Antimuscarinic Use in Men Treated With Bladder Outlet Obstruction Medication Therapy.
To assess changes over time in the use of antimuscarinics (AM) among visits in adult men treated with bladder outlet obstruction (BOO) medication therapy (ie, alpha blocker and 5-alpha reductase inhibitors). We used the National Ambulatory Medicare Care Survey database (2006-2014) to identify men aged 40 or older, who initiated or continued on BOO medication therapy. Among these visits, we assessed the percentage of AM and evaluated trends of AM use across between 2006 and 2014 using multivariable logistic regression. Overall, there were 7561 patient visits in men aged 40 or older, who were treated with BOO medication therapy between 2006 and 2014 which equates to approximately 158 million visits in the United States after incorporating National Ambulatory Medicare Care Survey weights. Overall, AM was used in 3.7% of visits, among those who were treated with BOO medication therapy; use of AM increased with age. In the multivariable analysis, there was no increasing trend in the use of AM in 2006 relative to subsequent years through 2014 (P = .8104). Despite a previous study that showed an increasing trend in antimuscarinic use among patients coded for lower urinary tract symptoms or benign prostatic hyperplasia between 1993 and 2010, several recent randomized-controlled trials, and a recommendation in a clinical practice guideline in 2010, we found no increasing trend in antimuscarinic use among visits in men who were treated with BOO medication therapy in 2006 compared to subsequent years. This suggests the potential undertreatment of antimuscarinics and an area for improved prescribing.


Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds.
The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using (3)H- and (14)C-labelled (ring- or side chain labelled) deramciclane and (14)C-dimethylamino-ethanol ((14)C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration-time curves revealed that an intensive cleavage (30-40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (t(1/2)(beta): 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC(0-infinity) and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration-time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.


A thalamo-centric neural signature for restructuring negative self-beliefs.
Negative self-beliefs are a core feature of psychopathology. Despite this, we have a limited understanding of the brain mechanisms by which negative self-beliefs are cognitively restructured. Using a novel paradigm, we had participants use Socratic questioning techniques to restructure negative beliefs during ultra-high resolution 7-Tesla functional magnetic resonance imaging (UHF 7 T fMRI) scanning. Cognitive restructuring elicited prominent activation in a fronto-striato-thalamic circuit, including the mediodorsal thalamus (MD), a group of deep subcortical nuclei believed to synchronize and integrate prefrontal cortex activity, but which has seldom been directly examined with fMRI due to its small size. Increased activity was also identified in the medial prefrontal cortex (MPFC), a region consistently activated by internally focused mental processing, as well as in lateral prefrontal regions associated with regulating emotional reactivity. Using Dynamic Causal Modelling (DCM), evidence was found to support the MD as having a strong excitatory effect on the activity of regions within the broader network mediating cognitive restructuring. Moreover, the degree to which participants modulated MPFC-to-MD effective connectivity during cognitive restructuring predicted their individual tendency to engage in repetitive negative thinking. Our findings represent a major shift from a cortico-centric framework of cognition and provide important mechanistic insights into how the MD facilitates key processes in cognitive interventions for common psychiatric disorders. In addition to relaying integrative information across basal ganglia and the cortex, we propose a multifaceted role for the MD whose broad excitatory pathways act to increase synchrony between cortical regions to sustain complex mental representations, including the self.


Intensification of Hydrogen Production by a Co-culture of Syntrophomonas wolfei and Rhodopseudomonas palustris Employing High Concentrations of Butyrate as a Substrate.
The purpose of this study is to present an effective form of developing a sequential dark (DF) and photo (PF) fermentation using volatile fatty acids (VFAs) and nitrogen compounds as bonding components between both metabolic networks of microbial growing in each fermentation. A simultaneous (co-)culture of Syntrophomonas wolfei (with its ability to consume butyrate and produce acetate) and Rhodopseudomonas palustris (that can use the produced acetate as a carbon source) performed a syntrophic metabolism. The former bacteria consumed the acetate/butyrate mixture reducing the butyrate concentration below 2.0 g/L, permitting Rhodopseudomonas palustris to produce hydrogen. Considering that the inoculum composition (Syntrophomonas wolfei/Rhodopseudomonas palustris) and the nitrogen source (yeast extract) define the microbial biomass specific productivity and the butyrate consumption, a response surface methodology defined the best inoculum design and yeast extract (YE) yielding to the highest biomass concentration of 1.1 g/L after 380.00 h. A second culture process (without a nitrogen source) showed the biomass produced in the previous culture process yields to produce a total cumulated hydrogen concentration of 3.4 mmol. This value was not obtained previously with the pure strain Rhodopseudomonas palustris if the culture medium contained butyrate concentration above 2.0 g/L, representing a contribution to the sequential fermentation scheme based on DF and PF.


Trabeculectomy Outcomes by Supervised Trainees in a Veterans Affairs Medical Center.
To evaluate the outcomes of trabeculectomy performed in an ophthalmology training program. Retrospective study. A total of 160 patients undergoing trabeculectomy performed by a resident or fellow under attending supervision. Trabeculectomy surgeries performed by a supervised resident or fellow surgeon between October 2000 and April 2010 were reviewed. Success was considered to be complete or partial if intraocular pressure (IOP)-lowering medications were not or were required to achieve IOP≤21 mm Hg, respectively. Failure was defined as IOP>21 mm Hg on 2 consecutive visits, loss of light perception vision, IOP≤5 on 2 consecutive visits with associated visual acuity loss of ≥2 lines, or need for surgical intervention. Trabeculectomy survival was determined using Kaplan-Meier analysis through 60 months of follow-up. Final IOP, success/failure rate. Complete success was achieved in 65 patients (41%). The average final IOP of this group was 9.1±3.7 mm Hg. Qualified success was achieved in 56 patients (35%). The average final IOP of this group was 11.5±6.4 mm Hg. At 60 months, the estimated cumulative probability of survival for complete and qualified successes was 28.9% and 63.7%, respectively. Among patients undergoing trabeculectomy by supervised residents or glaucoma fellows in a large Veterans Affairs Medical Center, IOP reduction was significant and similar to published studies. Trabeculectomy remains a successful intervention to lower IOP, with satisfactory success rates in the hands of trainee surgeons.


Early skeletal muscle deconditioning and reduced exercise capacity during (neo)adjuvant chemotherapy in patients with breast cancer.
Fatigue is a hallmark of breast cancer and is associated with skeletal muscle deconditioning. If cancer-related fatigue occurs early during chemotherapy (CT), the development of skeletal muscle deconditioning and its effect on exercise capacity remain unclear. The aim of this study was to investigate the evolution of skeletal muscle deconditioning and exercise capacity in patients with early-stage breast cancer during CT. Patients with breast cancer had a visit before undergoing CT, at 8 weeks, and at the end of chemotherapy (post-CT). Body composition was determined through bioelectrical impedance analysis. Knee extensor, handgrip muscle force and fatigue was quantified by performing maximal voluntary isometric contractions and exercise capacity using the 6-min walking test. Questionnaires were also administered to evaluate quality of life, cancer-related fatigue, and physical activity level. Among the 100 patients, reductions were found in muscle mass (-2.3%, p = .002), exercise capacity (-6.7%, p < .001), and knee extensor force (-4.9%, p < .001) post-CT, which occurred within the first 8 weeks of treatment with no further decrease thereafter. If muscle fatigue did not change, handgrip muscle force decreased post-CT only (-2.5%, p = .001), and exercise capacity continued to decrease between 8 weeks and post-CT (-4.6%, p < .001). Quality of life and cancer-related fatigue were impaired after 8 weeks (p < .001) and remained stable thereafter, whereas the physical activity level remained stable during chemotherapy. Similar to cancer-related fatigue, skeletal muscle deconditioning and reduced exercise capacity occurred early during breast cancer CT. Thus, it appears essential to prevent these alterations through exercise training implemented during CT.


Inhibition of in vitro RNA binding and replicase activity by phosphorylation of the p33 replication protein of Cucumber necrosis tombusvirus.
Tombusviruses, which are small plus-strand RNA viruses of plants, require the viral-coded p33 replication co-factor for template selection and recruitment into replication in infected cells. As presented in the accompanying paper [Shapka, N., Stork, J., Nagy, P.D., 2005. Phosphorylation of the p33 replication protein of Cucumber necrosis tombusvirus adjacent to the RNA binding site affects viral RNA replication. J. Virol. 343, 65-78.], p33 can be phosphorylated in vitro at serine and threonine residues adjacent to its arginine-proline-rich RNA binding site. To test the effect of phosphorylation on p33 function, in this paper, we used phosphorylation-mimicking aspartic acid mutants of Cucumber necrosis virus (CNV) p33 and in-vitro-phosphorylated p33 in gel mobility shift experiments. We found that phosphorylation inhibited the ability of p33 to bind to the viral RNA. In contrast, the nonphosphorylation-mimicking alanine mutants of p33 bound to viral RNA as efficiently as the nonphosphorylated wild type p33 did. In vitro assays with purified CNV replicase preparations revealed that phosphorylation-mimicking mutants of p33 did not support the assembly of functional CNV replicase complexes in yeast, a model host. Based on these results, we propose that the primary function of reversible phosphorylation of p33 is to regulate the RNA binding capacity of p33, which could affect the assembly of new viral replicase complexes, recruitment of the viral RNA template into replication and/or release of viral RNA from replication. Thus, phosphorylation of p33 might help in switching the role of the viral RNA from replication to other processes, such as viral RNA encapsidation and cell-to-cell movement in infected hosts.


Lanigerol: a new antimicrobial icetexane diterpene from Salvia lanigera.
Roots of Salvia lanigera Poir. yielded a new icetexane [10,12-dihydroxy-9(10-->20)-abeo-8,11,13-abietatriene], named lanigerol, which had activity (MIC 1 mg/ml) against Gram-positive bacteria.


Ultra-late EEG potential evoked by preferential activation of unmyelinated tactile afferents in human hairy skin.
Human tactile sensibility in hairy skin is mediated not only by fast conducting myelinated (Aβ) afferents, but also by a system of slow conducting, unmyelinated afferents that respond preferentially to light touch, C-tactile (CT) afferents. This system has previously been shown to correlate with the pleasantness of tactile stimuli, where a soft brush moving at 1-3cm/s activates CT afferents strongly. Functional magnetic resonance imaging (fMRI) studies have shown that preferential CT fiber stimulation activates the posterior insula cortex. The present study aims to assess brain activity evoked by the activation of CT afferents using electroencephalography (EEG). We present evidence for a late cortical potential over frontal electrodes, evoked from slow, gentle brush strokes at 3cm/s. We relate this to the CT afferent input based on the conduction velocity of the CT fibers and the force feedback from the brush; the potential started 0.7s after the brush contacted the skin and continued throughout the brush stimulation. Furthermore, results from brushing at lower and higher speeds showed that the CT potential was modulated by this stimulation. We conclude that the late potential is consistent with activity in a frontal cortical network following hairy skin peripheral stimulation. This provides an important tool for further studies of the CT fiber system and for clinical examination of peripheral unmyelinated afferents.


Low-income children's reported motivators of and barriers to healthy eating behaviors: a focus group study.
Despite national attention to the childhood obesity epidemic, there are few US-based studies that directly ask children--especially children from low-income families and from multiple racial/ethnic groups--why they do or do not engage in healthy eating behaviors. The purpose of this study was to identify motivators of and barriers to healthy eating behaviors, as reported by black, Hispanic, and white children from low-income families. Six gender- and race/ethnicity-concordant focus groups were conducted with 37 children who were aged 9 to 12 years and from families with an annual household income of $40000 or less. Multiple strategies were used to employ a culturally sensitive approach to both data collection and data analysis (eg, a team of culturally diverse researchers utilized inductive qualitative analysis to analyze focus group transcripts). The motivators of and barriers to healthy eating behaviors most commonly reported across the 6 focus groups included social influence, taste, issues of availability, weight concerns, and the desire to be healthy. A variety of less commonly reported motivators and barriers were also discussed. Findings were generally similar across gender and race/ethnicity. Children in this age range can indeed identify a variety of motivators and barriers that influence their engagement in healthy eating behaviors. Interventions targeting obesity and eating behaviors should include an assessment of children's own perceived motivators of and barriers to healthy eating.


Persistent HPV infection after conization of cervical intraepithelial neoplasia-- a systematic review and meta-analysis.
To systematically evaluate several factors of persistent human papillomavirus (HPV) infection following conization in patients with cervical intraepithelial neoplasia (CIN). PubMed, EMBASE and the Cochrane Library were searched from January 1, 1998 to September 10, 2021. Random-effects models for meta-analyses were used and pooled relative risks with 95% confidence intervals were reported. Literature screening, data extraction, and assessment of the risk of bias in the included studies were conducted independently by two researchers. Data analysis was performed with Stata software, version 12.0. A total of 28 studies were included in this study. Meta-analysis revealed that surgical margin and residual disease were positively correlated with persistent HPV infection after conization. Compared with patients infected with other types of HPV, CIN patients with HPV 16 had a higher persistent infection rate (OR = 1.967, 95% CI (1.232-3.140), P < 0.05). CIN patients who are postmenopausal, have positive surgical margins and residual lesions, and are positive for HPV 16 are prone to persistent HPV infection after conization.


Antitumor effect of melatonin on breast cancer in experimental models: A systematic review.
Breast cancer is the most frequent malignant neoplasm in females. While conventional treatments such as chemotherapy and radiotherapy are available, they are highly invasive and toxic to oncological patients. Melatonin is a promising molecule for the treatment of breast cancer with antitumor effects on tumorigenesis and tumor progression. The aim of this systematic review was to synthesize knowledge about the antitumor effect of melatonin on breast cancer in experimental models and propose the main mechanisms of action already described in relation to the processes regulated by melatonin. PubMed, Web of Science, and Embase databases were used. The inclusion criteria were in vitro and in vivo experimental studies that used different formulations of melatonin as a treatment for breast cancer, without year or language restrictions. Risk of bias for studies was assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. Data from selected articles were presented as narrative descriptions and tables. Seventy-five articles on different breast cancer cell lines and experimental models treated with melatonin alone, or in combination with other compounds were included. Melatonin showed antitumor effects on proliferative pathways related to the cell cycle and tumorigenesis, tumor death, angiogenesis, and tumor metastasis, as well as on oxidative stress and immune regulatory pathways. These effects were either dependent or independent of melatonin receptors. Herein, we clarify the antitumor action of melatonin on different tumorigenic processes in breast cancer in experimental models. Systematic review registration: PROSPERO database (CRD42022309822/https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022309822).


ER stress-induced adipocytes secrete-aldo-keto reductase 1B7-containing exosomes that cause nonalcoholic steatohepatitis in mice.
Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent liver disease linked to obesity and associated complications. Endoplasmic reticulum (ER) stress provokes dysfunction in lipid metabolism, which often leads to a progression of obesity-induced hepatic steatosis to NASH. However, the underlying mechanisms in which ER stress in adipose tissue induces hepatic pathology remain elusive. Here, we used male C57BL/6J mice to develop an animal model of NASH induced by a high fat (HFD) diet and methionine- and choline-deficient (MCD) diets. Using a gene-silencing approach with a recombinant lentiviral vector and extensive LC-MS/MS-based proteomics and lipidomics, we demonstrate that the ER stress-induced adipocyte-secreted exosome (ATEx) orchestrates lipid dynamics in the liver. We also noted that ATEx causes hepatic steatosis, inflammation, and fibrosis that lead to NASH through initial accumulation of glycerol and triglycerides in hepatocytes. We also determined that aldo-keto-reductase 1B7 (Akr1b7), a key mediator in liver lipid metabolism, is involved in ATEx-mediated NASH induction. Of note, Akr1b7 deficiency in ER stress-induced ATEx strongly protected the murine liver against HFD and MCD-induced NASH. Our results indicated that ER stress-induced, adipocyte-secreted ATEx triggers NASH by delivering exosomal AKR1B7 to, and elevating glycerol level, in hepatocytes. These findings suggest potential therapeutic strategie that target ATEx to prevent or manage obesity-induced NASH.


A Prospective Randomized Controlled Trial Comparing Enoxaparin & Rivaroxaban for Venous Thromboembolism Prophylaxis in Orthopaedic Trauma.
To determine whether there is a difference in orthopaedic trauma patient medication satisfaction and adherence using an oral versus subcutaneous injectable anticoagulant for venous thromboembolism chemoprophylaxis. Randomized controlled trial. Single academic Level 1 trauma center. One hundred twenty adult orthopaedic trauma patients with operative pelvic or lower extremity fractures were randomized and completed the study. Three weeks of either the service standard 40 mg once daily enoxaparin versus trial medication 10 mg once daily rivaroxaban postoperatively. Patient satisfaction as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM-9). Medication adherence as measured by the Morisky Medication Adherence Scale (MMAS-8). Medication adherence was similar in both groups. Medication satisfaction was significantly higher in the oral rivaroxaban group based on the TSQM-9 and patient-reported data. Secondary outcomes found no significant difference in the incidence of bleeding events or clinically relevant venous thromboembolism. The enoxaparin group experienced more adverse medication-related events. The rivaroxaban medication regimen costs 7.5-10× less out of pocket for uninsured patients. The results of this randomized controlled trial demonstrate that patients with surgical orthopaedic trauma prefer an oral anticoagulant for postoperative venous thromboembolism chemoprophylaxis and suggest that rivaroxaban may be a viable option. Furthermore, large-scale studies are needed to confirm safety and efficacy for rivaroxaban in this population as a potential alternative to enoxaparin and aspirin. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Policy and Payment Factors Affecting the PMH-NP in the United States.
There are unique policy and reimbursement issues pertinent to the Psychiatric Mental Health-Nurse Practitioner (PMH-NP) that are complex and ever-evolving. In the past decade specifically, mental health legislation at the federal level has made, and will continue to make, a serious impact on PMH-NP practice. Pending legislation and policy trends, namely telehealth, affect how and where PMH-NPs will practice and the rates of reimbursement. This article summarizes some recent developments and trends regarding delivery of care and payment that are germane to the PMH-NP. The Center for Medicaid and Medicare Services' (CMS) guidelines for mental health billing and telehealth also are discussed.


TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.
Pustular psoriasis (PP) is a chronic inflammatory disease associated with multiple complications, often with hyperthermia and hypoproteinemia, and its continued progression can be life-threatening. Toll-like receptor 7 (TLR7) induces dendritic cell (DC) production of inflammatory factors that exacerbate the inflammatory response in PP. A membrane-bound chemokine expressed on DCs, CXC motif chemokine ligand 16 (CXCL16) is overexpressed in PP lesions, and neutrophils express its receptor CXC chemokine receptor 6 (CXCR6). There are few studies on the PP immune microenvironment and it is unclear whether TLR7 and CXCL16 can be used as targets in PP therapy. Skin tissue (n = 5) and blood (n = 20) samples were collected from PP and healthy normal controls. The skin tissue transcriptome was analyzed to obtain the differentially expressed genes, and the immune microenvironment was deciphered using pathway enrichment. Tissue sequencing analysis indicated that TLR7, CXCL16, DCs, and neutrophils were involved in the PP process. The enzyme-linked immunosorbent assay, reverse transcription-PCR, and scoring table results demonstrated that TLR7 induced DC secretion of CXCL16, which enabled neutrophil activation of the secretion of the inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). The co-culture of neutrophils with DCs treated with TLR7 inhibitor or TLR7 agonist demonstrated that TLR7 regulated neutrophil activation, migration, and apoptosis. We constructed imiquimod-induced psoriasis-like skin lesions in wild-type, Cd11c-Cre Myd88f/f, and Mrp8-Cre Cxcr6f/f mice. The mouse models suggested that TLR7 might influence DC release of CXCL16 and neutrophil proinflammatory effects by interfering with the myeloid differentiation primary response gene 88 (MyD88) signaling pathway. In conclusion, the TLR7-MyD88-DC-CXCL16 axis is an important mechanism that promotes neutrophil migration to PP skin lesions and stimulates the inflammatory response.


Attitude and risk of substance use in adolescents diagnosed with Asperger syndrome.
Adolescence is a stage of development with increased risk of drug use. Individual personality traits are among those factors that influence the onset of substance use in adolescence and its psychiatric comorbidity. Little research has been done on the comorbidity between substance abuse risk and Asperger syndrome, and none specifically in adolescence. The objective of this study is to assess the risk of drug use by adolescents with Asperger syndrome and compare it with that risk in control subjects. A secondary objective was to analyze the personality factors that may be associated with substance use in the same two groups. We used three self-administered questionnaires, one for drug risk assessment (FRIDA) and the other two for personality trait assessment (MACI and SSS-V). Adolescents diagnosed with Asperger syndrome are at less risk for drug use derived from family and access to drugs factors. Subjects with Asperger syndrome did score higher on introversive, inhibited, doleful, and borderline tendency prototypes than healthy controls, and scored lower on all sensation-seeking traits. Being male, a diagnosis of Asperger syndrome, and unruly, introversive, and sensation-seeking traits were all independently associated with the risk of drug abuse. Both identified personality factors and other variables associated with the Asperger syndrome contribute to the low risk of drug abuse observed in this population. Exploring protective factors for drug use in these subjects may prove useful for interventions with adolescents at risk for consumption.


Adaptation of myocardial twist in the remodelled athlete's heart is not related to cardiac output.
What is the central question of this study? What is the role of heart muscle function in the increased output of remodelled, larger hearts? What is the main finding and its importance? The greater stroke volume of endurance athletes is not associated with enhanced function of the heart muscle (i.e. left ventricular twist, torsion and twist-to-shortening) in normal and low-oxygen environments. These data indicate that, in the process of cardiac adaptation, left ventricular twist may play an important role that is not related to generating a larger output. Since enlarged hearts with low output can develop in disease, the present findings may influence the future interpretation of heart muscle function in patients. Despite increased stroke volume (SV), 'athlete's heart' has been proposed to have a similar left ventricular (LV) muscle function - as represented by LV twist - compared with the untrained state. However, the underpinning mechanisms and the associations between SV/cardiac output and LV twist during exercise are unknown. We hypothesised that endurance athletes would have a significantly lower twist-to-shortening ratio (TwSR, a parameter that relates twist to the shortening of heart muscle layers) at rest, but significantly greater LV muscle function during exercise. Eleven endurance trained male runners and 13 untrained males were tested at rest and during supine cycling exercise in normoxia and hypoxia (increased cardiac output but unaltered SV). Despite the expected cardiac remodelling in endurance athletes, LV twist, torsion, TwSR, strain and strain rate ('LV systolic mechanics') did not differ significantly between groups (P > 0.05). Structural remodelling, as per relative wall thickness, and LV twist did not correlate (r2 = 0.04, P = 0.33). In normoxia and hypoxia, exercise increased LV systolic mechanics in both groups (P < 0.001), but with different relationships to SV and cardiac output. Conversely to our hypothesis, hearts of different size had similar LV systolic mechanics, suggesting that similar twist, torsion and TwSR at rest and during exercise irrespective of cardiac output may be an important mechanism in healthy hearts. We hypothesise that the regulatory 'purpose' of LV twist may be related to the sensing of maximal cardiac myofibre stress, which may act as a biologically purposeful limiter to contraction.


BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action.
Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants causing developmental neurotoxicity (DNT) in humans and rodents. Their DNT effects are suspected to involve thyroid hormone (TH) signaling disruption. Here, we tested the hypothesis whether disturbance of neural progenitor cell (NPC) differentiation into the oligodendrocyte lineage (O4+ cells) by BDE-99 involves disruption of TH action in human and mouse (h,m)NPCs. Therefore, we quantified differentiation of NPCs into O4+ cells and measured their maturation via expression of myelin-associated genes (hMBP, mMog) in presence and absence of TH and/or BDE-99. T3 promoted O4+ cell differentiation in mouse, but not hNPCs, and induced hMBP/mMog gene expression in both species. BDE-99 reduced generation of human and mouse O4+ cells, but there is no indication for BDE-99 interfering with cellular TH signaling during O4+ cell formation. BDE-99 reduced hMBP expression due to oligodendrocyte reduction, but concentrations that did not affect the number of mouse O4+ cells inhibited TH-induced mMog transcription by a yet unknown mechanism. In addition, ascorbic acid antagonized only the BDE-99-dependent loss of human, not mouse, O4+ cells by a mechanism probably independent of reactive oxygen species. These data point to species-specific modes of action of BDE-99 on h/mNPC development into the oligodendrocyte lineage.


[A decrease in the acute toxicity of ethanol produced by zinc sulfate].
It was shown that zinc sulphate injection during the acute alcohol intoxication resulted in the decrease of anaesthetic and toxic effects of ethanol. The most effective dose was 15 mkg/kg i.p. The possible mechanisms are discussed.


An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons.
We have developed a highly effective method for in vivo gene silencing in the spinal cord and dorsal root ganglia (DRG) by a cationic lipid facilitated delivery of synthetic, small interfering RNA (siRNA). A siRNA to the delta opioid receptor (DOR), or a mismatch RNA, was mixed with the transfection reagent, i-Fect (vehicle), and delivered as repeated daily bolus doses (0.5 microg to 4 microg) via implanted intrathecal catheter to the lumbar spinal cord of rats. Twenty-four hours after the last injection, rats were tested for antinociception by the DOR selective agonist, [D-Ala(2), Glu(4)]deltorphin II (DELT), or the mu opioid receptor (MOR) selective agonist, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO). Pretreatment with the siRNA, but not the mismatch RNA or vehicle alone, blocked DELT antinociception dose-dependently. The latter was concomitant with a reduction in the spinal immunoreactivity and receptor density of DOR, and in DOR transcripts in the lumbar DRG and spinal dorsal horn. Neither siRNA nor mismatch RNA pretreatment altered spinal immunoreactivity of MOR or antinociception by spinal DAMGO, and had no effect on the baseline thermal nociceptive threshold. The inhibition of function and expression of DOR by siRNA was reversed by 72 hr after the last RNA injection. The uptake of fluorescence-tagged siRNA was detected in both DRG and spinal cord. The low effective dose of siRNA/i-Fect complex reflects an efficient delivery of the siRNA to peripheral and spinal neurons, produced no behavioral signs of toxicity. This delivery method may be optimized for other gene targets.


Oxygen-induced changes in mitochondrial DNA and DNA repair enzymes in aging rat lens.
The treatment of patients with hyperbaric oxygen (HBO), vitrectomy and loss of vitreous gel during aging is associated with a high risk of subsequent development of nuclear cataract. Many studies proved that oxidation is the key reason of nuclear cataract. Reactive oxygen species (ROS) are formed in mitochondria as a by-product of normal metabolism and as a consequence of exposure to environmental compounds. Therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases and aging. However, the effect of mtDNA damage to the lens has not been studied. The goals of the study were to identify if there was increased mtDNA damage in lens when the eye were exposed to hyperoxic or hypoxic conditions and also to evaluate the changes in gene expression of mtDNA base excision repair (mtBER) enzymes. Our data have shown that the damage of mtDNA, the expression of mtBER enzymes and the level of 8-OHdG in lens increased after inspired hyperoxia, which is likely associated with oxidative stress. However, there was no effect to mtDNA and mtBER enzymes in lens after inspired hypoxia. Nuclear cataract appeared rapidly at 14 month old rats in hyperoxia group, and lens kept transparency in other groups.


LRP130 protein remodels mitochondria and stimulates fatty acid oxidation.
Impaired oxidative phosphorylation (OXPHOS) is implicated in several metabolic disorders. Even though mitochondrial DNA encodes several subunits critical for OXPHOS, the metabolic consequence of activating mitochondrial transcription remains unclear. We show here that LRP130, a protein involved in Leigh syndrome, increases hepatic β-fatty acid oxidation. Using convergent genetic and biochemical approaches, we demonstrate LRP130 complexes with the mitochondrial RNA polymerase to activate mitochondrial transcription. Activation of mitochondrial transcription is associated with increased OXPHOS activity, increased supercomplexes, and denser cristae, independent of mitochondrial biogenesis. Consistent with increased oxidative phosphorylation, ATP levels are increased in both cells and mouse liver, whereas coupled respiration is increased in cells. We propose activation of mitochondrial transcription remodels mitochondria and enhances oxidative metabolism.


DNA damage in clinical radiation therapy studied by microelectrophoresis in single tumour cells. A preliminary report.
Aspiration biopsy specimens were taken from malignant tumours--1 Hodgkin's lymphoma, 3 non-Hodgkin lymphomas, 1 squamous cell carcinoma and 1 adenocarcinoma-before and after irradiation. Individual cells were analysed by micro-electrophoresis, a new technique which estimates radiation-induced DNA strand breaks. The cells were embedded in agarose gel; after lysis of the cells in a neutral detergent solution, an electric field (5 V/cm) was applied for five minutes. DNA showed a tendency to migrate, some cell diameters, and was more pronounced in irradiated than in control cells. The DNA migration was evaluated by a microscope photometer which estimated the fluorescence in cells stained with acridine orange. This technique was found to be suitable for human material in vivo as only a few cells are needed and no radioactive prelabelling is necessary.


Increased levels of interleukin 31 (IL-31) in osteoporosis.
Several inflammatory cytokines play a key part in the induction of osteoporosis. Until now, involvement of the Th2 cytokine interleukin-31 (IL-31) in osteoporosis hadn't yet been studied. IL-31 is a proinflammatory cytokine mediating multiple immune functions, whose involvement in a wide range of diseases, such as atopic dermatitis, inflammatory bowel diseases and cutaneous lymphomas, is now emerging. Given the important role of IL-31 in inflammation, we measured its serum levels in postmenopausal osteoporotic patients. In fifty-six postmenopausal females with osteoporosis and 26 healthy controls, bone mineral density (BMD) measurements were performed by using calcaneal quantitative ultrasound (QUS) technique, confirmed at the lumbar spine and hip by dual energy X-ray absorptiometry (DXA). Both patients and controls were divided according to age (less or more than 65 years) and disease severity (T-score levels and presence of fractures). Serum IL-31 levels were measured by ELISA technique. Osteoporotic patients exhibited elevated levels of serum IL-31 compared with healthy controls (43.12 ± 6.97 vs 29.58 ± 6.09 pg/ml; p < 0.049). IL-31 expression was higher in over 65 years old patients compared to age-matched controls (45 ± 11.05 vs. 17.92 ± 5.92; p < 0.01), whereas in younger subjects no statistically significant differences were detected between patients and controls (37.91 ± 6.9 vs 32.08 ± 8.2). No statistically significant differences were found between IL-31 levels in patients affected by mild (T-score > -3) compared to severe (T-score < -3) osteoporosis (59.17 ± 9.22 vs 37.91 ± 10.52), neither between fractured and unfractured osteoporotic women (33.75 ± 9.16 vs 51.25 ± 8.9). We showed for the first time an increase of IL-31 serum levels in postmenopausal women with decreased BMD. Although they did not reflect the severity of osteoporosis and/or the presence of fractures, they clearly correlated with age, as reflected by the higher levels of this cytokine in aged patients.


Mitochondria in pluripotent stem cells: stemness regulators and disease targets.
Beyond their canonical role in efficient ATP production through oxidative metabolism, mitochondria are increasingly recognized as critical in defining stem cell function and fate. Implicating a fundamental interplay within the epigenetics of eukaryotic cell systems, the integrity of mitochondria is found vital across the developmental/differentiation spectrum from securing pluripotency maintenance to informing organotypic decisions. This overview will discuss recent progress on examining the plasticity of mitochondria in enabling the execution of programming and reprogramming regimens, as well as the application of nuclear reprogramming and somatic cell nuclear transfer as rescue techniques to generate genetically and functionally corrected pluripotent stem cells from patients with mitochondrial DNA-based disease.


Longitudinal study in patients with myotonic dystrophy type 1: correlation of brain MRI abnormalities with cognitive performances.
Myotonic dystrophy type 1 (DM1) is a muscular dystrophy with neurological, cognitive, and radiological abnormalities. The developmental or degenerative nature of these abnormalities, and their progression over time, remains unclear. The aim of this study is to perform a longitudinal assessment of imaging and cognitive performances in a group of patients with DM1. A longitudinal observational study was conducted in a group of 33 DM1 patients. All patients underwent cognitive and MRI evaluation, including the use of structural and diffusion tensor imaging techniques, at baseline and follow-up evaluation (4 years). Longitudinal changes in white matter lesion (WML), volumetric analysis, and diffusivity values were assessed and correlated with neuropsychological test findings. An increase in WML was observed in 16 patients (48.5%). An increase in ventricular system volume and a decrease in volume of the left thalamus, caudates, putamen, and hippocampus were observed (p < 0.001). Global cortical volume showed a significant decrease (p < 0.001), although no changes were observed in white matter volume. A significant increase in mean diffusivity and decrease in fractional anisotropy for the white matter were found (p < 0.001). Neuropsychological evaluation showed a significant deterioration in test performance that measures working memory (Letter-Number Sequencing, p = 0.049) and visuospatial skills (Benton Visual Retention Test, p = 0.001). These findings were significantly associated with WML load (working memory p = 0.002 and visuospatial skills p = 0.021) and mean diffusivity increase (visuospatial skills p = 0.003 in the corpus callosum and working memory p = 0.043 in the right cerebral white matter). White matter and grey matter involvement in DM1 patients is progressive. Patients experience a worsening in cognitive impairment that correlates with white matter involvement. These findings support the neurodegenerative nature of this disease.


Computer programs for nucleic acids studies. Atomic coordinates of helices and their graphic display.
For the purpose of calculation of NMR and other physiocochemical properties of nucleic acids, a computer program in FORTRAN language has been written. This program provides the printout of the Cartesian and cylindrical coordinates of all atoms of a double-stranded helix of nucleic acid in either A, A' or B conformation with any specified base sequence up to 50 nucleotides or longer. In addition, the interatomic distances between any two atoms or distances (with both perpendicular and parallel components) from the centers of the base rings to any atom in the helix can be calculated. This information has been used for the calculation of the ring current effects of the 1H chemical shift of two short helices. Satisfactory agreement has been found in the comparison between the present data and that obtained from model construction and from the table prepared by Arter and Schmidt. The structure of the helix can also be illustrated in graphic form on a Tektronix 4006 CRT terminal. The presentation can be manipulated, such as selection, enlargement, translation and rotation.


Quinine di-hydro-chloride hemihydrate.
Numerous non-covalent inter-actions link together discrete mol-ecules in the crystal structure of the title compound, 2C20H26N2O2 2+·4Cl-·H2O {systematic name: 4-[(5-ethenyl-1-azonia-bicyclo-[2.2.2]octan-2-yl)(hy-droxy)meth-yl]-6-meth-oxy-quinolin-1-ium dichloride hemihydrate}. A combination of hydrogen bonding between acidic H atoms and the anions in the asymmetric unit forms a portion of the observed hydrogen-bonded network. π-π inter-actions between the aromatic portions of the cation appear to play a role in the formation of the long-range ordering. One ethyl-ene double bond was found to be disordered. The disorder extends to the neighboring carbon and hydrogen atoms.


Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions.
To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration-time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.


Role of NQO1 polymorphisms as risk factors for squamous cell carcinoma of the head and neck.
A case: control study was carried out to determine if inactivating polymorphisms of the NQO1 gene at bases 609 and 465 are associated with altered risk of developing squamous cell carcinoma of the head and neck (SCCHN). Genotyping was carried out by PCR RFLP analysis on whole blood samples. The frequency of the inactive 609T and active 609C forms, and the inactive 465T and active 465C forms, of NQO1 were compared in patient and control groups by a logistic regression analysis and odds ratios (ORs) were calculated. Participants were stratified by tobacco and alcohol use, and genotype distributions in these sub-groups were compared. There were no significant differences in genotype distribution between SCCHN patients and the control population for the base 609 or 465 polymorphisms. There were also no significant differences in genotype distributions between patient and control groups for tobacco and/or alcohol users and non-users. Genotype distributions were similar for SCCHN patients at all disease sites with the exception of the nasopharynx where there was a higher incidence of the 609C:609T and 609T:609T genotypes. These results suggest that individuals having either 609T or 465T alleles generally do not have an altered risk of developing SCCHN.


Idiopathic punctate necrosis of the phalanges of the feet.
Small areas of discrete radiolucency surrounded by well-defined margins of sclerosis are incidental asymptomatic findings in the proximal phalanges of the feet, usually in young males. Histologic examination of similar lesions discovered in the feet of cadavers shows fat necrosis. Although the etiology of these lesions is as yet unproven, musculoskeletal stress is suggested.


Effects of ileal glucose infusion on enteropancreatic hormone secretion in humans: relationship to glucose absorption.
The distal small intestine plays an important role in regulating the secretion of entero-pancreatic hormones that are critical to the control of glucose metabolism and appetite, but the quantitative contribution of a specific segment to these effects is unknown. To determine the effects of 30 cm of the ileum exposed to glucose on the secretion of ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) insulin, C-peptide and glucagon, in relation to glucose absorption in non-diabetic subjects. 10 non-diabetic subjects with a loop ileostomy after early-stage rectal cancer resection were studied on 2 days in a double-blind, randomized and crossover fashion, when a catheter was inserted retrogradely 30 cm from the ileostomy for infusion of a glucose solution containing 30 g glucose and 3 g 3-O-methylglucose (as a marker of active glucose absorption), or 0.9% saline, over 60 min. Ghrelin, GIP, GLP-1, insulin, C-peptide, glucagon and ileal glucose absorption (from concentrations of 3-O-methylglucose in serum and glucose in ileostomy effluent) were measured over 180 min. 12.0 ± 1.2 g glucose was absorbed over 180 min. Compared to saline, ileal glucose resulted in minimal increases in blood glucose and plasma insulin and C-peptide, but substantial increases in plasma GLP-1, without affecting ghrelin, GIP or glucagon. The magnitude of the GLP-1 response to glucose was strongly related to the increase in serum 3-O-methylglucose. Stimulation of the terminal ileum by glucose, even over a short length (30 cm), induces substantial GLP-1 release, coupled primarily to active glucose absorption. NCT05030376 (ClinicalTrials.gov).


Cyclophosphamide-dependent lymph node modification in lymph node metastasis of MM48 tumor cells in syngeneic mice.
We investigated the role of immunosuppressive activity induced in the regional lymph nodes (RLN, popliteal lymph nodes) in the establishment of lymph node metastasis by cyclophosphamide (CY) administration. The CY treatment led to the elimination of suppressive activity with the appearance of positive immune responses, and the inhibition of lymph node metastasis of MM48 tumor cells. In CY-treated mice, the removal of RLN together with the primary tumor lowered the survival rate compared with the mice in which the RLN remained intact. During 4 days after primary tumor resection, the proliferation of tumor cells in the RLN was significantly decreased in CY-treated mice. These results suggested that the induction of suppressive activity in the lymph node is closely associated with the establishment of lymph node metastasis.


Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo.
beta2-Adrenergic receptors (beta2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta2-AR variants; Thr164Ile beta2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta2-AR polymorphisms affect beta2-AR-mediated venodilation in healthy subjects in vivo. We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common beta2-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile beta2-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily. Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous beta2-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile beta2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta2-AR subjects. beta2-AR-mediated dilation of human hand veins is influenced by the 3 most common beta2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta2-AR. Long-term terbutaline treatment desensitizes venous beta2-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).


Precordial QT dispersion does not predict inducibility of ventricular tachyarrhythmias at post-revascularization electrophysiologic study.
We tested the hypothesis that revascularization would decrease QT interval dispersion and that QT interval dispersion would predict the outcome of the electrophysiologic study following revascularization. QT interval dispersion may be a measure of the inhomogeneity of ventricular repolarization. The value of the QT interval dispersion for predicting inducibility of ventricular tachyarrhythmias (VT) during electrophysiologic studies after coronary artery revascularization in patients with hemodynamically significant VT is unknown. QT interval dispersions were measured from electrocardiograms recorded before and after coronary artery revascularization, but before an electrophysiologic study during the same hospitalization. Fifty-six patients (93% male, 65.1 +/- 9.6 years) were studied. QT interval dispersion decreased significantly following revascularization from 69 +/- 31 ms to 53 +/- 23 ms (p=0.002). Inducibility of VT could not be predicted by the QT interval dispersion following revascularization (50 +/- 30 ms in patients with VT induced vs. 58 +/- 25 ms in patients without VT induced at electrophysiologic study; p=0.2). The change in QT interval dispersion with revascularization (-15 +/- 33 ms vs. -17 +/- 46 ms; p=0.9) could not predict VT inducibility. Actuarial survival after 80 months follow-up was similar in the patients in whom VT was induced (82%) and those patients in whom VT was not induced (83%; p=NS). Coronary artery revascularization decreased QT interval dispersion in patients with hemodynamically significant VT, but QT interval dispersion was not predictive of inducibility of VT at follow-up electrophysiologic study. Actuarial survival was similar in patients in whom VT was induced and patients in whom VT was not induced.


Isolation and diversity of planctomycetes from the sponge Niphates sp., seawater, and sediment of Moreton Bay, Australia.
Planctomycetes are ubiquitous in marine environment and were reported to occur in association with multicellular eukaryotic organisms such as marine macroalgae and invertebrates. Here, we investigate planctomycetes associated with the marine sponge Niphates sp. from the sub-tropical Australian coast by assessing their diversity using culture-dependent and -independent approaches based on the 16S rRNA gene. The culture-dependent approach resulted in the isolation of a large collection of diverse planctomycetes including some novel lineages of Planctomycetes from the sponge as well as sediment and seawater of Moreton Bay where this sponge occurs. The characterization of these novel planctomycetes revealed that cells of one unique strain do not possess condensed nucleoids, a phenotype distinct from other planctomycetes. In addition, a culture-independent clone library approach identified unique planctomycete 16S rRNA gene sequences closely related to other sponge-derived sequences. The analysis of tissue of the sponge Niphates sp. showed that the mesohyl of the sponge is almost devoid of microbial cells, indicating this species is in the group of 'low microbial abundant' (LMA) sponges. The unique planctomycete 16S rRNA gene sequences identified in this study were phylogenetically closely related to sequences from LMA sponges in other published studies. This study has revealed new insights into the diversity of planctomycetes in the marine environment and the association of planctomycetes with marine sponges.


Development and internal validation of a prediction model to identify older adults at risk of low physical activity levels during hospitalisation: a prospective cohort study.
Inactive behaviour is common in older adults during hospitalisation and associated with poor health outcomes. If patients at high risk of spending little time standing/walking could be identified early after admission, they could be given interventions aimed at increasing their time spent standing/walking. This study aims to identify older adults at high risk of low physical activity (PA) levels during hospitalisation. Prospective cohort study of 165 older adults (≥ 70 years) admitted to the department of Internal Medicine of Maastricht University Medical Centre for acute medical illness. Two prediction models were developed to predict the probability of low PA levels during hospitalisation. Time spent standing/walking per day was measured with an accelerometer until discharge (≤ 12 days). The average time standing/walking per day between inclusion and discharge was dichotomized into low/high PA levels by dividing the cohort at the median (50.0%) in model 1, and lowest tertile (33.3%) in model 2. Potential predictors-Short Physical Performance Battery (SPPB), Activity Measure for Post-Acute Care (AM-PAC), age, sex, walking aid use, and disabilities in activities of daily living-were selected based on literature and analysed using logistic regression analysis. Models were internally validated using bootstrapping. Model performance was quantified using measures of discrimination (area under the receiver operating characteristic curve (AUC)) and calibration (Hosmer and Lemeshow (H-L) goodness-of-fit test and calibration plots). Model 1 predicts a probability of spending ≤ 64.4 min standing/walking and holds the predictors SPPB, AM-PAC and sex. Model 2 predicts a probability of spending ≤ 47.2 min standing/walking and holds the predictors SPPB, AM-PAC, age and walking aid use. AUCs of models 1 and 2 were .80 (95% confidence interval (CI) = .73-.87) and .86 (95%CI = .79-.92), respectively, indicating good discriminative ability. Both models demonstrate near perfect calibration of the predicted probabilities and good overall performance, with model 2 performing slightly better. The developed and internally validated prediction models may enable clinicians to identify older adults at high risk of low PA levels during hospitalisation. External validation and determining the clinical impact are needed before applying the models in clinical practise.


A review of basic to clinical targeted therapy and immunotherapy in uterine serous cancer.
Uterine serous carcinomas show more frequent mutations of TP53, FBXW7, PIK3CA, and PP2R1A. Furthermore, cyclin-dependent kinase, human epidermal growth factor receptor 2, phosphatidylinositol 3-kinase/protein kinase B, and mammalian target of rapamycin signaling pathways are involved in uterine serous carcinoma progression. However, most patients with uterine serous carcinoma develop chemoresistance to paclitaxel and carboplatin. Moreover, uterine serous carcinoma shows immunosuppressive microenvironment with lower frequency of microsatellite instability. However, some clinical trials of human epidermal growth factor receptor 2/neu and WEE1 targeted therapies showed good effects in prolonging the survival in patients with uterine serous carcinoma. More effective targeted therapies and immunotherapies need to be developed in recurrent uterine serous carcinomas.


The induction of dominant lethal mutations in Tilapia mossambica by alkane sulphonic esters.
A serial mating system has been used to enable study of the effect of chemical mutagens in Tilapia mossambica. Embryopathies incompatible with survival are attributed to dominant lethal mutations induced in developing male germ cells by methyl methanesulphonate and the isomeric forms of dimethyl-myleran.


Rapid Growth Rates of Suspected Pancreatic Cyst Branch Duct Intraductal Papillary Mucinous Neoplasms Predict Malignancy.
The majority of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are recommended for surveillance imaging based on consensus guidelines. However, growth rates that should prompt concern for malignant transformation of BD-IPMN are unknown. To determine whether BD-IPMN growth can predict an increased risk of malignancy and define growth rates concerning for malignant BD-IPMN. The study is a retrospective, multicenter study of suspected BD-IPMN patients undergoing imaging surveillance. All patients underwent EUS evaluation followed by surveillance imaging. Two hundred and eighty-four patients with suspected BD-IPMN without worrisome features or high-risk stigmata were followed for a median 56 months and underwent a median of four imaging studies. Nine patients (3.2 %) developed malignant BD-IPMN. Malignant BD-IPMN grew at a faster rate (18.6 vs. 0.8 mm/year; P = 0.05) compared to benign BD-IPMN. BD-IPMN growth rate between 2 and 5 mm/year was associated with an increased risk of malignancy with hazard ratio (HR) of 11.4 (95 % CI 2.2-58.6) when compared to subjects with BD-IPMN growth rate <2 mm/year (P = 0.004). BD-IPMN growth rate ≥5 mm/year had a hazard ratio of 19.5 (95 % CI 2.4-157.8) (P = 0.005). BD-IPMN growth rate of 2 mm/year had a sensitivity of 78 %, specificity of 90 %, and accuracy of 88 % to identify malignancy. Total BD-IPMN growth was also associated with increased risk of malignancy (P = 0.003) with all malignant IPMNs growing at least 10 mm prior to cancer diagnosis. BD-IPMN growth rates ≥2 mm/year and total growth of ≥10 mm should be considered worrisome features for BD-IPMN at increased risk of malignancy.


Applying Rasch methodology to examine and enhance precision of the Edinburgh Postnatal Depression Scale.
The 10-item Edinburgh Postnatal Depression Scale (EPDS) is a widely used depression measure with acceptable psychometric properties, but it uses ordinal scaling that has limited precision for assessment of outcomes in clinical and research settings. This study aimed to apply Rasch methodology to examine and enhance psychometric properties of the EPDS by developing ordinal-to-interval conversion algorithm. The Partial Credit Rasch model was implemented using a sample of 621 mothers of infants (birth to 2 years old) who completed the EPDS as a part of a larger online survey. Initial analysis indicated misfit to the Rasch model attributed to local dependency between individual EPDS items. The best model fit was achieved after combining six locally dependent items into three super-items resulting in non-significant item-trait interaction (χ2(49) = 46.61, p < 0.57), strong reliability (PSI = 0.86), unidimensionality and item invariance across personal factors such as age and mothers' education. This permitted generation of ordinal-to-interval conversion algorithms derived from person estimates of the Rasch model. Ordinal-to-interval conversion cannot be applied for individuals with missing data. The EPDS met expectations of the unidimensional Rasch model after internal modifications, and its precision can be enhanced by using ordinal-to-interval conversion tables published in this article without the need to alter the original scale format. Scores derived from these conversion tables should decrease error and improve conformity with statistical assumptions in both clinical and research use of the EPDS, making monitoring of clinical status and outcomes more accurate.


Biological effects and bioaccumulation of steroidal and phenolic endocrine disrupting chemicals in high-back crucian carp exposed to wastewater treatment plant effluents.
Endocrine disrupting chemicals (EDCs) found in wastewater treatment plant (WWTP) effluents have been shown to cause adverse effects, but the uptake of EDCs from effluents (measured in fish muscle) are not known. In this study, the biological effects and bioaccumulation of steroidal and phenolic EDCs were assessed in high-back crucian carp (Carassius auratus) exposed to WWTP effluents for 141 days. Compared with fish controls caged in Dianchi Lake, a significant reduction in gonadosomatic index (GSI) and increase in hepatosomatic index (HSI) and plasma vitellogenin (VTG) levels were observed in effluent-exposed fish. The concentrations of steroids and phenols in effluent-exposed fish showed time-dependent increase during the exposure. In addition, bioconcentration factors (BCFs) for steroids and phenols were between 17 and 59 on day 141. The results confirm that steroids and phenols bioconcentrate in fish muscle and this accumulation may account for the biological effects associated with exposures to WWTP effluents.


Enhanced antitumor effect of combined replicative adenovirus and nonreplicative adenovirus expressing interleukin-12 in an immunocompetent mouse model.
For cancer gene therapy, replicative adenovirus is a promising vector to overcome low infectivity and poor gene delivery of nonreplicative adenovirus in vivo, but its therapeutic efficacy is still unsatisfactory because of the limited spread of replicative virus in a solid tumor. Therefore, the combined therapy with other antitumor agents may be necessary. Nonreplicative adenovirus expressing a therapeutic gene may be a promising candidate because E1 proteins expressed by replicative adenovirus would render nonreplicative adenovirus replicative, augmenting a transgene expression. In this study, we first found that mouse hepatoma Hepa 1-6 cells were permissive for the replication and cytopathic effect of human adenovirus, which enabled us to examine the potential of combined replicative adenovirus and nonreplicative adenovirus expressing an immunostimulator in an immunocompetent mouse-syngeneic Hepa 1-6 tumor model. Nonreplicative adenovirus expressing interleukin-12 (AdIL-12) was used as a model. In vitro coinfection of two adenoviruses produced higher concentrations of IL-12 than infection of AdIL-12 alone in this cell line. In vivo experiments with Hepa 1-6 tumors in syngeneic immunocompetent C57BL/6 mice showed higher concentrations of serum IL-12 and greater therapeutic efficacy in the combination therapy than infection of either adenovirus. These data indicate that the combination of replicative adenovirus and nonreplicative adenovirus expressing an immunostimulator appears to be very efficacious for cancer gene therapy.


The childbirth experience: obstetric and psychological predictors in Italian primiparous women.
The experience of childbirth crucially impacts a mother's psychological well-being and the mother-infant relationship. It is recognised that negative births can be linked to different forms of discomfort, both for the mother as well as for the infant. This prospective longitudinal study aimed to study the effect of obstetric and psychological variables on women's subjective experience of childbirth. 111 primiparous Italian women completed a set of questionnaires at 38-40 weeks of pregnancy (Time 1) and 1-5 days after childbirth (Time 2). Sociodemographic and obstetric information were collected. Data about the childbirth were obtained from the mother's ward birth records. Women completed the Wijma Delivery Expectancy/Experience Questionnaire both before and after childbirth. The subjective experience of birth was significantly predicted by the duration of the expulsive phase (β = .26; p < .05), the use of epidural analgesia (β = .21; p< .05) and by fear of birth (β = .21; p < .05). The effect of mode of birth and duration of the dilatation phase on women's birth experience was not found. In our study, neither instrumental childbirth nor caesarean section have a significant effect on women's birth experience. Instead, both a longer expulsion phase and epidural analgesia contribute to the negative experience. Moreover, the higher the fear of birth, the worse the women's emotional experience. These findings confirmed the role of obstetric and psychological variables on birth experience. More investigation about this topic could be useful to develop specific interventions to prepare women for birth.


Visualization of Actin Assembly and Filament Turnover by In Vitro Multicolor TIRF Microscopy.
In response to chemotactic signals, motile cells develop a single protruding front to persistently migrate in direction of the chemotactic gradient. The highly dynamic reorganization of the actin cytoskeleton is an essential part during this process and requires the precise interplay of various actin filament assembly factors and actin-binding proteins (ABPs). Although many ABPs have been implicated in cell migration, as yet only a few of them have been well characterized concerning their specific functions during actin network assembly and disassembly. In this chapter, we describe a versatile method that allows the direct visualization of the assembly of single actin filaments and higher structures in real time by in vitro total internal reflection fluorescence microscopy (TIRF-M) using purified and fluorescently labeled actin and ABPs.


Abnormal Degree Centrality of Bilateral Putamen and Left Superior Frontal Gyrus in Schizophrenia with Auditory Hallucinations: A Resting-state Functional Magnetic Resonance Imaging Study.
Dysconnectivity hypothesis of schizophrenia has been increasingly emphasized. Recent researches showed that this dysconnectivity might be related to occurrence of auditory hallucination (AH). However, there is still no consistent conclusion. This study aimed to explore intrinsic dysconnectivity pattern of whole-brain functional networks at voxel level in schizophrenic with AH. Auditory hallucinated patients group (n = 42 APG), no hallucinated patients group (n = 42 NPG) and normal controls (n = 84 NCs) were analyzed by resting-state functional magnetic resonance imaging. The functional connectivity metrics index (degree centrality [DC]) across the entire brain networks was calculated and evaluated among three groups. DC decreased in the bilateral putamen and increased in the left superior frontal gyrus in all the patients. However, in APG, the changes of DC were more obvious compared with NPG. Symptomology scores were negatively correlated with the DC of bilateral putamen in all patients. AH score of APG positively correlated with the DC in left superior frontal gyrus but negatively correlated with the DC in bilateral putamen. Our findings corroborated that schizophrenia was characterized by functional dysconnectivity, and the abnormal DC in bilateral putamen and left superior frontal gyrus might be crucial in the occurrence of AH.


Effects of organic loading rate and pretreatments on digestion performance of corn stover and chicken manure in completely stirred tank reactor (CSTR).
The performance, system stability, and microbial community response in anaerobic co-digestion (AcoD) of corn stover (CS) and chicken manure (CM) were investigated by running completely stirred tank reactor (CSTR) under controlled organic loading rate (OLR). Prior to anaerobic digestion (AD), potassium hydroxide (KOH) or liquid fraction of digestate (LFD) was applied to pretreat CS, respectively. The results showed that the daily biogas production (DBP) in co-digestion showed a gradual increasing trend with an increase in the OLR from 65 g TS·L-1 to 100 g TS·L-1. The daily methane production per g volatile solids (DMP-VS) in co-digestion increased by 23.0%-27.1%, 18.7%-18.8%, and 17.5%-18.0% at the OLRs of 65, 80, and 100 g TS·L-1, respectively, upon pretreatment with KOH or LFD, as compared to that in co-digestion CSTR without any pretreatment. In addition, all co-digestion CSTRs were operated in stable state. Approximately half of the total carbon in the substrates was recovered in the form of a biogas product, with the carbon mass balance being impacted by the OLR as well as pretreatment. The diversity as well as function of the microbial community varied in response to different OLRs and pretreatment methods. The majority of bacterial genera were strongly correlated with operational parameters. The study indicates that management of OLR and selection of proper pretreatment method could enhance the efficiency and productivity of CS and CM co-digestion in CSTR.


Aging in retinas and optic nerves of 2.5- to 9-month-old mice.
Aging of the retina and optic nerve was studied in 2.5- to 9-month-old albino mice. A change was found in the number of visual cells and in the distribution of large versus small optic nerve fibers. No significant change was found in the number of retinal phagosomes and in the total number of optic nerve fibers.


MR-PET of the body: Early experience and insights.
MR-PET is a novel imaging modality that combines anatomic and metabolic data acquisition, allowing for simultaneous depiction of morphological and functional abnormalities with an excellent soft tissue contrast and good spatial resolution; as well as accurate temporal and spatial image fusion; while substantially reducing radiation dose when compared with PET-CT. In this review, we will discuss MR-PET basic principles and technical challenges and limitations, explore some practical considerations, and cover the main clinical applications, while shedding some light on some of the future trends regarding this new imaging technique.


Discrete and heterogeneous high molecular weight RNAs complementary to a long dispersed repeat family (a possible transposon) of human DNA.
Approximately 1% of heterogeneous nuclear RNA and approximately 0.035% of cytoplasmic RNA from a cultured line of human lymphoblastoid cells is complementary to a long dispersed repetitious sequence that comprises at least 6% of human DNA. The complementary nuclear RNA is both heterogeneously and discretely sized and is present in both poly(A)-terminated and non-poly(A)-terminated molecules. The complementary cytoplasmic RNA is mainly in discretely sized molecules ranging in size from approximately 600 to 8200 bases, some of which are most abundantly represented in poly(A)-terminated molecules, whereas others are most abundantly represented in non-poly(A)-terminated molecules. Few, if any, of the complementary cytoplasmic RNAs can be found associated with polyribosomes. The dispersed repeat sequence exhibits substantial restriction enzyme fragment length polymorphisms in human DNA and is also present in mouse DNA, although some regions of the human repeat appear to be more abundantly represented in mouse DNA than are other regions.


Beating the wavelength limit: three-dimensional imaging of buried subwavelength fractures in sculpture and construction materials by terahertz time-domain reflection spectroscopy.
We use reflection terahertz spectroscopy to locate and produce three-dimensional images of air gaps between stones that resemble fractures, even of subwavelength thicknesses. This technique is found to be promising tool for sculpture and building damage evaluation as well as structural quality control in other dielectric materials.


A role for cyclic hydroxamates in aluminium resistance in maize?
Hydroxamate siderophores have been found to alleviate Al toxicity in bacteria. In Poaceae plants cyclic hydroxamates, like DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one) and its derivatives have mostly been studied in relation to either defence against insects or allelopathy. In this study the influence of Al on concentrations of these benzoxazinoids (Bx) in root tips, whole roots and root xylem exudates of Zea mays L. varieties differing in Al resistance was analyzed by HPLC-MS. Aluminium resistant maize variety Sikuani maintained considerably higher Bx levels in root tips than the Al sensitive variety Bakero. In vitro binding of Al to DIMBOA was shown by fluorescence quenching. Addition of DIMBOA to Al-containing nutrient solution protected the sensitive maize against Al toxicity as shown by bioassays using callose and haematoxylin staining of root tips as stress indicators. This is the first study showing that Bx can detoxify Al in solution. Tissue analysis data provide first, circumstantial, support for a role of Bx in defence against Al toxicity also in planta.


Primary immature teratoma of the thigh: a review.
Teratomas are a subtype of germ cell tumors composed of a variety of somatic tissues derived from more than one of the three germinal layers (ectoderm, endoderm and mesoderm). They can be classified as mature tumors and immature tumors. Teratomas most commonly arise at the sacrococcygeal region and the gonads. The occurrence of a teratoma outside the common gonadal and midline locations is exceptional. This review article lists the reported primary and metastatic malignant teratomas in extragonadal locations and discusses the possible explanation for the atypical location, their treatment and prognosis.


Impacts of photoaging on the interactions between graphene oxide and proteins: Mechanisms and biological effect.
Graphene oxide (GO) are subjected to photoaging in aquatic environment, and inevitably enter biota and then interact with proteins. Here, the interactions of pristine and photoaged GO with two typical proteins (bovine serum albumin (BSA) and lysozyme) were systematically investigated. Due to long term photoirradiation (1-3 day), the lateral size of GO decreased greatly, and the oxygen-containing groups decreased as well while the graphitic carbon contents increased. Compared to pristine GO, the photoaged GO displayed stronger binding affinities with both proteins, which was mainly attributed to the increased binding sites as a result of smaller lateral size and increased hydrophobicity. The photoaging effect was more obvious for the negatively charged BSA, because hydrogen bonding and van der Waals force were mainly involved in the enthalpy-driven interactions between them. While, the strong electrostatic attraction between the positively charged lysozyme and GO diminished the photoaging effect. Analyses of synchronous, three-dimensional fluorescence spectra and fibrillation experiments intensified that the photoaged GO induced more serious changes in conformational structure of BSA and exhibited stronger inhibition on fibrillation of BSA compared to pristine GO. This study provided novel insights into the increased ecological risks of GO as a result of photoaging.


Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine beta-synthase deficiency.
Homocysteine is an amino acid considered to cause vascular injury, arteriosclerosis, and thromboembolism. Total plasma homocysteine (free and protein-bound) was found to be twice as high in asymptomatic vitamin B12-deficient subjects (23.8 +/- 3.8 mumol/L, means +/- SEM, n = 20) as in controls (11.5 +/- 0.9 mumol/L, P less than .0001, n = 21), and higher than in heterozygotes for homocystinuria due to cystathionine beta-synthase deficiency (13.8 +/- 1.6 mumol/L, P less than .01, n = 14), who were recently shown to be much more common among patients with premature vascular disease than expected. Eight (40%) vitamin B12-deficient and two (14%) heterozygote subjects had significant homocysteinemia (greater than mean +2 SD for controls). After administration of hydroxycobalamin to vitamin B12-deficient subjects, homocysteine levels decreased to normal (-49%, 12.2 +/- 1.5 mumol/L, P less than .0001, n = 20). Thus, if homocysteine does cause vascular injury, theoretically vitamin B12-deficiency might be associated with an increased frequency of vascular disease.


Poor sleep quality and associated factors among prisoners of the Diredawa correctional facility in eastern Ethiopia.
Impaired sleep quality affects judgment, psychomotor skills, memory, decision-making, concentration, and attention. It might also contribute to the development of new physical health problems, as well as exacerbating already existing physical problems. Despite this, there is a scarcity of research done in Africa including Ethiopia that addressed this issue. So this study assessed the quality of sleep and related factors among prisoners of the Diredawa correctional facility, Diredawa, eastern Ethiopia. A cross-sectional study was done using a simple random sampling technique to recruit 421 participants from May 21 to June 21; 2017. A semi-structured questionnaire, Pittsburgh Sleeps Quality Index (PSFIG), Patient Health Questionnaire-9 (PQ-9), and Sleep Hygiene Index (SHI) were used to assess participants' socio-demographic data, sleep quality, depression, and sleep hygiene, respectively. The collected data were entered into EPA-data 3.1 and analyzed by using SPAS-20. Descriptive and analytical statistics were used. Bivariate and multivariable logistic regression with odds ratio and 95% CI were employed. The statistical significance was declared at p value < 0.05. A total of 421 out of 423 prisoners were interviewed, resulting in a response rate of 99.5%. The prevalence of poor sleep quality was 227 (53.9%) with 95% CI (49.2, 58.7). Having co-morbidity of depression (adjusted odds ratio; OAR = 3.47, 95% CI 1.38,8.76), lifetime use of cigarette (OAR = 2.16, 95% CI 1.21,5.58), marijuana and hashish (OAR = 5.02, 95% CI 1.63,15.46), current use of coffee (OAR = 2.75, CI 1.37, 7.05), poor sleep hygiene (OAR = 3.19, CI 1.32,7.69), committing assault crime (OAR = 4.12, CI 1.29,10.63) and crime of rape (OAR = 5.57, CI (1.45, 13.89) were the associated factors for poor sleep quality in this study. More than half of the participants (53.9%) have poor sleep quality. Depression, lifetime use of cigarettes, using cannabis and hashish, current use of coffee, poor sleep hygiene, and crime types were the associated factors that should be taken into consideration and evaluated early to minimize poor sleep quality.


Suicide: a guide to risk factors, assessment, and treatment of suicidal patients.
This article summarizes what is known about risk factors for suicide in both adolescent and adult populations. It also translates this knowledge base into practical considerations for the physician on the assessment and treatment of suicidal patients. Since most patients who commit suicide have seen a physician in the weeks to month prior to their deaths, and many kill themselves with medications prescribed by their doctors, the physician's early detection and treatment of suicidal behaviors and associated psychiatric disorders in his or her patients becomes a major suicide prevention strategy.


Minimally invasive surgery in neonates.
Minimally invasive surgery (MIS) has been one of the most important developments in surgery in the last century. By reducing the incision to small puncture wounds, morbidity, pain, adhesions and scarring are reduced. Due to their small size, neonates have not benefited from the advances in endoscopic surgery as rapidly as their adult counterparts. In the last 5 years, miniaturization of instruments and the development of sophisticated new techniques have enabled paediatric surgeons to apply endoscopic surgery to neonates. MIS is now being performed in both the neonatal chest and abdomen. This article reviews these new developments and discusses the potential for even further improvements in neonatal surgery in the future.


Standardization of 89Sr at the National Office of Measures.
Strontium-89 is an important radiotherapy nuclide in bone palliation. The standardization of 59Sr has been performed at the National Office of Measures (OMH) within the frame of the BIPM CCRI(II)-K2.Sr-89 key comparison. The activity concentration of the 89Sr solution was measured by two different methods. The conventional 4pi beta counting technique was used with two proportional counting measurement systems. The 4pi beta-gamma-coincidence efficiency tracing method was used with a 4pi beta-gamma-coincidence measurement system using 24Na as the tracer radionuclide. The beta efficiencies of each of these counting techniques were nearly 100%. The combined uncertainties of the activity concentration determined by these absolute methods are 0.3%. The general agreement of results between the two methods was 0.5%. The measurement equipment, evaluation methods and results of activity concentration measurements with their uncertainty budgets are reported.


Separation and partial characterization of new apoproteins from human plasma high density lipoproteins.
In four patients receiving parenteral fluids, human plasma high density lipoproteins were obtained by sequential ultracentrifugation and delipidated. Apoproteins were resolved by gel filtration on Sephadex G-200, DEAE-cellulose chromatography, and polyacrylamide gel electrophoresis. Sephadex-Fraction V was unusually large (11--33% compared to 3--7% in normal subjects) and was found to contain seven new apoprotein components of an apparent molecular weight (by SDS gel electrophoresis) between 8000 and 11 000. Amino acid analysis showed that all these peptides had a high glycine and arginine content and a very low content of threonine and valine. Isoelectric focusing gave isoelectric points ranging from 5.00 to 8.00. In two patients injected with L-[1-17C]-leucine, incorporation of radioactivity into these peptides gave specific activities of the same order of magnitude as apo C-II and apo C-III. IT may be postulated that these peptides increased significantly when proteins are deficient in the diet or have low levels in plasma. The structural and functional significance of these peptides remains to be determined.


Subcellular localization of enterokinase (enteropeptidase EC 126.96.36.199) in rat small intestine.
The subcellular localization of enterokinase is controversial. In this study, enterokinase was extracted from a soluble fraction and a brush border fraction of rat small intestine by differential centrifugation. The soluble fraction contained 41% of the initial enterokinase activity while the brush border fraction contained only 4.6% of the initial activity. In contrast, alkaline phosphatase monitored as a brush border marker, yielded 26.3% in the brush border fraction and only 6% in the soluble fraction. Further separation of the soluble fraction on a Sepharose 4B column revealed three peaks of enterokinase activity. One small peak (3%) of a bound enzyme (Mr, 2 - 10(6)) and two larger peaks of free enzyme (Mr, 3 - 10(5) and 9 -10). In contrast, alkaline phosphatase major fraction was in a high molecular weight peak of bound enzyme. When the brush border fraction was chromatographed only a single peak of bound enterokinase and alkaline phosphatase were found. In the lower part of the small intestine, no brush border-bound enterokinase was found, while the peak of alkaline phosphatase was the same as in the upper intestine. These data suggest that enterokinase activity in the rat intestine is mainly in a free form localized in the mucin and soluble fraction and to a negligible extent in the brush border.


Cyclic AMP-binding proteins and protamine kinases in porcine thyroid cytosol.
Partial purification of cyclic AMP-binding proteins from porcine thyroid cytosol was performed by gel filtration on Bio Gel 1.5 m followed by ion exchange chromatography on DEAE Sephadex A25. Three fractions presenting cyclic AMP-binding activities were resolved by gel filtration (I, II, III). Approximate molecular weights were respectively 280 000, 145 000 and 65 000. Fraction I was further resolved into two peaks (Ialpha and Ibeta) on DEAE-Sephadex A25. Fractions I, Ialpha, Ibeta comigrated with protein kinase activity whereas peaks II and III did not. These fractions differed with respect to the folling characteristics: rate and stability of cyclic AMP binding to isolated fractions were differently affected by pH (4.0 or 7.5). Electrophoretic mobility on polyacrylamide gels (5%) of fractions preincubated with cyclic [3H]AMP showed similar mobilities for Ialpha, Ibeta or II (Rf 0.37) whereas fraction III displayed a much greater mobility (RF 0.73); Scatchard plots were linear for fractions Ialpha, II and III with an apparent Kd in the same range (2 to 5 nM) whereas fraction Ibeta generated a biphasic plot with Kd 0.4 nM and 20 nM; cyclic [3H] AMP added to fraction I, Ialpha or Ibeta generated a cyclic [3H] AMP-binding protein complex of lower molecular weight as shown by Sephadex G 150 filtration; on the basis of the elution volume, this complex was not distinguished from fraction II. In the course of this work, we separated at the first step of purification (Bio Gel 1.5 m) a protein kinase not associated with cyclic AMP binding activity which exhibited marked specificity for protamine as compared to histone II A.


Local inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue.
Inflammation was induced in rats by intraplantar administration of carrageenan (500 micrograms in 0.1 ml). Nociceptive thresholds were measured on both inflamed and contralateral hindpaws with the pressure test of Randal and Sellito. Low doses (0.03-10 micrograms/kg) of naloxone hydrochloride (Nx) or of methylnaloxone methylsulfonate (MeNx) were injected 4 h after carrageenan in the inflamed paw: Nx (3 micrograms) and MeNx (1-10 micrograms) diminished inflammatory pain; a slight, nonspecific hyperalgesia was observed in the contralateral paw after Nx, MeNx or NaCl. Neither drug was effective when injected s.c. at the same doses and time; however activities were shown to be influenced by the experimental schedule. Low s.c. doses of Nx antagonized the analgesia produced by s.c. morphine whereas MeNx did not. This work demonstrates the local site of the analgesic action of the doses of Nx and MeNx used here, bringing new evidence in favour of the existence of cutaneous opioid receptors. Opiate antagonists might inhibit inflammatory pain by interacting with a particular population of cutaneous receptors and (or) by being dealkylated locally into agonists.


The Role of Environmental Tax in Alleviating the Impact of Environmental Pollution on Residents' Happiness in China.
Background: Environmental tax has been implemented by the government in response to the demands of the residents to control environmental pollution. However, a tax has a wide effect on many interacting aspects of the society. It remains unknown whether enacting an environmental tax for the government can improve the residents' happiness. This study aimed to examine the impact of air and water pollution on residents' happiness and evaluate whether an environmental tax can alleviate the impact of air and water pollution on residents' happiness. Methods: Based on the 2015 Chinese General Social Survey Data, 28 provinces in China were divided into two categories according to their environmental tax rates: baseline-tax areas (n = 13) and high-tax areas (n = 15). The ordered probit model was used to analyze the impact of air and water pollution on the residents' happiness in baseline-tax areas and high-tax areas, respectively. The Chow Test was used to test whether the impact of environmental pollution on happiness was different between baseline-tax areas and high-tax areas. Results: The impact of air pollution on residents' happiness was statistically significant in the baseline-tax areas (coefficient -0.162, 95% confidence interval (CI) -0.239, -0.086, p < 0.001), but the significance was weakened in the high-tax areas (coefficient -0.030, 95% CI -0.060, 0.000, p = 0.051). The Chow Test showed that the absolute value of the regression coefficient in the baseline-tax areas was significantly higher than the value in the high-tax areas (F = 12.712, p < 0.001). Similarly, the impact of water pollution on residents' happiness was statistically significant (coefficient -0.264, 95% CI -0.353, -0.174, p < 0.001) in the baseline-tax areas and in the high-tax areas (coefficient -0.063, 95% CI -0.091, -0.035, p < 0.001), but the Chow Test showed that the absolute value of the regression coefficient in the baseline-tax areas was significantly higher than the value in the high-tax areas (F = 13.758, p < 0.001). Conclusions: Both air and water pollution impair residents' happiness. The present study shows for the first time that enacting an environmental tax significantly alleviates the negative effect of air and water pollution on residents' happiness. The findings of the present study provide empirical evidence for the government to levy environmental tax.


Intraventricular tumors.
To describe the neuroendoscopic technique to deal with intraventricular tumors. Details of the endoscopic approach to intraventricular tumors of the lateral, third, and fourth ventricle are presented. Intraventricular tumors are ideal indications for neuroendoscopic surgery. They often cause cerebrospinal fluid (CSF) pathway obstruction, resulting in ventricular dilation, which provides sufficient space for maneuvering with the endoscope. The general principle of the endoscopic removal of intraventricular tumors is interruption of the blood supply to the tumor and subsequent tumor debulking. In general, a piecemeal resection is performed; however, in some tumors, it is possible to detach the lesion from the surrounding brain tissue and remove it in toto. In unilateral hydrocephalus caused by obstruction of one foramen of Monro, the burr hole is placed more laterally to get good access to the foramen for biopsy and to the septum for septostomy. When the tumor arises in the anterior part of the third ventricle, the burr hole is made at the coronal suture. When the tumor is located in the posterior part, the entry point is selected more anteriorly in order to pass the foramen of Monro in a straight line. In pineal region tumors, which cause occlusive hydrocephalus due to aqueductal compression, third ventriculostomy as well as tumor biopsy are required. Intraventricular tumors and related CSF pathway obstructions can be safely and effectively treated with endoscopic techniques. Small tumors may be totally removed via a ventriculoscope.


2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design.
This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). This is endorsed by the governing bodies of the ACC Foundation, the AHA, the ECAS, the EHRA, the STS, the APHRS, and the HRS.


Use of focussed beam reflectance measurement (FBRM) for monitoring changes in biomass concentration.
The potential of focussed beam reflectance measurement (FBRM) as a tool to monitor changes in biomass concentration was investigated in a number of biological systems. The measurement technique was applied to two morphologically dissimilar plant cell suspension cultures, Morinda citrifolia and Centaurea calcitrapa, to a filamentous bacteria, Streptomyces natalensis, to high density cultures of Escherichia coli and to a murine Sp2/0 hybridoma suspension cell line, 3-2.19. In all cases, the biomass concentration proved to be correlated with total FBRM counts. The nature of the correlation varied between systems and was influenced by the concentration, nature, size and morphology of the particle under investigation.


Heat and cold related-mortality in 18 French cities.
Understanding the dynamics of the temperature-mortality relationship is an asset to support public health interventions. We investigated the lag structure of the mortality response to cold and warm temperatures in 18 French cities between 2000 and 2010. A distributed lag non-linear generalized model using a quasi-Poisson distribution and controlling for classical confounding factors was built in each city. A fitted meta-analytical model combined the city-specific models to derive the best linear unbiased prediction of the association, and a meta-regression explored the influence of background characteristics of the cities. The fraction of mortality attributable to cold and heat was estimated with reference to the minimum mortality temperature. Between 2000 and 2010, 3.9% [CI 95% 3.2:4.6] of the total mortality was attributed to cold, and 1.2% [1.1:1.2] to heat. The immediate increase in mortality following high temperatures was partly compensated by a harvesting effect when temperatures were below the 99.2 percentiles of the mean temperature distributions. Cold represents a significant public health burden, mostly driven by moderate temperatures (between percentiles 2.5 and 25). The population is better adapted to warm temperatures, up to a certain intensity when heat becomes an acute environmental health emergency (above percentile 99). The rapid increase in mortality risk at very high temperatures percentiles calls for an active adaptation in a context of climate change.


Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials.
Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD < or = 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC 50 = 60 nM.


Augmentation of interleukin-2 production and delayed hypersensitivity in mice infected with Mycobacterium bovis and fed a diet supplemented with vitamin A acetate.
High-dose Mycobacterium bovis-infected mice fed a vitamin A acetate-supplemented diet developed a positive skin reaction to purified protein derivative of mycobacteria, and their spleen cells showed an increased IL-2 production in vitro.


Extensive miRNA expression analysis in craniopharyngiomas.
Craniopharyngiomas are benign tumors of the sellar or parasellar regions. They arise from the remnants of Rathke's pouch and are considered a "developmental disease." microRNAs are short non-coding RNAs that play a key regulatory role in the control of expression of entire gene networks. We performed an extensive analysis of miRNAs in craniopharyngiomas aiming to identify a miRNA expression signature that might aid in the prognosis of disease progression and outcome. Thirty-seven craniopharyngioma samples from twenty-three patients, ten age-matched controls from autopsy, and ten infant controls from the developing pituitary from autopsy were evaluated for the expression of 754 miRNAs using TaqMan® Low Density Arrays (TLDAs) v2.0 (Applied Biosystems, Foster City, CA). Among the most differentially expressed miRNAs, downregulation of miR-132 appears to be a marker of aggressiveness and also plays a role in epithelial-mesenchymal transition. This is the first time that an extensive study of miRNA expression has been performed in craniopharyngiomas. Further research needs to be performed to investigate the potential role of miR-132 in the development and progression of craniopharyngiomas, and its value as a prognostic marker of aggressiveness.