis have also been highlighted as silymarin-likely targets in cancer therapy. Therefore, the main challenge of this review is to discuss the diverse molecular mechanisms for silymarin antiproliferative and apoptotic effects; most of them largely studied in various types of cancers so far. Clinical trials and combination therapies related to silymarin application in cancer prevention and treatment are presented as well.


Primary adenoid cystic carcinoma of the bronchus in a female teenager.
Primary adenoid cystic carcinoma (ACC) of the lung is an extremely rare malignant lung neoplasm. ACC of salivary glands of the head and neck, lachrymal glands, breast, skin, vulva and trachea have been frequently reported disease patterns in the literature, but it is unique to see this rare lung tumour in a patient as young as 14 years old. No double blind placebo, multicentre treatment data are available. Surgery is considered as the cornerstone of the treatment. Prognosis is variable and adjuvant radiotherapy has been found beneficial for prolonged survival. Our report of primary lung ACC in a young girl is a complex case due to young age, a different way of presentation and staging on diagnosis. It has been a quite challenging clinical scenario for the multidisciplinary lung cancer treating team involved in the clinical care. Prognosis remains unpredictable and uncertain despite the best present day evidence-based treatment.


Immunoglobulin G anti-endothelial cell antibodies: inducers of endothelial cell apoptosis in pulmonary arterial hypertension?
Endothelial cell (EC) apoptosis seems to play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). We aimed to test the hypothesis that circulating anti-endothelial cell antibodies (AECA) of PAH patients induce EC apoptosis. Immunoglobulin (Ig)G was purified from sera of PAH patients (n = 26), patients with systemic lupus erythematosus (SLE) nephritis without PAH (n = 16), patients with systemic sclerosis (SSc) without PAH (n = 58) and healthy controls (n = 14). Human umbilical vein endothelial cells (HUVECs) were incubated with patient or healthy control IgG for 24 h. Thereafter, apoptosis was quantified by annexin A5 binding and hypoploid cell enumeration by flow cytometry. Furthermore, real-time cell electronic sensing (RT-CES™) technology was used to monitor the effects of purified IgG from patient and healthy control IgG on HUVECs. As demonstrated previously, IgG of AECA-positive SLE nephritis patients (n = 7) induced a higher percentage of apoptosis of HUVECs compared to IgG of AECA-negative SLE nephritis patients and healthy controls. Furthermore, IgG of AECA-positive SLE nephritis patients induced a marked decrease in cell index as assessed by RT-CES™ technology. IgG of AECA-positive PAH patients (n = 12) and SSc patients (n = 13) did not alter the percentage of HUVEC apoptosis or cell index compared to IgG of AECA-negative PAH and SSc patients and healthy controls. AECA-positive PAH patients, in contrast to SLE nephritis patients, do not have circulating IgG AECA that enhances apoptosis of HUVECs in vitro. Further studies should focus on other mechanisms by which AECA may enhance EC apoptosis in PAH, such as antibody-dependent cell-mediated cytotoxicity.


[Bone-seeking radiopharmaceuticals in evaluating the treatment of skeletal metastases of malignant tumors].
Data on 97 patients were analysed. Of these, 42 received combined therapy, 30 radiotherapy and 25 chemotherapy. The utmost therapeutic effect (by the selected criteria) was obtained with combined treatment (88.1%). Radionuclide signs of the efficacy of radiotherapy were noted in 70% of the patients, whereas 23.3% did not respond. The least effect was obtained with chemotherapy: the absence of improvement or deterioration were noted in 48% of the patients. The correlation of the data obtained with the clinical ones (the painful syndrome) was observed. A high sensitivity of the method does not only help reveal pathological skeletal changes but also plan adequate therapy.


The construction of visual-spatial situation models in children's reading and their relation to reading comprehension.
Readers construct mental models of situations described by text to comprehend what they read, updating these situation models based on explicitly described and inferred information about causal, temporal, and spatial relations. Fluent adult readers update their situation models while reading narrative text based in part on spatial location information that is consistent with the perspective of the protagonist. The current study investigated whether children update spatial situation models in a similar way, whether there are age-related changes in children's formation of spatial situation models during reading, and whether measures of the ability to construct and update spatial situation models are predictive of reading comprehension. Typically developing children from 9 to 16 years of age (N=81) were familiarized with a physical model of a marketplace. Then the model was covered, and children read stories that described the movement of a protagonist through the marketplace and were administered items requiring memory for both explicitly stated and inferred information about the character's movements. Accuracy of responses and response times were evaluated. Results indicated that (a) location and object information during reading appeared to be activated and updated not simply from explicit text-based information but from a mental model of the real-world situation described by the text; (b) this pattern showed no age-related differences; and (c) the ability to update the situation model of the text based on inferred information, but not explicitly stated information, was uniquely predictive of reading comprehension after accounting for word decoding.


Theoretical calculations of physico-chemical and spectroscopic properties of bioinorganic systems: current limits and perspectives.
In the last decade, we have witnessed substantial progress in the development of quantum chemical methodologies. Simultaneously, robust solvation models and various combined quantum and molecular mechanical (QM/MM) approaches have become an integral part of quantum chemical programs. Along with the steady growth of computer power and, more importantly, the dramatic increase of the computer performance to price ratio, this has led to a situation where computational chemistry, when exercised with the proper amount of diligence and expertise, reproduces, predicts, and complements the experimental data. In this perspective, we review some of the latest achievements in the field of theoretical (quantum) bioinorganic chemistry, concentrating mostly on accurate calculations of the spectroscopic and physico-chemical properties of open-shell bioinorganic systems by wave-function (ab initio) and DFT methods. In our opinion, the one-to-one mapping between the calculated properties and individual molecular structures represents a major advantage of quantum chemical modelling since this type of information is very difficult to obtain experimentally. Once (and only once) the physico-chemical, thermodynamic and spectroscopic properties of complex bioinorganic systems are quantitatively reproduced by theoretical calculations may we consider the outcome of theoretical modelling, such as reaction profiles and the various decompositions of the calculated parameters into individual spatial or physical contributions, to be reliable. In an ideal situation, agreement between theory and experiment may imply that the practical problem at hand, such as the reaction mechanism of the studied metalloprotein, can be considered as essentially solved.


Th17 cells promote tumor growth in an immunocompetent orthotopic mouse model of prostate cancer.
Interleukin-17 (IL-17) has been demonstrated to promote development of a variety of cancers including prostate cancer in genetically modified mouse models. IL-17 is the main product secreted by T helper 17 (Th17) cells. A recent study has shown that Th17 cells and related genes are upregulated in human prostate cancers. However, there is no direct experimental evidence to demonstrate Th17's role in prostate cancer. In the present study, we co-implanted mouse prostate cancer MPC3-luc cells with Th17-polarized mouse splenocytes in the prostate of immunocompetent C57BL/6J male mice. We found that Th17-polarized splenocytes promoted orthotopic allograft prostate tumor growth compared to the control splenocytes. The numbers of IL-17-positive lymphocytes and macrophages were higher in the prostate tumors grown from co-implantation of MPC3-luc cells and Th17-polarized splenocytes, compared to the prostate tumors grown from co-implantation of MPC3-luc cells and control splenocytes. Our findings provide the first direct experimental evidence that Th17 cells may promote prostate cancer growth.


Silent functional magnetic resonance imaging (FMRI) of tonotopicity and stimulus intensity coding in human primary auditory cortex.
The aims of this study were to determine the feasibility of obtaining auditory cortex activation evoked by pure tones presented at threshold and suprathreshold hearing levels, to evaluate tonotopicity of the primary auditory cortex, and to determine the effect of stimulus intensity on auditory cortex activation using silent functional magnetic resonance imaging (fMRI). Sixteen subjects with normal hearing underwent silent fMRI. An audiometer was used to deliver pure tones of 1000, 2000, and 4000 Hz to the left ear. Two levels of acoustic stimulation were used: 1). threshold, hearing level determined in the scanner room and 2). suprathreshold, 70 dB hearing loss (HL). Tonotopicity and stimulus intensity coding was assessed on the basis of the location, extent, and amount of the auditory cortex activation. The localization of activation moved to more medial and posterior regions of the primary auditory cortex as the frequency of the pure tone increased. Compared with a threshold stimulus, a suprathreshold stimulus evoked the same regions with increased spatial extent. The average increase in the right auditory cortex activation in response to suprathreshold stimulus was 57% at 1000, 51% at 2000, and 45% at 4000 Hz compared with that activated by the threshold stimulus. Silent fMRI can be used to evaluate auditory cortex activation using low-intensity stimuli. The level of stimulus intensity increases the amount of auditory cortex activation and influences the fMRI mapping of the tonotopic organization of the primary auditory cortex.


Implications of Demographics and Socioeconomic Factors in Breast Cancer Reconstruction.
Not all women undergo breast reconstruction despite its vital role in the recovery process. Previous studies have reported that women who are ethnically diverse and of lower socioeconomic status are less likely to undergo breast reconstruction, but the reasons remain unclear. The purpose of this study is to evaluate the demographic characteristics of our patient population and their primary reason for not undergoing breast reconstruction. An institutional review board-approved, single-institution study was designed to evaluate all female breast cancer patients of all stages who underwent mastectomy but did not undergo breast reconstruction from 2008 to 2014. Patients were contacted via telephone and asked to participate in a validated, prompted survey. Data regarding their demographic information and primary reason for not undergoing breast reconstruction were collected. Inclusion criteria were met by 181 patients, of which 61% participated in the survey. Overall, the most common reason for not undergoing breast reconstruction (26%) was unwillingness to undergo further procedures. However, the most common reason for patients that identified as Hispanic, Spanish-speaking, high school graduates, or having an annual income less than US $25,000 (P < 0.05) was insufficient information received. This study demonstrates that ethnicity and socioeconomic factors play a key role in determining why patients forego breast reconstruction. Ethnicity, language, education, income, and employment status are associated with patients not receiving appropriate education regarding their reconstructive options. Breast surgeons with a diverse patient population should ensure that these patients are adequately educated regarding their options, and if perhaps, more of these patients would decide to partake in the reconstruction process.


Establishing a priori and a posteriori predictive models to assess patients' peak skin dose in interventional cardiology. Part 2: results of the VERIDIC project.
Optimizing patient exposure in interventional cardiology is key to avoid skin injuries. To establish predictive models of peak skin dose (PSD) during percutaneous coronary intervention (PCI), chronic total occlusion percutaneous coronary intervention (CTO), and transcatheter aortic valve implantation (TAVI) procedures. A total of 534 PCI, 219 CTO, and 209 TAVI were collected from 12 hospitals in eight European countries. Independent associations between PSD and clinical and technical dose determinants were examined for those procedures using multivariate statistical analysis. A priori and a posteriori predictive models were built using stepwise multiple linear regressions. A fourfold cross-validation was performed, and models' performance was evaluated using the root mean square error (RMSE), mean absolute percentage error (MAPE), coefficient of determination (R²), and linear correlation coefficient (r). Multivariate analysis proved technical parameters to overweight clinical complexity indices with PSD mainly affected by fluoroscopy time, tube voltage, tube current, distance to detector, and tube angulation for PCI. For CTO, these were body mass index, tube voltage, and fluoroscopy contribution. For TAVI, these parameters were sex, fluoroscopy time, tube voltage, and cine acquisitions. When benchmarking the predictive models, the correlation coefficients were r = 0.45 for the a priori model and r = 0.89 for the a posteriori model for PCI. These were 0.44 and 0.67, respectively, for the CTO a priori and a posteriori models, and 0.58 and 0.74, respectively, for the TAVI a priori and a posteriori models. A priori predictive models can help operators estimate the PSD before performing the intervention while a posteriori models are more accurate estimates and can be useful in the absence of skin dose mapping solutions.


[Pure alexia secondary to progressive multifocal leukoencephalopathy as first manifestation of HIV infection].
Pure alexia, or alexia without agraphia, is usually caused by disconnection between the gyrus angularis and visual areas of both hemispheres. Cerebrovascular disease is the most frequent cause of this syndrome. We report the first case of a patient with pure alexia secondary to progressive multifocal leukoencephalopathy (PML) as the first manifestation of Human Immunodeficiency Virus (HIV) infection. Polymerase chain reaction in cerebrospinal fluid was positive for JC virus. Despite favorable immunological and virological response to highly active antiretroviral therapy, neurological symptoms and demyelinating lesions progressed during the first months, and right homonyous hemianopsia, acalculia, and color anomia were noted. In magnetic resonance imaging (MRI) demyelinating lesions involved white matter of both occipital lobes, with left predominance, forceps major and splenium of the corpus callosum, together with white matter of the left temporal lobe and both hippocampal regions. During the following months, coinciding cidofovir treatment, the patient had partial clinical improvement, but neurological deficits persisted. The size of MRI lesions significantly improved. PML is frequently the first manifestation of AIDS (acquired immunodeficiency syndrome). It should be considered as a possible diagnosis of pure alexia.


Plant 7SL RNA genes belong to type 4 of RNA polymerase III- dependent genes that are composed of mixed promoters.
The genes transcribed by RNA polymerase III (pol III) display a great diversity in terms of promoter structure and are placed in four groups accordingly. Type 3 subset of pol III genes has promoter elements which reside entirely upstream of the coding region of the gene whereas type 4 consists of genes with mixed promoters that enclose intra- and extragenic regulatory sequences. Plant 7SL RNA genes have been previously classified as type 3 of pol III genes requiring an upstream sequence element and a canonical TATA box for transcriptional activity in transfected plant protoplasts. We have identified two novel functional control regions within the coding region of an Arabidopsis 7SL RNA gene (At7SL-1) that resemble tRNA gene-specific A and B boxes with respect to sequence and position. Single and multiple nucleotide substitutions in either of these regions resulted in a pronounced reduction of transcription activity in tobacco nuclear extract that was not caused by a decreased stability as shown by decay kinetics of wild type and mutant RNA transcripts. These findings suggest that plant 7SL RNA genes should be actually placed in type 4 of pol III-transcribed genes. As a consequence of substantially different upstream promoters utilized by plant and human pol III, in vitro transcription of 7SL RNA genes in heterologous systems is severely impaired. A chimeric human 7SL RNA gene that contains the 5' flanking region up to position -300 of At7SL-1 is yet transcribed with a reduced efficiency in tobacco extract when compared with the plant wild-type gene, supporting the notion that internal regulatory elements contribute to full activity.


Effect of streptavidin-biotin on endothelial vasoregulation and leukocyte adhesion.
The current study examines whether the adhesion promoting arginine-glycine-aspartate-streptavidin mutant (RGD-SA) also affects two important endothelial cell (EC) functions in vitro: vasoregulation and leukocyte adhesion. EC adherent to surfaces via fibronectin (Fn) or Fn plus RGD-SA were subjected to laminar shear flow and media samples were collected over a period of 4h to measure the concentration of nitric oxide (NO), prostacyclin (PGI(2)), and endothelin-1 (ET-1). Western blot analysis was used to quantify the levels of endothelial-derived nitric oxide synthase (eNOS) and cyclooxygenase II (COX II). In a separate set of experiments, fluorescent polymorphonuclear leukocyte (PMN) adhesion to EC was quantified for EC with and without exposure to flow preconditioning. When cell adhesion was supplemented with the SA-biotin system, flow-induced production of NO and PGI(2) increased significantly relative to cells adherent on Fn alone. Previous exposure of EC to shear flow also significantly decreased PMN attachment to SA-biotin supplemented EC, but only after 2h of exposure to shear flow. The observed decrease in PMN-EC adhesion was negated by NG-nitro-L-arginine methyl ester (L-NAME), an antagonist of NO synthesis, but not by indomethacin, an inhibitor to PGI(2) synthesis, indicating the induced effect of PMN-EC interaction is primarily NO-dependent. Results from this study suggest that the use of SA-biotin to supplement EC adhesion encourages vasodilation and PMN adhesion in vitro under physiological shear-stress conditions. We postulate that the presence of SA-biotin more efficiently transmits the shear-stress signal and amplifies the downstream events including the NO and PGI(2) release and leukocyte-EC inhibition. These results may have ramifications for reducing thrombus-induced vascular graft failure.


Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips.
We present characterization of the metabolic performance of human cryopreserved hepatocytes cultivated in a platform of parallelized microfluidic biochips. The RTqPCR analysis revealed that the mRNA levels of the cytochromes P450 (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) were reduced after the adhesion period (when compared to the post-thawing step). The microfluidic perfusion played a part in stabilizing and partially recovering the levels of the HNF4α, PXR, OAPT2, CYP 1A2, 2B6, 2C19 and 3A4 mRNA on contrary to non-perfused cultures. Fluorescein diacetate staining and P-gp mRNA level illustrated the hepatocytes' polarity in the biochips. Drug metabolism was assessed using midazolam, tolbutamide, caffeine, omeprazole, dextromethorphan, acetaminophen and repaglinide as probes. Metabolite detection and quantification revealed that CYP1A2 (via the detection of paraxanthine), CYP3A4 (via 1-OH-midazolam, and omeprazole sulfone detection), CYP2C8 (via hydroxyl-repaglinide detection), CYP2C19 (via hydroxy-omeprazole detection) and CYP2D6 (via dextrorphan detection) were functional in our microfluidic configurations. Furthermore, the RTqPCR analysis showed that the drugs acted as inductors leading to overexpression of mRNA levels when compared to post-thawing values (such as for HNF4α, PXR and CYP3A4 by dextromethorpahn and omeprazole). Finally, intrinsic in vitro biochip clearances were extracted using a PBPK model for predictions. The biochip predictions were compared to literature in vitro data and in vivo situations.