Changes in local school policies and practices in Washington State after an unfunded physical activity and nutrition mandate.
Policies and practices in schools may create environments that encourage and reinforce healthy behaviors and are thus a means for stemming the rising rates of childhood obesity. We assessed the effect of a 2005 statewide school physical activity and nutrition mandate on policies and practices in middle and high schools in Washington State. We used 2002, 2004, and 2006 statewide School Health Profiles survey data from Washington, with Oregon as a comparison group, to create longitudinal linear regression models to describe changes in relevant school policies after the Washington statewide mandate. Policy area composite measures were generated by principal component factor analysis from survey questions about multiple binary measure policy and practice. Relative to expected trends without the mandate, we found significant percentage-point increases in various policies, including restricted access to competitive foods in middle and high schools (increased by 18.8-20.0 percentage points); school food practices (increased by 10.4 percentage points in middle schools); and eliminating exemptions from physical education (PE) for sports (16.6 percentage-point increase for middle schools), exemptions from PE for community activities (12.8 and 14.4 percentage-point increases for middle and high schools, respectively) and exemptions from PE for academics (18.1 percentage-point increase for middle schools). Our results suggest that a statewide mandate had a modest effect on increasing physical activity and nutrition policies and practices in schools. Government policy is potentially an effective tool for addressing the childhood obesity epidemic through improvements in school physical activity and nutrition environments.


Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data.
Environmental Protection Agency's ToxCast project is profiling the in vitro bioactivity of chemicals to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesized that developmental toxicity in guideline animal studies captured in the ToxRefDB database would correlate with cell-based and cell-free in vitro high-throughput screening (HTS) data to reveal meaningful mechanistic relationships and provide models identifying chemicals with the potential to cause developmental toxicity. To test this hypothesis, we built statistical associations based on HTS and in vivo developmental toxicity data from ToxRefDB. Univariate associations were used to filter HTS assays based on statistical correlation with distinct in vivo endpoint. This revealed 423 total associations with distinctly different patterns for rat (301 associations) and rabbit (122 associations) across multiple HTS assay platforms. From these associations, linear discriminant analysis with cross-validation was used to build the models. Species-specific models of predicted developmental toxicity revealed strong balanced accuracy (> 70%) and unique correlations between assay targets such as transforming growth factor beta, retinoic acid receptor, and G-protein-coupled receptor signaling in the rat and inflammatory signals, such as interleukins (IL) (IL1a and IL8) and chemokines (CCL2), in the rabbit. Species-specific toxicity endpoints were associated with one another through common Gene Ontology biological processes, such as cleft palate to urogenital defects through placenta and embryonic development. This work indicates the utility of HTS assays for developing pathway-level models predictive of developmental toxicity.


Spectroscopic Analysis of Vibronic Relaxation Pathways in Molecular Spin Qubit [Ho(W5O18)2]9-: Sparse Spectra Are Key.
Vibrations play a prominent role in magnetic relaxation processes of molecular spin qubits as they couple to spin states, leading to the loss of quantum information. Direct experimental determination of vibronic coupling is crucial to understand and control the spin dynamics of these nano-objects, which represent the limit of miniaturization for quantum devices. Herein, we measure the magneto-infrared properties of the molecular spin qubit system Na9[Ho(W5O18)2]·35H2O. Our results place significant constraints on the pattern of crystal field levels and the vibrational excitations allowing us to unravel vibronic decoherence pathways in this system. We observe field-induced spectral changes near 63 and 370 cm-1 that are modeled in terms of odd-symmetry vibrations mixed with f-manifold crystal field excitations. The overall extent of vibronic coupling in Na9[Ho(W5O18)2]·35H2O is limited by a modest coupling constant (on the order of 0.25) and a transparency window in the phonon density of states that acts to keep the intramolecular vibrations and MJ levels apart. These findings advance the understanding of vibronic coupling in a molecular magnet with atomic clock transitions and suggest strategies for designing molecular spin qubits with improved coherence lifetimes.


How often does ultrasound marking change the liver biopsy site?
The aim of this study was to answer the question: How often does ultrasound change the liver biopsy position, when a percussion technique is applied, because of intervening structures? A secondary objective is to compare the performance of the hepatologist to a radiology technician to demonstrate safety of a self-training technique. One hundred sixty-five consecutive outpatient liver biopsies were studied. Using a standard percussion technique, a biopsy site was chosen and marked. Ultrasound was applied to the marked site. An adequate site was determined to be one without intervening structure within 6 cm of liver depth. If an intervening structure was found, an alternative site was chosen by ultrasound. Data recorded included reason for change of position, distance of moved site from original site, and complications. The first third of liver biopsies were done with assistance of a certified radiology technician performing ultrasound, the last two-thirds were done by the hepatologist after observing the first 64 biopsies. Ultrasound changed the position in 21 of 165 patients. The ultrasound caused an abortion of the procedure in 4 of 165 patients. Ultrasound changed management in 15.1% of patients. Reasons for change were lung (10 patients), gallbladder (6), large central vessel (4), >4-cm rim of ascites (2), colonic loop (1), slim liver edge (1), and focal liver lesions (1 patient). There was a 1.8% multiple pass rate. No serious complications occurred. Ultrasound changed management 15.1% of patients. A hepatologist could perform ultrasound marking after a period of observation, without compromising results. A low multiple pass rate was observed when applying ultrasound and percussion. Avoided structures could explain decrease in pain when ultrasound is applied.


Allograft inflammatory factor 1 (AIF-1) is a new human adipokine involved in adipose inflammation in obese women.
Allograft inflammatory factor 1 (AIF-1) is a putative obesity gene. Our aim was to examine the expression of AIF-1 in human white adipose tissue (WAT) in relation to obesity and metabolic phenotypes in women. WAT secretion of AIF-1 was determined in subcutaneous adipose tissue pieces in vitro by ELISA from 5 subjects. mRNA expression of AIF-1 was determined by RT-qPCR in the isolated cell fractions of adipose tissue (n = 5-6 per group), in subcutaneous and visceral WAT pieces from non-obese (n = 12) and obese women (n = 23), and in some subcutaneous WAT also before and after weight reduction (n = 10). Finally, adipose AIF-1 mRNA was related to metabolic phenotypes in 96 subjects with a wide range of BMI. AIF-1 was secreted in a time dependent fashion from WAT. The major source of AIF-1 was WAT resident macrophages. Expression of AIF-1 was similar in visceral and subcutaneous WAT and was two-fold increased in obese women (P < 0.01). AIF-1 mRNA expression levels were normalized after weight reduction (P < 0.01). Expression of AIF-1 was inversely correlated with insulin sensitivity as assessed by insulin tolerance test (KITT), and circulating levels of adiponectin (P = 0.02), and positively correlated with insulin resistance as estimated by HOMA (=0.0042). AIF-1 is a novel adipokine produced mainly by macrophages within human WAT. Its expression is increased in obese women and associates with unfavourable metabolic phenotypes. AIF-1 may play a paracrine role in the regulation of WAT function through cross-talk between macrophages and other cell types within the adipose tissue.


Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population.
To explore the distribution frequencies of four common single nucleotide polymorphisms (SNPs) of MRP1/ABCC1 in a mainland Chinese population and investigate whether these SNPs affect the expression and function of the MRP1/ABCC1. The genotype of 208 healthy volunteers was determined using PCR-restriction fragment length polymorphism. The four candidated SNPs were recreated by site-directed mutagenesis and tested for their effect on MRP1/ABCC1 expression and multidrug resistance function in stable transfected HEK293 and CHO-K1 cell lines. Real-time PCR, western blot and confocal microscopy were used to determine the mRNA, protein expression, and protein trafficking. At last, the effect of mutations on MRP1/ABCC1-mediate drug resistance was determined using methyl thiazolyl tetrazolium assay. The allelic frequencies of Cys43Ser (128G>C), Thr73Ile (218C>T), Arg723Gln (2168G>A), and Arg1058Gln (3173G>A) in mainland Chinese were 0.5, 1.4, 5.8, and 0.5%, respectively. None of these mutations had any effect on MRP1/ABCC1 expression and trafficking, but that Arg723Gln mutation significantly reduced MRP1/ABCC1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine, and vincristine. The Cys43Ser mutation did not affect all tested drug resistance. In contrast, the Thr73Ile mutation reduced resistance to methotrexate and etoposide, whereas the Arg1058Gln mutation increased the response of two anthracycline drugs and etoposide in HEK293 and CHO-K1 cells as well as vinblastine and methotrexate in CHO-K1 cells. The allelic frequency of the Arg723Gln mutation is relatively higher than other SNPs in mainland Chinese population and therefore this mutation significantly reduces MRP1/ABCC1 activity in multidrug resistance.


Perception of Coherent Motion in Infantile Nystagmus Syndrome.
Research on infantile nystagmus syndrome (INS) and motion perception is limited. We investigated how individuals with INS perform coherent motion tasks. Particularly, we assessed how the null position affects their performance. Subjects with INS and controls identified the direction of coherent motion stimuli (22 subjects with INS and 13 controls) in a two-alternative forced-choice design. For subjects with INS, testing was done at the null position and 15 degrees away from it. If there was no null, testing was done at primary gaze position and 15 degrees away from primary. For controls, testing was done at primary gaze position and 20 degrees away from primary. Horizontal and vertical motion coherence thresholds were determined. Subjects with INS showed significantly higher horizontal and vertical motion coherence thresholds compared with controls at both gaze positions (P < 0.001). Within the INS group, for 12 subjects with INS who had an identified null position, no differences in coherence thresholds were found between their null and 15 degrees away from it (P > 0.05). Coherent motion perception was impaired in subjects with INS. The null position did not significantly influence motion coherence thresholds for either horizontal or vertical motion.


A technique for measuring family physician priorities for patient care.
Family physicians frequently choose which elements of patient care to emphasize in order to balance the idealized principles of medical care with the real constraints of medical practice. Colleagues at several residency programs agreed to help us to find out if these choices can be quantified and whether personal characteristics of respondents or the acuteness or chronicity of the patient's illness influence these priorities. Two sets of 15 forced-choice item pairs, one set in reference to chronic illness and one set in reference to acute illness, were used in the study. Responses from 346 family physicians and non-physician colleagues ranked six hypothetical elements of patient care for acute and chronic illness: continuity, comprehensiveness, family orientation, community orientation, coordination and prevention. The data were analyzed using the psychometric scaling technique of paired comparisons. The analysis yielded a set of rankings which showed that these choices were quantifiable and made with a high degree of individual consistency and greater intragroup agreement than would result from chance. Patterns of choice differed for acute and chronic illness in a manner consistent with observed clinical practice.


The relationship between hispanic parents and their preschool-aged children's physical activity.
The goal of this study was to examine activity pattern associations between Hispanic parents and their preschool-aged children. We examined baseline data collected as part of a randomized controlled trial. Self-defined Hispanic parents with children aged 3 to 5 years were randomly assigned to either a weekly healthy lifestyle group (intervention) or a monthly school-readiness group (control) for 3 months. There were no weight eligibility criteria. All participants were instructed to wear an accelerometer for up to 7 consecutive days to measure physical activity. Of the 106 dyads enrolled in the study, 80 children and 85 parents provided useable actigraphy data. Mean percentage of time spent in sedentary behaviors was 82.0% (SD: 10.4) for parents and 69.8% (SD: 18.5) for preschool-aged children. Percentage of awake time per day spent in sedentary behavior was strongly correlated for parents and children (r = 0.597; P < .001). Correlations between activity level were large (r = 0.895 and 0.739 for low and moderate activity levels, respectively), except for vigorous activity level, for which the parent-child correlation was nonsignificant (P = .64) because of a near-0 level of vigorous parental activity. Child's age (P = .81) and gender (P = .43) were nonsignificant predictors of child activity levels. These results suggest that parental activity levels are a powerful explanation of preschool-aged child activity levels, except for vigorous activity, which children do on their own without parental participation. Hispanic parents play a critical role in setting physical activity patterns in their children.


Responsiveness of canine bronchial vasculature to excitatory stimuli and to cooling.
Changes in bronchial vascular tone, in part due to cooling during ventilation, may contribute to altered control of airflow during airway inflammation, asthma, and exercise-induced bronchoconstriction. We investigated the responses of canine bronchial vasculature to excitatory stimuli and cooling. Electrical stimulation evoked contractions in only some (8 of 88) tissues; these were phentolamine sensitive and augmented by N(omega)-nitro-L-arginine. However, sustained contractions were evoked in all tissues by phenylephrine [concentration evoking a half-maximal response (EC(50)) approximately 2 microM] or the thromboxane A(2) mimetic U-46619 (EC(50) approximately 5 nM) and less so by beta,gamma-methylene-ATP or histamine. Cooling to room temperature markedly suppressed ( approximately 75%) adrenergic responses but had no significant effect against U-46619 responses. Adrenergic responses, but not those to U-46619, were accompanied by an increase in intracellular Ca(2+) concentration. Chelerythrine (protein kinase C antagonist) markedly antagonized adrenergic responses (mean maxima reduced 39% in artery and 86% in vein) but had no significant effect against U-46619, whereas genistein (a nonspecific tyrosine kinase inhibitor) essentially abolished responses to both agonists. We conclude that cooling of the airway wall dramatically interferes with adrenergic control of bronchial perfusion but has little effect on thromboxane-mediated vasoconstriction.


Dehydrogenation of 1-Phenylethanol Catalyzed by Nickel(II)diphosphine Complexes.
Catalytic efficacy of the nickel(II)-diphosphine systems in the dehydrogenation of 1-phenylethanol to acetophenone under acceptorless conditions was investigated. Steric and electronic factors of the phosphine ligands were found to play an important role in the catalysis, while the nature of the base used and the reaction conditions, viz. time, temperature, and stoichiometry, have also shown major influence. Based on the preliminary analysis, a homogeneous pathway, perhaps involving nickel hydride species, was proposed. Due to the gradual disintegration of the catalytic species, deterioration of catalytic activity was observed resulting into low to moderate conversions. Among the series of catalysts examined, the highest conversion of 52% was exhibited by the catalyst C4, dichloro(1,2-bis(diphenylphosphino)ethane)nickel(II) (5 mol%), when loaded with 50 mol% of sodium ethoxide in toluene at 120 °C.


Intestinal and systemic immune development and response to vaccination are unaffected by dietary (1,3/1,6)-β-D-glucan supplementation in neonatal piglets.
Infants are susceptible to infections in early life and must rely on their innate immune system for protection. β-Glucans potentiate immune responses. Therefore, we evaluated the influence of purified yeast (1,3/1,6)-β-d-glucan (Wellmune WGP, here referred to as WGP) on the development of the gastrointestinal tract and the intestinal and systemic immune systems in neonatal piglets. Piglets were fed formula containing 0 (control), 1.8, 18, or 90 mg WGP/kg body weight (BW) and were vaccinated against human influenza. Piglets were euthanized at 7 or 21 days of age. Piglet weight and small intestinal length and weight were unaffected by dietary WGP. In addition, WGP did not affect ileal crypt depth, villus height, or ascending colon cuff depth. Immune parameters not affected by WGP supplementation included T cell phenotypes, cytokine gene expression, and cell proliferation. However, vaccination and developmental effects were seen. Overall, the doses of 1.8, 18, and 90 mg/kg BW of dietary WGP had no effect on intestinal or immune development and did not improve the antibody response to vaccination in neonatal piglets.


Aminolaevulinic acid-induced protoporphyrin IX pharmacokinetics in central and peripheral arteries of the rat.
Photodynamic therapy (PDT) based on the photosensitive protoporphyrin IX (PpIX) may prevent restenosis after transluminal angioplasty. PpIX is synthesized in mitochondria, which differ in number and activity among various tissues. Therefore, we questioned whether the course of PpIX concentration after systemic aminolaevulinic acid (ALA) administration differed among various arteries. ALA was administered intravenously (200 mg/kg) to male Wistar rats (n = 21). At varying time intervals (0, 1, 2, 3, 6, 12 and 24 h) both central and peripheral arteries were isolated and homogenized, and the concentration of the various heme intermediates was determined by a fluorometric extraction method. The maximal PpIX concentration was more than two-fold higher in peripheral arteries (20.49 +/- 3.0 to 24.0 +/- 7.5 pmol/mg protein) than in central arteries (0-9.46 +/- 0.01 pmol/mg protein) (P < 0.004). However, the amount of citrate synthase, reflecting the mitochondrial mass, was lower (0.14-0.61 and 1.87-2.32 U/mg protein, respectively). Apparently, the level of PpIX cannot simply be explained by the mitochondrial content of the arteries. The time interval of maximal PpIX accumulation was similar in peripheral and central arteries (2 h and 27 min vs. 2 h and 8 min) (P = 0.13). Thus, if the efficacy of PDT in vivo is directly related to the tissue concentration of PpIX, more effect can be expected in peripheral arteries than in central arteries.


Do Tibial Eminence Fractures and Anterior Cruciate Ligament Tears Have Similar Outcomes?
Avulsion fractures involving the tibial eminence are considered equivalent in terms of the cause to anterior cruciate ligament (ACL) tears; however, there are limited data comparing the outcomes of adolescent patients undergoing surgical fixation of a tibial eminence fracture (TEF) with those undergoing ACL reconstruction. To compare the clinical outcomes, subsequent ACL injury rates, and activity levels between adolescent patients who underwent TEF fixation with patients with midsubstance ACL tears who required acute reconstruction. Cohort study; Level of evidence, 3. This study included a group of patients with TEFs treated with surgical fixation matched to a group of similar patients with ACL tears treated with reconstruction between the years 2001 and 2015. Data regarding the initial injury, surgical intervention, ACL/ACL graft injury rates, and physical examination findings were recorded. Clinical and functional outcomes were obtained using a physical examination, the International Knee Documentation Committee (IKDC) subjective score, the Lysholm score, and the Tegner activity score. Sixty patients with a mean follow-up of 57.7 months (range, 24-206 months) were included; 20 patients (11 male, 9 female; mean age, 11.9 years [range, 7-15 years]) who underwent surgical fixation for a TEF were matched to a group of 40 patients (23 male, 17 female; mean age, 12.5 years [range, 8-5 years]) who underwent reconstruction for ACL tears. The TEF group demonstrated significantly lower postoperative IKDC scores (TEF group, 94.0; ACL group, 97.2; P = .04) and Lysholm scores (TEF group, 92.4; ACL group, 96.9; P = .02). The TEF group returned to sport 119 days sooner (P < .01), but there was no difference in postoperative Tegner scores (TEF group, 7.3; ACL group, 7.6; P = .16). The TEF group demonstrated increased postoperative anterior laxity (P = .02) and a higher rate of postoperative arthrofibrosis (P = .04). There was no difference in subsequent ACL injuries (P = .41). Both groups demonstrated quality outcomes at a minimum 2-year follow-up. Patients with TEFs demonstrated lower mean clinical outcome scores compared with patients with ACL tears, but the differences were less than reported minimal clinically important difference values. Additionally, the TEF group experienced more postoperative anterior laxity and had a higher rate of postoperative arthrofibrosis. There was no difference in the rate of subsequent ACL injuries. The TEF group returned to sport sooner than the ACL group, but the postoperative activity levels were similar.


Assessment of risk of bias among pediatric randomized controlled trials.
The goal was to assess the risk of bias among pediatric, randomized, controlled trials (RCTs) reported in 8 high-impact journals. We searched PubMed for all pediatric RCTs reported between July 1, 2007, and June 30, 2008, in 8 journals with high impact factors. Using Cochrane Collaboration methods for risk assessment, we evaluated all reports for risk of bias according to domain (ie, randomized sequence generation, allocation concealment, masking, incomplete outcome data, selective outcome reporting, and other). We used multiple logistic regression to test for associations between the presence of a high risk of bias according to domain and funding source, intervention type, trial registration, and multicenter status. Industry-funded RCTs were more likely to show a high risk of bias for sequence generation, compared with government-funded RCTs (adjusted odds ratio [aOR]: 6.1 [95% confidence interval [CI]: 1.70- 21.89]), and behavioral/educational trials were more likely to show a high risk of bias for sequence generation (aOR: 2.8 [95% CI: 1.06-7.36]) and allocation concealment (aOR: 4.09 [95% CI: 1.69-9.90]), compared with drug trials. Registered trials were less likely to have a high risk of bias for sequence generation, compared with nonregistered trials (aOR: 0.33 [95% CI: 0.15-0.71]). Overall, we found a large proportion of pediatric RCT reports with a high risk of bias for sequence generation and allocation concealment. Factors associated with a high risk of bias included industry funding and assessment of behavioral/educational interventions, whereas trial registration was associated with a lower risk of bias.


Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA.
ATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the translocase overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA unidirectionally. The sliding is initiated at the remodeler binding location via the generation of a pair of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning, explaining several past experimental observations. These results offer a detailed mechanistic picture of remodeling important for the complete understanding of these key biological processes.


Regulation of mouse microglia activation and effector functions by bone marrow-derived mesenchymal stem cells.
Mesenchymal stems or stromal cells (MSCs) are rare multipotent cells with potent regenerative and immunomodulatory properties. Microglial cells (MGs) are specialized tissue macrophages of the central nervous system (CNS) that continuously survey their environment with highly motile extensions. Recently, several studies have shown that MSCs are capable of reprogramming microglia into an "M2-like" phenotype characterized by increased phagocytic activity and upregulated expression of anti-inflammatory mediators in vitro. However, the precise polarization states of microglia in the presence of MSCs under physiological or under inflammatory conditions remain largely unknown. In this study, we found that MSCs induce a mixed microglia phenotype defined as Arg1-high, CD86-high, CD206-high, IL-10-high, PGE2-high, MCP-1/CCL2-high, IL-1β-moderate, NALP-3-low, and TNF-α-low cells. These MSC-elicited MGs have high phagocytic activity and antigen-presenting ability. Lipopolysaccharide is able to shape this microglia phenotype quantitatively, but not qualitatively in the presence of MSCs. This unique polarization state resembles a novel regulatory microglia phenotype, which might contribute to the resolution of inflammation and to tissue repair in the CNS.


Effect of changes in intrathoracic pressure on cardiac function at rest and during moderate exercise in health and heart failure.
This study investigated the effect of changes in inspiratory intrathoracic pressure on stroke volume at rest and during moderate exercise in patients with heart failure and reduced ejection fraction (HFREF) as well as healthy individuals. Stroke volume was obtained by echocardiography during 2 min of spontaneous breathing (S), two progressive levels of inspiratory unloading (UL1 and UL2) using a ventilator, and two progressive levels of inspiratory loading using resistors in 11 patients with HFREF (61 ± 9 years old; ejection fraction 32 ± 4%; NYHA class I-II) and 11 age-matched healthy individuals at rest and during exercise at 60% of maximal aerobic capacity on a semi-recumbent cycle ergometer. At rest, inspiratory unloading progressively decreased stroke volume index (SVI; S, 35.2 ± 5.4 ml m(-2); UL1, 33.3 ± 5.1 ml m(-2); and UL2, 32.2 ± 4.4 ml m(-2)) in healthy individuals, while it increased SVI (S, 31.4 ± 4.6 ml m(-2); UL1, 32.0 ± 5.9 ml m(-2); and UL2, 34.0 ± 7.2 ml m(-2)) in patients with HFREF (P = 0.04). During moderate exercise, inspiratory unloading decreased SVI in a similar manner (S, 43.9 ± 7.1 ml m(-2); UL1, 40.7 ± 4.7 ml m(-2); and UL2, 39.9 ± 3.7 ml m(-1)) in healthy individuals, while it increased SVI (S, 40.8 ± 6.5 ml m(-2); UL1, 42.8 ± 6.9 ml m(-2); and UL2, 44.1 ± 4. ml m(-2)) in patients with HFREF (P = 0.02). Inspiratory loading did not significantly change SVI at rest or during moderate exercise in both groups. It is concluded that inspiratory unloading improved SVI at rest and during moderate exercise in patients with HFREF, possibly due to a reduction in left ventricular afterload.


Appropriate Recommendations for Surgical Debulking in Stage IV Ovarian Cancer.
Epithelial ovarian cancer continues to be the leading cause of death due to gynecologic malignancy, and it is the fifth leading cause of cancer death in women in the USA and seventh worldwide. In most women with ovarian cancer, the disease is diagnosed at an advanced stage and primary cytoreductive surgery is considered standard of care. Traditionally, the gynecologic oncology literature supports the dictum that aggressive radical debulking to reduce intra-abdominal tumor burden to minimal or less than 1 cm of disease has significant impact on overall survival. However, the European Organization for Research and Treatment of Cancer (EORTC) trial found that survival after neoadjuvant followed by interval debulking surgery was similar to survival with the standard approach of primary surgery followed by chemotherapy. Many gynecologic oncologists have now adopted neoadjuvant chemotherapy for the treatment of stage IV ovarian cancer given the complex nature of this disease. Currently, there are conflicting results in the literature with regards to neoadjuvant chemotherapy versus primary debulking for stage IV ovarian cancer. While there is evidence that neoadjuvant treatment is not inferior to primary debulking, the literature also supports that maximizing debulking efforts with radical surgery can provide a survival benefit in patients with stage IV ovarian carcinoma.


Inhibition kinetics of green crab (Scylla serrata) alkaline phosphatase activity by dithiothreitol or 2-mercaptoethanol.
Green crab (Scylla serrata) alkaline phosphatase (EC 188.8.131.52) is a metalloenzyme which catalyzes the nonspecific hydrolysis of phosphate monoesters. Some pollutants in seawater affect the enzyme activity causing loss of the biological function of the enzyme, which affects the exuviating crab-shell and threatens the survival of the animal. The present paper studies the effects of thiohydroxyal compounds on the activity of green crab alkaline phosphatase. The results show that thiohydroxyal compounds can lead to reversible inhibition. The equilibrium constants have been determined for dithiothreitol (DTT) and mercaptoethanol (ME) binding with the enzyme and/or the enzyme-substrate complexes. The results show that both DTT and ME are non-competitive inhibitors. The kinetics of enzyme inactivation by ME at low concentrations has been studied using the kinetic method of the substrate reaction. The results suggest that at pH 10.0, the action of ME on green crab ALP is first quick equilibrium binding and then slow inactivation. The microscopic rate constants were determined for inactivation and reactivation. The rate constant of the forward inactivation (k(+0)) is much larger than that of the reverse reactivation (k(-0)). Therefore, when the ME concentration is sufficiently large, the enzyme is completely inactivated.


C-H activation and metalation at electrode surfaces: 2,3-dimethyl-1,4-dihydroxybenzene on Pd(pc) and Pd(111) studied by TLE, HREELS and DFT.
Previous studies, based on thin-layer electrochemistry (TLE), in situ scanning tunneling microscopy (EC-STM), high-resolution electron energy loss spectroscopy (HREELS) and density functional theory (DFT) computations, on the chemical adsorption of hydroquinone from aqueous solutions onto atomically smooth Pd (and Pt) electrode surfaces indicated two modes of attachment that depended upon the solution concentration. At low activities, the diphenol was oxidatively chemisorbed as benzoquinone in a flat orientation, suggestive of a Pd(2,3,5,6-η-C6H4O2) surface complex; at higher concentrations, vertical chemisorption was effected via two C-H bond activations (or metalations) at the 2 and 3 ring positions, evocative of an o-phenylene organopalladium compound. We have extended the work to 2,3-dimethyl-1,4-dihydroxybenzene on Pd(pc) and Pd(111) electrodes to probe the effect of two methyl substituents on only one side of the diphenol ring. Surface coverage and adsorbed-molecule cross section data from TLE and HREELS measurements revealed non-random concentration-dependent adsorbate orientations similar to the oxidative chemisorption of hydroquinone: flat at low concentrations and edgewise at elevated concentrations. The DFT results suggested that, for the flat structure, surface coordination is via the two double bonds of the quinone ring as in [Pd(2,3,5,6-η)-2,3-dimethyl-p-quinone]. For the edge-vertical orientation, a structure analogous to an o-phenylene compound is generated in which C-H bonds at the 5 and 6 ring positions are activated and then metalated. DFT-simulated HREELS spectra helped identify the observed peaks that distinguish the surface-coordinated quinone from the surface-metalated diphenol.


Nazarov-type reactions in water.
Different in water! We have developed Nazarov-type reactions in water. Different reaction courses compared with those in organic solvents are observed in water. In the presence of a scandium based, surfactant-type catalyst, water-trapping products are obtained exclusively. The results presented are unprecedented and provide a valuable extension to information available regarding organic reactions in water.


Computer-Aided Multiclass Classification of Corn from Corn Images Integrating Deep Feature Extraction.
Corn has great importance in terms of production in the field of agriculture and animal feed. Obtaining pure corn seeds in corn production is quite significant for seed quality. For this reason, the distinction of corn seeds that have numerous varieties plays an essential role in marketing. This study was conducted with 14,469 images of BT6470, Calipso, Es_Armandi, and Hiva types of corn licensed by BIOTEK. The classification of images was carried out in three stages. At the first stage, deep feature extraction of the four types of corn images was performed with the pretrained CNN model SqueezeNet 1000 deep features were obtained for each image. In the second stage, in order to reduce these features obtained from deep feature extraction with SqueezeNet, separate feature selection processes were performed with the Bat Optimization (BA), Whale Optimization (WOA), and Gray Wolf Optimization (GWO) algorithms among optimization algorithms. Finally, in the last stage, the features obtained from the first and second stages were classified by using the machine learning methods Decision Tree (DT), Naive Bayes (NB), multi-class Support Vector Machine (mSVM), k-Nearest Neighbor (KNN), and Neural Network (NN). In the classification processes of the features obtained in the first stage, the mSVM model has achieved the highest classification success with 89.40%. In the second stage, as a result of the classifications performed through the active features selected by using three types of feature selection algorithms (BA, WOA, GWO), the classification success obtained with the mSVM model was 88.82%, 88.72%, and 88.95%, respectively. The classification accuracies of the tested methods and the classification accuracies obtained in the first stage are close to each other in terms of classification success. However, with the algorithms used in feature selection, successful classification processes have been carried out with fewer features and in a shorter time. The results of the study, in which classification was carried out in the inexpensive, the objective, and the shorter time of processing for the corn types, present a different perspective in terms of classification performance.


Relationships between advance oak regeneration and biotic and abiotic factors.
Relationships between advance regeneration of four tree species (red maple (Acer rubrum L.), white oak (Quercus alba L.), chestnut oak (Q. montana Willd.) and northern red oak (Q. rubra L.)) and biotic (non-tree vegetation and canopy composition) and abiotic (soil series and topographic variables) factors were investigated in 52, mature mixed-oak stands in the central Appalachians. Aggregate height was used as a composite measure of regeneration abundance. Analyses were carried out separately for two physiographic provinces. Associations with tree regeneration were found for all biotic and abiotic factors both in partial models and full models. Red maple was abundant on most of the sites, but high red maple abundance was commonly associated with wet north-facing slopes with little or no cover of mountain-laurel (Kalmia latifolia L.) and hay-scented fern (Dennstaedtia punctilobula (Michx.) Moore). Regeneration of the three oak species was greatly favored by the abundance of overstory trees of their own kind. White oak regeneration was most abundant on south-facing, gentle, lower slopes with soils in the Buchanan series. Chestnut oak regeneration was more common on south-facing, steep upper slopes with stony soils. There was a positive association between chestnut oak and huckleberry (Gaylussacia baccata (Wangh.) Koch) cover classes. Northern red oak was more abundant on north-facing wet sites with Hazleton soil, and was associated with low occurrence of mountain-laurel and hay-scented fern.


Population effects of heavy metal pollution in wild Algerian mice (Mus spretus).
Heavy metal mining is one of the largest sources of environmental pollution. The analysis of different types of biomarkers in sentinel species living in contaminated areas provides a measure of the degree of the ecological impact of pollution and is thus a valuable tool for human and environmental risk assessments. In previous studies we found that specimens from two populations of the Algerian mice (Mus spretus) living in two abandoned heavy metal mines (Aljustrel and Preguiça, Portugal) had higher body burdens of heavy metals, which led to alterations in enzymatic activities and in haematological, histological and genotoxic parameters, than mice from a nearby reference population. We have now analysed individuals from the same sites at the biometric and genetic levels to get a broader portrayal of the impact of heavy metal pollution on biodiversity, from molecules to populations. Size and shape variations of the mouse mandible were searched by implementing the geometric morphometric method. Population genetic differentiation and diversity parameters (φST estimates; nucleotide and haplotype diversities) were studied using the mitochondrial cytochrome b gene (Cytb) and the control region (CR). The morphometric analyses revealed that animals from the three sites differed significantly in the shape of the mandible, but mandibular shape varied in a more resembling way within individuals of both mine sites, which is highly suggestive for an effect of environmental quality on normal development pathways in Algerian mice. Also, antisymmetry in mandible size and shape was detected in all populations, making these traits not reliable indicators of developmental instability. Overall little genetic differentiation was found among the three populations, although pairwise φST comparisons revealed that the Aljustrel and the Preguiça populations were each differentiated from the other two populations in Cytb and in CR, respectively. Genetic diversity parameters revealed higher genetic diversity for Cytb in the population from Aljustrel, while in the population from Preguiça diversity of the two markers changed in opposite directions, higher genetic diversity in CR and lower in Cytb, compared to the reference population. Demographic changes and increased mutation rates may explain these findings. We show that developmental patterns and genetic composition of wild populations of a small mammal can be affected by chronic heavy metal exposure within a relatively short time. Anthropogenic stress may thus influence the evolutionary path of natural populations, with largely unpredictable ecological costs.


No association of anti-osteoporosis drugs with COVID-19-related outcomes in women: a nationwide cohort study.
This study was performed to evaluate whether the use of drugs in the treatment of osteoporosis in women is associated with COVID-19 outcomes. The results showed that the risk of hospitalization, intensive care unit admission, and mortality was not altered in individuals taking anti-osteoporosis drugs, suggesting no safety issues during a COVID-19 infection. Whether patients with COVID-19 receiving anti-osteoporosis drugs have lower risk of worse outcomes has not been reported yet. The aim of this study was to evaluate the association of anti-osteoporosis drug use with COVID-19 outcomes in women. Data obtained from a nationwide, multicenter, retrospective cohort of patients diagnosed with COVID-19 from March 11th to May 30th, 2020 was retrieved from the Turkish Ministry of Health Database. Women 50 years or older with confirmed COVID-19 who were receiving anti-osteoporosis drugs were compared with a 1:1 propensity score-matched COVID-19 positive women who were not receiving these drugs. The primary outcomes were hospitalization, ICU (intensive care unit) admission, and mortality. A total of 1997 women on anti-osteoporosis drugs and 1997 control patients were analyzed. In the treatment group, 1787 (89.5%) women were receiving bisphosphonates, 197 (9.9%) denosumab, and 17 (0.9%) teriparatide for the last 12 months. Hospitalization and mortality rates were similar between the treatment and control groups. ICU admission rate was lower in the treatment group (23.0% vs 27.0%, p = 0.013). However, multivariate analysis showed that anti-osteoporosis drug use was not an independent associate of any outcome. Hospitalization, ICU admission, and mortality rates were similar among bisphosphonate, denosumab, or teriparatide users. Results of this nationwide study showed that preexisting use of anti-osteoporosis drugs in women did not alter the COVID-19-related risk of hospitalization, ICU admission, and mortality. These results do not suggest discontinuation of these drugs during a COVID-19 infection.


Graft site morbidity with autogenous semitendinosus and gracilis tendons.
To distinguish between morbidity caused by harvesting semitendinosus and gracilis tendons and morbidity associated with anterior cruciate ligament reconstruction surgery, we performed a prospective randomized study using 65 patients who underwent anterior cruciate ligament reconstruction using these tendons. The patients underwent either contralateral (N = 34) or ipsilateral (N = 31) graft harvest. For the nonoperated knees in the ipsilateral harvest group, isometric and isokinetic strength of the quadriceps and hamstring muscles increased to approximately 120% of the preoperative value at 12 months after surgery. Compared with these knees, the tendon harvest did not affect quadriceps muscle strength at all. However, harvest did decrease hamstring muscles strength for 9 months after surgery. The graft harvest in the knees with anterior cruciate ligament reconstruction also did not significantly affect quadriceps muscle strength, but it did significantly decrease hamstring muscles strength only at 1 month. Activity-related soreness at the donor site was rarely restricting and resolved by 3 months. This study demonstrated that the semitendinosus and gracilis tendon graft is a reasonable choice to minimize the donor site morbidity in ligament reconstruction using autografts.


45Calcium localization in islets of Langerhans, a study by electron-microscopic autoradiography.
Attempts were made to localize the sites of uptake of 45calcium in B cells of islets of Langerhans by electron-microscopic autoradiography. Despite the potential sources of error inherent in the partial loss of radioactivity during fixation, and in the relatively high energy of emission of this isotope, distribution of silver grains differed signficantly from random in all experiments. Grains were concentrated over mitochondria and to a lesser extent over storage granules. Incubation of islets in the presence of 10 mM glucose and isobutylmethyl-xanthine before fixation and autoradiography resulted in a small but not statistically significant reduction in silver grains associated with the mitochondria. These results further indicate a dominant role of mitochondria in the regulation of cytosolic calcium concentrations in pancreatic B cells.


Circadian rhythms of osteocalcin in equine serum. Correlation with alkaline phosphatase, calcium, phosphate and total protein levels.
The purpose of the study was to determine whether there were circadian variations in serum osteocalcin in normal horses and to determine whether it was important to regulate the time of blood sampling in clinical investigations. Osteocalcin or bone Gla-protein (BGP), alkaline phosphatase, total calcium, phosphate and total protein were studied over a 24 h period. Blood samples were taken every 60 min from nine adult Standardbred horses. There was a correlation between serum levels of alkaline phosphatase (r = 0.3, p less than 0.01), phosphate (r = 0.42, p less than 0.01) and serum osteocalcin levels. There was a very marked individual effect on serum levels of osteocalcin and alkaline phosphatase (p less than 0.01). This effect was present for phosphate levels but not significant for total calcium. The individual effect was lower and time effect was higher for serum osteocalcin if the subjects were divided into two age groups, one of horses of five years or less (n = 4) and a second group older than five years (n = 5). In both groups a circadian rhythmicity was observed. Serum osteocalcin showed a biphasic pattern. Levels were constant during daytime (light period) and underwent significant variations during the night (dark period), going through a nadir at 2000 h and through a maximum peak at 0500 h. It was concluded that in normal horses the blood osteocalcin level follows a circadian variation. Also daytime (light period) seems to be the more appropriate period for blood sampling.


Human in vivo fluorescence microimaging of the alveolar ducts and sacs during bronchoscopy.
The aim of the present study was to assess fibred confocal fluorescence microscopy (FCFM) as a tool for imaging the alveolar respiratory system in vivo during bronchoscopy. A 488-nm excitation wavelength FCFM device was used in 41 healthy subjects including 17 active smokers. After topical anaesthesia, the 1.4-mm miniprobe was introduced into the bronchoscope working channel and advanced distally to the alveoli. Morphometric and cellular analyses were performed on selected frames harbouring a minimal compression effect. In vivo acinar microimaging was obtained from each lung segment except for the apical and posterior segments of both upper lobes. Reproducible patterns, corresponding to the elastic framework of the axial and peripheral interstitial systems, were recorded from 192 separate acini. The mean+/-sd thickness of the acinar elastic fibres was 10+/-2.7 microm. Alveolar mouth diameters (mean+/-sd 278+/-53 microm) were normally distributed but appeared smaller in the right upper lobe and right medial basal segment. Lobular microvessels (median diameter 90 microm) were equally distributed throughout the lungs. Alveolar macrophages were not detectable in nonsmokers, whereas a specific tobacco-tar-induced fluorescence was observed in smoking subjects, providing fine details of the alveolar walls and macrophages. A strong correlation was found between the number of cigarettes smoked per day and the amount of large and mobile macrophages observed in vivo, as well as with the intensity of the macrophage alveolitis. Fibred confocal fluorescence microscopy enables accurate exploration of the peripheral lung in vivo in both smokers and nonsmokers.


Pan-cancer analysis of cuproptosis-promoting gene signature from multiple perspectives.
Cuproptosis is a newly discovered cell death form with a unique mechanism. Seven genes have been identified to facilitate the process. To explore the roles of cuproptosis in different cancers, we first used Gene Expression Profiling, Interactive Analysis, version 2, and cBioPortal to analyze expression, prognosis and mutation conditions in different cancers from The Cancer Genome Atlas (TCGA). Then, we conducted single sample gene set enrichment analysis to combine the signature of the cuproptosis-promoting genes for all TCGA cancers. Moreover, we performed a survival analysis to explore if cuproptosis-score could independently influence clinical outcomes. Next, we compared pathway enrichment, immune infiltration, gene set activity and gene mutation between different cuproptosis-score groups. Finally, based on the intersected genes from difference analysis and weighted gene co-expression network analysis, consensus clustering and Least Absolute Shrinkage and Selection Operator Cox regression were performed and nomograms were constructed. Cuproptosis-score was associated with a favorable prognosis in eight TCGA cancers. Cancer-associated fibroblasts, B cells, neutrophils and mast cells were generally less abundant, and ferroptosis activity was higher in high cuproptosis-score groups. The novel classifications could differentiate patients' overall survival, and the risk models could effectively predict patients' outcomes in kidney, renal clear cell carcinoma, liver hepatocellular carcinoma, mesothelioma and stomach adenocarcinoma. Cuproptosis activity was closely related to the prognosis of several cancers. Its effects on the immune microenvironment and its relationship with other cell death modes, especially ferroptosis, may become the focus of further research.


Reverse epidemiology of hypertension and cardiovascular death in the hemodialysis population: the 58th annual fall conference and scientific sessions.
Maintenance hemodialysis patients in the United States have a high prevalence (approximately 80%) of systolic hypertension and a high mortality (approximately 20% per year). Some reports indicate a paradoxical association between hypertension and mortality in hemodialysis patients (ie, a normal to low blood pressure is associated with poor outcome), whereas high pressure confers survival advantages, a phenomenon referred to as "reverse epidemiology." We hypothesized that malnutrition-inflammation complex syndrome may be a cause of this paradoxical association. We studied a 15-month cohort of 40 933 hemodialysis patients in the United States whose predialysis and postdialysis blood pressure values were recorded routinely during each hemodialysis treatment. Patients were 59.8+/-15.3 years old; 54% were women and 46% diabetics. Cox proportional hazard models were used for blood pressure categories (systolic <110, > or =190 mm Hg; diastolic <50, > or =110; and increments of 10 mm Hg in between). Unadjusted, case-mix and dialysis dose-adjusted, and additional malnutrition-inflammation-adjusted hazard ratios of all-cause and cardiovascular death showed progressively increasing all-cause and cardiovascular death risk for decreasing blood pressure values. The lowest mortality was associated with predialysis systolic pressure of 160 to 189 mm Hg, whereas normal to low predialysis pressure values were associated with significantly increased mortality. Adjustment for the malnutrition-inflammation mitigated only a small portion of paradoxical associations between the low blood pressure and mortality. Predialysis systolic hypertension remained a significant predictor of highest all-cause and cardiovascular survival rate. Although these associations may not be causal, they call into question whether treatment goals for the general population can be applied to dialysis patients or other similar populations.


[Mitral valve repair versus mitral valve replacement].
Over the past 40 years mitral valve surgery has changed dramatically. After initial enthusiasm with the introduction of valve prostheses in the 1960s, a renewed interest in repair techniques began in the 1970s with the introduction of annuloplasty rings. These repair techniques revealed that the integrity of the subvalvular apparatus plays an important role in left ventricular function. When considering the major series comparing early and late results of mitral valve repair versus prosthetic mitral valve replacement, operative mortality rate is lower for patients with mitral valve repair. Long-term results also show a superior survival rate after mitral valve reconstruction. In addition, several problems can occur with the prosthetic valve, such as thromboembolism and endocarditis. All of these factors favor valve repair over replacement. The success of mitral valve repair depends on many factors: etiology of the mitral valve disease and the resultant pathomorphology of the valve, patient's circumstances such as age or contraindication for anticoagulation, and the experience of the surgeon. The decision whether to repair or replace the mitral valve depends on these factors. Data in the literature and in large collective databases reflect the advantages of mitral valve repair, with over 75 % of current mitral valve surgeries being repairs.In the past 5 years the exposure of the mitral valve through a right lateral minithoracotomy using video assistance has developed into a widespread technique. This approach allows complex mitral valve repair as well as mitral valve replacement even with biological stentless prostheses, with decreased morbidity. The addition of radiofrequency ablation for restoration of sinus rhythm enhances the outcome after mitral valve surgery, and can also be easily performed through a minithoracotomy technique.


Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE.
Mutations in the autosomal genes TMPRSS3, TMC1, USHIC, CDH23 and TMIE are known to cause hereditary hearing loss. To study the contribution of these genes to autosomal recessive, non-syndromic hearing loss (ARNSHL) in India, we examined 374 families with the disorder to identify potential mutations. We found four mutations in TMPRSS3, eight in TMC1, ten in USHIC, eight in CDH23 and three in TMIE. Of the 33 potentially pathogenic variants identified in these genes, 23 were new and the remaining have been previously reported. Collectively, mutations in these five genes contribute to about one-tenth of ARNSHL among the families examined. New mutations detected in this study extend the allelic heterogeneity of the genes and provide several additional variants for structure-function correlation studies. These findings have implications for early DNA-based detection of deafness and genetic counseling of affected families in the Indian subcontinent.


Lymphoid organogenesis in brief.
The recognition that lymphocytes existed in different varieties and that lymphoid organs were important for their differentiation greatly influenced immunological research. The growing awareness that started in the mid-fifties of the previous century has shifted the emphasis of immunology from a molecular, mostly serological science to the cell-oriented modern immunology of today. Matters such as hematopoietic differentiation, cell-cell interaction, cellular activation, as well as migratory behavior of hematopoietic cells received much attention and deepened our insight in the immune system. The relatively recent generation of mutant mice lacking lymphoid organs prompted the realization that the organogenesis of lymphoid organs could be dissected at the cellular and molecular level. Now we can distinguish several phases of development for lymphoid organs, and can assign molecules and cells to be essentially involved in these phases. Future research will identify additional molecules and cells required for the formation of the various lymphoid organs, because the picture is not complete yet.


Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome.
The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.


Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial.
To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m2 ). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. Compared with the iGlar treatment group, patients treated with iGlarLixi showed consistently greater reductions in HbA1c during the treatment period, with higher percentages of patients achieving the HbA1c target level of <7% (<53 mmol/mol) in all of the subpopulations tested (P < .0001 for all), having consistent mitigation of body weight gain and with no major differences in the incidence of hypoglycaemia. iGlarLixi consistently improved glycaemic control compared with iGlar in all baseline characteristic subgroups of patients with T2DM inadequately controlled with insulin, including difficult-to-treat subgroups of patients with long duration of diabetes, obesity and high HbA1c. Clinical trial number: NCT02058160 (clinicaltrials.gov).


Benefits of angular expression to reconstruction algorithms for collimators with spatially varying focal lengths.
Fan-beam collimators with spatially varying focal lengths are used in single photon emission computed tomography (SPECT) to improve the imaging sensitivity and to reduce the reconstruction artifacts resulting from the truncation of projection data. An angular representation of the detector coordinates for the projection data is adopted to investigate several aspects of the reconstruction problem for this type of collimation. A rebinning reconstruction algorithm is derived. We prove a conjecture posed by Zeng and Gullberg and obtain a simplified form of their backprojection filtering algorithm. Some computer simulations are presented to investigate the performance of the rebinning algorithm.


Retropubic, laparoscopic, or robotic radical prostatectomy: is there any real difference?
The surgical management of localized prostate cancer has evolved over the last 20 years. The "gold standard" open radical prostatectomy (ORP) has been replaced largely by the robotic-assisted laparoscopic radical retropubic prostatectomy (RALP) as the most common surgical approach to treat localized prostate cancer. Pure laparoscopic radical prostatectomy (LRP), still performed by a limited number of surgeons, was more commonly utilized before the widespread availability of the robotically assisted technique. The general consensus based on the current literature is that RALP is associated with less blood loss and a shorter hospital stay but at a higher cost when compared to ORP. The literature continues to be conflicted concerning outcome measures such as impotence and urinary incontinence. Large series of long-term oncologic follow-up are not yet available; however, the data suggest that oncologic control is similar between RALP and ORP. Considerable disparities in measurement and reporting practices of perioperative outcomes continue to make direct comparisons difficult. Future prospective studies of perioperative outcomes should aim to use rigorous methodology and established criteria for standardized reporting.


Thrombin-activated human platelets release two NAP-2 variants that stimulate polymorphonuclear leukocytes.
Thrombin-activated human platelets release substance(s) of a proteic nature which induce an increase in the intracellular calcium concentration in polymorphonuclear leukocytes (PMN). Aim of this study was to characterize the platelet released product(s) responsible for PMN stimulation. PMN-stimulating activity was isolated from platelet supernatant by FPLC and HPLC. The N-terminal sequence analysis revealed that the purified fractions consisted in 90% of a peptide of 73 amino acids and in 10% of a peptide of 74 amino acids; both are truncated forms of the connective tissue-activating peptide III (CTAP-III), a platelet alpha-granule product, and have 3 and 4 additional amino acids at the N-terminus compared with the neutrophil-activating peptide 2 (NAP-2): Asp-Leu-Tyr and Ser-Asp-Leu-Tyr, respectively. Treatment of platelet supernatant (previously depleted of PMN-activating nucleotides) with Affi-gel heparin resulted in the disappearance of PMN-stimulating effects, suggesting that NAP-2 variants, which are heparin-binding proteins, account for ATP-independent PMN-stimulating activity of the supernatant. Cross-desensitization between rNAP-2 and the platelet supernatant and inhibition by the anti-NAP-2 antibody are in agreement with this conclusion. Although NAP-2 and its variants are reportedly generated from the inactive precursors, CTAP-III and platelet basic protein, through a proteolytic cleavage, NAP-2 variants were not generated in our system by proteases deriving from platelets or contaminating leukocytes. Indeed, treatment of intact platelet suspensions with different protease inhibitors failed to modify the calcium stimulating activity of the resulting supernatants. In conclusion, thrombin-activated platelets release NAP-2 variants which are not generated outside the platelets by proteolytic processing but are released in an active form. This finding enhances our understanding of platelet-PMN interaction in thrombosis and inflammation.


Rational design of photo-cleavable alkoxyamines for polymerization and synthesis.
Theoretical calculations have been performed in order to investigate the impact of different substitution patterns on predicted photoreactivity of alkoxyamines fused to an anthraquinone chromophore. Amino and hydroxy groups (similar to those which have been previously synthesized) are introduced and their effect on excited state energies and charge transfer is assessed. Analogous to formally oxidized alkoxyamines, the charge-separated nNπ* state can undergo mesolytic cleavage or bimolecular or SN2 reactions with nucleophiles, according to the substitution patterns and other reagents present. While homolytic cleavage is in principle promoted by triplet ππ* states, the accessible ππ* triplet states in this system are centered on the chromophore and unreactive. We show that the reactive nNπ* state, which bears a negative charge, is stabilized by hydroxy substitution while amino substitution will destabilize it. After mesolysis to a carbon centred radical, the nitroxide radical re-forms; however, when carbocations are produced the remaining open-shell singlet is stable and unable to undergo coupling with the carbocation.


Unraveling the impact of ORF3a Q57H mutation on SARS-CoV-2: insights from molecular dynamics.
ORF3a is a conserved accessory protein of SARS-CoV-2, linked to viral infection and pathogenesis, with acquired mutations at various locations. Previous studies have shown that the occurrence of the Q57H mutation is higher in comparison to other positions in ORF3a. This mutation is known to induce conformational changes, yet the extent of structural alteration and its role in the viral adaptation process remain unknown. Here we performed molecular dynamics (MD) simulations of wt-ORF3a, Q57H, and Q57A mutants to analyze structural changes caused by mutations compared to the native protein. The MD analysis revealed that Q57H and Q57A mutants show significant structural changes in the dimer conformation than the wt-ORF3a. This dimer conformer narrows down the ion channel cavity, which reduces Na + or K + permeability leading to decrease the antigenic response that can help the virus to escape the host immune system. Non-bonding interaction analysis shows the Q57H mutant has more interacting residues, resulting in more stability within dimer conformation than the wt-ORF3a and Q57A. Moreover, both mutant dimers (Q57H and Q57A) form a novel salt-bridge interaction at the same position between A:Asp142 and B:Lys61, whereas such an interaction is absent in the wt-ORF3a dimer. We have also noticed that the TM3 domain's flexibility in Q57H is increased because of strong inter-domain interactions of TM1 and TM2 within the dimer conformation. These unusual interactions and flexibility of Q57H mutant can have significant impacts on the SARS-CoV-2 adaptations, virulence, transmission, and immune system evasion. Our findings are consistent with the previous experimental data and provided details information on the structural perturbation in ORF3a caused by mutations, which can help better understand the structural change at the molecular level as well as the reason for the high virulence properties of this variant.Communicated by Ramaswamy H. Sarma.


Disseminating Evidence-Based Interventions in Small, Low-Wage Worksites: A Randomized Controlled Trial in King County, Washington (2014-2017).
Objectives. To determine whether (1) participating in HealthLinks, and (2) adding wellness committees to HealthLinks increases worksites' evidence-based intervention (EBI) implementation.Methods. We developed HealthLinks to disseminate EBIs to small, low-wage worksites. From 2014 to 2017, we conducted a site-randomized trial in King County, Washington, with 68 small worksites (20-200 employees). We assigned worksites to 1 of 3 arms: HealthLinks, HealthLinks plus wellness committee (HealthLinks+), or delayed control. At baseline, 15 months, and 24 months, we assessed worksites' EBI implementation on a 0% to 100% scale and employees' perceived support for their health behaviors.Results. Postintervention EBI scores in both intervention arms (HealthLinks and HealthLinks+) were significantly higher than in the control arm at 15 months (51%, 51%, and 23%, respectively) and at 24 months (33%, 37%, and 24%, respectively; P < .001). Employees in the intervention arms perceived greater support for their health at 15 and 24 months than did employees in control worksites.Conclusions. HealthLinks is an effective strategy for disseminating EBIs to small worksites in low-wage industries.Public Health Implications. Future research should focus on scaling up HealthLinks, improving EBI maintenance, and measuring impact of these on health behavior.


Maternal feeding practices and children's eating behaviours: A comparison of mothers with healthy weight versus overweight/obesity.
This study aimed to explore differences between mothers with healthy weight versus overweight/obesity in a wide range of their reported child feeding practices and their reports of their children's eating behaviours. Mothers (N = 437) with a 2-6-year-old child participated. They comprised two groups, based on their BMI: healthy weight (BMI of 18.0-24.9, inclusive) or overweight/obese (BMI of 25.0 or more). All mothers provided demographic information and completed self-report measures of their child feeding practices and their child's eating behaviour. In comparison to mothers with healthy weight, mothers with overweight/obesity reported giving their child more control around eating (p < 0.001), but encouraged less balance and variety around food (p = 0.029). They also had a less healthy home food environment (p = 0.021) and demonstrated less modelling of healthy eating in front of their children (p < 0.001). There were no significant differences in mothers' use of controlling feeding practices, such as pressure to eat or restriction, based on their own weight status. Mothers with overweight/obesity reported their children to have a greater desire for drinks (p = 0.003), be more responsive to satiety (p = 0.007), and be slower eaters (p = 0.034). Mothers with overweight/obesity appear to engage in generally less healthy feeding practices with their children than mothers with healthy weight, and mothers with overweight/obesity perceive their children as more avoidant about food but not drinks. Such findings are likely to inform future intervention developments and help health workers and clinicians to better support mothers with overweight/obesity with implementing healthful feeding practices and promoting healthy eating habits in their children.


Expression of CD44 and CD29 by PEComa cells suggests their possible origin of mesenchymal stem cells.
Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell (PEC) co-expresses melanocytic and muscle markers. Since no normal counterpart to the PEC has ever been identified in any normal tissue, the cell origin of these tumors is still uncertain. Although, several hypotheses have recently been advanced to explain the histogenesis of PEComa, it remains unclear. The aim of this study was to discuss whether differential expression of stem cell-associated proteins could be used to aid in determining the histogenesis of PEComa. For this purpose, we detected the immunoexpression of 5 kinds of stem cell markers on PEComas, including CD29, CD44, CD133, ALDH1, and nestin. In addition to observed histopathologic morphology, we also performed PEComa relevant clinical diagnostic markers (HMB-45, SMA, melan-A, Desmin, Ki-67, S-100 and TFE3) to identify whether they belonged to PEComas. Our study included 13 PEComa samples, and we obtained positive immunoexpression results as follows: CD29 (13/13), CD44 (8/13), ALDH1 (10/13), nestin (1/13), and CD133 (0/13). Since CD44 and CD29 are surface proteins associated with MSCs, these results suggest that PEComa might arise from MSCs. However, whether MSCs are the origin of PEComa needs to be further explored in the future.


Intermediates in SARS-CoV-2 spike-mediated cell entry.
SARS-CoV-2 cell entry is completed after viral spike (S) protein-mediated membrane fusion between viral and host cell membranes. Stable prefusion and postfusion S structures have been resolved by cryo-electron microscopy and cryo-electron tomography, but the refolding intermediates on the fusion pathway are transient and have not been examined. We used an antiviral lipopeptide entry inhibitor to arrest S protein refolding and thereby capture intermediates as S proteins interact with hACE2 and fusion-activating proteases on cell-derived target membranes. Cryo-electron tomography imaged both extended and partially folded intermediate states of S2, as well as a novel late-stage conformation on the pathway to membrane fusion. The intermediates now identified in this dynamic S protein-directed fusion provide mechanistic insights that may guide the design of CoV entry inhibitors.


Rebinding of Tetrahymena 13 S and 21 S dynein ATPases to extracted doublet microtubules. The inner row and outer row dynein arms.
Ciliary axonemes from Tetrahymena contain a second salt-extractable ATPase distinguishable from outer arm 21 S dynein by sedimentation velocity (congruent to 13 S), electrophoretic mobility and substrate specificity. As characterized by turbidimetric assay, gel electrophoresis in the presence of sodium dodecyl sulphate, ATPase activity and electron microscopy, the 13 S dynein ATPase rebinds to extracted doublet microtubules. Compared to structural-side (ATP-insensitive) 21 S dynein binding, which is moderately specific for the 24 nm outer row arm position, rebinding of 13 S dynein is highly specific but for the inner row arm position. However, 13 S dynein rebinds to the A subfibre with a spacing that coincides with the triplet spacing of the radial spokes (24-32-40 nm periods; 96 nm repeat). All of the major protein components present in the 13 S or 21 S fractions rebind to extracted doublets under conditions that both restore and activate dynein ATPase activity. Unlike active-side (ATP-sensitive) rebound 21 S dynein, rebound 13 S dynein is completely insensitive to dissociation by ATP-vanadate and does not independently decorate the B subfibre. The saturation profile for rebinding of 13 S dynein exhibits a lack of cooperativity between binding events (h = 1.0) similar to structural-side rebinding of 21 S dynein. At low 21 S/doublet stoichiometry there is no measureable competition between the 13 S and 21 S dyneins for binding sites on the A subfibre lattice, although at saturating concentrations of 21 S dynein, rebinding of 13 S dynein is blocked completely.


[Ruminal acidosis complex--new observations and experiences (2). A review].
By "Rumen acidosis" until recently only the acute indigestion with intoxication caused by excessive production of lactic acid was understood. Meanwhile, however, it has become evident that further pathologic changes can take place in the acid-base status of the rumen contents which may also be referred to as "Rumen acidosis". Basing on new literature and own experiences the paper gives a review of that "Rumen acidosis complex": Fundamentals of the regulation of pH in the rumen; chronic latent rumen acidosis (hyper- and parakeratosis, chronic hyperplastic rumenitis, rumenitis-liver abscess complex, hyperlipodeposition, low milk fat syndrome, atypical ketosis, chronic laminitis, cerebrocortical necrosis, acid-base metabolism); acute lactic acidosis (etiology, pathogenesis, therapy, prophylaxis).


Peeled mammalian skeletal muscle fibers. Possible stimulation of Ca2+ release via a transverse tubule-sarcoplasmic reticulum mechanism.
Single muscle fibers from rabbit soleus and adductor magnus and from semitendinosus muscles were peeled to remove the sarcolemma and then stimulated to release Ca2+ by (a) caffeine application or (b) ionic depolarization accomplished via substitution of choline chloride for potassium propionate at constant [K+] X [Cl-] in the bathing solution. Each stimulus, ionic or caffeine, elicited an isometric tension transient that appeared to be due to Ca2+ released from the sarcoplasmic reticulum (SR). The peak magnitude of the ionic (Cl- -induced) tension transient increased with increasing Cl- concentration. The application of ouabain to fibers after peeling had no effect on either type of tension transient. However, soaking the fibers in a ouabain solution before peeling blocked the Cl- -induced but not the caffeine-induced tension transient, which suggests that ouabain's site of action is extracellular, perhaps inside transverse tubules (TTs). Treating the peeled fibers with saponin, which should disrupt TTs to a greater extent than SR membrane, greatly reduced or eliminated the Cl- -induced tension transient without significantly altering the caffeine-induced tension transient. These results suggest that the Cl- -induced tension transient is elicited via stimulation of sealed, polarized TTs rather than via ionic depolarization of the SR.


Erectile dysfunction is a common problem in interstitial lung diseases.
Introduction: Erectile dysfunction (ED) is related to chronic diseases, including COPD. The pathogenesis may involve chronic hypoxia, which is common in interstitial lung disease (ILD). We aimed to study the relationship between ILD and ED. Method: Male patients with ILD detected by high-resolution computed tomography (HR-CT) and/or histopathological findings in a lung biopsy were prospectively enrolled at two European ILD centers. Participants were asked to fill in the International Index of Erectile Function questionnaire (Danish or Dutch version). Information on type of ILD, lung function tests, 6-minute walking test (6MWT), co-morbidities, medication and smoking history was obtained from patient records.Results: Of 82 enrolled patients, 54 patients (65.9%) returned the questionnaire. Mean age was 66.8 years (SD: 9.03). Twenty-six patients (48.1%) had IPF. Overall, 38 (70.4%) had some degree of ED, thirty (56.6%) had moderate to severe ED, and 23 (43.4%) had severe ED. Low diffusion capacity and high body mass index showed a trend of increasing risk of moderate to severe ED. The risk increased with age (OR per 5-year increase=2.63 (1.25; 5.53)) and decreased with 6MWT distance (OR per 50 m increase=0.60 (0.41; 0.89). Only two patients (6.7%) received specific treatment with phosphodiesterase-5 inhibitors. Conclusion: Severe ED is a common problem in men with ILD, and is associated with poor walking distance and high age. Treatment coverage is low, and physicians should address this problem as a part of the routine care. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 356-364).


Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?
Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the arteriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors.


Lipid components of bile increase the protective effect of conjugated bile salts against antifungal drugs.
Fungi and bacteria can persist in the human gall bladder. Previous studies have shown that bile protects Candida albicans in this cryptic host niche from antifungals, providing a reservoir for intestinal re-colonization after discontinuation of antifungal therapy. Bile and conjugated bile salts trap antifungals in micelles, thereby reducing their bioavailability and possibly promoting the development of drug resistance. Here we show that the protective effect of bile and conjugated bile salts is not limited to C. albicans, but also observed with other fungi. Interestingly, bile, but not conjugated bile salts conferred resistance of C. albicans against fluconazole and only bile mediated resistance of Aspergillus terreus against voriconazole. To investigate this higher potency of bile we aimed in a step-wise reconstitution of bile from conjugated bile salts. Neither addition of phospholipids nor saturated fatty acids protected from azoles. In contrast, supplementation with polyunsaturated fatty acids increased azole resistance and decreased the critical micelle concentration of conjugated bile salts to the level of bile. Therefore, polyunsaturated fatty acids are vital for mixed micelle formation with high potential to trap antifungals. As biliary infections are difficult to treat, drug efficacy in the biliary system should be tested by using reconstituted synthetic bile.


KRAS Mutations in Papillary Fibroelastomas: A Study of 50 Cases With Etiologic and Diagnostic Implications.
Papillary fibroelastoma (PFE) is an increasingly recognized cardiac tumor. Despite its prevalence, controversy exists as to whether it represents a reactive or neoplastic process due to histopathologic similarities with Lambl excrescences (LEs), an accepted reactive phenomenon. Recently, KRAS mutations were reported in a small collection of PFEs, but the incidence of mutations and conditions in which they arise in are unknown. Furthermore, the relationship between PFE and LE has yet to be investigated. Institutional archives were queried for cases of PFE (2001-2017). Paraffin-embedded tissue was microdissected for tumor isolation. Prospectively identified LEs (2018) were collected and wholly isolated. Extracted DNA underwent droplet digital polymerase chain reaction analysis of the most common KRAS mutations (codons 12/13 and 61). Relevant clinical information was abstracted from the medical record. Fifty-two PFEs were tested from 50 patients (32 women). The median patient age was 67 years. Seventeen (33%) PFEs harbored pathogenic variants in tested KRAS codons (12 in codons 12/13; 5 in codon 61). Mutations were mutually exclusive. No clinical or pathologic correlates differed significantly from cases without detectable pathogenic variants. No pathogenic mutation were detected in LEs (n=20; P=0.002). Herein, we report on the largest series of PFE tested for KRAS mutations and present the largest cohort of KRAS-mutant PFEs to date, providing evidence in support of the notion that at least a subset of PFEs represents neoplasia. Moreover, the lack of KRAS mutations in LEs provides evidence as to the separate etiology of this accepted reactive lesion.


Pharmacological characterization of the behavioural syndrome induced by the NK-3 tachykinin agonist senktide in rodents: evidence for mediation by endogenous 5-HT.
The effects of various manipulations of brain 5-HT mechanisms on the behavioural responses induced by the selective NK-3 tachykinin agonist senktide in rodents were assessed. Senktide elicited wet dog shakes in the rat which were attenuated by the 5-HT1C/2 antagonist mianserin and the selective 5-HT2 antagonist altanserin. Senktide-induced forepaw treading was stereospecifically attenuated by the 5-HT1A + B antagonist (-)-alprenolol. Senktide also elicited chewing mouth movements and yawning, which were unaffected by mianserin, altanserin, (+)- or (-)-alprenolol, or the selective 5-HT3 antagonist ICS 205-930, but attenuated by the muscarinic antagonist scopolamine. Penile grooming elicited by senktide was attenuated by mianserin, but was unaffected by the other antagonists. Senktide-induced wet dog shakes were enhanced by the 5-HT reuptake inhibitors citalopram and fluoxetine, suppressed by the monoamine oxidase (MAO)-B inhibitor pargyline, but unaffected by the MAO-A inhibitor clorgyline. Forepaw treading was potentiated by citalopram and clorgyline, but not significantly altered by fluoxetine or pargyline. Depletion of 5-HT by p-chlorophenylalanine (PCPA) in the rat attenuated senktide-induced wet dog shakes and forepaw treading. Neither PCPA nor 5,7-dihydroxytryptamine affected senktide-induced behaviours in the mouse, but the degree of brain 5-HT depletion caused by these treatments in mice was relatively small. These findings indicate that stimulation of NK-3 tachykinin receptors by senktide results in a complex behavioural syndrome which is mediated by multiple 5-HT receptors, and dependent upon intact stores of endogenous 5-HT. Independent stimulation of brain cholinergic mechanisms by senktide is also confirmed.


[Why can it be difficult for clinicians to diagnose acute lyme disease? From physiopathology to diagnosis, via abductive reasoning and Bayes theorem].
The diagnosis of acute neuroborreliosis may be difficult if it's regarded as a "classical" infectious disease. Through a clinical case, we illustrate the difficulties met and we suggest two ways of reflexion to assist in the diagnosis:--firstly, we explain how the comprehension of the behavior of the pathogen agent, which is similar to a parasitic behavior, can help to choose and interpret the results of additional tests;--secondly, we develop practically the clinical form of Bayes's theorem to demonstrate the interest of a rational Bayesian and abductive approach which should be preferred to the classical hypothetical and deductive reasoning.


Mode conversion losses in silicon-on-insulator photonic wire based racetrack resonators.
Two complimentary types of SOI photonic wire based devices, the add/drop (A/D) filter using a racetrack resonator and the Mach-Zehnder interferometer with one arm consisting of an identical resonator in all-pass filter (APF) configuration, were fabricated and characterized in order to extract the optical properties of the resonators and predict the performance of the optical delay lines based on such resonators. We found that instead of well-known waveguide bending and propagation losses, mode conversion loss in the coupling region of such resonators dominates when the air gap between the racetrack resonator and access waveguide is smaller than 120nm. We also show that this additional loss significantly degrades the performance of the optical delay line containing cascaded resonators in APF configuration.


Ontogenetic changes of the soluble and membrane-bound D2 glycoprotein in rat forebrain.
A soluble form of the D2 glycoprotein, detected in the rat brain hypotonic extract, is described. Its specific relative concentration did not differ significantly in the three examined cerebral regions (forebrain, brainstem and cerebellum), while in the cerebellum the membrane-bound form was about three and four times more concentrated than in the forebrain and brainstem, respectively. No sizeable developmental variations of the soluble D2 concentration could be detected in forebrain, whereas the amount of the membrane-bound protein rose from birth to postnatal day 6 and then decreased to the adult value (about 40% of the newborn concentration). Ontogenetic modifications of the membranous D2 glycans (studied through the binding of the molecule to several lectins) occur around postnatal day 18 when the binding to Ricinus communis lectin, specific for galactose, becomes evident. At all ages both soluble and membrane-bound forms bind to Concanavalin A, specific for mannose and glucose, and to wheat germ agglutinin, specific for N-acetylglucosamine, while the lack of binding to Ulex europeus lectin suggests the absence of discrete amount of fucose. The results are discussed in relation to the possible involvement of D2 glycoprotein in cell-to-cell adhesion.


Compliance with tuberculosis treatment after the implementation of the directly observed treatment, short-course strategy in the city of Carapicuíba, Brazil.
To determine the compliance with tuberculosis treatment among patients enrolled the tuberculosis control program in the city of Carapicuíba, Brazil, before and after the implementation of the directly observed treatment, short-course (DOTS) strategy. A retrospective historical cohort study of operational aspects based on records of attendance and treatment evolution of patients in self-administered treatment (SAT) and of those submitted to DOTS. Monthly treatment outcome tables were created, and the probability of compliance with the treatment was calculated for both groups of patients. A total of 360 patients with tuberculosis met the inclusion criteria: 173 (48.1%) in the SAT group; and 187 (51.9%) in the DOTS group. Treatment compliance was 6.1% higher in the DOTS group than in the SAT group. The proportion of patients completing the six months of treatment was 91.6% and 85.5% in the DOTS group and in the SAT group, respectively. The results of this study show that DOTS can be successfully implemented at primary health care clinics. In this population of patients, residents of a city with low incomes and a high burden of tuberculosis infection, DOTS was more effective than was SAT.


Nf1 loss promotes Kras-driven lung adenocarcinoma and results in Psat1-mediated glutamate dependence.
Mutations to KRAS are recurrent in lung adenocarcinomas (LUAD) and are daunting to treat due to the difficulties in KRAS oncoprotein inhibition. A possible resolution to this problem may lie with co-mutations to other genes that also occur in KRAS-driven LUAD that may provide alternative therapeutic vulnerabilities. Approximately 3% of KRAS-mutant LUADs carry functional mutations in NF1 gene encoding neurofibromin-1, a negative regulator of focal adhesion kinase 1 (FAK1). We evaluated the impact of Nf1 loss on LUAD development using a CRISPR/Cas9 platform in a murine model of Kras-mutant LUAD We discovered that Nf1 deactivation is associated with Fak1 hyperactivation and phosphoserine aminotransferase 1 (Psat1) upregulation in mice. Nf1 loss also accelerates murine Kras-driven LUAD tumorigenesis. Analysis of the transcriptome and metabolome reveals that LUAD cells with mutation to Nf1 are addicted to glutamine metabolism. We also reveal that this metabolic vulnerability can be leveraged as a treatment option by pharmacologically inhibiting glutaminase and/or Psat1. Lastly, the findings advocate that tumor stratification by co-mutations to KRAS/NF1 highlights the LAUD patient population expected to be susceptible to inhibiting PSAT1.


Protein- and metal-dependent interactions of a prominent protein in mussel adhesive plaques.
The adhesive plaques of Mytilus byssus are investigated increasingly to determine the molecular requirements for wet adhesion. Mfp-2 is the most abundant protein in the plaques, but little is known about its function. Analysis of Mfp-2 films using the surface forces apparatus detected no interaction between films or between a film and bare mica; however, addition of Ca(2+) and Fe(3+) induced significant reversible bridging (work of adhesion W(ad) approximately 0.3 mJ/m(2) to 2.2 mJ/m(2)) between two films at 0.35 m salinity. The strongest observed Fe(3+)-mediated bridging approaches the adhesion of oriented avidin-biotin complexes. Raman microscopy of plaque sections supports the co-localization of Mfp-2 and iron, which interact by forming bis- or tris-DOPA-iron complexes. Mfp-2 adhered strongly to Mfp-5, a DOPA-rich interfacial adhesive protein, but not to another interfacial protein, Mfp-3, which may in fact displace Mfp-2 from mica. In the presence of metal ions or Mfp-5, Mfp-2 adhesion was fully reversible. These results suggest that plaque cohesiveness depends on Mfp-2 complexation of metal ions, particularly Fe(3+) and also by Mfp-2 interaction with Mfp-5 at the plaque-substratum interface.


Comparison of Vibrational Spectroscopic Techniques for Quantification of Water in Natural Deep Eutectic Solvents.
Vibrational spectroscopic techniques, i.e., attenuated total reflectance infrared (ATR-IR), near infrared spectroscopy (NIRS) and Raman spectroscopy (RS), coupled with Partial Least Squares Regression (PLSR), were evaluated as cost-effective label-free and reagent-free tools to monitor water content in Levulinic Acid/L-Proline (LALP) (2:1, mol/mol) Natural Deep Eutectic Solvent (NADES). ATR-IR delivered the best outcome of Root Mean Squared Error (RMSE) of Cross-Validation (CV) = 0.27% added water concentration, RMSE of Prediction (P) = 0.27% added water concentration and mean % relative error = 2.59%. Two NIRS instruments (benchtop and handheld) were also compared during the study, respectively yielding RMSECV = 0.35% added water concentration, RMSEP = 0.56% added water concentration and mean % relative error = 5.13% added water concentration, and RMECV = 0.36% added water concentration, RMSEP = 0.68% added water concentration and mean % relative error = 6.23%. RS analysis performed in quartz cuvettes enabled accurate water quantification with RMECV = 0.43% added water concentration, RMSEP = 0.67% added water concentration and mean % relative error = 6.75%. While the vibrational spectroscopic techniques studied have shown high performance in relation to reliable determination of water concentration, their accuracy is most likely related to their sensitivity to detect the LALP compounds in the NADES. For instance, whereas ATR-IR spectra display strong features from water, Levulinic Acid and L-Proline that contribute to the PLSR predictive models constructed, NIRS and RS spectra are respectively dominated by either water or LALP compounds, representing partial molecular information and moderate accuracy compared to ATR-IR. However, while ATR-IR instruments are common in chemistry and physics laboratories, making the technique readily transferable to water quantification in NADES, Raman spectroscopy offers promising potential for future development for in situ, sample withdrawal-free analysis for high throughput and online monitoring.


[Pharmacotherapy of chronic venous diseases in the light of the Russian and International Guidelines].
The article reviews present-day data on pathogenesis of chronic venous diseases, as well as formulates the strategic missions of treatment, with an emphasis placed on the criteria ol evidence-based medicine, followed by critically analysing the standards of pharmacotherapy of chronic venous diseases, reflected in the European, American and Russian clinical guidelines. A conclusion is drawn on the necessity and advisability, from the point of view ol evidence-based medicine, of using phlebotropic drugs in patients suffering from various forms of chronic venous diseases.


Chest ultrasonography in lung contusion.
Despite the high prevalence of chest trauma and its high morbidity, lung contusion (LC) often remains undiagnosed in the emergency department (ED). The present study investigates the possible clinical applicability of chest ultrasonography for the diagnosis of LC in the ED in comparison to radiography and CT. One hundred twenty-one patients admitted to the ED for blunt chest trauma were investigated using ultrasonography by stage III longitudinal scanning of the anterolateral chest wall to detect LC. Data were retrospectively collected in an initial series of 109 patients (group 1) and prospectively in the next 12 patients (group 2). All patients who presented with pneumothorax were excluded. After the ultrasound study, all patients were submitted to chest radiography (CXR) and CT. The sonographic patterns indicative of LC included the following: (1) the alveolointerstitial syndrome (AIS) [defined by increase in B-line artifacts]; and (2) peripheral parenchymal lesion (PPL) [defined by the presence of C-lines: hypoechoic subpleural focal images with or without pleural line gap]. The diagnosis of LC was established by CT scan in 37 patients. If AIS is considered, the sensitivity of ultrasound study was 94.6%, specificity was 96.1%, positive and negative predictive values were 94.6% and 96.1%, respectively, and accuracy was 95.4%. If PPL is alternatively considered, sensitivity and negative predictive values drop to 18.9% and 63.0%, respectively, but both specificity and positive predictive values increased to 100%, with an accuracy of 65.9%. Radiography had sensitivity of 27% and specificity of 100%. Chest ultrasonography can accurately detect LC in blunt trauma victims, in comparison to CT scan.


Draft genome sequences of Neurospora crassa clade B, isolated from burned Cytisus sp. plants in France.
Neurospora crassa clade A is a model system for genetics, biochemistry, molecular biology, and experimental evolution. Here, we present the draft genome sequences of four isolates of N. crassa clade B. These data represent a valuable resource to investigate the population biology and evolutionary history of N. crassa sensu lato.