Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.
Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.


[The clinical, histopathological and imaging methods characteristics of Non-Hodgkin lymphomas in patients with brain involvement].
The Non- Hodgkin-lymphoma (NHL) brain infiltration carries a poor prognosis. Because of relatively rare incidence, we decided to share our experience. Retrospective analysis of patients with NHL brain infiltration dia-gnosed in 2001- 2011 at our university hospital. Twenty -seven patients with median age of 61 (range 42- 82) years were analyzed. The primary diffuse large cell B cell lymphoma of CNS was defined in 22/ 27 (81%) patients, in the others systemic NHL was present. Median positivity of the proliferative marker Ki 67 was 80%, the number of NHL lesions 1 (1- 8), diameter 28 × 30 × 29 (11 × 16 × 20 to 85 × 76 × 65) mm. The fundamental finding in brain lymphoma MRI imaging was lesion with predominantly homogenous contrast enhancement, diffusion restriction and collateral edema. Thirteen out of 27 (48%) patients underwent lumbar puncture, and lymphoma presence in fluid was detected in only two of them. The most frequent symptoms were limb paresis or hemiparesis (55%), bradypsichysm (22%), expressive aphasia (22%), cephalea (18%). Corticosteroid therapy, as a primary treatment option, was indicated in 15% of patients with a median overall survival of one month, CNS radiotherapy in 37% with a median survival of three months, and chemotherapy in 48% patients with a median overall survival 10 (2- 45) months. The brain lymphomas are rare and prognostically very unfavorable affection. When specifying brain focal lesions on MRI, it is necessary to consider this etiology and to elect imaging protocols with contrast agents and diffusion weighted sequence. Biopsy should be performed prior to start of corticosteroid therapy. Intensive chemotherapy or radiotherapy indication must be individually considered, and proposed treatment should be initiated immediately with a potential for somewhat prolonged survival.


A Novel Sensory Wave (P25) in Myelin Oligodendrocyte Glycoprotein-induced Experimental Autoimmune Encephalomyelitis Murine Model.
Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is a murine model for multiple sclerosis. This model is characterized by chronic and progressive demyelination, leading to impairment of motor function and paralysis. While the outcomes of the disease, including impaired motor function and immunological changes, are well-characterized, little is known about the impact of EAE on the electrophysiology of the motor and sensory systems. In this study, we assessed evoked potentials as a quantitative marker for in vivo monitoring of nervous system damage. Motor-evoked potentials (MEPs) and sensory-evoked potentials (SEPs) were first standardized in naïve C57BL mice and studied thoroughly in EAE mice. The duration of MEPs and the number of connotative potentials increased significantly alongside an increase in temporal SEP amplitudes. Moreover, a new SEP wave was identified in naïve animals, which significantly increased in MOG-induced EAE animals with no or mild symptoms (clinical score 0-2, 0-5 scale). This wave occurred ∼25 milliseconds poststimulation, thus named p25. P25 was correlated with increased vocalization and was also reduced in amplitude following treatment with morphine. As the EAE score progressed (clinical score 3-4, 0-5 scale), the amplitude of MEPs and SEPs decreased drastically. Our results demonstrate that desynchronized neural motor activity, along with hypersensitivity in the early stages of EAE, leads to a complete loss of motor and sensory functions in the late stages of the disease. The findings also suggest an increase in p25 amplitude before motor deficits appear, indicating SEP as a predictive marker for disease progression. PERSPECTIVE: This article assesses p25, a new sensory electrophysiology wave that correlates with pain-related behavior in MOG-induced EAE mice and appears prior to the clinical symptoms. Motor electrophysiology correlates with traditional motor behavior scoring and histology.


Three-way interaction model with switching mechanism as an effective strategy for tracing functionally-related genes.
Introduction: Identification of functionally-related genes is an important step in understanding biological systems. The most popular strategy to infer functional dependence is to study pairwise correlations between gene expression levels. However, certain functionally-related genes may have a low expression correlation due to their nonlinear interactions. The use of a three-way interaction (3WI) model with switching mechanism (SM) is a relatively new strategy to trace functionally-related genes. The 3WI model traces the dynamic and nonlinear nature of the co-expression relationship of two genes by introducing their link to the expression level of a third gene. Areas covered: In this paper, we reviewed a variety of existing methods for tracing the 3WIs. Furthermore, we provide a comprehensive review of the previous biological studies based on 3WI models. Expert commentary: Comparison of features of these methods indicates that the modified liquid association algorithm has the best efficiency for tracing 3WI between others. The limited number of biological studies based on the 3WI suggests that high computational demand of the available algorithms is a major challenge to apply this approach for analyzing high-throughput omics data.


Broiler litter ammonia emissions near sidewalls, feeders, and waterers.
Ammonia (NH3) volatilized from broiler litter diminishes indoor air quality, which can potentially decrease bird productivity. Emissions of NH3 exhausted from broiler houses pose environmental concerns for ecosystem biodiversity, aquatic nutrient enrichment, and particulate formation in the atmosphere. Research was conducted sampling litter (rice hull base) in 3 tunnel-ventilated commercial broiler houses during wk 3 (mid-growout) of 6 flocks. The purpose was to assess NH3 generated near the sidewalls, waterers, and feeders. Litter samples (100 g) were placed in chambers receiving constant air flow. Boric acid (H3BO3) titration each 24 h for 4 d was used to determine NH3 volatilized from the samples. Litter located near waterers emitted the most cumulative NH3 (approximately 12.3 mg of N•kg of litter(-1)•h(-1)) with less NH3 associated with feeders and sidewalls (2.9 to 7.6 mg of N•kg of litter(-1)•h(-1)). Moisture content of litter samples was greatest at waterers (45%) followed by sidewalls (26%) and feeders (20%). In addition, litter pH at the sidewalls and feeders could be predicted by linear equations associated with the number of flocks on the litter. At the waterers, litter pH was differentiated based on the half of house where higher litter pH existed in the nonbrood half (8.55 vs. 8.13). The results indicate that controlling NH3 near watering lines to a level consistent with feeding lines and near the house wall could reduce NH3 generated by 38 to 77%. These findings support efforts for NH3 control at mid-growout, especially considering zone litter treatments near waterers and appropriate attention to waterer management.


Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic lateral sclerosis.
Abnormal glutamate metabolism is implied in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and cerebrospinal fluid (CSF) glutamate levels appear to be elevated. Since nitric oxide (NO) inhibits glutamate transport, excessive amounts of nitric oxide could underlie the glutamate induced neurotoxicity in ALS. Stable metabolites of NO (NO2- + NO3-) levels were determined in serum and CSF of sporadic ALS patients and control subjects. NO2- + NO3- levels were higher in ALS, in males and in serum samples compared to controls, females and CSF, respectively. Furthermore, while the difference between serum and CSF NO2- + NO3- levels was significant in males (higher in serum) no such difference was observed in females. Our results suggest that nitric oxide may be involved in the pathogenesis of ALS directly or indirectly and in a sexually dimorphic manner.


Upper and lower tear menisci in the diagnosis of dry eye.
To measure the upper and lower tear menisci in patients with aqueous tear deficiency (ATD) dry eye by real-time optical coherence tomography (OCT) and to determine the most effective meniscus variables for the diagnosis of dry eye. Eyes of 48 pre-screened ATD patients were compared with those of 47 healthy subjects. Upper and lower tear menisci were imaged simultaneously by real-time OCT immediately after blinking. The height, radius, and cross-sectional area of upper and lower tear menisci were obtained. The tear meniscus radius, height, and cross-sectional area were significantly smaller in patients with dry eye than in healthy subjects (P < 0.01). The lower tear meniscus variables were higher than the upper menisci (P < 0.01) in normal subjects; however, no significant differences between menisci were found in ATD patients. In both groups, the upper and lower tear meniscus variables were strongly correlated with each other. Good dry eye diagnostic accuracies were obtained with cutoff values for an abnormal lower tear meniscus radius (LTMR) of 182 microm and a lower tear meniscus height (LTMH) of 164 microm. The LTMR diagnostic sensitivity and specificity were 0.92 and 0.87, respectively. The LTMH diagnostic sensitivity and specificity were 0.92 and 0.90. Upper tear meniscus variables in ATD patients were assessed by real-time OCT. The tear meniscus was smaller in ATD patients than in healthy subjects. LTMR and LTMH may have potential in the diagnosis of ATD.


The role of filgotinib in ulcerative colitis and Crohn's disease.
Filgotinib is an oral small molecule that selectively inhibits JAK1. It is already approved for the treatment of moderately to severely active ulcerative colitis (UC). Ongoing studies are evaluating the efficacy and safety of filgotinib in Crohn's disease (CD). The purpose of this review is to summarize the available data regarding filgotinib in the management of UC and CD. We used Pubmed, Embase and clinicaltrials.gov websites to search all available data and currently ongoing studies regarding the efficacy and safety of filgotinib in inflammatory bowel diseases. Filgotinib is an effective and safe drug for the management of biologic-naive and biologic-experienced patients with moderate-to-severe UC. The same efficacy results have not been achieved in CD.


Accuracy of prediction equations for determining one repetition maximum bench press in women before and after resistance training.
Repetitions to fatigue (RTF) using less than a 1 repetition maximum (1RM) load (RepWt) have been shown to be a good predictor of 1RM strength in men, but such information is scarce in women. The purpose of this study was to evaluate the accuracy of current prediction equations to estimate 1RM bench press performance and to determine whether resistance training changes the capability to predict 1RM from muscular endurance repetitions in young women. Members (n = 103) of a required wellness course were measured for 1RM bench press and RTF using randomly assigned percentages between 60% and 90% of the 1RM (RepWt) before and after 12 weeks of progressive resistance training. The %1RM used to perform RTF remained the same for each individual after training (75.6% +/- 10.3%) as before. One repetition maximum bench press increased significantly after training (28% +/- 21%). Although the change in the group average for RTF (0.6 +/- 6.1) was not significant, the correlation between pretraining and posttraining RTF was moderate (r = 0.66; p < 0.01), and individual differences in percentage change in RTF were substantial (27% +/- 99%). The percentage change in 1RM was not significantly related to initial 1RM (r = -0.05), but it was negatively related to the change in RTF (r = -0.40; p < 0.01). Prediction equations were more accurate in the pretraining and posttraining conditions, in which fewer than 10 RTF were used. Resistance training may alter the relationship between strength and muscle endurance across a wide range of RTF in young women without compromising the accuracy of predicting maximal strength.


Neighborhood Influences on Physical Activity Among Low-Income African American Adults With Type 2 Diabetes Mellitus.
The purpose of the study was to explore the influences of the neighborhood environment on physical activity (PA) among people living with type 2 diabetes mellitus (T2DM) in a community with limited resources. Participants were adults with T2DM and their family members or friends who help in the management of T2DM and who were living in a low-income African American (AA) community. Health care providers working in the neighborhood were also included. Using an emergent design, qualitative data were collected through 7 focus group discussions (N = 63) and 13 in-depth interviews. Verbatim transcriptions were analyzed via thematic coding to explore contextual factors that limit PA and meaning around neighborhood features that promote or discourage PA. Levels of PA were strongly limited by neighborhood insecurity and a lack of recreational facilities in the neighborhood. People with T2DM and physical/mobility disabilities were more affected by the neighborhood environment than those without disabilities, particularly due to perceived safety concerns and social stigma. Despite socioeconomic inequalities within neighborhoods, participants showed resilience and made efforts to overcome social-environmental barriers to PA, applied various coping strategies, and received social support. Results suggested that in an underserved neighborhood, individual barriers to physical activity were amplified by neighborhood-level factors such as crime, especially among individuals who have T2DM and disabilities. Socioeconomic inequalities should be addressed further to improve management of T2DM and its complications.


Sex differences in sucrose reinforcement in Long-Evans rats.
There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using Long-Evans rats. Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data provide a pre-clinical model to further evaluate sex differences in addiction behaviors and manipulations designed to reduce them.


Cytotoxic effects of alkaline tetrasodium EDTA irrigating solutions.
The aim of this study is to determine the cytotoxic effects of tetrasodium ethylenediaminetetraacetic acid (EDTANa4) when used alone or when combined with sodium hypochlorite (NaOCl), with and without the addition of cetrimide (CTR). Human pulmonary fibroblast cell line was exposed to the following irrigating solutions: group 1, 2.5% NaOCl; group 2, 10% EDTANa4; group 3, 20% EDTANa4; group 4, 2.5% NaOCl/5% EDTANa4; group 5, 2.5% NaOCl/10% EDTANa4; group 6, 2.5% NaOCl/5% EDTANa4/0.2% CTR; group 7, 2.5% NaOCl/10% EDTANa4/0.2% CTR; group 8, control, cells in Dulbecco's modified Eagle's medium. Methyl thiazol tetrazolium assay was used to determine the viability of cells after 1 and 24 h. Viability percentages were analyzed for global comparison using the Welch test followed by the Games-Howell test to determine groups with similar viability, and the Student's t test was used to compare the two times. The lowest viability was obtained with a 2.5% NaOCl solution at both time periods. The association of NaOCl with EDTANa4 increased the cellular viability in direct relation with the concentration of the chelating agent. Globally, after 24 h of exposure, cell viability reduced. The solutions of EDTANa4 showed moderate cytotoxic effects when compared with NaOCl alone.


Purification, identification and characterisation of seprase from bovine serum.
The study and identification for the first time of a soluble form of a seprase activity from bovine serum is presented. To date, this activity has only been reported to be an integral membrane protease but has been known to shed from its membrane. The activity was purified 30,197-fold to homogeneity, using a combination of column chromatographies, from bovine serum. Inhibition by DFP, resulting in an IC(50) of 100:nM confirms classification as a serine protease. The protease after separation and visualisation by native PAGE was subjected to tryptic digestion and the subsequent peptides sequenced. Each peptide sequenced was found to be present in the primary structure of seprase/fibroblast activation protein (FAP), a serine gelatinase specific for proline-containing peptides and macromolecules. Substrate specificity studies using kinetic, RP-HPLC and LC-MS analysis of synthetic peptides suggest that this peptidase has an extended substrate-binding region in addition to the primary specificity site S(1). This analysis revealed at least five subsites to be involved in enzyme-substrate binding, with the smallest peptide cleaved being a tetrapeptide. A proline residue in position P(1) was absolutely necessary therefore showing high primary substrate specificity for the Pro-X bond, while a preference for a hydrophobic residue at the C-terminal end of the scissile bond (P'(1)) was evident. The enzyme also showed complete insensitivity to the prolyl oligopeptidase specific inhibitors, JTP-4819, Fmoc-Ala-pyrrCN and Z-Phe-Pro-BT. To date, no physiological substrate has clearly been defined for this protease but its ability to effectively degrade gelatin suggests a candidate protein substrate in vivo and a possible role in extracellular matrix protein degradation.


Peripheral oxytocin is inversely correlated with cognitive, but not emotional empathy in schizophrenia.
Endogenous oxytocin has been associated with different aspects of social cognition in healthy subjects and patients with schizophrenia. In this pilot study, we investigated the relationship between plasma oxytocin and oxytocin level changes induced by empathy-eliciting, attachment-related movie scenes with correlates of cognitive and emotional empathy in patients and healthy controls. The Multifaceted Empathy Test (MET) and the Interpersonal Reactivity Index (IRI) were administered to patients with schizophrenia (N = 35, 12 females) and healthy controls (N = 35, 12 females) to estimate dimensions of cognitive and emotional empathy. Peripheral basal oxytocin concentrations and oxytocin responses to movie-based emotional stimuli were assessed using radioimmunoassay with sample extraction. In patients, induced oxytocin level changes were inversely correlated with MET cognitive empathy regarding negative emotional states. Controlling for non-social cognition and age revealed a significant negative association between basal oxytocin levels and MET cognitive empathy for positive emotions. In healthy subjects, oxytocin reactivity was inversely correlated with the IRI subscale "fantasy". Oxytocin was not related to any measure of emotional empathy. A hyper-reactive oxytocin system might be linked to impaired cognitive empathy as a part of a dysfunctional regulative circuit of attachment-related emotions and interpersonal stressors or threats by attribution of meaning. Healthy adults with a disposition to identify with fictional characters showed lower oxytocin reactivity, possibly indicating familiarity with movie-based stimuli. The oxytocinergic system may be involved in maladaptive coping mechanisms in the framework of impaired mentalizing and associated dysfunctional responses to interpersonal challenges in schizophrenia.


The murG gene of Escherichia coli codes for the UDP-N-acetylglucosamine: N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase involved in the membrane steps of peptidoglycan synthesis.
Physiological properties of the murG gene product of Escherichia coli were investigated. The inactivation of the murG gene rapidly inhibits peptidoglycan synthesis in exponentially growing cells. As a result, various alterations of cell shape are observed, and cell lysis finally occurs when the peptidoglycan content is 40% lower than that of normally growing cells. Analysis of the pools of peptidoglycan precursors reveals the concomitant accumulation of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylmuramyl-pentapeptide (UDP-MurNAc-pentapeptide) and, to a lesser extent, that of undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide (lipid intermediate I), indicating that inhibition of peptidoglycan synthesis occurs after formation of the cytoplasmic precursors. The relative depletion of the second lipid intermediate, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)GlcNAc, shows that inactivation of the murG gene product does not prevent the formation of lipid intermediate I but inhibits the next reaction in which GlcNAc is transferred to lipid intermediate I. In vitro assays for phospho-MurNAc-pentapeptide translocase and N-acetylglucosaminyl transferase activities finally confirm the identification of the murG gene product as the transferase that catalyzes the conversion of lipid intermediate I to lipid intermediate II in the peptidoglycan synthesis pathway. Plasmids allowing for a high overproduction of the transferase and the determination of its N-terminal amino acid sequence were constructed. In cell fractionation experiments, the transferase is essentially associated with membranes when it is recovered.


Towards the definition of Microstates of the Cortical Brain-Heart Axis.
Brain microstates are defined as states with quasi-stable scalp activity topography and have been widely studied in literature. Whether those states are brain-specific or extend to the body level is unknown yet. We investigate the extension of cortical microstates to the peripheral autonomic nerve, specifically at the brain-heart axis level as a functional state of the central autonomic network. To achieve this, we combined Electroencephalographic (EEG) and heart rate variability (HRV) series from 36 healthy volunteers undergoing a cognitive workload elicitation after a resting state. Our results showed the existence of microstates at the functional brain-heart axis with spatio-temporal and quasi-stable states that exclusively pertained to the efferent direction from the brain to the heart. Some of the identified microstates are specific for neural or cardiovascular frequency bands, while others topographies are recurrent over the EEG and HRV spectra. Furthermore, some of the identified brain-heart microstates were associated with specific experimental conditions, while others were nonspecific to tasks. Our findings support the hypothesis that EEG microstates extend to the brain-heart axis level and may be exploited in future neuroscience and clinical research.


Zr-Porphyrin Metal-Organic Framework as nanoreactor for boosting the formation of hydrogen clathrates.
We report the first experimental evidence for rapid formation of hydrogen clathrates under mild pressure and temperature conditions within the cavities of a zirconium-metalloporphyrin framework, specifically PCN-222. PCN-222 has been selected for its 1D mesoporous channels, high water-stability, and proper hydrophilic behavior. Firstly, we optimize a microwave (MW)-assisted method for the synthesis of nanosized PCN-222 particles with precise structure control (exceptional homogeneity in morphology and crystalline phase purity), taking advantage of MW in terms of rapid/homogeneous heating, time and energy savings, as well as potential scalability of the synthetic method. Second, we explore the relevance of the large mesoporous 1D open channels within the PCN-222 to promote the nucleation and growth of confined hydrogen clathrates. Experimental results show that PCN-222 drives the nucleation process at a lower pressure than the bulk system (1.35 kbar vs 2 kbar), with fast kinetics (minutes), using pure water, and with a nearly complete water-to-hydrate conversion. Unfortunately, PCN-222 cannot withstand these high pressures, which lead to a significant alteration of the mesoporous structure while the microporous network remains mainly unchanged.


Former child soldiers' problems and needs: Congolese experiences.
With this article, we explore how staff working at transit centers and vocational training centers in the eastern Democratic Republic of the Congo experienced the problems and needs of former child soldiers. We argued that the staff's experience of the children's daily lives and their understanding of the sociocultural context of the conflict make their perspective a valuable source of information when trying to understand the phenomenon of child soldiering. Additionally, we reasoned that how the staff frame these children's problems influences how they attempt to aid the children. We conducted 11 semistructured interviews and analyzed these using a hermeneutical-phenomenological approach. We clustered our findings around six themes: unfavorable contextual factors, acting as if still in the army, addiction, symptoms of psychopathology, social rejection, and reintegration needs. The overarching message we observed was that the informants experienced that former child soldiers require help to be transformed into civilians who participate proactively in their society.


Effects of fullerenol nanoparticles on kidney tissue in sevoflurane‑treated rats.
The aim of this study is to demonstrate whether fullerenol C60 protects renal injury in sevoflurane‑administered rats. Rats (n: 24) were randomly divided into four groups: Control (Group C), Fullerenol C60 (Group F), Sevoflurane (Group S), Fullerenol C60-Sevoflurane (Group FS). Thirty minutes before the procedure, Fullerenol C60, 100 mg/kg, was administered intraperitoneally. Sevoflurane (2.3 %) was applied for 3 hours to rats in S and FS groups. Biochemical and histopathological parameters were analyzed in renal tissue samples. Kruskal-Wallis and Mann-Whitney U tests were used in statistical analyzes. Malondialdehyde (MDA) level and catalase (CAT) enzyme activity in Group S were significantly higher than that in all other groups. Paraoxanase (PON) enzyme activity in Group S was significantly lower than in Groups C and FS. The histopathological examination showed that vascular vacuolization and hypertrophy (VVH) and lymphocyte infiltration (LI) were significantly higher in the Group S compared to the Group C. Renal histopathology revealed that the administration of Fullerenol C60 prior to sevoflurane inhalation reduced oxidative stress and partially corrected the damage caused by anesthesia. We concluded that Fullerenol C60 has a renal protective effect in rats when administered before sevoflurane anesthesia (Tab. 2, Fig. 4, Ref. 40).


Protein structure-sensitive electrocatalysis at dithiothreitol-modified electrodes.
Dithiothreitol (DTT)-mercury and DTT-solid amalgam electrodes are proposed for protein microanalysis by means of constant current chronopotentiometric stripping (CPS). At the DTT-modified hanging mercury drop electrode (DTT-HMDE), proteins at nanomolar concentrations produce the CPS peak H, which is due to the protein catalyzed hydrogen evolution. Self-assembled monolayers (SAMs) of DTT at the electrode surface protected surface-attached proteins from the electric field-driven denaturation, but did not interfere with the electrocatalysis. Using CPS peak H, native and denatured forms of bovine serum albumin (BSA) and of other proteins were easily distinguished. On the other hand, in usual slow scan voltammetry (scan rates between 50 mV/s and 1 V/s), the adsorbed BSA behaved as fully or partially denatured. BSA-modified DTT-HMDE was exposed to different potentials, E(B) for 60 s, followed by CPS measurement. Three E(B) regions were observed, in which either BSA remained native (A, -0.1 to -0.3 V), was denatured (B, -0.35 to -1.4 V), or underwent desorption (C, at potentials more negative than -1.4 V). At potentials more positive than the reduction potential of the DTT Hg-S bond (approximately -0.65 V against Ag|AgCl|3 M KCl), the densely packed DTT SAM was impermeable to [Ru(NH(3))(6)](3+). At more negative potentials, the DTT SAM was disturbed, but under conditions of CPS (with very fast potential changes), this SAM still protected the protein from surface-induced denaturation. Thiol-modified Hg electrodes in combination with CPS represent a new tool for protein analysis in biomedicine and proteomics.


[Cryptococcal meningitis in AIDS: successful long-term prophylaxis with fluconazole].
A 30-year-old, HIV-positive, man who had been repeatedly treated with amphotericin B for oral thrush, developed headaches, fever up to 38.5 degrees C, dizzy spells with falling tendency, as well as disorder of speech and word finding. Cerebrospinal fluid (CSF) contained 5700/3 cells, of which 90% were encapsulated yeast-fungus. Cryptococcal antigen titres were elevated both in serum (1:256) and CSF (1:1024), providing the diagnosis of cryptococcal meningitis. Intravenous treatment was started with amphotericin B, 0.3 mg/kg daily and flucytosine, 150 mg/kg daily. The clinical, microbiological and serological findings regressed after 4 weeks. After 8 weeks the creatinine concentration rose to 2.5 mg/dl. Because amphotericin B nephrotoxicity was suspected, further intravenous administration was stopped after a cumulative dosage of 2 g. He was placed on a prophylactic dosage of fluconazole, 100 mg by mouth twice daily. The cryptococcal antigen titre had fallen to normal within one year. The prophylactic regimen has been continued now for three years without recurrence or other fungal infection.


Psychosomatic factors in borderline hypertensive subjects and offspring of hypertensive parents.
Psychosomatic factors, sympathoneural and sympathoadrenal as well as cardiovascular mechanisms, were studied in 24 patients 18-24 years of age with borderline hypertension, 50 age-matched normotensive offspring of hypertensive parents, and 49 controls with no family history of hypertension. They were compared by projective and questionnaire-based psychological tests and their circulatory and neurohormonal reactivity to mental (Stroop color-word conflict test and arithmetic test) and physical stressors (orthostasis and bicycle ergometry test) were measured. Borderline hypertensive subjects externalized aggression less (p less than 0.05) but internalized it more (p less than 0.05) and were more submissive (p less than 0.05) when compared with controls. Offspring of hypertensive parents showed a similar but weaker pattern. Both risk groups reported more positive interactions with their parents (genetic risk subjects versus controls, p less than 0.05; borderline hypertensive patients versus controls, p = 0.08) and had higher state-anxiety levels (p less than 0.05). There were more subjective symptoms of beta-adrenergic receptor-mediated functions (e.g., tachycardia, tremor) in borderline hypertensive subjects and offspring of hypertensive parents, elevated heart rates (analysis of repeated measures, p less than 0.001), and enhanced plasma norepinephrine concentrations (p less than 0.05) when compared with controls. These findings in subjects at risk for the development of hypertension suggest that psychosomatic factors and sympathetic overactivity are involved in the early phase of hypertension.


Electron tomography imaging methods with diffraction contrast for materials research.
Transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM) enable the visualization of three-dimensional (3D) microstructures ranging from atomic to micrometer scales using 3D reconstruction techniques based on computed tomography algorithms. This 3D microscopy method is called electron tomography (ET) and has been utilized in the fields of materials science and engineering for more than two decades. Although atomic resolution is one of the current topics in ET research, the development and deployment of intermediate-resolution (non-atomic-resolution) ET imaging methods have garnered considerable attention from researchers. This research trend is probably not irrelevant due to the fact that the spatial resolution and functionality of 3D imaging methods of scanning electron microscopy (SEM) and X-ray microscopy have come to overlap with those of ET. In other words, there may be multiple ways to carry out 3D visualization using different microscopy methods for nanometer-scale objects in materials. From the above standpoint, this review paper aims to (i) describe the current status and issues of intermediate-resolution ET with regard to enhancing the effectiveness of TEM/STEM imaging and (ii) discuss promising applications of state-of-the-art intermediate-resolution ET for materials research with a particular focus on diffraction contrast ET for crystalline microstructures (superlattice domains and dislocations) including a demonstration of in situ dislocation tomography.


Mechanistic studies on the cyclization of (Z)-1,2,4-heptatrien-6-yne in methanol: a possible nonadiabatic thermal reaction.
Myers et al. pyrolyzed (Z)-1,2,4-heptatrien-6-yne (1) in methanol at 100 degrees C and observed benzylmethyl ether (2) as a major product and 2-phenylethanol (3) as a minor product. If a biradical intermediate, such as the open-shell singlet state of alpha,3-didehydrotoluene (4), was the only intermediate generated by the cyclization, then reaction with methanol might be expected to afford 2-phenylethanol as the principal product. The question that has been of interest since its first discovery is the origin of the principal product of the title reaction, benzylmethyl ether. This report considers three mechanisms for formation of the benzylmethyl ether: direct methanol participation in the cyclization of the reactant, partial ether formation from the biradical 4, or involvement of the closed-shell zwitterionic state of alpha,3-didehydrotoluene (5). A fourth mechanism, involving a cyclic allene intermediate, has been ruled out by earlier studies. In the present work, the first two mechanisms are ruled out by experiment and/or calculation. The remaining one, involving the zwitterion, is shown to be consistent with experimental and computational data only if a component of the reaction follows a nonadiabatic course.


Advances in Optoacoustic Neurotomography of Animal Models.
Unlike traditional optical methods, optoacoustic imaging is less sensitive to scattering of ballistic photons, so it is capable of high-resolution interrogation at a greater depth. By integrating video-rate visualization with multiplexing and sensing a range of endogenous and exogenous chromophores, optoacoustic imaging has matured into a versatile noninvasive investigation modality with rapidly expanding use in biomedical research. We review the principal features of the technology and discuss recent advances it has enabled in structural, functional, and molecular neuroimaging in small-animal models. In extending the boundaries of noninvasive observation beyond the reach of customary photonic methods, the latest developments in optoacoustics have substantially advanced neuroimaging inquiry, with promising implications for basic and translational studies.


Ethical considerations of maternal-fetal surgery.
The practice of maternal-fetal surgery (MFS) has expanded from lethal fetal conditions to conditions which are significantly disabling but not a lethal fetal abnormality. The inclusion of myelomeningocele within the scope of MFS in the 1990s sparked a renewed debate over the ethics of MFS. While demonstrating increasing efficacy and range of application, MFS continues to be ethically fraught due to the inherent tension between maternal and fetal interests. Ethical issues central to MFS include the patienthood of the fetus; the balance of risks and benefits between the woman and fetus; informed consent for experimental procedures; and determination of conditions that meet ethical qualifications for MFS intervention. These concerns are likely to persist and evolve as perinatal medicine continues to advance. Here we summarize the current state of MFS ethics, highlighting the major positions in the literature thus far as well as examine future directions. It is essential robust discussions of these important issues continue both to ensure ethical medical practice and to provide support to clinicians, pregnant women, and their families.


Chronic inflammation of the vagina: treatment and relationship to autoimmunity.
To investigate noninfective, symptomatic, chronic inflammation (CI) of the vaginal mucosa to determine its prevalence and immunologic basis and to initiate an immunologic approach to treatment and assess the response. A prospective, observational, clinical study of 55 women with dyspareunia and/or discharge of vaginal mucosal origin. Vaginal biopsies and immune investigations were carried out. Treatment was instituted utilizing immune-modifying agents. The prevalence of CI of the vagina in symptom-free women was 0-4.3% and in the symptomatic group, 89%. Systemic immune activation was demonstrated in 43 of the 55, with 21 suffering from an autoimmune disease or a condition in which immune activation plays a part, including endometriosis in 20. Thirty-one were treated; intravaginal hydrocortisone acetate 10% foam was given in 24, giving full relief in 14 and inadequate relief in 10. Hydroxychloroquine, an immune-modifying, antirheumatic drug, was added and largely gave relief in these 10. Hydroxychloroquine alone was given in 4 and was effective in 3. Overall, immune-modifying drugs were successful in 97%. CI of the vaginal mucosa stems from local immune activation and is generally associated with evidence of other immune abnormalities, including autoimmune diseases and disorders in which immune activation play a part, including endometriosis. It can be successfully treated by immune modification.


Identification of proteins that interact with two regulators of appressorium development, adenylate cyclase and cAMP-dependent protein kinase A, in the rice blast fungus Magnaporthe grisea.
Adenylate cyclase (MAC1) and the catalytic subunit of cAMP-dependent protein kinase A (CPKA) are required for appressorium development and pathogenesis in the rice blast pathogen Magnaporthe grisea. To identify new components in the cAMP signal transduction pathway, we used the yeast two-hybrid system to screen MAC1 and CPKA against an appressorium cDNA library. The cDNA library was constructed by GATEWAY recombinational cloning, enabling transfer of the library to various alternative vectors. The protein phosphatase domain in MAC1, which is unique to fungal adenylate cyclases, interacted with a MAP kinase kinase and a Ser/Thr kinase. Interactions of MAC1 with the kinases may prove to be part of feedback loops between the corresponding signaling pathways. A predicted membrane protein, ACI1, which is highly expressed under conditions that are conducive to appressorium formation, also interacted with MAC1. ACI1 has an extracellular domain containing eight-cysteines, which is also present in other fungal proteins implicated in pathogenesis. The N-terminal half of CPKA, which includes a glutamine-rich sequence unique to a group of fungal sequences, interacted with a putative transcriptional regulator and two different glycosyl hydrolases. Phosphorylation motifs in these sequences suggest that they could be CPKA substrates. The protein interaction assay employed here can now be scaled up to identify interactions between a larger set of proteins in the M. grisea interactome.


A knowledge-interpretable multi-task learning framework for automated thyroid nodule diagnosis in ultrasound videos.
Ultrasound has become the most widely used modality for thyroid nodule diagnosis, due to its portability, real-time feedback, lack of toxicity, and low cost. Recently, the computer-aided diagnosis (CAD) of thyroid nodules has attracted significant attention. However, most existing techniques can only be applied to either static images with prominent features (manually selected from scanning videos) or rely on 'black boxes' that cannot provide interpretable results. In this study, we develop a user-friendly framework for the automated diagnosis of thyroid nodules in ultrasound videos, by simulating the typical diagnostic workflow used by radiologists. This process consists of two orderly part-to-whole tasks. The first interprets the characteristics of each image using prior knowledge, to obtain corresponding frame-wise TI-RADS scores. Associated embedded representations not only provide diagnostic information for radiologists but also reduce computational costs. The second task models temporal contextual information in an embedding vector sequence and selectively enhances important information to distinguish benign and malignant thyroid nodules, thereby improving the efficiency and generalizability of the proposed framework. Experimental results demonstrated this approach outperformed other state-of-the-art video classification methods. In addition to assisting radiologists in understanding model predictions, these CAD results could further ease diagnostic workloads and improve patient care.


Design of anthropomorphic flow phantoms based on rapid prototyping of compliant vessel geometries.
Anatomically realistic flow phantoms are essential experimental tools for vascular ultrasound. Here we describe how these flow phantoms can be efficiently developed via a rapid prototyping (RP) framework that involves direct fabrication of compliant vessel geometries. In this framework, anthropomorphic vessel models were drafted in computer-aided design software, and they were fabricated using stereolithography (one type of RP). To produce elastic vessels, a compliant photopolymer was used for stereolithography. We fabricated a series of compliant, diseased carotid bifurcation models with eccentric stenosis (50%) and plaque ulceration (types I and III), and they were used to form thin-walled flow phantoms by coupling the vessels to an agar-based tissue-mimicking material. These phantoms were found to yield Doppler spectrograms with significant spectral broadening and color flow images with mosaic patterns, as typical of disturbed flow under stenosed and ulcerated disease conditions. Also, their wall distension behavior was found to be similar to that observed in vivo, and this corresponded with the vessel wall's average elastic modulus (391 kPa), which was within the nominal range for human arteries. The vessel material's acoustic properties were found to be sub-optimal: the estimated average acoustic speed was 1801 m/s, and the attenuation coefficient was 1.58 dB/(mm·MHz(n)) with a power-law coefficient of 0.97. Such an acoustic mismatch nevertheless did not notably affect our Doppler spectrograms and color flow image results. These findings suggest that phantoms produced from our design framework have the potential to serve as ultrasound-compatible test beds that can simulate complex flow dynamics similar to those observed in real vasculature.


What role might lampbrush chromosomes play in maternal gene expression?
The biological significance of lampbrush chromosomes from urodelan amphibians is far from being elucidated. Their particularly well developed lateral loops are the site of intense transcriptional activity, which can be visualized in electron microscopy using the Miller spreading procedure. All transcription units functioning in lampbrush loops synthesize RNA at a maximum rate. In situ hybridization has provided evidence for transcription of both unique coding sequences and highly repetitive sequences. The role of lampbrush transcripts in the production of maternal information remains unclear. RNAs transcribed from unique coding sequences are exported to the cytoplasm; there, they contribute either to maintaining the required level of maternal messenger RNA in a basal state during late oogenesis, or to increasing the store of these maternal RNAs throughout oocyte growth, i.e., until stage VI. For repetitive sequences, their intense transcription appears to be non-productive, in that RNAs are not translatable and might be useless products of readthrough transcription. The non-productive transcription of repetitive sequences, the expression of which is directly related to hyperdevelopment of lateral loops, raises the issue of the role of lampbrush chromosome transcription.


Methods of melanoma detection and of skin monitoring for individuals at high risk of melanoma: new Australian clinical practice.
The evidence-based national clinical practice guidelines for the management of cutaneous melanoma published in 2008 are currently being updated. This article summarises the findings from multiple chapters of the guidelines on different methods of melanoma detection and of monitoring the skin for patients at high risk of melanoma. Early detection of melanoma is critical, as thinner tumours are associated with enhanced survival; therefore, strategies to improve early detection are important to reduce melanoma-related mortality. Clinicians who perform skin examinations for the purpose of detecting skin cancer should be trained in and use dermoscopy. The use of short term sequential digital dermoscopy imaging to detect melanomas that lack dermoscopic features of melanoma is recommended to assess individual melanocytic lesions of concern. The use of long term sequential digital dermoscopy imaging to detect melanomas that lack dermoscopic features of melanoma is recommended to assess individual or multiple melanocytic lesions for routine surveillance of high risk patients. The use of total body photography should be considered in managing patients at increased risk for melanoma, particularly those with high naevus counts and dysplastic naevi. There is insufficient evidence to recommend the routine use of automated instruments for the clinical diagnosis of primary melanoma. Determining the relative indications for each diagnostic method and how each method should be introduced into the surveillance of a patient requires careful consideration and an individualised approach.


Adjusting body mass for measurement error with invalid validation data.
We propose a new method for using validation data to correct self-reported weight and height in surveys that do not measure respondents. The standard correction in prior research regresses actual measures on reported values using an external validation dataset, and then uses the estimated coefficients to predict actual measures in the primary dataset. This approach requires the strong assumption that the expectations of measured weight and height conditional on the reported values are the same in both datasets. In contrast, we use percentile ranks rather than levels of reported weight and height. Our approach requires the weaker assumption that the conditional expectations of actual measures are increasing in reported values in both samples. This makes our correction more robust to differences in measurement error across surveys as long as both surveys represent the same population. We examine three nationally representative datasets and find that misreporting appears to be sensitive to differences in survey context. When we compare predicted BMI distributions using the two validation approaches, we find that the standard correction is affected by differences in misreporting while our correction is not. Finally, we present several examples that demonstrate the potential importance of our correction for future econometric analyses and estimates of obesity rates.


Analysis of COVID-19 Pandemic on Supplement Usage and Its Combination with Self-Medication within the State of Arkansas.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the COVID-19 pandemic that can lead to severe respiratory distress requiring hospitalization and can be fatal. Media have reported that various dietary supplements (DS) or their combination with different medications can prevent infection or decrease disease severity. Here, we analyzed data collected from 15,830 patient follow-up telephone interviews from the University of Arkansas for Medical Sciences COVID-19 testing sites from March 15 to August 1, 2020. Within the REDCap database, we recorded patient demographics and DS and medication use. In total, data on DS and medication use was available for 8,150 study participants, of whom 21.9% and 4.1% reported using DS or medications, respectively, to either prevent or treat COVID-19. The majority of respondents were female (64%) and non-Hispanic whites (44.5%). Most individuals (64.5%) who took DS were younger than 50 years of age. Products such as vitamin C (1,013, 33.2%), multivitamins (722, 23.6%), and vitamin D (294, 9.6%) were the most commonly used DS among the responders. Analysis of the DS use and symptom scores association did not provide a strong evidence of beneficial health effects of DS. The results of this study demonstrate that a significantly higher proportion of study participants considered usage of DS to mitigate or prevent COVID-19-related symptoms compared to those who preferred medications. However, lack of observable health benefits associated with ingestion of DS suggests that more rigorous research is needed to substantiate the label claims.


Declining Utilization and Inflation-Adjusted Expenditures for Epidural Procedures in Chronic Spinal Pain in the Medicare Population.
Despite epidurals being one of the most common interventional pain procedures for managing chronic spinal pain in the United States, expenditure analysis lacks assessment in correlation with utilization patterns. This investigation was undertaken to assess expenditures for epidural procedures in the fee-for-service (FFS) Medicare population from 2009 to 2018. The present study was designed to assess expenditures in all settings, for all providers in the FFS Medicare population from 2009 to 2018 in the United States. In this manuscript: • A patient was described as receiving epidural procedures throughout the year.• A visit was considered to include all regions treated during the visit. • An episode was considered as one treatment per region utilizing primary codes only.• Services or procedures were considered as all procedures including bilateral and multiple levels. A standard 5% national sample of the Centers for Medicare and Medicaid Services (CMS) physician outpatient billing claims data for those enrolled in the FFS Medicare program from 2009 to 2018 was utilized. All the expenditures were presented with allowed costs and adjusted to inflation to 2018 US dollars. Total expenditures were $723,981,594 in 2009, whereas expenditures of 2018 were $829,987,636, with an overall 14.6% increase, or an annual increase of 1.5%. However, the inflation-adjusted rate was $847,058,465 in 2009, compared to $829,987,636 in 2018, a reduction overall of 2% and an annual reduction of 0.2%. Inflation-adjusted per patient annual costs decreased from $988.93 in 2009 to $819.27 in 2018 with a decrease of 17.2% or an annual decline of 2.1%. In addition, inflation-adjusted costs per procedure decreased from $399.77 to $377.94, or 5.5% overall and 0.6% annually. Per procedure, episode, visit, and patient expenses were higher for transforaminal epidural procedures than lumbar interlaminar/caudal epidural procedures. Overall, costs of transforaminal epidurals increased 27.6% or 2.7% annually, whereas lumbar interlaminar and caudal epidural injections cost were reduced 2.7%, or 0.3% annually. Inflation-adjusted costs for transforaminal epidurals increased 9.1% or 1.0% annually and declined 16.9 or 2.0% annually for lumbar interlaminar and caudal epidural injections. Expenditures for epidural procedures in chronic spinal pain were assessed only in the FFS Medicare population. This excluded over 30% of the Medicare population, which is enrolled in Medicare Advantage plans. After adjusting for inflation, there was a decrease of expenditures for epidural procedures of 2%, or 0.2% annually, from 2009 to 2018. However, prior to inflation, the increases were noted at 14.6% and 1.5%. Inflation-adjusted costs per patient, per visit, and per procedure also declined. The proportion of Medicare patients per 100,000 receiving epidural procedures decreased 9.1%, or 1.1% annually. However, assessment of individual procedures showed higher costs for transforaminal epidural procedures compared to lumbar interlaminar and caudal epidural procedures.


Rituximab as a new therapeutic option in granulomatosis with polyangiitis: a report of two cases.
Findings of several reports suggest that rituximab, a chimeric monoclonal anti-CD20 antibody causing B-lymphocyte depletion, might represent a treatment option for people with granulomatosis with polyangiitis (GPA) (former Wegener's granulomatosis). This study presents the results of rituximab treatment in two patients with treatment-refractory GPA. First patient received rituximab for a granulomatous posterior orbital mass lesion, and eye symptoms were resolved after three courses of treatment. The second patient had eye and paranasal sinus involvement and benefited from two courses of rituximab treatment, with significant clinical improvement. Rituximab may represent an effective novel treatment for remission induction in GPA.


Overland flow transport of pathogens from agricultural land receiving faecal wastes.
Considerable investment has been made in recent years in improvements to the microbiological quality of urban wastewater discharges to surface waters, particularly in coastal towns, with the aim of reducing the exposure of bathers and surfers to gastrointestinal pathogens. As this source of pollution has come under greater control, attention has started to focus on diffuse catchment sources of faecal contamination which have been shown to be dominant during high river flows associated with storm events. This association with storm events suggests that rapidly responding hydrological pathways such as overland flow are likely to be important. The aim of this paper is to establish the current state of knowledge of pathogen transport processes in overland flow. In addition, the paper will attempt to convey the way that soil erosion science may aid our understanding of this environmental problem. The scale and nature of faecal waste applications to land in the UK is briefly reviewed, with data presented on both livestock slurry and manure, and human sewage sludge. Particular emphasis is placed on factors influencing the likelihood of pathogens making their way from infected livestock and humans to the soil surface, and therefore the chances of them being available for transport by overland flow. The literature relating to pathogen transport in overland flow is reviewed. Existing pathogen transport models treat pathogens as particles and link pathogen transport models to pathogen die-off kinetics. Such models do not attempt to describe the interactions that may occur between pathogens and soil and waste particles. Although conceptual models describing the possible states in which pathogen transport may occur have been proposed, an understanding of the factors controlling the partitioning of the microorganisms between the different states is only just beginning to emerge. The apparent poor performance of overland flow mitigation measures such as grass buffer strips in controlling the movement of faecal indicators highlights the need for a better understanding the dynamics of microbial transport so that better management approaches may be developed. Examples of on-going research into overland flow transport processes are briefly described and gaps in knowledge identified.


Two modified selenite media for the recovery of Yersinia enterocolitica from meats.
Yersinia enterocolitica is one of the few human pathogens that grows at the proper food refrigeration temperatures of 0 to 5 degrees C. Although the isolation of environmental biotypes of Y. enterocolitica from many types of food and water has been reported in the literature, the recovery of the sensitive strains inoculated into foods has been slow and uncertain. Rapid recovery of several clinical strains inoculated into meats was accomplished by using two modified selenite broths without added nutrients. It was critical to restrict the sample size of the blended meat suspension at the 0.2-g/100 ml level, thereby restricting the growth of the total bacterial population in the selenite enrichment media. Otherwise, the slower growing Y. enterocolitica would be overwhelmed by the faster growing normal bacterial flora from the meat. Both the resistant serotype O:3 and the sensitive O:8 clinical isolates of Y. enterocolitica were recovered from the modified selenite enrichment media after 2 and 3 days of incubation at 22 degrees C.


Evidence for mantle metasomatism by hydrous silicic melts derived from subducted oceanic crust.
The low concentrations of niobium, tantalum and titanium observed in island-arc basalts are thought to result from modification of the sub-arc mantle by a metasomatic agent, deficient in these elements, that originates from within the subducted oceanic crust. Whether this agent is an hydrous fluid or a silica-rich melt has been discussed using mainly a trace-element approach and related to variable thermal regimes of subduction zones. Melting of basalt in the absence of fluid both requires high temperatures and yields melt compositions unlike those found in most modern or Mesozoic island arcs. Thus, metasomatism by fluids has been thought to be the most common situation. Here, however, we show that the melting of basalt under both H2O-added and low-temperature conditions can yield extremely alkali-rich silicic liquids, the alkali content of which increases with pressure. These liquids are deficient in titanium and in the elements niobium and tantalum and are virtually identical to glasses preserved in mantle xenoliths found in subduction zones and to veins found in exhumed metamorphic terranes of fossil convergent zones. We also found that the interaction between such liquids and mantle olivine produces modal mineralogies that are identical to those observed in metasomatized Alpine-type peridotites. We therefore suggest that mantle metasomatism by slab-derived melt is a more common process than previously thought.


Moderation of genetic factors by parental divorce in adolescents' evaluations of family functioning and subjective wellbeing.
Adolescents' evaluations of family functioning may have a significant impact on their subjective well-being and adjustment. The aim of the study was to investigate the degree to which genetic and environmental influences affect variation in evaluations of general family functioning, family conflict, and quality of life and the overlap between them. We assessed whether genetic and environmental influences are moderated by parental divorce by analyzing self-report data from 6,773 adolescent twins and their non-twin siblings. Genetic, shared, and nonshared environmental influences accounted for variation in general family functioning and family conflict, with genetic influences being relatively more important in girls than boys in general family functioning. Genetic and nonshared environmental influences accounted for variation in quality of life, with genetic influences being relatively more important in girls. Evidence was found for interaction between genetic factors and parental divorce: genetic influence on general family functioning was larger in participants from divorced families. The overlap between general family functioning and quality of life, and family conflict and quality of life was accounted for the largest part by genetic effects, with nonshared environmental effects accounting for the remaining part. By examining the data from monozygotic twins, we found evidence for interaction between genotype and nonshared, non-measured, environmental influences on evaluations of general family functioning, family conflict, and quality of life.


Health status and internal radiocontamination assessment in children exposed to the fallout of the Chernobyl accident.
The Chernobyl fallout caused release of radioisotope contaminants in a very large area that includes Belarus, the Ukraine, and the Russian Federation. In this study, the authors monitored the health status and level of internal contamination in 422 children who resided in the aforementioned areas and who were < or = 10 y of age at the time of the accident. The children came to Italy for a 1-mo period between 1991 and 1992. During this time, the children underwent pediatric checkups and biochemical, immunological, and thyroid analyses. All children underwent whole-body counter measurements, and urine radiotoxicological analysis was performed for 224 of them. The 24 children evacuated from Pripiat, a village very close to the Chernobyl reactor site, were selected for cytogenetic analysis. All of these children continue to have a detectable internal contamination of caesium radioisotopes. This condition is likely the result of ground and foodstuff contamination in the various areas. The children did not evidence overt pathologies related to ionizing radiation. However, minor alterations in immunological and thyroid parameters were observed in the group of the evacuated children. Traditional cytogenetic dosimetry was not possible, but the occurrence of acentric fragments was observed-indicating a persistent effect of continuous exposure to low doses of radiation.


Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways.
Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM⁺/CD45⁻ cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention.


Final analysis of a prospective trial on functional imaging for nodal staging in patients with prostate cancer at high risk for lymph node involvement.
Accurate staging modalities to diagnose lymph node involvement in patients with prostate cancer (PCa) are lacking. We wanted to prospectively assess sensitivity, specificity, and positive predictive value (PPV) and negative predictive value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for nodal staging in patients with PCa at high risk for lymph node involvement. In total, 75 patients with a risk≥10% but<35% for lymph node (LN) metastases (Partin tables) who had N0 lesions based on the findings of contrast-enhanced CT scans were included. Patients underwent (11)C-choline PET-CT and DW MRI before surgery, which consisted of a superextended lymph node dissection followed by radical prostatectomy. LNs were serially sectioned and histopathologically examined after pankeratin staining. These results were used as the gold standard to compare with the imaging results. Of 1,665 resected LNs (median = 21, range: 7-49), 106 affected LNs (median = 2, range: 1-10) were found in 37 of 75 patients (49%). On a region-based analysis, we found a low sensitivity of 8.2% and 9.5% and a PPV of 50.0% and 40.0% for (11)C-choline PET-CT and DW MRI, respectively. The patient-based analysis showed a sensitivity of 18.9% and 36.1% for and a PPV of 63.6% and 86.7% (11)C-choline PET-CT and DW MRI, respectively. Even when both imaging modalities were combined, sensitivity values remained too low to be clinically useful. Because of the low sensitivity, there is no indication for routine clinical use of either (11)C-choline PET-CT or DW MRI for LN staging in patients with PCa, in whom CT scan findings were normal.


Plant ferritin--a source of iron to prevent its deficiency.
Iron deficiency anemia affects a significant part of the human population. Due to the unique properties of plant ferritin, food enrichment with ferritin iron seems to be a promising strategy to prevent this malnutrition problem. This protein captures huge amounts of iron ions inside the apoferritin shell and isolates them from the environment. Thus, this iron form does not induce oxidative change in food and reduces the risk of gastric problems in consumers. Bioavailability of ferritin in human and animal studies is high and the mechanism of absorption via endocytosis has been confirmed in cultured cells. Legume seeds are a traditional source of plant ferritin. However, even if the percentage of ferritin iron in these seeds is high, its concentration is not sufficient for food fortification. Thus, edible plants have been biofortified in iron for many years. Plants overexpressing ferritin may find applications in the development of bioactive food. A crucial achievement would be to develop technologies warranting stability of ferritin in food and the digestive tract.


Factors affecting the impact of olfactory loss on the quality of life and emotional coping ability.
Olfactory impaired patients have decreased quality of life and may need to develop a coping ability for the olfactory loss. This study investigated how factors like olfactory function, disease duration, etiology, age, and gender affect patients` quality of life and emotional ability to cope. Four hundred and thirteen consecutive patients with the chief complaint of olfactory dysfunction were evaluated. The Questionnaire of Olfactory Disorders (QOD) included negative statements (QOD-NS) that indicated the impact on the quality of life, and positive statements (QOD-PS) reflecting the emotional coping ability. Relations between studied factors and QOD-NS or QOD-PS were analyzed. Poorer olfaction and younger age correlated with increased QOD-NS scores, whereas longer disease duration and older age correlated with increased QOD-PS scores. Females had poorer coping than males. QOD-PS scores were inversely related to QOD-NS scores. The impact of olfactory loss is more significantly felt by younger patients with poorer olfaction. Older patients or those with longer disease duration develop better emotional coping abilities so as to reduce the impact on quality of life. It may be helpful for the patients with olfactory loss to develop emotional coping as early as possible to decrease the olfactory impact.


Influence of thiamine deficiency on the response to ethanol in two inbred rat strains.
We investigated whether thiamine deficiency (TD), a frequent concomitant of chronic alcoholism, differentially modifies the response to ethanol in two inbred rat strains with highly different genetic susceptibilities to development of TD encephalopathy. Ethanol-induced (3 g/kg i.p.) behavioral impairment and hypothermia were studied after 2, 5 and 7 weeks of TD and after 6 weeks of repletion on normal diet. Controls of the M520/N (TD-sensitive) strain metabolized ethanol more rapidly, had a greater liver to body weight ratio, greater total body water, earlier and lower peak blood ethanol concentrations (BEC), diminished area under the BEC curve and lesser behavioral impairment and hypothermia (even at equivalent BEC values) than those of the F344/N (TD-resistant) strain. In both strains, TD resulted in reduced ethanol metabolic rate and liver to body weight ratio and equivalent ethanol-induced hypothermia and behavioral impairment at lower BEC. Lower and delayed peak BEC and unchanged area under the BEC curve suggest an increased volume of ethanol distribution during TD. Recovery appeared complete after 6 weeks of normal diet. Both strains lost an equivalent proportion of body weight during TD but M520/N rats had lesser decrements in ethanol metabolic rate, had greater reductions in liver weight, peak BEC and baseline body temperature and developed overt encephalopathy whereas F344/N rats did not. Therefore, in the chronic alcoholic, TD may modify ethanol's effects via pharmacokinetic and pharmacodynamic mechanisms. Relatively high ethanol tolerance of the strain with a genetic predisposition to TD encephalopathy is consistent with the hypothesized role of this avitaminosis in the pharmacogenetics of alcoholism.


Hericium erinaceus (Bull.: Fr.) Pers., a medicinal mushroom, activates peripheral nerve regeneration.
To study the ability of aqueous extract of Hericium erinaceus mushroom in the treatment of nerve injury following peroneal nerve crush in Sprague-Dawley rats. Aqueous extract of Hericium erinaceus was given by daily oral administration following peroneal nerve crush injury in Sprague-Dawley rats. The expression of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways; and c-Jun and c-Fos genes were studied in dorsal root ganglia (DRG) whereas the activity of protein synthesis was assessed in peroneal nerves by immunohistochemical method. Peripheral nerve injury leads to changes at the axonal site of injury and remotely located DRG containing cell bodies of sensory afferent neurons. Immunofluorescence studies showed that DRG neurons ipsilateral to the crush injury in rats of treated groups expressed higher immunoreactivities for Akt, MAPK, c-Jun and c-Fos as compared with negative control group (P <0.05). The intensity of nuclear ribonucleoprotein in the distal segments of crushed nerves of treated groups was significantly higher than in the negative control group (P <0.05). H. erinaceus is capable of promoting peripheral nerve regeneration after injury. Potential signaling pathways include Akt, MAPK, c-Jun, and c-Fos, and protein synthesis have been shown to be involved in its action.


The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei.
The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are implicated in the photic entrainment of circadian rhythms in the suprachiasmatic nuclei (SCN). We now report that mice carrying a null mutation of the VPAC(2) receptor for VIP and PACAP (Vipr2(-/-)) are incapable of sustaining normal circadian rhythms of rest/activity behavior. These mice also fail to exhibit circadian expression of the core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene arginine vasopressin (AVP) in the SCN. Moreover, the mutants fail to show acute induction of mPer1 and mPer2 by nocturnal illumination. This study highlights the role of intercellular neuropeptidergic signaling in maintenance of circadian function within the SCN.


Effect of stomatognathic alignment exercise on temporomandibular joint function and swallowing function of stroke patients with limited mouth opening.
[Purpose] This study investigated the effects of stomatognathic alignment exercise on temporomandibular joint function and swallowing function of stroke patients presenting limited mouth opening. [Subjects] Fourteen subjects with post-stroke hemiparesis presenting limited mouth opening were randomly assigned to either the experimental group or the control group, with 7 subjects in each group. [Methods] Subjects in the experimental group participated in a stomatognathic alignment exercise program that consisted of mobility exercises of the TMJ and neck and postural correction. Main outcome measures were neck mobility, the active maximum range of mouth opening, the craniomandibular index (CMI), and the Mann assessment of swallowing ability (MASA) score. [Results] The changes in the values of the range of mouth opening, CMI, MASA, and all the parameters of neck mobility were significantly different between the groups. Furthermore, post-test values appeared to be significantly different for the range of mouth opening, the craniomandibular index, and the MASA scores between the groups (p>0.05). [Conclusion] Stomatognathic alignment exercise may improve TMJ function and swallowing function of patients with post-stroke hemiparesis.


Degenerative lumbar stenosis: the neurosurgical perspective.
Degenerative lumbar stenosis is a complex entity caused by predictable patterns of degenerative pathoanatomy. Patients with spinal stenosis are treated by orthopaedic surgeons and neurosurgeons, who often have slightly different ideas regarding treatment strategies. However, data exist to support several recommendations, regarding fusion with or without instrumentation, surgical versus conservative treatment, and limitation of procedures to symptomatic levels. In the current study, the typical patterns of degenerative disease and surgical treatment and a view of the neurosurgical perspective of the treatment of patients with lumbar stenosis are presented.


Molecular determinant of ion selectivity of a (Na+ + K+)-coupled rat brain glutamate transporter.
Glutamate transporters remove this neurotransmitter from the synaptic cleft by a two-stage electrogenic process, in which glutamate is first cotransported with three sodium ions and a proton. Subsequently, the cycle is completed by translocation of a potassium ion in the opposite direction. Recently, we have identified an amino acid residue of the glutamate transporter GLT-1 (Glu-404) that influences potassium coupling. We have now analyzed the effect of seven other amino acid residues in the highly conserved region surrounding this site. One of these residues, Tyr-403, also proved important for potassium coupling, because mutation to Phe (Y403F) resulted in an electroneutral obligate exchange mode of glutamate transport. This mutation in the transporter also caused an approximately 8-fold increase in the apparent sodium affinity, with no change in the apparent affinity for L-glutamate or D-aspartate. Strikingly, although exchange catalyzed by the wild-type transporter is strictly dependent on sodium, the selectivity of Y403F mutant transporters is altered so that sodium can be replaced by other alkaline metal cations including lithium and cesium. These results indicate the presence of interacting sites in or near the transporter pore that control selectivity for sodium and potassium.


Percutaneous drainage of retroperitoneal abscesses: variables for success, failure, and recurrence.
We aimed to evaluate the success and failure rates and minor and major complications of percutaneous drainage of retroperitoneal abscesses. Between 1990 and 2010, percutaneously drained 170 retroperitoneal abscesses in 150 patients (83 males, 67 females, median age 44.2 years, age range, 1-86 years) were included retrospectively. Percutaneous drainage of retroperitoneal abscesses was performed under the guidance of ultrasonography and fluoroscopy or computed tomography. Six abscesses were drained via single needle aspiration whereas 164 abscesses were drained via catheters of 6-14 F calibre using the Seldinger technique. When all retroperitoneal abscesses are considered, success rates were found as follows: 75.3% cure (128/170), 7.7% temporization (13/170), 4.1% palliation (7/170). Failure rate was 12.9% (22/170). Recurrence rate was 10.6% (18/170), and 13 of the recurred abscesses were treated via second session percutaneous drainage. Mortality rate was 2.7% (4/150). Percutaneous drainage is the first treatment option for retroperitoneal abscesses due to procedural reliability, elimination of need for general anesthesia, better tolerability, and lower morbidity and mortality rates compared with the surgical methods. High cure, temporization, or palliation rates can be obtained via imaging-guided percutaneous drainage for all retroperitoneal abscesses with a safe access route.


PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity.
Vaginal microbicides should protect against infection without disrupting the mucosal environment or its mediators of host defense. The objective of this study was to examine the effect of 14 daily applications of 0.5% PRO 2000 or placebo gel on mediators of mucosal immunity and intrinsic antimicrobial activity. A randomized, prospective, double-blind, placebo-controlled study was conducted among 24 healthy, abstinent women. Levels of cytokines, chemokines, defensins, and other protective factors and intrinsic antimicrobial activity were determined in cervicovaginal lavage samples collected on study days 0, 7, 14, and 21. No increase in pro-inflammatory cytokines was observed. Rather cytokines and protective factors including interleukin (IL)-1 receptor antagonist, immunoglobulins and human beta-defensin 2 were lower in the drug compared with the placebo group. All of the mediators returned towards baseline on day 21. Women who were cycling had lower levels of most proteins on study days 7 and/or 14 compared with women on oral contraceptives; however, the magnitude of decline was greater in women who received PRO 2000 compared with placebo gel. The reduction in protective factors was not associated with a loss in the intrinsic anti-viral (HIV or herpes simplex virus) activity or anti-bacterial activity (Escherichia coli or Staphylococcus aureus). In contrast to experience with nonoxynol-9, PRO 2000 did not trigger an inflammatory response in cervicovaginal secretions. There was a modest reduction in mucosal immune mediators, but this loss was not associated with a reduction in intrinsic antimicrobial activity.


Arginine-supplemented diet decreases expression of inflammatory cytokines and improves survival in burned rats.
We examined whether the expression of inflammatory cytokines in organs was influenced by the enteral diet supplemented with arginine in burned rats. Male Wistar rats weighing about 200 g underwent catheter jejunostomy and received scald burns covering 30% of the whole-body surface area. Animals were divided into two groups: a control group (no supplemental arginine, n = 12) and an arginine group (supplemental arginine: 7.7 g/L, n = 10), which continuously received total enteral nutrition for 7 days (250 kcal/kg/d, 1.72 gN/kg/d). The following were measured after the experiment: (1) messenger RNA (mRNA) expression of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and IL-6 in the spleen, thymus, lung, and liver by a semiquantitative reverse transcription-polymerase chain reaction method, (2) inflammatory cytokines in the plasma and supernatant of cultured splenic lymphocytes by enzyme-linked immunosorbant assay, (3) nitric oxide (NO) product, NO2-/NO3-, in the plasma and supernatant of cultured splenic lymphocytes by the Griess method, and (4) survival rate by the Kaplan-Meier method. The mRNA expression of TNF-alpha was significantly decreased in the spleen and lung (p < .01, p < .05), IFN-gamma in the lung (p < .05), IL-1beta in the spleen (p < .05), and IL-6 in the thymus and liver (p < .05, p < .05) in the arginine group when compared with the control group. The production of TNF-alpha by splenic lymphocytes was suppressed in the arginine group in both concanavalin A (Con A)-treated and -untreated cultures (p < .01, p < .05). The production of IFN-gamma by splenic lymphocytes treated with Con A was suppressed in the arginine group (p < .05). The NO product in the supernatant without Con A was increased in the arginine group (p < .05). The mortality rate of the arginine group (0%) was lower than that in the control group (33.3%) on day 7 after the burn injury (p < .05). The data suggest that dietary arginine supplementation decreases the mRNA expression of inflammatory cytokines in organs and improves the survival rate after thermal injury.


The lipid sulfatide is a novel myelin-associated inhibitor of CNS axon outgrowth.
CNS myelin is strongly inhibitory to growing axons and is thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in myelin, including Nogo, MAG, and oligodendrocyte-myelin glycoprotein (OMgp), have been identified as myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS myelin remain to be identified. Here we have investigated the hypothesis that myelin lipids contribute to CNS regenerative failure. We identified sulfatide, a major constituent of CNS myelin, as a novel myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition may share features with other known inhibitors, because the Rho inhibitor C3 transferase lessened these effects. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowth in vitro than was wild-type myelin, indicating that sulfatide is a major component of the inhibitory activity of CNS myelin. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild-type littermates under normal conditions but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failure in vivo.


Cytokine induced inflammatory bowel disease model using organ-on-a-chip technology.
Over 2 million people in North America suffer from inflammatory bowel disease (IBD), a chronic and idiopathic inflammatory condition. While previous research has primarily focused on studying immune cells as a cause and therapeutic target for IBD, recent findings suggest that non-immune cells may also play a crucial role in mediating cytokine and chemokine signaling, and therefore IBD symptoms. In this study, we developed an organ-on-a-chip co-culture model of Caco2 epithelial and HUVEC endothelial cells and induced inflammation using pro-inflammatory cytokines TNF-α and IFN-γ. We tested different concentration ranges and delivery orientations (apical vs. basal) to develop a consistently inducible inflammatory response model. We then measured pro-inflammatory cytokines and chemokines IL-6, IL-8, and CXCL-10, as well as epithelial barrier integrity. Our results indicate that this model 1. induces IBD-like cytokine secretion in non-immune cells and 2. decreases barrier integrity, making it a feasible and reliable model to test the direct actions of potential anti-inflammatory therapeutics on epithelial and endothelial cells.


A molecular-based magnet with a fully interlocked three-dimensional structure.
A compound has been synthesized with the formula (rad)(2)Mn(2)[Cu(opba)](3)(DMSO)(2).2H(2)O, where rad(+) is 2-(4-N-methylpyridinium)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, opba is orthophenylenebis(oxamato), and DMSO is dimethyl sulfoxide. It consists of two nearly perpendicular graphite-like networks with edge-sharing Mn(II)(6)Cu(II)(6) hexagons. The two networks are fully interlocked with the same topological relationship as that between adjacent rings of a necklace. The compound has three kinds of spin carriers: Mn(II) and Cu(II) ions, antiferromagnetically coupled through oxamato bridges, and rad(+) radical cations, bridging the Cu(II) ions through the nitronyl nitroxide groups and forming Cu-rad chains. The temperature dependence of the magnetization reveals that below 22.5 K, the compound behaves as a magnet.


Efficacy and Safety of Prasugrel by Stroke Subtype: A Sub-Analysis of the PRASTRO-I Randomized Controlled Trial.
The efficacy of antiplatelet therapy may vary among different disease subtypes. Prasugrel is generally a more potent, consistent, and fast-acting platelet inhibitor than clopidogrel. This sub-analysis of the phase III comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO-I) trial aimed to assess the differences in efficacy of these treatments for each stroke subtype. In the PRASTRO-I trial, a total of 3,753 patients with ischemic stroke were recruited from 224 centers throughout Japan and randomized (1:1) to prasugrel (3.75 mg/day) or clopidogrel (75 mg/day) for 96 weeks. For the sub-analysis, strokes were classified as large-artery atherosclerosis, small-artery occlusion (lacunar), stroke of other etiology, and stroke of undetermined etiology. The cumulative incidence of primary events (ischemic stroke, myocardial infarction, and death from other vascular cause) and hazard ratios (HRs) were calculated for each subgroup. For patients with large-artery atherosclerosis, the primary event incidence was 3.8% in the prasugrel group and 4.8% in the clopidogrel group (HR 0.79; 95% confidence interval [CI] 0.45-1.41). For patients with small-artery occlusion, the incidence was 3.3% in the prasugrel group and 3.9% in the clopidogrel group (HR 0.82; 95% CI 0.45-1.50). For patients with stroke of undetermined etiology, the incidence was 4.6% in the prasugrel group and 3.0% in the clopidogrel group (HR 1.56; 95% CI 0.90-2.72). The incidence of bleeding was similar across subtypes. Although statistical significance was not reached, the efficacy of prasugrel was potentially different between stroke subtypes, warranting further studies.


Corticospinal projections to lower limb motoneurons in man.
The projections of cortical neurons activated by transcranial magnetic stimulation to single lower limb spinal motoneurons were examined in 34 normal subjects. Peristimulus time histograms of the discharge times of single, voluntarily activated motor units were used to derive information about postsynaptic potentials in single spinal motoneurons produced by magnetic stimuli applied over the contralateral scalp. All tibialis anterior motor units and the majority of motoneurons innervating the small muscles of the foot showed strong short latency facilitation. About half of the motoneurons of proximal lower limb muscles showed this facilitation. Short latency facilitation of the motoneurons of soleus and medial gastrocnemius was only rarely observed and when present was weak. The short latency facilitation is attributed to the projections of the fast corticospinal pathway with monosynaptic projections to motoneurons. The relative strength of the facilitation in different motoneuron pools is considered to reflect the density of corticospinal projections to that motoneuron pool. The observed pattern of projections in man shows some differences from the pattern of projections in subhuman primates that might reflect the different use of the limb.


Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells.
As part of a biomarker discovery effort in peripheral blood, we acquired an immunological profile of cell-surface markers from healthy control and untreated subjects with relapsing-remitting MS (RRMS). Fresh blood from each subject was screened ex vivo using a panel of 50 fluorescently labelled monoclonal antibodies distributed amongst 56 pools of four antibodies each. From these 56 pools, we derived an immunological profile consisting of 1018 'features' for each subject in our analysis using a systematic gating strategy. These profiles were interrogated in an analysis with a screening phase (23 patients) and an extension phase (15 patients) to identify cell populations in peripheral blood whose frequency is altered in untreated RRMS subjects. A population of CD8(low)CD4(-) cells was identified as being reduced in frequency in untreated RRMS subjects (P = 0.0002), and this observation was confirmed in an independent sample of subjects from the Comprehensive Longitudinal Investigation of MS at the Brigham & Women's Hospital (P = 0.002). This reduction in the frequency of CD8(low)CD4(-) cells is also observed in 38 untreated subjects with a clinically isolated demyelination syndrome (CIS) (P = 0.0006). We also show that these differences may be due to a reduction in the CD8(low)CD56(+)CD3(-)CD4(-) subset of CD8(low) cells, which have a natural killer cell profile. Similarities between untreated CIS and RRMS subjects extend to broader immunological profiles: consensus clustering of our data suggests that there are three distinct populations of untreated RRMS subjects and that these distinct phenotypic categories are already present in our sample of untreated CIS subjects. Thus, our large-scale immunophenotyping approach has yielded robust evidence for a reduction of CD8(low)CD4(-) cells in both CIS and RRMS in the absence of treatment as well as suggestive evidence for the existence of immunologically distinct subsets of subjects with a demyelinating disease.


Effects and predictors of shoulder muscle massage for patients with posterior shoulder tightness.
Clinical approaches like mobilization, stretching, and/or massage may decrease shoulder tightness and improve symptoms in subjects with stiff shoulders. We investigated the effect and predictors of effectiveness of massage in the treatment of patients with posterior shoulder tightness. A randomized controlled trial was conducted in a hospital-based outpatient practice (orthopedic and rehabilitation). Forty-three women and 17 men (mean age = 54 years, range 43-73 years) with posterior shoulder tightness participated and were randomized into massage and control groups (n = 30 per group). A physical therapist provided the massage on the posterior deltoid, infraspinatus, and teres minor of the involved shoulder for 18 minutes [about 6 minutes for each muscle] two times a week for 4 weeks. For the control group, one therapist applied light hand touch on the muscles 10 minutes two times a week for 4 weeks. Glenohumeral internal rotation ROM, functional status, and muscle tightness were the main outcomes. Additionally, the potential factors on the effectiveness of massage were analyzed by multivariate logistic regression. For this analysis, patients with functional score improvement at least 20% after massage were considered responsive, and the others were considered nonresponsive. Fifty-two patients completed the study (29 for the massage and 23 for the control). The overall mean internal rotation ROM increased significantly in the massage group compared to the control (54.9° v.s. 34.9°; P ≤ 0.001). There were 21 patients in the responsive group and 8 in the nonresponsive group. Among the factors, duration of symptoms, functional score, and posterior deltoid tightness were significant predictors of effectiveness of massage. Massage was an effective treatment for patients with posterior shoulder tightness, but was less effective in patients with longer duration of symptoms, higher functional limitation, and less posterior deltoid tightness. This clinical trial is registered at Trial Registration "Trial registration: Clinicaltrials.gov NCT01022827".