[Synergism and antagonism between estrogens and progestins: an update].
Our purpose is to provide a review of studies performed since forty five years, concerning interactions of natural or synthetic estrogens and progestins. In this paper, the terms synergism and antagonism have to be considered in a broader sense than usually done. In addition to the classical concepts of succession and of simultaneity synergism between estradiol and progesterone, notions of "saving" and of "necessity" synergism came from decidualization studies in the rabbit (1949). The necessity synergism put definitively and end to the idea that estradiol was only a female hormone and progesterone a mother one. Our research in the field of ovum implantation showed also that estrogens might be secreted by mammalian ova (1949), which is now well established. The participation of estrogens to the process of decidualization in the rat suggested even (1958, 1959) their role in the starting implantation. From 1960, synthetic estrogens and progestins were tested, in a first step especially ethynylestradiol and chlormadinone acetate. In the rabbit and in the rat, these new tools permitted us to dissociate the hormonal needs of embryonic growth and of morphogenesis (1965). The studies related to the effects of these analogs upon the adrenal gland, as upon the hypophysis (1963), led to their clinical use in the treatment of advanced breast cancers, and the studies concerning their effects in the ovulation to the discovery of the antiovulatory synergism of synthetic estrogens and progestins (1966, 1982). These observations are in agreement with the Courrier rules with regard to the relationships between the relative, but also absolute, quantities of estradiol and of progesterone administered, and the obtained biological effects. Nevertheless, progestins exist with incomplete or, on the contrary, superfluous pharmacological activities. In the extreme, the estrogenic properties of norethisterone take precedence over its progestogenic properties when administered doses are growing (1977). These phenomena have now to be understood at a molecular level. Though explanations are presently available for some processes, many of them remain to day unexplained, and inversely other explanations are coming into sight.


Effect of flavoring chemicals on free radical formation in electronic cigarette aerosols.
Flavoring chemicals, or flavorants, have been used in electronic cigarettes (e-cigarettes) since their inception; however, little is known about their toxicological effects. Free radicals present in e-cigarette aerosols have been shown to induce oxidative stress resulting in damage to proliferation, survival, and inflammation pathways in the cell. Aerosols generated from e-liquid solvents alone contain high levels of free radicals but few studies have looked at how these toxins are modulated by flavorants. We investigated the effects of different flavorants on free radical production in e-cigarette aerosols. Free radicals generated from 49 commercially available e-liquid flavors were captured and analyzed using electron paramagnetic resonance (EPR). The flavorant composition of each e-liquid was analyzed by gas chromatography mass spectroscopy (GCMS). Radical production was correlated with flavorant abundance. Ten compounds were identified and analyzed for their impact on free radical generation. Nearly half of the flavors modulated free radical generation. Flavorants with strong correlations included β-damascone, δ-tetradecalactone, γ-decalactone, citral, dipentene, ethyl maltol, ethyl vanillin, ethyl vanillin PG acetal, linalool, and piperonal. Dipentene, ethyl maltol, citral, linalool, and piperonal promoted radical formation in a concentration-dependent manner. Ethyl vanillin inhibited the radical formation in a concentration dependent manner. Free radical production was closely linked with the capacity to oxidize biologically-relevant lipids. Our results suggest that flavoring agents play an important role in either enhancing or inhibiting the production of free radicals in flavored e-cigarette aerosols. This information is important for developing regulatory strategies aimed at reducing potential harm from e-cigarettes.


[Effect of triptolide on the expression of RANTES in the renal tissue of diabetic nephropathy rats].
To investigate the effect of triptolide (TPL) on the renal tissue of diabetic rats and its possible mechanisms. SD rats were randomly divided into the normal control group (as the normal group), the diabetic model group (the model group), the low dose TPL treatment group (the low dose TPL group, TPL 0.2 mg/kg by gastrogavage), the high dose TPL treatment group (the high dose TPL group, TPL 0.4 mg/kg by gastrogavage). Equal volume of normal saline was given to rats in the normal group and the model group. Five rats were randomly selected from each group at week 4, 8, and 12 of the experiment to detect body weight, kidney weight, 24 h urinary albumin (24 h UAL), plasma glucose (FBG), total cholesterol (TC), total triglyeride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), and hemoglobin A1c (HbA1c). The mRNA and protein expression of regulated upon activation normal T-cell expressed and secreted (RANTES) in the renal tissue was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). The renal tissue was pathologically stained by HE, PAS, and Masson staining. The glomerular and renal tubular interstitial lesions were observed at each time point. The glomerular sclerosis index (GSI) was observed by PAS staining, and the renal interstitial filrosis index (RIFI) was calcutated. Compared with the same group at week 4, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 significantly decreased in two TPL groups (P <0.01). Compared with the same group at week 8, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 also significantly decreased in the two TPL groups (P <0. 05, P <0.01). Compared with the normal group, body weight and the kidney weight obviously decreased at week 4, 8, and 12 in the model group (P <0. 01); 24 h UAL, FBG, TG, TC, HbA1c, RANTES, GSI, and RIFI were obviously elevated (P <0.01). Compared with the model group, 24 h UAL, RANTES, GSI, and RIFI also decreased in the two TPL treatment groups (P <0.01). Compared with the low dose TPL group, they were attenuated in the high dose TPL group (P <0. 05, P <0. 01). TPL could not only inhibit the over-expression of RANTES, but also improve the glomerular sclerosis and renal interstitial fibrosis in the renal tissue of diabetic rats.


Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.
Because serum magnesium does not reflect intracellular magnesium, the latter making up more than 99% of total body magnesium, most cases of magnesium deficiency are undiagnosed. Furthermore, because of chronic diseases, medications, decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency. Certain individuals will need to supplement with magnesium in order to prevent subclinical magnesium deficiency, especially if trying to obtain an optimal magnesium status to prevent chronic disease [corrected]. Subclinical magnesium deficiency increases the risk of numerous types of cardiovascular disease, costs nations around the world an incalculable amount of healthcare costs and suffering, and should be considered a public health crisis. That an easy, cost-effective strategy exists to prevent and treat subclinical magnesium deficiency should provide an urgent call to action.


Mild cognitive impairment in type 2 diabetes mellitus and related risk factors: a review.
Type 2 diabetes mellitus (T2DM) is a global epidemic disease and has become a significant health problem. Many studies have raised concern about the mild cognitive impairment (MCI) with T2DM and even the Alzheimer's disease patients with T2DM. The incidence of MCI is higher in individuals with T2DM than those without diabetes. Cognitive changes might affect everyday activities depending on the work and situation. Although the exact pathophysiology of MCI in T2DM is unclear, many studies suggest that the alterations in pathoglycemia, diabetic complications, related end products, and physical/psychological status are significant risk factors. In this article, we systematically overview the studies to illustrate the related risk factors of cognitive impairment in patients with T2DM. Further high quality studies and treatment need to be initiated and it will become incumbent on clinicians to identify and cure the earliest signs of clinical impairment.


Acyl-protected hydroxylamines as spin label generators for EPR brain imaging.
In a search for novel electron paramagnetic resonance (EPR) brain imaging agents, we have designed and synthesized the acyl-protected hydroxylamines 1-acetoxy-4-methoxycarbonyl-2,2,6,6-tetramethylpiperidine (AMCPe), 1-acetoxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (AMCPy), and 1-acetoxy-3-(acetoxymethoxy)carbonyl-2,2,5,5-tetramethylpyrrolidine (DACPy), in which both the ring size and the number of ester functions were varied. In all of them, the nitroxide was first reduced and the resultant hydroxylamine was then protected with an acetyl group. These compounds are lipophilic, which is a major prerequisite for blood-brain barrier penetration. Once in the brain, esterases and oxidants quickly convert these derivatives into ionic, water-soluble radicals and thus EPR detectable species that then reside in the central nervous system for periods of time sufficient for detection and imaging. The biological relevancy of these new compounds in mice has been assessed, and their biodistribution patterns have been compared. The five-membered ring derivative AMCPy emerged as a potent EPR brain imaging agent while the other two derivatives, AMCPe and DACPy, were quite ineffective.


Strain-induced nonlinearity of filled rubbers.
Dynamic strain-induced nonlinearity in the modulus of filled rubbers shows a striking similarity to what is known about the glass transition of solid materials and the jamming transition of granular materials. This analogy stems from the reality that shear strain in dynamic mechanical measurements introduces fluctuations in a filler network by forcing the system to explore different configurations. Such fluctuations can be described by an "effective temperature" that has many attributes of a true temperature, and particularly is proportional to the strain amplitude. Thus, filled rubbers with respect to strain will display many unusual phenomena that are usually observed in glass-forming materials, but now demonstrated in filled rubbers, including asymmetric kinetics, crossover effects, and glasslike kinetic transitions. The nonlinearity in the modulus of filled rubbers simply reflects a dejamming transition of fillers in rubber matrices. The agglomeration of filler in an elastomeric matrix shares a common ground of physics with the jamming process and glass formation.


Presence of interferon during bacterial otitis media.
To examine the possibility that interferon (IFN) production plays a role in otitis media, specimens of middle ear fluid (MEF) were cultured for bacteria and viruses and assayed for IFN. Twenty (33%) of 81 MEF specimens from children attending a pediatric clinic contained 50-600 units of IFN/ml. Characterization of high-titered samples by cell species specificity, stability at pH 2, nonspecificity for virus, and cell-bound antiviral activity showed the major properties of IFN. With or without the addition of antibody to IFN to 88 specimens of MEF before viral culture, viruses were recovered from only four specimens (5%) whereas bacteria were isolated from 62 specimens (70%). IFN was present in most MEF specimens from which bacteria were isolated. Among the MEF specimens that contained bacteria and IFN, there was no association with a particular bacterial species.


Electrophysiological properties of neurons in guinea pig bronchial parasympathetic ganglia.
Active and passive membrane membrane properties of parasympathetic neurons were examined in vitro in a newly localized ganglion on the right bronchus of the guinea pig. Neurons could be classified as "tonic" or "phasic" based on their action potential discharge response to suprathreshold depolarizing constant current steps. Tonic neurons (39%) responded with repetitive action potentials sustained throughout the current step, whereas phasic neurons (61%) responded with an initial burst of action potentials at the onset of the step but then accommodated. Tonic and phasic neurons could not be differentiated by other active or passive membrane properties. Electrical stimulation of the vagus nerve elicited one to three temporally distinct fast nicotinic excitatory potentials, and tetanic stimulation of the vagus nerve evoked slow depolarizing (10% of neurons) and hyperpolarizing (25% of neurons) potentials; the latter was mimicked by muscarinic receptor activation. Similar slow and fast postsynaptic potentials were observed in both tonic and phasic neurons. We suggest neurons within the bronchial ganglion possess membrane and synaptic properties capable of integrating presynaptic stimuli.


[Infusion of sclerosant through direct cannulation of the coronary vein in the prevention and treatment of esophageal varices bleeding in portal hypertension].
To control bleeding from esophageal varices in portal hypertension, infusion of sclerosant through direct cannulation of the coronary vein at splenectomy was carried out in 50 patients, either as an emergent procedure or during bleeding interval. In all cases complete obliteration of the varices was revealed by coronary venography after the infusion. Prompt control of bleeding was obtained in 94% of patients. Three Child C grade patients died within one month postoperatively. Rebleeding occurred in only 6.7% during a follow-up of 1-4 years (an average of 36.4 months). One, two, and three year complication-free survival rate was 97.5%, 95.6%, and 93.5% respectively. The procedure is thus considered satisfactory and recommendable.


Urinary Incontinence of Women in a Nationwide Study in Sri Lanka: Prevalence and Risk Factors.
Urinary incontinence, be stress incontinence or urge incontinence or a mixed type incontinence affects women of all ages. The aim of this study was to describe the prevalence and risk factors of urinary incontinence in Sri Lanka. A community based cross-sectional study was performed in Sri Lanka. The age group of the women in Sri Lanka was categorized into 3 age groups: Less than or equal to 35 years, 36 to 50 years of age and more than or equal to 51 years of age. A sample size of 675 women was obtained from each age category obtaining a total sample of 2025 from Sri Lanka. An interviewer-administered questionnaire consisting of two parts; Socio demographic factors, Medical and Obstetric History, and the King's Health Questionnaire (KHQ), was used for data collection. Stepwise logistic regression analysis was performed. The Prevalence of women with only stress incontinence was 10%, with urge incontinence was 15.6% and with stress and urge incontinence was 29.9%. Stepwise logistic regression analysis showed that the age groups of 36 - 50 years (OR = 2.03; 95% CI = 1.56 - 2.63) and 51 years and above (OR = 2.61; 95% CI= 1.95 - 3.48), Living in one of the districts in Sri Lanka (OR = 4.58; 95% CI = 3.35 - 6.27) and having given birth to multiple children (OR = 1.1; 95% CI = 1.02 - 1.21), diabetes mellitus (OR = 1.97; 95% CI = 1.19 - 3.23), and respiratory diseases (OR = 2.17; 95% CI = 1.48 - 3.19 ) showed a significant risk in the regression analysis. The risk factor, mostly modifiable, if prevented early, could help to reduce the symptoms of urinary incontinence.


[Commemorative lecture of receiving Imamura Memorial Prize. I. Studies on bacteriological diagnostic methods for mycobacteria].
Two systems, radiometric BACTEC and biphasic MB-Check, based on liquid media proved to be significantly better than the egg-based solid media for the isolation of mycobacteria from clinical specimens. The difference in the rates of isolation of mycobacteria between two groups of media was more remarkable with smear-negative specimens. The time to the detection of the Mycobacterium tuberculosis complex with MB- Check was shorter than that with the 3% Ogawa egg method but longer than that with BACTEC. The polymerase chain reaction (PCR) using oligonucleotides based on the repetitive sequence (IS986) of M. tuberculosis as a primer and the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test (MTD), which combines an M. tuberculosis rRNA amplification method with the hybridization protection assay format, were evaluated for detection of M. tuberculosis in clinical samples. Although the sensitivities of the PCR and MTD appeared to be similar to that of culture with the MB-Check system, the two methods based on nucleic acid amplification should be very useful for rapid detection of M. tuberculosis infections without the long time required for culture of M. tuberculosis. Epidemiological studies with techniques which allow differentiation of strains within M. tuberculosis groups are important for limiting the dissemination of the disease. We analyzed six groups of small outbreaks of M. tuberculosis infections by restriction fragment length polymorphism (RFLP) analysis. Five showed identical fingerprints within each group, but one which as also suspected to have a common source of infection showed different banding patterns, emphasizing that RFLP analysis using IS986 as a probe is useful in epidemiological studies of tuberculosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Measuring HIV reservoirs: Do we need to choose between quantity and quality?
The persistence of latent viral genomes in people receiving antiretroviral therapy (ART) is the main obstacle to a cure for HIV infection. Viral reservoirs can be defined as cells harboring HIV genomes that have the ability to produce infectious virions. Precise quantification of the cellular reservoirs of HIV is challenging because these cells are rare, heterogeneous and outnumbered by a larger number of cells carrying defective genomes. In addition, measuring the inducibility of these proviruses requires functional assays and remains technically difficult. The recent development of single cell and single viral genome approaches revealed additional layers of complexity: the cell subsets that harbor proviruses are heterogeneous and their ability to be induced is variable. A substantial fraction of intact HIV genomes may be permanently silenced after years of ART, revealing the underappreciated importance of induction assays. As such, a simple approach that would assess simultaneously the genetic intactness and the inducibility of the reservoir is still lacking. In here, we review recent advances in the development of methods to quantify and characterize persistently infected cells, and discuss how these findings can inform the design of future assays aimed at measuring the size of the intact and inducible HIV reservoir.


First trimester screening of circulating C19MC microRNAs can predict subsequent onset of gestational hypertension.
The objective of the study was to evaluate risk assessment for gestational hypertension based on the profile of circulating placental specific C19MC microRNAs in early pregnancy. The prospective longitudinal cohort study of women enrolled at first trimester screening at 10 to 13 weeks was carried out (n = 267). Relative quantification of placental specific C19MC microRNAs (miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR-525 and miR-526a) was determined in 28 normal pregnancies and 18 pregnancies which developed gestational hypertension using real-time PCR and a comparative Ct method relative to synthetic C. elegans microRNA (cel-miR-39). Increased extracellular C19MC microRNA plasmatic levels (miR-516-5p, p<0.001; miR-517*, p = 0.007; miR-520h, p<0.001; miR-518b, p = 0.002) were detected in patients destined to develop gestational hypertension. MiR-520h had the best predictive performance with a PPV of 84.6% at a 7.1% false positive rate. The combination of miR-520h and miR-518b was able to predict 82.6% of women at the same false positive rate. The overall predictive capacity of single miR-518b (73.3% at 14.3% FPR), miR-516-5p (70.6% at 17.9% FPR) and miR-517* (57.9% at 28.6% FPR) biomarkers was lower. The study brought interesting finding that the up-regulation of miR-516-5p, miR-517*, miR-520h and miR-518b is associated with a risk of later development of gestational hypertension. First trimester screening of extracellular miR-520h alone or in combination with miR-518b identified a significant proportion of women with subsequent gestational hypertension.


Elucidating the Synergistic Effect of Multiple Chinese Herbal Prescriptions in the Treatment of Post-stroke Neurological Damage.
Background: Traditional Chinese medicine (TCM) has been widely used in the treatment of human diseases. However, the synergistic effects of multiple TCM prescriptions in the treatment of stroke have not been thoroughly studied. Objective of the study: This study aimed to reveal the mechanisms underlying the synergistic effects of these TCM prescriptions in stroke treatment and identify the active compounds. Methods: Herbs and compounds in the Di-Tan Decoction (DTD), Xue-Fu Zhu-Yu Decoction (XFZYD), and Xiao-Xu-Ming Decoction (XXMD) were acquired from the TCMSP database. SEA, HitPick, and TargetNet web servers were used for target prediction. The compound-target (C-T) networks of three prescriptions were constructed and then filtered using the collaborative filtering algorithm. We combined KEGG enrichment analysis, molecular docking, and network analysis approaches to identify active compounds, followed by verification of these compounds with an oxygen-glucose deprivation and reoxygenation (OGD/R) model. Results: The filtered DTD network contained 39 compounds and 534 targets, the filtered XFZYD network contained 40 compounds and 508 targets, and the filtered XXMD network contained 55 compounds and 599 targets. The filtered C-T networks retained approximately 80% of the biological functions of the original networks. Based on the enriched pathways, molecular docking, and network analysis results, we constructed a complex network containing 3 prescriptions, 14 botanical drugs, 26 compounds, 13 targets, and 5 pathways. By calculating the synergy score, we identified the top 5 candidate compounds. The experimental results showed that quercetin, baicalin, and ginsenoside Rg1 independently and synergistically increased cell viability. Conclusion: By integrating pharmacological and chemoinformatic approaches, our study provides a new method for identifying the effective synergistic compounds of TCM prescriptions. The filtered compounds and their synergistic effects on stroke require further research.


Complex network-based classification of radiographic images for COVID-19 diagnosis.
In this work, we present a network-based technique for chest X-ray image classification to help the diagnosis and prognosis of patients with COVID-19. From visual inspection, we perceive that healthy and COVID-19 chest radiographic images present different levels of geometric complexity. Therefore, we apply fractal dimension and quadtree as feature extractors to characterize such differences. Moreover, real-world datasets often present complex patterns, which are hardly handled by only the physical features of the data (such as similarity, distance, or distribution). This issue is addressed by complex networks, which are suitable tools for characterizing data patterns and capturing spatial, topological, and functional relationships in data. Specifically, we propose a new approach combining complexity measures and complex networks to provide a modified high-level classification technique to be applied to COVID-19 chest radiographic image classification. The computational results on the Kaggle COVID-19 Radiography Database show that the proposed method can obtain high classification accuracy on X-ray images, being competitive with state-of-the-art classification techniques. Lastly, a set of network measures is evaluated according to their potential in distinguishing the network classes, which resulted in the choice of communicability measure. We expect that the present work will make significant contributions to machine learning at the semantic level and to combat COVID-19.


High Seropositivity of Brucella melitensis Antibodies among Pregnant Women Attending Health Care Facilities in Mwanza, Tanzania: A Cross-Sectional Study.
Brucellosis is one of the most prevalent zoonotic neglected tropical diseases across the globe. Brucella melitensis (B. melitensis), the most pathogenic species is responsible for several pregnancy adverse outcomes in both humans and animals. Here, we present the data on the magnitude of B. melitensis antibodies among pregnant women in Mwanza, Tanzania, the information that might be useful in understanding the epidemiology of the disease and devising appropriate control interventions in this region. Methodology. A hospital-based cross-sectional study involving pregnant women was conducted at two antenatal clinics in Mwanza between May and July 2019. The pretested structured questionnaire was used for data collection. Blood samples were collected aseptically from all consenting women followed by the detection of B. melitensis antibodies using slide agglutination test. Descriptive data analysis was done using STATA version 17. A total of 635 pregnant women were enrolled with the median age of 25 (interquartile range (IQR): 16-48) years and median gestation age of 21 (IQR: 3-39) weeks. Seropositivity of B. melitensis antibodies was 103 (16.2 (95% CI:13.3-19.1)). On the multivariate logistic regression analysis, as the gestation age increases, the odds of being seropositive decreases (aOR:0.972 (95% CI: 0.945-0.999), P = 0.045). Furthermore, being a housewife (aOR:3.902 (95% CI:1.589-9.577), P = 0.003), being employed (aOR:3.405 (95% CI:1.412-8.208), P = 0.006), and having history of miscarriage (aOR:1.940 (95% CI:1.043-3.606), P = 0.036) independently predicted B. melitensis seropositivity among pregnant women in Mwanza. High seropositivity of B. melitensis was observed among employed and housewife pregnant women in Mwanza. This calls for the need of more studies in endemic areas that might lead to evidence-based control interventions.


[The life and work of Carl Weigert (1845-1904) in Leipzig 1878-1885].
Coming from Breslau, together with J. Cohnheim (1839-1884), Carl Weigert arrived at the University of Leipzig in 1878. Here, in 1879, he was appointed extraordinary professor at the Department of Pathology. Apart from his growing commitment to autopsy and teaching, due to progressive illness of Cohnheim and the resulting involvement in management of the Department. Weigert studied topical issues of pathology, such as coagulation necrosis and pathogenesis of tuberculosis. His studies into histological staining techniques (principle of elective staining, mordant staining, staining of myelin sheaths) as well as into microtome techniques proved essential to progress in pathology and bacteriology. Weigert left the Leipzig Department of Pathology at the end of March 1885, after the Medical Faculty had failed to appoint him as the successor to Cohnheim. On the 1st of April, 1885, Weigert accepted the position of Director of Senckenberg's Pathological Institute at Frankfurt/Main.


Characteristics and oil absorption in deep-fat fried batter prepared from ball-milled wheat flour.
The porous structure generated during frying influences oil absorption and textural qualities. The alteration in physical properties of wheat flour is suspected to affect the structure formation. The present study investigated the effect of physicochemical changes in wheat flour by the ball-milling process on structure formation and consequently oil absorption of a fried wheat flour batter model. Batter models containing 600 g kg(-1) moisture were made of 0-10 h ball-milled wheat flour and then fried in frying oil at 150 degrees C for 1-7 min. The samples made of milled flour possess larger pores and exhibit lower oil absorption than sample made of 0 h milled flour. The fracture force of a fried sample prepared from 5 and 10 h milled flour is lower than that of a sample prepared from 0 h milled flour. The decrease in glass transition temperature (T(g)) and melting temperature (T(m)) of milled flour affect the microstructure formation in the fried wheat flour batter. The microstructure is responsible for oil absorption and fracturability in fried food. The samples made of flour of longer ball-milling time have lower oil absorption and higher crispness. Ball-milling may be a tool to produce mechanically modified wheat flour which can reduce oil absorption for fried batter.


Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst.
Access to leading olefin metathesis catalysts, including the Grubbs, Hoveyda, and Grela catalysts, ultimately rests on the nonscaleable transfer of a benzylidene ligand from an unstable, impure aryldiazomethane. The indenylidene ligand can be reliably installed, but to date yields much less reactive catalysts. A fast-initiating, dimeric indenylidene complex (Ru-1) is reported, which reconciles high activity with scaleable synthesis. Each Ru center in Ru-1 is stabilized by a state-of-the-art cyclic alkyl amino carbene (CAAC, C1) and a bridging chloride donor: the lability of the latter elevates the reactivity of Ru-1 to a level previously attainable only with benzylidene derivatives. Evaluation of initiation rate constants reveals that Ru-1 initiates >250× faster than indenylidene catalyst M2 (RuCl2(H2IMes)(PCy3)(Ind)), and 65× faster than UC (RuCl2(C1)2(Ind)). The slow initiation previously regarded as characteristic of indenylidene catalysts is hence due to low ligand lability, not inherently slow cycloaddition at the Ru=CRR' site. In macrocyclization and "ethenolysis" of methyl oleate (i.e., transformation into α-olefins via cross-metathesis with C2H4), Ru-1 is comparable or superior to the corresponding, breakthrough CAAC-benzylidene catalyst. In ethenolysis, Ru-1 is 5× more robust to standard-grade (99.9%) C2H4 than the top-performing catalyst, probably reflecting steric protection at the quaternary CAAC carbon.


Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy.
To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls. Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups. S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (chi2: p = 0.08 for all four groups; chi2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (chi2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (chi2: p < 0.0001). Among men with epilepsy who had abnormally low bioactive testosterone, 50.0% had low S-scores; among men with normal bioactive testosterone, 8.2% had low S-scores (chi2: p < 0.0001). Bioactive testosterone decline with age was significantly greater among men with epilepsy than among controls and notably greater in the CBZ and PHT groups than in the LTG and untreated groups. Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.


Ex-ante moral hazard and health insurance: Evidence from China's urban residence basic medical insurance scheme.
This study examines whether implementing Urban Residents Medical Insurance Scheme decreased an individual's risky lifestyle behavior before illness, termed ex-ante moral hazard. Ex-ante moral hazard is predicted by the classical economic theory suggesting that health insurance coverage reduces an individual's incentive to take preventive efforts to remain healthy. Studies have provided mixed evidence for this prediction. China's 2006 nationwide social experiment of implementing the Urban Residents Basic Medical Insurance Scheme offers an excellent opportunity for examining the effect of the transition from uninsured to insured on an individual's health behaviors. We exploit the longitudinal dimension of a representative survey data for 2007-2010 and employ the instrumental variable technique, thereby addressing the issue of self-selection into voluntary health insurance schemes. The results do not provide evidence for and contrast the prediction of the ex-ante moral hazard. Significant differences exist between insured and uninsured groups with respect to smoking, drinking habits, and being overweight. People with insurance care more about their health than people without insurance do. The main results still hold if we use alternative estimation methods and other robustness tests.


[Laser lithotripsy of ureteral calculi].
A total of 149 patients with 152 ureteral stones were treated with intraureteral lithotripsy by Dye-laser (83.55%), Alexandrite-laser (41.27%), electrohydraulic lithotripsy adapted for use in the ureter (25.16%) or neodymium: YAG laser with optomechanic coupling (3.2%). The Dye-laser has an automatic pulse shut-off mechanism with spectral analysis of the reflected laser beam, so that effective laser pulses can only be released by contact with a stone. Most (127 of 83.5%) of the stones could be completely fragmented, so that no further treatment was necessary. In 16 cases (10.5%) the stone was too hard for fragmentation and had to be removed by alternative techniques. Intraureteral lithotripsy is a save and effective method of treating ureteral stones that cannot be reached or have not been treated successfully by shockwave lithotripsy. No significant differences in outcome were found between the different lasers or electrohydraulic lithotripsy. In selected cases endoscopic treatment may be recommended as treatment of first choice.


Crystal structure of Rv1220c, a SAM-dependent O-methyltransferase from Mycobacterium tuberculosis.
Rv1220c from Mycobacterium tuberculosis is annotated as an O-methyltransferase (MtbOMT). Currently, no structural information is available for this protein. Here, the crystal structure of MtbOMT refined to 2.0 Å resolution is described. The structure reveals the presence of a methyltransferase fold and shows clear electron density for one molecule of S-adenosylmethionine (SAM), which was apparently bound by the protein during its production in Escherichia coli. Although the overall structure of MtbOMT resembles the structures of O-methyltransferases from Cornybacterium glutamicum, Coxiella burnetti and Alfa alfa, differences are observed in the residues that make up the active site. Notably, substitution of Asp by His164 seems to abrogate metal binding by MtbOMT. A putative catalytic His-Asp pair located in the vicinity of SAM is absolutely conserved in MtbOMT homologues from all species of Mycobacterium, suggesting a conserved function for this protein.


Global optimization and monotonicity in entropy production of weak drivings.
Knowing if an optimal solution is local or global has always been a hard question to answer in more sophisticated situations of optimization problems. In this paper, for finite-time and weak isothermal driving processes, we show the existence of a global optimal protocol for the entropy production. We prove this by showing its convexity as a functional in the derivative of the protocol. This property also proves its monotonicity in such a context, which leads to the satisfaction of the second law of thermodynamics. In the end, we exemplify that the analytical technique of the Euler-Lagrange equation applied to overdamped Brownian motion delivers the global optimal protocol, by comparing it with the results of the global optimization technique of genetic programming.


Morpho-Anatomy and Mathematical Modelling in Lilium philippinense Baker from Cordillera Central Range, Philippines.
The study presents the morphology, anatomy and mathematical modelling in Benguet lily (Lilium philippinense Baker), a threatened species from the Cordillera Central Range and was often misidentified with the weedy L. formosanum. The plant is an annual herb with linear, spiral leaves; pure white, perfect, funnel-shaped, showy flowers; septicidal elongated capsule; and, brown, light, winged seeds. New findings in the study include the description of the capsule and seeds, biometric measurements of the different plant organs, the significant correlation and regression model of plant height and stem diameter for certain floral measurement, and its diagnostic characteristics vis-à-vis L. formosanum. Interesting findings on the taxon's anatomy show a cross between a typical monocot and a typical dicot anatomy. It has a bifacial leaf structure (a common dicot character) but its spongy layer is not as widely spaced like in dicot leaf. The stem has a distinct cortex and pith (a dicot character) but has a scattered vascular bundles (a monocot character). Lastly, some roots have a narrow pith at the centre of the stele (a monocot character) while some roots have metaxylem elements at the centermost structure (a dicot character). Further studies need to be conducted to determine the ecological significance of these features.


Genetic and phenotypic parameters of carcass and organ traits of broiler chickens.
The objective of this study was to estimate the genetic and environmental parameters for carcass, carcass part, and organ weights in a paternal strain of broiler chickens that was selected mainly for body weight at 42 days of age (BW42) to provide support for poultry genetic improvement programs. A total of 1448 chickens were used that resulted from the expansion of a pure paternal strain named TT, which was developed by Embrapa Suínos e Aves. The following weights were evaluated: BW42, chilled carcass, wing, drumstick meat, thigh meat, breast meat, breast fillet, back, liver, heart (HRT), and gizzard (GIZ). The variance component was estimated by the restricted maximum likelihood method using a multi-trait animal model. The general model included the additive genetic and residual random effects and the fixed effect of the sex-hatch group (10 levels). The heritability estimates ranged from 0.27 ± 0.06 for HRT to 0.44 ± 0.08 for GIZ. These results indicated that all the traits have enough additive genetic variability to respond to selection. The genetic correlation estimates between BW42 and the carcass and carcass part weights were high and positive. However, the genetic correlation estimates between BW42 and organ weights were low. In this population, the carcass traits might respond indirectly to selection applied to BW42. It can be concluded that selection to increase BW42 is not effective in improving broiler organ weight. Therefore, to obtain suitable genetic improvement for these traits, the selection indexes for broilers should include organ weight-based criteria.


The incidence of uterine leiomyoma and other pelvic ultrasonographic findings in 2,034 consecutive women in a north London hospital.
New generation technologies provide alternative ways of assessing the female pelvis, and provide improved estimates of the incidence of uterine leiomyoma. To determine the incidence of uterine leiomyoma and other incidental findings, the request forms for pelvic ultrasound scan and the scan results of 2,034 consecutive women was reviewed. There were 586 women with scan-detected uterine leiomyoma giving an incidence of 29.9%, although only 3% of the women had clinically suspected leiomyoma. Pain was the leading indication for a pelvic ultrasound scan in women without a uterus, whereas in women with a uterus, bleeding was the leading indication. Other scan findings included ovarian cyst, 11.4% and polycystic ovaries, 7.5%. Uterine leiomyoma was four times more frequent in women over 40 years (odds ratio 4.1, 95% confidence interval, 3.3-5.0). These women were two times more likely to have multiple leiomyomas (OR 2.01, 95% CI, 1.4-2.8) and 30% more likely to have large leiomyomas (OR 1.3, 95% CI, 1.0-2.1).


The ABCs (Antibody, B cells, and Carbohydrate epitopes) of cholera immunity: considerations for an improved vaccine.
Cholera, a diarrheal disease, is known for explosive epidemics that can quickly kill thousands. Endemic cholera is a seasonal torment that also has a significant mortality. Not all nations with extensive rural communities can achieve the required infrastructure or behavioral changes to prevent epidemic or endemic cholera. For some communities, a single-dose cholera vaccine that protects those at risk is the most efficacious means to reduce morbidity and mortality. It is clear that our understanding of what a protective cholera immune response is has not progressed at the rate our understanding of the pathogenesis and molecular biology of cholera infection has. This review addresses V. cholerae lipopolysaccharide (LPS)-based immunogens because LPS is the only immunogen proven to induce protective antibody in humans. We discuss the role of anti-LPS antibodies in protection from cholera, the importance and the potential role of B cell subsets in protection that is based on their anatomical location and the intrinsic antigen-receptor specificity of various subsets is introduced.


State-of-the-art fertility preservation in children and adolescents undergoing haematopoietic stem cell transplantation: a report on the expert meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015.
Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.


Noninvasive intravital high-resolution imaging of pancreatic neuroendocrine tumours.
Preclinical trials of cancer drugs in animal models are important for drug development. The Rip1Tag2 (RT2) transgenic mouse, a model of pancreatic neuroendocrine tumours (PNET), has provided immense knowledge about PNET biology, although tumour progression occurs in a location inaccessible for real-time monitoring. To overcome this hurdle we have developed a novel platform for intravital 3D imaging of RT2 tumours to facilitate real-time studies of cancer progression. Pre-oncogenic islets retrieved from RT2 mice were implanted into the anterior chamber of the eye (ACE) of host mice, where they engrafted on the iris, recruited blood vessels and showed continuous growth. Noninvasive confocal and two-photon laser-scanning microscopy through the transparent cornea facilitated high-resolution imaging of tumour growth and angiogenesis. RT2 tumours in the ACE expanded up to 8-fold in size and shared hallmarks with tumours developing in situ in the pancreas. Genetically encoded fluorescent reporters enabled high-resolution imaging of stromal cells and tumour cell migration. Sunitinib treatment impaired RT2 tumour angiogenesis and growth, while overexpression of the vascular endothelial growth factor (VEGF)-B increased tumour angiogenesis though tumour growth was impaired. In conclusion, we present a novel platform for intravital high-resolution and 3D imaging of PNET biology and cancer drug assessment.


Excitation-contraction coupling model to estimate the recirculating fraction of activator calcium in intact cardiac muscle.
Potentiated contractions were evoked with rapid pace pause maneuver in 14 length-clamped ferret papillary muscles paced 12 times/min at 25 degrees C. At 1.25 mM [Ca2+]o the average steady-state force was 2.94 +/- 1.08 g/mm2 and the potentiated contraction averaged 10.96 +/- 1.61 g/mm2. At 5.0 mM [Ca2+]o the steady-state force increased to 6.18 +/- 1.23 g/mm2 and the potentiated contraction averaged 12.08 +/- 1.15 g/mm2. Under the conditions of these experiments the potentiated contraction obtained at 5.0 mM [Ca2+]o is equal to the maximum twitch tension (Fmax) these muscles can generate. We have previously shown that Fmax is an equivalent of maximal calcium activated force. Since there is a beat to beat nearly exponential decay of the evoked potentiation, the fraction (= fraction x) of the potentiation that is not dissipated with each beat is nearly constant. Using an excitation-contraction coupling model we have previously found that x reflects a measure of the recirculating fraction of activator calcium. Because the tension-calcium relationship is better characterized by a sigmoidal curve, we have now incorporated the Hill equation in the model. To account for the inverse relationship between [Ca2+]i and the magnitude of the slow inward current, a term for negative feedback (h) was also included. We have determined the quantity (x-h) because x and h could not be determined separately. The quantity (x-h) was denoted as x'. The average values of x' at 1.25 and 5.0 mM [Ca2+]o were significantly different (p less than 0.0001), approximately 20% at the lower [Ca2+]o and about 50% at the higher [Ca2+]o.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationship between problematic Internet use and age at initial weekly Internet use
An important proportion of infants and adolescents in Japan are using Internet-equipped devices, including smartphones, tablets, and game consoles. However, the relationship between the risk of IA and the age at initial habitual Internet use remains unknown. We aimed to investigate this relationship among adolescents. We surveyed 1,775 subjects in seven public junior high schools in Kanagawa prefecture, Japan, in November 2017. Students were asked to complete the Young's Diagnostic Questionnaire (YDQ), which captured information regarding gender, school grade, night sleep, age at which they first started using the Internet at least once weekly, Internet usage situation, and Internet use time for purposes other than study. Data from subjects who reported experience of weekly Internet use were analyzed. Junior high school students who were younger at initial weekly Internet use tended to have problematic Internet use (PIU) and to spend more time on Internet activities. In particular, initial weekly Internet use before the age of five in boys was associated with a significantly increased risk of PIU (YDQ ≥ 5), with an odds ratio of 14.955, compared with initial weekly Internet use after the age of 12. Smartphone ownership significantly increased the risk of PIU compared with no ownership among the total population and among girls. Junior high school male students displayed a robust relationship between initial weekly Internet use and PIU, whereas junior high school female students displayed a particularly strong relationship between smartphone ownership and PIU. Therefore, longitudinal IA preventive education from an early age is necessary.


Hypoxia-associated genes predicting future risk of myocardial infarction: a GEO database-based study.
Patients with unstable angina (UA) are prone to myocardial infarction (MI) after an attack, yet the altered molecular expression profile therein remains unclear. The current work aims to identify the characteristic hypoxia-related genes associated with UA/MI and to develop a predictive model of hypoxia-related genes for the progression of UA to MI. Gene expression profiles were obtained from the GEO database. Then, differential expression analysis and the WGCNA method were performed to select characteristic genes related to hypoxia. Subsequently, all 10 hypoxia-related genes were screened using the Lasso regression model and a classification model was established. The area under the ROC curve of 1 shows its excellent classification performance and is confirmed on the validation set. In parallel, we construct a nomogram based on these genes, showing the risk of MI in patients with UA. Patients with UA and MI had their immunological status determined using CIBERSORT. These 10 genes were primarily linked to B cells and some inflammatory cells, according to correlation analysis. Overall, GWAS identified that the CSTF2F UA/MI risk gene promotes atherosclerosis, which provides the basis for the design of innovative cardiovascular drugs by targeting CSTF2F.


Revision cartilage cell transplantation for failed autologous chondrocyte transplantation in chronic osteochondral defects of the knee.
The management of failed autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI) for the treatment of symptomatic osteochondral defects in the knee represents a major challenge. Patients are young, active and usually unsuitable for prosthetic replacement. This study reports the results in patients who underwent revision cartilage transplantation of their original ACI/MACI graft for clinical or graft-related failure. We assessed 22 patients (12 men and 10 women) with a mean age of 37.4 years (18 to 48) at a mean of 5.4 years (1.3 to 10.9). The mean period between primary and revision grafting was 46.1 months (7 to 89). The mean defect size was 446.6 mm(2) (150 to 875) and they were located on 11 medial and two lateral femoral condyles, eight patellae and one trochlea. The mean modified Cincinnati knee score improved from 40.5 (16 to 77) pre-operatively to 64.9 (8 to 94) at their most recent review (p < 0.001). The visual analogue pain score improved from 6.1 (3 to 9) to 4.7 (0 to 10) (p = 0.042). A total of 14 patients (63%) reported an 'excellent' (n = 6) or 'good' (n = 8) clinical outcome, 5 'fair' and one 'poor' outcome. Two patients underwent patellofemoral joint replacement. This study demonstrates that revision cartilage transplantation after primary ACI and MACI can yield acceptable functional results and continue to preserve the joint.


Molecular cloning and expression of murine liver soluble epoxide hydrolase.
A clofibrate-induced mouse liver cDNA library was prepared and used to isolate the coding sequence for soluble epoxide hydrolase. A 1668-base pair (bp) clone was isolated and found to contain a 1269-bp open reading frame coding for 423 amino acids. Subsequent RNA polymerase chain reaction resulted in the isolation of 396 bp of additional 5'-sequence. Translation of the resulting 1659-bp open reading frame produced a 553-residue protein (62,527 Da) containing deduced peptide segments that matched the amino acid sequences of six peptide fragments isolated previously from CNBr digests of pure murine soluble epoxide hydrolase. Neither the DNA nor the protein sequence showed significant similarity to other currently published sequences. Structural analysis of the soluble epoxide hydrolase coding region suggested at least one potential regulatory motif. Expression of the composite cDNA in COS-7 cells resulted in a 5-10-fold increase in soluble epoxide hydrolase activity and a similar increase in soluble epoxide hydrolase protein amount compared to mock-transfected or vector control-transfected cells. Treatment of C57BL/6J mice with clofibrate led to an approximately 4-fold increase in both soluble epoxide hydrolase enzyme activity and steady-state mRNA levels.


Is women's labor a commodity?
...A commercial surrogate mother is anyone who is paid money to bear a child for other people and terminate her parental rights, so that the others may raise the child as exclusively their own. The growth of commercial surrogacy has raised with new urgency a class of concerns regarding the proper scope of the market. Some critics have objected to commercial surrogacy on the ground that it improperly treats children and women's reproductive capacities as commodities. The prospect of reducing children to consumer durables and women to baby factories surely inspires revulsion. But are there good reasons behind the revulsion? And is this an accurate description of what commercial surrogacy implies? This article offers a theory about what things are properly regarded as commodities which supports the claim that commercial surrogacy constitutes an unconscionable commodification of children and of women's reproductive capacities.


Human subcutaneous adipose tissue shows site-specific differences in fatty acid composition.
Adipose tissue was obtained from six women undergoing liposuction twice at 6-mo intervals. Samples obtained bilaterally from abdomen, inner thigh, and outer thigh had fatty acids quantified by gas chromatography. There were no important differences between sides or over time. The saturates 14:0, 16:0, 18:0, and 20:0 were higher in abdominal adipose than in outer thigh (P < 0.002 for all); 16:1 and 18:1 omega 9 were lower in abdomen vs outer thigh (P < 0.01), whereas 18:1 omega 7 and 20:1 omega 9 were unchanged. Polyunsaturates 18:2 omega 6, 20:3 omega 6, and 20:4 omega 6 were higher in outer thigh than in abdomen (P < 0.06), and inner thigh values were intermediate. These changes in fatty acid composition resulted in lower mean triglyceride melting points from abdomen to inner thigh to outer thigh, and suggest that temperature may influence the selection process determining the variation in adipose fatty acid composition with anatomical location. Because the site-specific differences included essential fatty acids, selective uptake as well as potential differences in in situ fatty acid modification are indicated.


The Bioinorganic Chemistry of Lead in the Context of Its Toxicity.
Owing to its abundance on earth and its multiple uses by humans, lead (Pb) is a major toxicant that has threatened human health for millennia and continues to do so. There is no safe level of exposure, necessitating a nuanced approach to its control in the food we consume, the water we drink, and the air we breathe. Turnover in soft tissues is within days. In contrast, lead accumulates in bone and turns over with a half-life of about 30 years, though it can be mobilized from bone under physiological and pathophysiological conditions of bone resorption. Children are particularly vulnerable to lead exposure and suffer irreversible neurological deficits affecting learning ability and behavior. In adults, chronic effects of exposure to lead include elevated blood pressure, development of cancers, and, as suggested more recently, neurodegeneration. Some pathways of systemic and cellular metabolism of Pb(II) are known. However, except for its action in δ-aminolevulinate dehydratase, its molecular toxicology remains largely speculative in terms of specific targets. One major molecular mechanism seems to be the replacement of zinc with lead in zinc proteins with functional consequences. Calcium binding proteins are also being discussed as possible targets. However, the affinities of lead for calcium sites in proteins are orders of magnitude lower than those for zinc sites. Therefore, it remains to be shown whether lead at the concentrations occurring in tissues can replace calcium in proteins in vivo. Despite humans having recognized the hazards of lead exposure for a very long time, uncertainties remain as to the threshold for adverse effects on our health and the low levels of exposure during our lives as a risk factor for chronic disease.


Infrared Spectroscopic Quantification of Methacrylation of Hyaluronic Acid: A Scaffold for Tissue Engineering Applications.
Methacrylated hyaluronic acid (MeHA) has been used extensively in tissue engineering and drug delivery applications. The degree of methacrylation (DM) of HA impacts hydrogel crosslinking, which is of pivotal importance for cell interactions. The methacrylation reaction occurs over several hours, and DM is currently assessed post reaction and after dialysis of the solution, using nuclear magnetic resonance (1H NMR) data. Thus, there is little control over exact DM in a specific reaction. Here, infrared (IR) spectroscopy in attenuated total reflection (ATR) mode was investigated as an alternate modality for assessment of the DM of HA hydrogels, including during the reaction progression. Attenuated total reflection is a low-cost technique that is widely available in research and industry labs that can be used online during the reaction process. Strong correlations were achieved with IR-derived peak heights from dialyzed and lyophilized samples at 1708 cm-1 (from the methacrylic ester carbonyl vibration), and 1H NMR values ( R = 0.92, P = 6.56E-11). Additional IR peaks of importance were identified using principal component analysis and resulted in significant correlations with the 1H NMR DM parameter: 1454 cm-1 ( R = 0.85, P = 2.81E-8), 1300 cm-1 ( R = 0.95, P = 4.50E-14), 950 ( R = 0.85, P = 3.55E-8), 856 cm-1 ( R = 0.94, P = 1.20E-12), and 809 cm-1 ( R = 0.93, P = 3.54E-12). A multiple linear regression model to predict 1H NMR-derived DM using the 1708, 1300, and 1200 cm-1 peak heights as independent variables resulted in prediction with an error of 3.2% using dialyzed and lyophilized samples ( P < 0.001). Additionally, a multilinear regression model to predict the DM in undialyzed liquid MeHA samples obtained during the reaction process using similar peak height positions as independent variables resulted in a prediction error of 0.81% ( P < 0.05). Thus, IR spectroscopy can be utilized as an alternate modality to 1H NMR for quantification of the DM of MeHA while sampling either on-line during the methacrylation reaction as well as in post-lyophilized products. This could greatly simplify workflow for tissue engineering and other applications.


Post Prostatectomy Vesicourethral Stenosis or Bladder Neck Contracture with Concomitant Urinary Incontinence: Our Experience and Recommendations.
To present our experience in the management of bladder neck contracture with concomitant post prostatectomy incontinence and to provide our recommendations based on the updated literature. Between Jan 2010 and June 2015, 37 patients from our cohort of 341 patients with post prostatectomy incontinence were evaluated. Patient data were retrospectively collected. Patients with bladder neck contracture confirmed on flexible cystoscopy underwent subsequent rigid cystoscopy and deep endoscopic bladder neck incision (BNI). A follow up flexible cystoscopy would be performed 3 months later. If there was no recurrence of the bladder neck contracture, an artificial urethral sphincter (AUS) or a male sling was recommended. The mean age of patients was 68 years (range 59-77) and the mean BMI was 31 (range 21-41) kg/m2. Twenty-five (67.7%) patients had open prostatectomy and 12 (32.4%) patients had laparoscopic prostatectomy. Fourteen patients (37.8%) underwent adjuvant radiotherapy. Twenty-four (64.8%) patients had one BNI procedure, 8 (21.6%) patients had two procedures and 5 (13.5%) patients had more than 2 procedures. Twenty-one (91.3%) patients had AUS implantation and 2 (8.7%) patients had male sling placement. Besides, 85.7% of AUS and 50% of male sling patients managed to achieve successful outcomes with a mean follow up period of 13.1 months (range 2-33 months). Initial management with aggressive BNI followed by implantation of an AUS or male sling when bladder neck is stable is essential to achieve a satisfactory urinary continence outcome.


Dual therapy: personality change in the therapist while working with patients.
This paper promotes a recognition that it is often necessary for therapists to engage in an extended therapeutic process of working on their own personality difficulties which arise in the course of treating various patients in order to help them more effectively. Although gradually it has become increasingly accepted that countertransferences frequently occur in the work of all therapists, such impediments to the therapeutic process almost inevitably have been considered to be overcome as soon as the therapist becomes aware of them. The focus of this paper is not on countertransference per se, about which much has already been written. Rather, it emphasizes the necessity for two parallel therapeutic processes which I have termed "dual therapy" in order to facilitate the benefits of psychotherapy.


Genetic and environmental influences on corticostriatal circuits in twins with autism
Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity. Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.


Molecular analysis of HLA-B35 alleles and their relationship to HLA-B15 alleles.
The HLA-B35 serotype is one of the largest allelic groups of HLA class I molecules and includes four isotypes. Of the four, the B35 variant isoform is relatively rare and is the most acidic form. DNA sequencing of the rare isoforms revealed three alleles, B*1522, B*3511, and B*3517. A phylogenetic tree of HLA-B15- and HLA-B35-related alleles for the exon 2 and 3 nucleotide sequences showed that exon 2 of B*1522 clusters with B35 alleles whereas exon 3 clusters with B15 alleles. Branches of the tree suggest that the serodeterminants of B35, B62, B63, and B70 may reside in the alpha 1 domain, encoded by exon 2. The B*1520 and B*1522 genes, which type as B62 and B35, respectively, are hybrid molecules alternatively using exon 2 and exon 3 sequences of B*3501 and B*1501. A comparison of intron 2 sequences for B*3501, B*1501 and B*1522 suggests that the recombination site may have been in the region at the 3' end of intron 2. Despite being flanked by two highly polymorphic exons (exons 2 and 3), intron 2 is relatively well conserved in the B-locus, and it is characterized by seven to eight tandem repeats of the CGGGG pentanucleotide. A high degree of sequence homology and repetitive sequences are essential for a significant frequency of recombination. In this report, we reveal more about the complex evolutionary history of the HLA-B alleles.


Of Testing and Treatment: Implications of Implementing New Regimens for Multidrug-Resistant Tuberculosis.
A novel, shorter-course regimen for treating multidrug-resistant (MDR) tuberculosis was recently recommended by the World Health Organization. However, the most appropriate use of drug susceptibility testing (DST) to support this regimen is less clear. Implementing countries must therefore often choose between using a standardized regimen despite high levels of underlying drug resistance or require more stringent DST prior to treatment initiation. The former carries a high likelihood of exposing patients to de facto monotherapy with a critical drug class (fluoroquinolones), whereas the latter could exclude large groups of patients from their most effective treatment option. We discuss the implications of this dilemma and argue for an approach that will integrate DST into the delivery of any novel antimicrobial regimen, without excessively stringent requirements. Such guidance could make the novel MDR tuberculosis regimen available to most patients while reducing the risk of generating additional drug resistance.


Interplay among platelet-activating factor, oxidative stress, and group I metabotropic glutamate receptors modulates neuronal survival.
Platelet-activating factor (PAF) is a potent phospholipid messenger in the nervous system that participates in synaptic plasticity and in pathologic processes, including neurodegeneration. Oxidative stress plays important roles in neuronal cell death. To define the interaction between PAF and oxidative radicals in neuronal death, we studied the effects of PAF in the presence of oxidative radicals in primary neurons in culture. Exogenous PAF (50 microM) caused PAF receptor-independent injury to neurons. A nonneurotoxic PAF concentration (500 nM) potentiated neuronal death caused by hydrogen peroxide as determined by lactate dehydrogenase (LDH) assay, Hoechst staining, and TUNEL analysis, but it did not potentiate neuronal death caused by menadione, a superoxide donor, or by the nitric oxide donors 3-morpholino-sydnonimine (SIN-1) and sodium nitroprusside (SNP). This potentiation of the hydrogen peroxide effect was selectively blocked by a PAF membrane-receptor antagonist, BN52021 (5 microM). The neurotoxic effect of PAF and hydrogen peroxide was also completely blocked by ebselen and partially decreased by pretreatment with (S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist. This study suggests that PAF-receptor antagonists may be useful for neuroprotection. A similar effect might also be obtained with group I mGluR agonists, probably by way of a different underlying mechanism.


Role of brain-derived neurotrophic factor in shaping the behavioural response to environmental stressors.
Brain-derived neurotrophic factor (BDNF) is an important neurotrophin involved in an integration of the brain activity in physiological and pathological conditions, with formation of a short- and long-term functional and structural neuroplasticity. This process proceeds, with a changeable dynamics, in the subsequent stages of ontogenesis. In addition to many other functions in the central nervous system, BDNF is also involved in shaping a response to stress stimuli in the form of precisely adjusted behavioural reactions involving the limbic system, and the endocrine system with stimulation of the hypothalamic-pituitary-adrenal axis (HPA). Although almost every stressor increases the activity of the HPA, the neuronal response to it can vary substantially. This may be due to involvement of different neurotransmitter pathways, neuromodulators and neurohormones, as well as changes in gene expression. It is widely accepted that BDNF synthesis and secretion are modulated by stress. Furthermore, age is an important factor influencing the BDNF expression in response to different stressors. In this work, we focused on the analysis of the role of mild stressful stimuli, which commonly occur in the natural environment, on changes in BDNF expression at various stages of ontogenetic development. Although, the presented data comes from animal studies, probably similar mechanisms of stress regulation are also present in humans. This comprehensive review shows that the influence of stressors on the BDNF expression depends on many factors, including a type and duration of a stressor, time of neurotrophin detection, animal's resistance to stress, brain area, and genotypic characteristics of an individual. A more detailed understanding of the mechanisms shaping stress reactions, including the role of BDNF, may be of both theoretical and practical importance, allowing designing more effective strategies for preventing and treating stress itself and the stress-related disorders.


Submillimeter-wave spectra of hypoiodous acid.
Pure rotational spectra of hypoiodous acid, HOI, and its deuterated species, DOI, were measured in the frequency range of 320-670 GHz. The molecule was efficiently produced by a reaction of atomic oxygen with iodoethane. Rotational constants and centrifugal distortion constants for the molecule were determined accurately. The vibrationally averaged structure for HOI was obtained by taking the isotopic difference of the OH bond length into consideration: r(z)(OH)=0.967(8) A, r(z)(OI)=1.9941(3) A, and theta(z)(HOI)=103.89 degrees, where the errors were estimated from the residual inertial defect. Equilibrium bond lengths for the OH and OI bonds were derived as 0.959(8) A and 1.9874(3) A, respectively, by assuming anharmonic constants of the corresponding diatomic molecules. Electric-quadrupole interaction constants and nuclear-spin-rotation coupling constants for the iodine nucleus were obtained. Nonaxial terms of the electric-quadrupole constant for HOI can be determined as well, which enabled us to derive the principal values of the coupling tensor. The values obtained were used to gauge the ionicity of the X-O bond in the HOX molecular system. The nuclear-spin-rotation coupling constant along the a inertial axis is found to be significantly smaller than others, which may be explained by a contribution from two low-lying singlet excited states.


Occlusive dressings and the healing of standardized abrasions.
Acute skin trauma during sport participation, resulting in partial-thickness abrasions, is common. The limited investigations focusing on the acute wound environment and dressing techniques and the subsequent lack of evidence-based standards complicate clinical wound care decisions. To examine the effects of occlusive dressings on healing of standardized, partial-thickness abrasions. Controlled, counterbalanced, repeated-measures design. University laboratory. Sixteen healthy women (n = 10) and men (n = 6). Four standardized, partial-thickness abrasions were inflicted. Film, hydrogel, and hydrocolloid occlusive dressings and no dressing (control) were applied. Participants returned on postwound days 1, 3, 5, 7, 10, and 14 for digital imaging. Wound healing time was measured by change in wound contraction (cm(2)) and change in wound color (chromatic red) and luminance in red, green, and blue color values. Wound contraction, color (chromatic red), and luminance. A day-by-dressing interaction was found for wound contraction, color, and luminance. Post hoc testing indicated that the film and hydrocolloid dressings produced greater wound contraction than the hydrogel and no dressing on days 7 and 10. Film, hydrogel, and hydrocolloid dressings also resulted in greater wound contraction than the control on day 14. Hydrocolloid dressings produced smaller measures of color and greater measures of luminance than no dressing on day 7. Film, hydrogel, and hydrocolloid dressings also resulted in smaller measures of color and greater measures of luminance compared with no dressing on days 10 and 14. When compared with the control (no dressing), the film, hydrogel, and hydrocolloid occlusive dressings were associated with a faster healing rate of partial-thickness abrasions across time measured by wound contraction, color, and luminance. Overall, these data indicate that occlusive dressings were more effective in healing than no dressing was.


Glutathione-Mediated Cu(I)/Cu(II) Complexes: Valence-Dependent Effects on Clearance and In Vivo Imaging Application.
Contrast imaging agents need to be cleared in a reasonable time (less than 72 h), so it is quite urgent to understand the structure, biocompatibility, and metabolism features of imaging agents. In this work, luminescent Cu(I)-GSH complex and their derivative oxidized Cu(II)-GSSG complex have been easily synthesized. Through systematically probing the renal clearance and biodistribution of the as-prepared copper complexes, we found that Cu(I)-GSH complex revealed much more efficient renal clearance and remarkably lower liver accumulation than that of their oxidation states, which could be due to strong protein binding of partial forms of Cu(II)-GSSG complex. Besides, we also attempted to incorporate radioactive copper-64 into Cu(I)-GSH complex for the synthesis of radioactive contrast agent. Indeed, the as-prepared radioactive Cu(I)-GSH complex also showed consistent high efficiency renal excretion, allowing them to be potential PET imaging agents in clinical translation.


Forbidden suffering: the Pollyanna syndrome of the disabled and their families.
Has suffering become an ugly word in the normalization debate? Are the disabled and their families forced into a Pollyanna culture in order to be acknowledged and accepted in good company as the worthy disabled? This essay poses a controversial question: I would like to start a debate and ask whether normalization also has an unseen, ideological downside.


Trace DNA evidence dynamics: An investigation into the deposition and persistence of directly- and indirectly-transferred DNA on regularly-used knives.
Empirical data on the transfer and persistence of trace DNA are crucial to the evaluation of forensic DNA evidence. This evaluation can be complicated by the occurrence of indirect DNA transfer; the possibility of which is well established, but research into such transfer is often focussed on unrealistic situations, e.g. handling of DNA-free items after participants have shaken hands for 1-2min. To simulate more realistic scenarios, this study investigated the deposition and persistence of both directly- and indirectly-transferred DNA on knives that had been artificially set up as 'regularly-used'. Each knife was handled in a prescribed manner by a specific participant over two consecutive days to simulate regular use. Each participant then shook hands for 10s with a fellow volunteer and immediately stabbed one of their knives into a foam block repeatedly for 60s. DNA was recovered by mini-taping from triplicate sets of knife handles from four pairings of volunteers after regular use, and at one hour, one day and one week after the handshaking and stabbing events. Total amounts of DNA recovered from the knives, regularly used by a single person, varied among individuals; one volunteer consistently deposited significantly greater amounts than the others, whilst another volunteer did not always leave complete profiles. DNA attributed to the regular user persisted for at least a week, declining with increasing time between DNA deposition and recovery. Non-donor DNA was co-deposited at <5% of the profiles recovered, except for one volunteer, who consistently left DNA from their romantic partner on their knives at ∼25% and ∼11% of the profiles before and after the handshaking and stabbing events, respectively. In three pairings of volunteers, after the handshaking and stabbing events, alleles that could be attributed to the respective handshakers' profiles were detected as partial minor profiles, equating to ∼10% of the profiles recovered. For the fourth pairing of volunteers, only complete single-source DNA profiles matching the regular user's profile were recovered. However, it is important to note that, when indirectly-transferred handshaker DNA was detected, it declined with increasing time between DNA deposition and recovery. These data provide an initial insight into the detection and persistence of directly- and indirectly-transferred DNA that extend the data already available on forensic DNA transfer. The results herein suggest that the sooner an item is sampled after an offence has occurred, the greater the chance of recovering indirectly-transferred DNA, which has implications for forensic reconstructions.


Estimating Trait Heritability in Highly Fecund Species.
Increasingly, researchers are interested in estimating the heritability of traits for nonmodel organisms. However, estimating the heritability of these traits presents both experimental and statistical challenges, which typically arise from logistical difficulties associated with rearing large numbers of families independently in the field, a lack of known pedigree, the need to account for group or batch effects, etc. Here we develop both an empirical and computational methodology for estimating the narrow-sense heritability of traits for highly fecund species. Our experimental approach controls for undesirable culturing effects while minimizing culture numbers, increasing feasibility in the field. Our statistical approach accounts for known issues with model-selection by using a permutation test to calculate significance values and includes both fitting and power calculation methods. We further demonstrate that even with moderately high sample-sizes, the p-values derived from asymptotic properties of the likelihood ratio test are overly conservative, thus reducing statistical power. We illustrate our methodology by estimating the narrow-sense heritability for larval settlement, a key life-history trait, in the reef-building coral Orbicella faveolata. The experimental, statistical, and computational methods, along with all of the data from this study, are available in the R package multiDimBio.


Molecular structure of maternal RNA.
The presence of a stable maternal mRNA population in mature oocytes of many species is well established. In this paper we show that the mature egg contains, in addition to these mature mRNAs, a structurally more complex population of RNA transcripts. This latter class of RNA consists of polyadenylated transcripts of repetitive and nonrepetitive DNA elements covalently linked into long interspersed molecules. As much as seventy percent of the polyadenylated egg RNA of Xenopus laevis and Strongylocentrotus purpuratus is represented in this interspersed population. Most of the nonrepetitive DNA sequences represented in the mature mRNA population are also present in the interspersed RNA. These transcripts have an organization similar to that of somatic cell nuclear RNA. Data are presented that suggests some of these interspersed maternal transcripts are unprocessed precursor-like molecules. Some possible functions of this novel class of RNA during early development are discussed.


[The correlation of black-pigmented bacteroides spp to symptoms associated with apical periodontitis].
The quantitative analysis of the incidence of black-pigmented Bacteroides (B.P.B.) spp. in 80 human dental root canal infections (56 with acute symptoms and 24 clinically asymptomatic) in 79 adults were studied. Altogether 101 strains including 7 species of B. P. B. were identified. It was found that the infection rate of B. P. B. in symptomatic group (192.86%) was higher than that in asymptomatic group (41.67%). The means of quantity of cultivable B. P. B. (CFU/ml) and percentage of B.P.B. (CFU/ml) in total CFU/ml of bacteria were not significant. But the percentage of asacchrolytic B.P.B. species in B.P.B. positive samples in symptomatic group (73.08%) was higher than that in B.P.B. positive samples in asymptomatic group (40%). These results suggest that there is a close correlation between symptoms and the asacchrolytic species of B. endodontalis and B. gingivalis.


Bivalirudin in patients undergoing percutaneous coronary intervention and independent predictors of postoperative adverse events in these patients: A real world retrospective study.
The efficacy and safety of bivalirudin in percutaneous coronary intervention (PCI) has always been a hot topic in perioperative antithrombotic therapy, but there are still some controversies. So studies are needed to provide more evidence, especially the real world study which includes patients excluded from previous RCT studys. Our study aimed to investigate these information and analyze the independent predictors of postoperative adverse events.A retrospective study enrolled 1416 patients underwent PCI in Tianjin Chest Hospital from May 2016 to October 2017. The incidence of stent-thrombosis and net clinical adverse events, including all-cause death, myocardial infarction, stroke, urgent target-vessel revascularization and bleeding, were followed up for 30 days and 1 year. Logistic regression and COX regression were respectively used to analyze independent predictors of bleeding events within 30-days, and independent predictors of Major adverse cardiovascular and cerebrovascular events (MACCE) in patients with stent implantation within 1-year.Seven hundred six patients were treated with bivalirudin while 710 with unfractionated heparin (UFH). The proportions of diabetes, hypertension, anemia, myocardial-infarction history, PCI history, moderate-to-severe renal-impairment, gastrointestinal-bleeding history in the bivalirudin group were significantly higher (P < .05). Women, anemia were independent risk factors for bleeding within 30-days (P < .05). Among 682 patients with stent implantation in bivalirudin group, anemia, Body Mass Index (BMI) >25 kg/m2, KILLIP ≥2, ejection fraction (EF) <45%, eGFR <60 ml/minutes were independent risk factors for MACCE, while Statins, proton pump inhibitor (PPI) were independent protective factors for MACCE with-in 1-year (P < .05).Bivalirudin have good anticoagulant effect and lower bleeding risk during PCI, especially in patients with higher bleeding risk. In patients treated with bivalirudin, female, anemia were independent predictors of bleeding within 30-days, BMI >25 kg/m2, anemia, KILLIP ≥2, EF <45%, eGFR <60 ml/minutes were independent risk factors and Statins, PPI were independent protective factors of MACCE within 1-year.


Investigation of associations between preoperative acepromazine or dexmedetomidine administration and development of arterial hypotension or bradycardia in dogs undergoing ovariohysterectomy.
OBJECTIVE To evaluate potential associations between preanesthetic administration of acepromazine or dexmedetomidine and development of arterial hypotension or bradycardia in isoflurane-anesthetized dogs undergoing ovariohysterectomy. ANIMALS 341 dogs. PROCEDURES Medical records were searched to identify dogs that underwent ovariohysterectomy between January 2009 and December 2010 and received hydromorphone with acepromazine or dexmedetomidine as preanesthetic agents. Demographic data, sedative and anesthetic drugs, duration of anesthesia, average vaporizer setting, positive pressure ventilation, occurrence of hypotension (mean arterial pressure < 60 mm Hg) or bradycardia (> 50% reduction in heart rate, compared with the preanesthetic value), time to first occurrence and duration of hypotension, and treatment with dopamine or anticholinergic agents were recorded. Data were compared between dogs that received acepromazine and dexmedetomidine. Logistic regression was used to investigate associations between the treatments of interest (and other putative risk factors) and development of hypotension or bradycardia. RESULTS For dogs that received acepromazine, the odds of developing hypotension were 2.61 times those for dogs that received dexmedetomidine. Hypotension occurred earlier and lasted longer in dogs that received acepromazine, and this group was treated with dopamine more frequently than the group that received dexmedetomidine. Lower body weight was associated with increased odds of hypotension. Odds of developing bradycardia were greater for dogs sedated with dexmedetomidine (vs acepromazine) and for dogs that underwent anesthetic induction with propofol or a ketamine-benzodiazepine combination (vs thiopental). CONCLUSIONS AND CLINICAL RELEVANCE Anesthetic complications differed between isoflurane-anesthetized dogs undergoing ovariohysterectomy after premedication with acepromazine or dexmedetomidine in this study; future prospective investigations are warranted to investigate these effects in other, less homogenous populations of dogs.


Stereoselective ring-opening polymerization of racemic lactide using aluminum-achiral ligand complexes: exploration of a chain-end control mechanism.
Stereoselective polymerization of racemic lactide (rac-LA) was examined using Al-achiral ligand complexes. By introduction of substituents in aromatic rings of Schiff base ligands, a higher selectivity was obtained without any chiral auxiliaries in the catalyst via a chain-end control mechanism. The T(m) values (T(m) 170-192 degrees C) were comparable to or higher than that of homochiral polymer, poly(L-LA) (T(m) 162 degrees C), and a thermally more stable polylactide than poly(L-LA) was prepared from rac-LA.


TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.
The capsaicin receptor, TRPV1, is regulated by phosphatidylinositol-4,5-bisphosphate (PIP(2)), although the precise nature of this effect (i.e., positive or negative) remains controversial. Here, we reconstitute purified TRPV1 into artificial liposomes, where it is gated robustly by capsaicin, protons, spider toxins, and, notably, heat, demonstrating intrinsic sensitivity of the channel to both chemical and thermal stimuli. TRPV1 is fully functional in the absence of phosphoinositides, arguing against their proposed obligatory role in channel activation. Rather, introduction of various phosphoinositides, including PIP(2), PI4P, and phosphatidylinositol, inhibits TRPV1, supporting a model whereby phosphoinositide turnover contributes to thermal hyperalgesia by disinhibiting the channel. Using an orthogonal chemical strategy, we show that association of the TRPV1 C terminus with the bilayer modulates channel gating, consistent with phylogenetic data implicating this domain as a key regulatory site for tuning stimulus sensitivity. Beyond TRPV1, these findings are relevant to understanding how membrane lipids modulate other "receptor-operated" TRP channels.


[The immunomodulating action of interferon preparations. 3. Changes in the phagocytic activity of human blood neutrophilic granulocytes under the influence of interferon preparations].
In vitro studies of phagocytosis-stimulating effects of interferon preparations differing in their origin and mode of purification were carried out with blood cells of dermatosis patients and healthy donors. Native preparations and preparations purified by sparing methods (alpha-interferon for intranasal administration and alpha-interferon for injections II) were found the most active: they induced a significant elevation of the activities of individual cells and of the count of actively phagocytizing cells. Phagocytosis-stimulating effect of well purified interferon preparations is essentially reduced. Recombinant alpha 2-interferon preparation has shown no such activity. A dose dependence of the effect of interferon preparations on blood neutrophil phagocytic activity has been revealed. The highest phagocytosis-stimulating effect of the above interferon preparations was observed in patients whose blood polymorphonuclear leukocyte phagocytic activity was essentially reduced.


Design and validation of a new immunoassay for soluble forms of thrombomodulin and studies on plasma.
Thrombomodulin (TM), purified from human placental homogeneate by affinity chromatography on DIP-Thrombin agarose, was used to develop monoclonal antibodies (MAbs). Two of them, 3E2 and 24FM (both IgG1, K), which were not calcium-dependent, were found convenient for developing a two-site enzyme immunoassay. Testing of recombinant and truncated forms of TM26 demonstrated that the species containing the amino terminus including the lectin-like domain and the epidermal growth factor (EGF)-like domains 1-4 were fully measured. The working range was from 2 to 100 ng/ml with a detection threshold of 2 ng/ml. Intraassay and interassay reproducibilities were, respectively, below 7.4% and 8.6%, whereas recovery of purified TM was between 88 and 114% in plasma. Mean plasma concentration was 42.1 (+/- 11.3) ng/ml (males 51.8 +/- 7.9 ng/ml, females 34.8 +/- 7.8 ng/ml) and it was established on 62 normal individuals between the ages of 21 and 55 (28 males and 34 females). This new assay is a convenient tool for measuring plasma TM and establishing its diagnostic and predictive value in diseases associated to endothelial damage.


Structural Proof for the First Dianion of a Polychloride: Investigation of [Cl8 ](2.).
The polychloride salt [CCl(NMe2 )2 ](+) 2 [Cl8 ](2-) was synthesized and crystallized in the ionic liquid [BMP]OTf. The compound was fully characterized by Raman spectroscopy as well as X-ray single-crystal structure determination, and represents the first example of a polychloride dianion to be described. Detailed gas-phase and solid-state calculations concerning the nature of the bonding situation were also performed.


Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma.
Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.


Prevalence of suicide thoughts, plans and attempts in a community sample from Karaj, Iran.
Aim of this study was to evaluate the prevalence of suicide ideation and behavior in a community sample of an Iranian city, Karaj. Study sample consisted of 2,300 subjects, chosen randomly from the community. The WHO/SUPRE-MISS survey questionnaire, used in this study. Lifetime prevalence for suicide thoughts, plans and attempts were 12.7, 6.2 and 3.3%, respectively and for the previous year they were 5.7, 2.9 and 1%, respectively. Although it is not possible to generalize the results to the country, but in some area of Iran, the prevalence of suicide ideation, plan and attempt appeared to be similar to that of many developed countries.


Breast-feeding and postpartum maternal weight trajectories.
We examined whether breast-feeding, and in particular exclusive breast-feeding, was associated with maternal weight and body composition changes at 4 months postpartum independently of other maternal variables. Prospective longitudinal study. Women were recruited in the first trimester after an ultrasound examination confirmed an ongoing singleton pregnancy. Weight and body composition were measured using advanced bio-electrical impedance analysis at the first antenatal visit and 4 months postpartum. Detailed questionnaires were completed on breast-feeding, socio-economic status, diet and exercise in addition to routine clinical and sociodemographic details. Large Irish university maternity hospital. Women who delivered a baby weighing ≥500 g between November 2012 and March 2014. At the postpartum visit, the mean weight was 70·9 (sd 14·2) kg (n 470) and the mean BMI was 25·9 (sd 5·0) kg/m2. 'Any breast-feeding' was reported by 65·1 % of women (n 306). Irish nativity (OR=0·085, P<0·001), current smoking (OR=0·385, P=0·01), relative income poverty (OR=0·421, P=0·04) and deprivation (OR=0·458, P=0·02) were negatively associated with exclusive breast-feeding. At 4 months postpartum there was no difference in maternal weight change between women who exclusively breast-fed and those who formula-fed (+2·0 v. +1·1 kg, P=0·13). Women who exclusively breast-fed had a greater increase in percentage body fat at 4 months postpartum compared with women who formula-fed (+1·0 v. -0·03 %, P=0·02), even though their dietary quality was better. Exclusive breast-feeding was not associated with postpartum maternal weight or body fat percentage change after adjusting for other maternal variables. There are many reasons why breast-feeding should be strongly promoted but we found no evidence to support postpartum weight management as an advantage of breast-feeding.


Hirtusneanoside, an unsymmetrical dimeric tetrahydroxanthone from the lichen Usnea hirta.
Hirtusneanoside, a new O-deoxyglycoside of a dimeric tetrahydroxanthone, was isolated from the lichen Usnea hirta. Its structure, including the absolute configuration, was determined by means of extensive spectroscopic data (UV, IR, MS, CD, 1D and 2D NMR) and chemical degradation. Hirtusneanoside has a unique structure comprising L-rhamnopyranoside of a tetrahydroxanthone dimer and showed growth inhibitory activities against Gram-positive bacteria.


Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents.
Nerve agents are organophosphates acting as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine and, consequently, the termination of the transmission of nerve impulses. The inhibition of AChE by an organophosphate can be reversed by a nucleophilic agent able to dephosphorylate a serine residue in the active site of AChE. In this sense, the oximes are compounds capable of removing the nerve agent and reactivate the enzyme. Here, we have applied a methodology involving theoretical docking and Quantum Mechanics/Molecular Mechanics, using the softwares Molegro(®) and Spartan(®), to evaluate the kinetic constants of reactivation and the interactions of the oxime BI-6 with AChE inhibited by different organophosphorus compounds in comparison to in vitro data. Results confirm that this method is suitable for the prediction of kinetic and thermodynamic parameters of oximes, which may be useful in the design and selection of new and more effective oximes.


Obesity, Weight Loss, Lifestyle Interventions, and Autosomal Dominant Polycystic Kidney Disease.
Obesity remains a growing public health concern in industrialized countries around the world. The prevalence of obesity has also continued to rise in those with chronic kidney disease. Epidemiological data suggests those with overweight and obesity, measured by body mass index, have an increased risk for rapid kidney disease progression. Autosomal dominant polycystic kidney disease causes growth and proliferation of kidney cysts resulting in a reduction in kidney function in the majority of adults. An accumulation of adipose tissue may further exacerbate the metabolic defects that have been associated with ADPKD by affecting various cell signaling pathways. Lifestyle interventions inducing weight loss might help delay disease progression by reducing adipose tissue and systematic inflammation. Further research is needed to determine the mechanistic influence of adipose tissue on disease progression.