A novel localized co-delivery system with lapatinib microparticles and paclitaxel nanoparticles in a peritumorally injectable in situ hydrogel.
The combination of high dose of oral lapatinib (LAPA), a HER2 tyrosine kinase inhibitor, with intravenous paclitaxel (PTX) exhibited a clinical survival advantage compared with PTX alone against HER2 positive breast cancer. However, localized delivery system with high regional drug level may greatly decrease the dose of drug, leading to higher safety and lower cost. In an attempt to imitate the fast and slow exposure of these two drugs in clinic use, we incorporated PTX nanoparticles and LAPA microparticles into a thermosensitive hydrogel (PL-gel) for peritumoral injection, using PTX-gel plus LAPA-oral (P-gel+L-oral) and so on as controls. To visually study in vitro or in vivo, PTX/DID and LAPA/DIR hybrid crystals were prepared. In vitro and in vivo studies demonstrated the fast and short-term release of PTX, as well as the slow and long-term release of LAPA from the PL-gel. The most synergistic effect was found between LAPA and PTX on the cell line overexpressing both HER2 and P-gp, and the mechanisms related to LAPA-induced inhibition on P-gp expression, more G2/M phase arrest of PTX and more uptake of PTX in tumor cells. With a dose of LAPA in PL-gel group only less than 5% of that in P-gel+L-oral group, PL-gel demonstrated significant tumor suppression similar to P-gel+L-oral group, and showed longer mice survival time. Besides, PL-gel achieved more steady LAPA accumulation in tumors and revealed significantly less toxicity compared with P-gel+L-oral group. To summarize, this localized co-delivery system with good synergistic effects between LAPA and PTX might offer a potential strategy for HER2 and P-gp positive breast cancer.


Retarded ejaculation reconceptualization and implications for treatment.
Retarded ejaculation, RE, has received little attention in the past; however with greater sexual awareness, therapists may find a significant increase in requests for help with this dysfunction. A major concern of this paper is that RE has been too narrowly defined. Additional problems in previous literature include conceptual confusion, poorly defined criteria, vague descriptors, and methodological problems. Incidence, definitions and categorizations are followed by a look at etiology, assessment, and treatment results. The present article broadens the definition of RE, presents psychophysiological stimulation deprivation as a generally overlooked cause, and offers a thorough bibliography for reference purposes.


Remote assessment of verbal memory in MS patients using the California Verbal Learning Test.
We used the California Verbal Learning Test, Second Edition (CVLT-II), one component of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), to determine feasibility of a remote assessment protocol. We compared telephone-administered CVLT-II data from MS patients to data acquired in person from an independent sample of patients and healthy controls. Mixed factor analyses of variance (ANOVAs) showed no significant differences between patient groups, but between-group effects comparing patients and healthy controls were significant. In this study, CVLT-II assessment by conventional in-person and remote telephone assessment yielded indistinguishable results. The findings indicate that telephone-administered CVLT-II is feasible. Further validation studies are underway.


Hybrid Finite Element-Smoothed Particle Hydrodynamics Modelling for Optimizing Cutting Parameters in CFRP Composites.
Carbon-fibre-reinforced plastic (CFRP) is increasingly being used in various applications including aerospace, automotive, wind energy, sports, and robotics, which makes the precision modelling of its machining operations a critical research area. However, the classic finite element modelling (FEM) approach has limitations in capturing the complexity of machining, particularly with regard to the interaction between the fibre-matrix interface and the cutting edge. To overcome this limitation, a hybrid approach that integrates smoothed particle hydrodynamics (SPHs) with FEM was developed and tested in this study. The hybrid FEM-SPH approach was compared with the classic FEM approach and validated with experimental measurements that took into account the cutting tool's round edge. The results showed that the hybrid FEM-SPH approach outperformed the classic FEM approach in predicting the thrust force and bounce back of CFRP machining due to the integrated cohesive model and the element conversion after failure in the developed approach. The accurate representation of the fibre-matrix interface in the FEM-SPH approach resulted in predicting precise chip formation in terms of direction and morphology. Nonetheless, the computing time of the FEM-SPH approach is higher than the classic FEM. The developed hybrid FEM-SPH model is promising for improving the accuracy of simulation in machining processes, combining the benefits of both techniques.


Willingness to pay for home- and community-based services for seniors in Florida.
States are increasingly interested in measuring the benefit of home- and community-based services (HCBS) programs in order to determine if continued provision of HCBS can be justified on a cost-benefit basis. This study attempts to assess the maximum dollar amount HCBS enrollees or eligible applicants are willing to pay as a measure of the value of the services to them. A contingent valuation survey was conducted on a random sample of 409 clients who were enrolled in or waitlisted for HCBS programs in Florida. Based on estimates from a random-effect model, the median and mean willingness to pay amounts are calculated to be $901 and $933 per month per person, respectively, with considerable variation across HCBS programs. The major determinants of willingness to pay include household income and individual functional status. The sizable values for willingness to pay reported in this study suggest that HCBS programs are perceived as a valuable resource for the elderly.


3D Morphology Analysis of TMJ Articular Eminence in Magnetic Resonance Imaging.
The objective of this study was to evaluate the computational reconstruction of the articular eminence of the temporomandibular joint (TMJ) based on magnetic resonance imaging (MRI) and semiautomatic volumetric segmentation techniques for morphological classification of the TMJ structure. A total of 36 MRI scans of TMJ individuals were selected and formatted by using the ITK-SNAP software, consisting of MRI segmentation and generation of 3D models. The TMJ articular eminences were also classified according to the morphology analysis of the articular eminence in 3D reconstructions. Two independent trained and calibrated investigators performed the image analysis, which was repeated after thirty days. There was no association between sex and eminence shape (p = 0.456). Fisher's test revealed no statistically significant association between disc classification and eminence shape on both sides (p = 0.629). Chi-square test showed a significant statistically association between disc classification and disc displacement (p = 0.000). Intra- and interrater correlation coefficients showed excellent reproducibility values. Anatomical variability of the sample investigated was found, with predominantly round shape and presence of correlation between this shape and normal disc position. The correlation of flattened and convex shapes with disc position reduction indicated that type of disc derangement is more prevalent.


[Hair follicle cell mixture forms hair follicle-like structures after subcutaneous implantation in nude mice].
To observe the hair follicle regeneration after subcutaneous implantation of hair follicle cell mixture in nude mice. The hair papilla cells, dermal sheath cells, outer root sheath and fibroblasts of human scalp were mixed with the hair follicle epithelial cells and implanted subcutaneously in nude mice to observe the regeneration of the hair follicle. Formation of intact hair follicle-like structures was observed in the skin sections of the recipient nude mice, suggesting the feasibility of this approach for hair follicle regeneration in vivo.


Virulence Gene Regulation in Shigella.
Shigella species are the causative agents of bacillary dysentery in humans, an invasive disease in which the bacteria enter the cells of the epithelial layer of the large intestine, causing extensive tissue damage and inflammation. They rely on a plasmid-encoded type III secretion system (TTSS) to cause disease; this system and its regulation have been investigated intensively at the molecular level for decades. The lessons learned have not only deepened our knowledge of Shigella biology but also informed in important ways our understanding of the mechanisms used by other pathogenic bacteria to cause disease and to control virulence gene expression. In addition, the Shigella story has played a central role in the development of our appreciation of the contribution of horizontal DNA transfer to pathogen evolution.A 30-kilobase-pair "Entry Region" of the 230-kb virulence plasmid lies at the heart of the Shigella pathogenesis system. Here are located the virB and mxiE regulatory genes and most of the structural genes involved in the expression of the TTSS and its effector proteins. Expression of the virulence genes occurs in response to an array of environmental signals, including temperature, osmolarity, and pH.At the top of the regulatory hierarchy and lying on the plasmid outside the Entry Region isvirF, encoding an AraC-like transcription factor.Virulence gene expression is also controlled by chromosomal genes,such as those encoding the nucleoid-associated proteins H-NS, IHF, and Fis, the two-component regulators OmpR/EnvZ and CpxR/CpxA, the anaerobic regulator Fnr, the iron-responsive regulator Fur, and the topoisomerases of the cell that modulate DNA supercoiling. Small regulatory RNAs,the RNA chaperone Hfq,and translational modulation also affect the expression of the virulence phenotypetranscriptionally and/orposttranscriptionally.


Association between type 2 diabetes and chronic arsenic exposure in drinking water: a cross sectional study in Bangladesh.
Chronic exposure to high level of inorganic arsenic in drinking water has been associated with Type 2 Diabetes (T2D). Most research has been ecological in nature and has focused on high levels of arsenic exposure with few studies directly measuring arsenic levels in drinking water as an index of arsenic exposure. The effect of low to moderate levels of arsenic exposure on diabetes risk is largely unknown thus our study is adding further knowledge over previous works. This cross sectional study was conducted in 1004 consenting women and men from 1682 eligible participants yielding a participation rate of 60%. These participants are aged >30 years and were living in Bangladesh and had continuously consumed arsenic-contaminated drinking water for at least 6 months. T2D cases were diagnosed using glucometer following the new diagnostic criteria (Fasting Blood Glucose > 126 mg/dl) from the WHO guideline (WHO 2006), or a self-reported physician diagnosis of type 2 diabetes. Association between T2D and chronic arsenic exposure was estimated by multiple logistic regression with adjustment for age, sex, education, Body Mass Index (BMI) and family history of T2D. A total of 1004 individuals participated in the study. The prevalence of T2D was 9% (95% CI 7-11%). After adjustment for diabetes risk factors, an increased risk of type 2 diabetes was observed for arsenic exposure over 50 μg/L with those in the highest category having almost double the risk of type 2 diabetes (OR=1.9 ; 95% CI 1.1-3.5). For most levels of arsenic exposure, the risk estimates are higher with longer exposure; a dose-response pattern was also observed. These findings suggest an association between chronic arsenic exposure through drinking water and T2D. Risks are generally higher with longer duration of arsenic exposure. The risk of T2D is highest among those who were exposed to the highest concentration of arsenic for more than 10 years.


Problems in pattern alopecia.
Female pattern hair loss (FPHL) was originally described as synonymous with androgenetic alopecia. However, the role of androgens in FPHL has not been proven, and the etiology is not yet defined. Several patterns of hair loss in women have been described, in addition to descriptions of scarring alopecias mimicking FPHL. In this paper, we discuss FPHL as an entity other than androgenetic alopecia and suggest that de-emphasizing the physicians reliance on pattern in the diagnosis of hair loss in women, and instead utilizing other tools including dermoscopy and histopathology, would benefit clinician's efforts in treating alopecias.


Ultrafast optical Stark mode-locked semiconductor laser.
We report on 260 fs transform-limited pulses generated directly by an optical Stark passively mode-locked semiconductor disk laser at a 1 GHz repetition rate. A surface recombination semiconductor saturable absorber mirror and a step-index gain structure are used. Numerical propagation modeling of the optical Stark effect confirms that this mechanism is able to form the pulses that we observe.


A phase 2, double-blind, multicenter, randomized, placebo-controlled, dose‑ranging study of the efficacy and safety of Astodrimer Gel for the treatment of bacterial vaginosis.
Astodrimer Gel contains a novel dendrimer intended to treat and prevent bacterial vaginosis. We assessed the efficacy and safety of Astodrimer Gel for treatment of bacterial vaginosis. 132 women with bacterial vaginosis were randomized 1:1:1:1 to Astodrimer 0.5% (N = 34), 1% (N = 33), or 3% (N = 32) Gel or hydroxyethyl cellulose placebo gel (N = 33) at a dose of 5 g vaginally once daily for 7 days at 6 centers in the United States. The primary endpoint was clinical cure (no bacterial vaginosis vaginal discharge and no more than one of 1) vaginal pH ≥4.5; 2) ≥20% clue cells; or 3) positive whiff test) at study days 21-30. Secondary analyses included clinical cure at study days 9-12, patient-reported symptoms, acceptability and adverse events. The Astodrimer 1% Gel dose was superior to placebo for the primary and selected secondary efficacy measures in the modified intent-to-treat population. Clinical cure rates at day 9-12 were superior to placebo for the Astodrimer 3%, 1% and 0.5% Gel groups (62.5% [15/24; P = .002], 74.1% [20/27; P < .001], and 55.2% [16/29; P = .001], respectively, vs. 22.2% [6/27]). At day 21-30, clinical cure rates were 46.2% (12/26) for the 1% dose vs. 11.5% for placebo (3/26; P = .006). A greater proportion of patients reported absence of vaginal discharge and vaginal odor at day 9-12 and day 21-30 for Astodrimer Gel groups compared with placebo. Adverse events considered potentially treatment-related occurred in only 25% of Astodrimer Gel-treated patients vs. 22% of placebo patients. Astodrimer Gel once daily for 7 days was superior to placebo for treatment of bacterial vaginosis and was well-tolerated. The 1% dose consistently showed the strongest efficacy across endpoints. These results support a role for Astodrimer Gel, 1%, as an effective treatment for bacterial vaginosis.


Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.
High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.


Conformational effects of calcium release from parvalbumin: comparison of computational simulations with spectroscopic investigations.
The effect of Ca2+ binding to parvalbumin was monitored by probes of conformation including absorption, fluorescence, circular dichroism (CD), infrared (IR) spectroscopy and differential scanning calorimetry. These experimental studies were compared with molecular dynamics computations on the structures of the Ca-bound and Ca-free forms of cod parvalbumin. The UV CD spectra show that removal of calcium results in a decrease in the alpha-helical content of the protein. The IR amide I' and III' regions are very much affected by Ca removal and are indicative of significant perturbation of secondary structure. The fluorescence of tryptophan, the IR markers, and UV ellipticity all show changes with temperature, pointing to a lowering of protein stability upon Ca removal. These results are consistent with the structures obtained for both the Ca-bound and Ca-free proteins after 200 ps of solvated molecular dynamics simulations which show a decrease in the secondary structure upon Ca removal.


DESICCATION AND STARVATION TOLERANCE OF ADULT DROSOPHILA: OPPOSITE LATITUDINAL CLINES IN NATURAL POPULATIONS OF THREE DIFFERENT SPECIES.
Desiccation and starvation tolerance were measured along latitudinal transects in three Drosophilid species (Drosophila ananassae, D. melanogaster, and Zaprionus indianus) of the Indian subcontinent. In each case, significant latitudinal clines were observed; desiccation tolerance increased with latitude while starvation tolerance decreased. Such field observations suggest that desiccation and starvation tolerance are fitness related traits that are independently selected in nature and genetically independent. It was, however, difficult to relate these genetic changes with precise climatic variables, except winter temperature. The overall negative correlation between the two traits, which was evidenced in natural populations, contrasts with a positive correlation generally observed in various laboratory selection experiments and that also seems to exist between different species. These observations point to the difficulty of interpreting correlations among fitness-related traits when different evolutionary levels are compared, and also different sets of data, that is, field versus laboratory studies.


Uptake and distribution of difenoconazole in rice plants under different culture patterns.
The effects of spraying and root irrigation on the uptake and transport of the fungicide difenoconazole under hydroponic and soil cultivation were investigated. Rice was used as the crop for a short-term exposure experiment. A modified QuEChERS pre-treatment combined with ultra-high-performance liquid chromatography-tandem mass spectrometry was used to extract and detect difenoconazole from rice plants, water and soil. The recoveries of difenoconazole were in the range of 72.8-110.5%, with a relative standard deviation of 2.4-19.5% for all the samples when spiked with 0.01, 0.1 and 1 mg kg-1 of difenoconazole, respectively. The limit of quantitation (LOQ) of this method was 0.01 mg kg-1. The exposure results showed that difenoconazole could be absorbed by rice plants and transmitted to different parts of rice plants in all the treatments. In the hydroponic experiment, difenoconazole was mainly distributed in the roots of rice regardless of whether irrigation or spraying was used. For rice cultivated in soil, difenoconazole mainly accumulated in leaves after the root irrigation treatment, whereas after the spraying treatment, the rice roots were the main site of accumulation of difenoconazole. This experiment extends our knowledge of the influence of the cultivation system and application mode on the translocation of difenoconazole in rice plants.


Salivary Levels of NLRP3 Inflammasome-Related Proteins as Potential Biomarkers of Periodontal Clinical Status.
Emerging evidence suggests that activation of inflammasomes plays a central mechanism in pathogenesis of periodontitis. This study aims to compare salivary levels of nod-like receptor family pyrin domain containing protein (NLRP) 3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cysteine aspartase (caspase)-1, and interleukin (IL)-1β from individuals with aggressive (AgP) or chronic periodontitis (CP) and healthy controls (HC), as well as elucidate its association with periodontal clinical status. Saliva samples from individuals with CP (n = 75), AgP (n = 20), and HC (n = 69) were collected. Periodontal status was assessed by measurement of probing depth, clinical attachment level, and extent and severity of disease. Salivary levels of analytes were analyzed by enzyme-linked immunosorbent assay. Association between biomarkers with CP or AgP was analyzed using multivariate binary logistic regression models. Significantly higher levels of NLRP3, ASC, and IL-1β were detected in periodontitis groups in comparison to the periodontally HC group. However, no significant differences were observed for caspase-1 levels between clinical groups, and only NLRP3 salivary concentration was significantly higher in AgP compared with CP patients. Also, positive significant correlations among NLRP3, ASC, and IL-1β salivary concentrations and clinical parameters were observed. Logistic regression analyses revealed a strong/independent association of NLRP3, ASC, and IL-1β salivary levels with CP and AgP. Although the concentration of caspase-1 in saliva samples makes its determination useless for detection of periodontal disease and/or its severity, salivary levels of NLRP3, ASC, and IL-1β may act as strong/independent indicators of amount and extent of periodontal breakdown in both CP and AgP and could potentially be used for prevention and therapy of this group of diseases.


Confocal Raman microscopy for in situ detection of solid-phase extraction of pyrene into single C18-silica particles.
Solid-phase extraction (SPE) is a well-known method for separating and preconcentrating analytes prior to ex situ detection and quantification. Despite advances in the miniaturization of solid-phase extraction, the technique has not evolved to meet the needs for detection in small-scale microfluidic devices. Although successful efforts have led to smaller-scale extractors that allow preconcentration from small volumes, detection within correspondingly small volumes has remained out of reach because of analyte dilution during a postextraction transfer or "wash-off" step prior to detection. In this work, successful extraction into subpicoliter collection volumes is accomplished by using a single chromatographic particle as an extractor; wash-off dilution is completely avoided by using confocal Raman microscopy for in situ detection within the single-particle collection phase. Specifically, micromolar concentrations of pyrene in methanol/water solution were equilibrated with an individual C18-functionalized silica particle, and Raman spectra were acquired from a small confocal sampling volume (∼1 fL) within the particle interior. By comparing the Raman scattering intensity of the pyrene with that of the C18 chains in the stationary phase, it was possible to quantify the equilibrium coverage of pyrene relative to the C18 chains. Spectroscopic isotherms were measured to determine the saturation surface coverage of pyrene relative to C18 chains and to study how the preconcentration equilibrium can be controlled by the source-phase solution composition. For extraction from aqueous solutions having the lowest methanol concentration (5% by volume), the preconcentration factor for pyrene into the particle was found to be 4.8 (±0.8) × 10(4), which allowed detection of pyrene extracted from a 10 nM solution into a 0.52-pL particle volume.


Antinociceptive activity of a neurosteroid tetrahydrodeoxycorticosterone (5alpha-pregnan-3alpha-21-diol-20-one) and its possible mechanism(s) of action.
The present study investigates the effects of a neurosteroid tetrahydrodeoxycorticosterone (5alpha-pregnan-3alpha-21-diol-20-one) in two experimental models of pain sensitivity in mice. Tetrahydrodeoxycorticosterone (2.5, 5 mg/kg, i.p.) dose dependently decreased the licking response in formalin test and increased the tail flick latency (TFL) in tail flick test. Bicuculline (2 mg/kg, i.p.), a GABA(A) receptor antagonist blocked the antinociceptive effect of tetrahydrodeoxycorticosterone in TFL test but failed to modulate licking response in formalin test. Naloxone (1 mg/kg, i.p.), an opioid antagonist effectively attenuated the analgesic effect of tetrahydrodeoxycorticosterone in both the models. Tetrahydrodeoxycorticosterone pretreatment potentiated the antinociceptive response of morphine, an opioid compound and nimodipine, a calcium channel blocker in formalin as well as TFL test. Thus, tetrahydrodeoxycorticosterone exerts an analgesic effect, which may be mediated by modulating GABA-ergic and/or opioid-ergic mechanisms and voltage-gated calcium channels.


Genetic basis for necrotizing enterocolitis--risk factors and their relations to genetic polymorphisms.
Necrotizing enterocolitis (NEC) is a common, life-threatening neonatal gastrointestinal disease; it affects approximately 11% of extremely premature neonates. The etiology of NEC is multifactorial. Risk factors may roughly be grouped into four main categories: prematurity; transient ischemia of the intestine; local/systemic inflammation predisposing the bowel to injury, and therapeutic interventions. Recent studies have shown that carrier state of genetic polymorphisms may be associated with perinatal morbidity, including NEC. In perinatal disorders, the significance of genetic variants of cytokines, the renin-angiotensin-aldosterone system, and surfactant proteins have been investigated most widely. Positive findings indicate the implication of genetic polymorphisms of proinflammatory cytokines in premature birth; angiotensin converting enzyme in perinatal adaptation and angiotensin type 1 receptor in the closure of ductus arteriosus; surfactant proteins A and B in respiratory distress syndrome; interleukin (IL)-6 in sepsis, and IL-4-receptor alpha chain and IL-18 in NEC. This review provides an insight into the genetics of NEC and summarizes genetic data in light of pathologic processes leading to NEC.


Biodegradability of leachates from Chinese and German municipal solid waste.
The quantitative and qualitative composition of Chinese municipal solid waste (MSW) differs significantly from German waste. The focus of this paper is on whether these differences also lead to dissimilar qualities of leachates during storage or landfilling. Leachates ingredients determine the appropriate treatment technique. MSW compositions of the two cities Guilin (China) and Essen (Germany), each with approx. 600 000 inhabitants, are used to simulate Chinese and German MSW types. A sequencing batch reactor (SBR) is used, combining aerobic and anaerobic reaction principles, to test the biodegradability of leachates. Leachates are tested for temperature, pH-value, redox potentials, and oxygen concentration. Chemical oxygen demand (COD) values are determined. Within 8 h, the biodegradation rates for both kinds of leachates are more than 90%. Due to the high organic content of Chinese waste, the degradation rate for Guilin MSW leachate is even higher, up to 97%. The effluent from SBR technique is suitable for direct discharge into bodies of water.


Nonlinear shallow water investigation of atmospheric disturbances generated by strong seismic events.
The upper portions of the Earth's atmospheric layer, e.g., the ionospheric plasma layer, can be significantly affected by perturbations generated in the lower layers. In fact, all perturbations formed within the troposphere can easily propagate, not only horizontally within the layer but also vertically reaching the highest regions of the atmosphere far from the Earth's surface, as depicted by the Wentzel-Kramers-Brillouin (WKB) approximation of atmospheric waves. Because all perturbations generated in the atmospheric boundary layer must take into account the effects of the medium's nonlinearity and thus the effects of atmospheric turbulence, in this work the impact of a strong seismic event and the disturbances generated in the flow are analyzed by means of a fully nonlinear model which incorporates a simple parametrization of the seismic event and is based on the classical shallow water. A strict dependence was observed between the model control parameters and the vertical nonvanishing modes from the WKB approximation, and only few specific bands of excited modes are nonvanishing and can eventually propagate to the ionosphere. Moreover, the flow disturbance, generated by a seismic event, presents a multiscale nature characterized by two fixed wavelengths, and the excited modes are harmonics of such distinctive scales.


Ultrastructural morphometric features of human sural nerve endoneurial microvessels.
We studied the morphometric features of 366 transversely sectioned endoneurial microvessels in sural nerves from 50 healthy volunteers (mean age 34.5 +/- 15.8, range 20 to 66 years). Nerves were obtained and processed by the same techniques and standards used to study biopsied nerves from patients with neuropathy. Endothelial area, basement membrane area, number of endothelial nuclei and junctions, and number of periendothelial nuclei all increase significantly with vessel size as judged by mural area. Periendothelial cell coverage of endothelial perimeter does not correlate with vessel size. Components of endoneurial microvessels, specifically the area containing basement membrane, do not change significantly with age. The present report provides a detailed characterization of the ultrastructural features of endoneurial microvessels with age in humans and provides optimal reference values for study of microvessel pathologic changes in disease.


A systematic review of the association between the Behavioral and Psychological Symptoms of Dementia and burden of care.
Several reports have indicated that the Behavioral and Psychological Symptoms of Dementia (BPSD) are associated with increased burden of care, carer depression and increased rates of institutionalization of patients. The present study aims to review the association between these variables in cross-sectional as well as longitudinal studies. Systematic review and meta-analysis of all available information published in English between January 1990 and December 2001 was made. Case-reports, case-series and studies with 20 or fewer subjects were excluded from the analyses. Thirty articles are included in the review of cross-sectional data and 12 in the systematic review of longitudinal data. Pooled correlation coefficients were generated for the relationship between BPSD and caregiver burden (r(pooled) = 0.57; 95% CI = 0.52 to 0.62), caregiver psychological distress (r(pooled) = 0.41; 95% CI = 0.32 to 0.49) and caregiver depression (r(pooled) = 0.30; 95% CI= 0.21 to 0.39), suggesting that these concepts have a moderately strong association. Multivariate data, on the whole, further supported the notion that BPSD are a predictor of burden of care and of psychological distress and depression. Limited longitudinal data made clarifying the temporal relationahip between BPSD and the psychological sequelae of care (PSC) difficult. The limited data pertaining to the relationship between BPSD and institutionalization suggest that caregiver variables may be more important in predicting institutionalization than BPSD. Methodological issues and limitations associated with this type of investigation were also considered. The results of this review support, but do not conclusively establish, the association between BPSD and PSC. We propose that the concept of burden of care be abandoned in favor of more clinically relevant outcomes such as caregiver depression.


Silencing c-Jun inhibits autophagy and abrogates radioresistance in nasopharyngeal carcinoma by activating the PI3K/AKT/mTOR pathway.
Radioresistance plays an important role in the failure of radiotherapy (RT) for nasopharyngeal carcinoma (NPC), leading to poor prognosis. The purpose of this study was to explore the relationship between the expression of the c-Jun oncogene and the prognosis of NPC. In addition, we investigated the potential mechanisms of c-Jun in the regulation of tumor growth and radioresistance in NPC. c-Jun expression in NPC tissues and nasopharyngeal mucosa tissues was evaluated using immunochemistry. c-Jun and its downstream targets were verified by dual-luciferase reporter assays. Inhibitors or activators were used to interfere with the PI3K/AKT/mTOR pathway. Protein expression was analyzed by western blotting. NPC nude mouse xenograft models were used to investigate the potential effects of c-Jun and ionizing radiation in vivo. The expression of c-Jun in NPC tissues was significantly higher than that in normal nasopharyngeal mucosa (NNM) tissues, and Cox regression analysis revealed that c-Jun overexpression was an independent risk factor for poor prognosis in NPC patients. Both in vitro and in vivo experiments verified that c-Jun targeted PI3K/AKT signaling. We also performed an in vivo study showing that c-Jun knockdown effectively suppressed NPC growth in a xenograft tumor model by autophagy inhibition, and these effects were accompanied by the upregulation of p-PI3K p-AKT, p-mTOR, and P62 and downregulation of LC3-II expression. High expression of c-Jun was correlated with poor prognosis in NPC patients. c-Jun knockdown increased cell sensitivity to radiation by inhibiting autophagy activation via the PI3K/AKT/mTOR signaling pathway. The present study provides a theoretical basis for a promising treatment for radioresistant NPC by inhibiting c-Jun expression.


Ultrasonic Interferometric Procedure for Quantifying the Bone-Implant Interface.
The loosening of an artificial joint is a frequent and critical complication in orthopedics and trauma surgery. Due to a lack of accuracy, conventional diagnostic methods such as projection radiography cannot reliably diagnose loosening in its early stages or detect whether it is associated with the formation of a biofilm at the bone-implant interface. In this work, we present a non-invasive ultrasound-based interferometric measurement procedure for quantifying the thickness of the layer between bone and prosthesis as a correlate to loosening. In principle, it also allows for the material characterization of the interface. A well-known analytical model for the superposition of sound waves reflected in a three-layer system was combined with a new method in data processing to be suitable for medical application at the bone-implant interface. By non-linear fitting of the theoretical prediction of the model to the actual shape of the reflected sound waves in the frequency domain, the thickness of the interlayer can be determined and predictions about its physical properties are possible. With respect to determining the layer's thickness, the presented approach was successfully applied to idealized test systems and a bone-implant system in the range of approx. 200 µm to 2 mm. After further optimization and adaptation, as well as further experimental tests, the procedure offers great potential to significantly improve the diagnosis of prosthesis loosening at an early stage and may also be applicable to detecting the formation of a biofilm.


The Biophysical Interaction of the Danger-Associated Molecular Pattern (DAMP) Calreticulin with the Pattern-Associated Molecular Pattern (PAMP) Lipopolysaccharide.
The endoplasmic reticulum (ER) chaperone protein, calreticulin (CRT), is essential for proper glycoprotein folding and maintaining cellular calcium homeostasis. During ER stress, CRT is overexpressed as part of the unfolded protein response (UPR). In addition, CRT can be released as a damage-associated molecular pattern (DAMP) molecule that may interact with pathogen-associated molecular patterns (PAMPs) during the innate immune response. One such PAMP is lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall. In this report, we show that recombinant and native human placental CRT strongly interacts with LPS in solution, solid phase, and the surface of gram-negative and gram-positive bacteria. Furthermore, LPS induces oilgomerization of CRT with a disappearance of the monomeric form. The application of recombinant CRT (rCRT) to size exclusion and anion exchange chromatography shows an atypical heterogeneous elution profile, indicating that LPS affects the conformation and ionic charge of CRT. Interestingly, LPS bound to CRT is detected in sera of bronchiectasis patients with chronic bacterial infections. By ELISA, rCRT dose-dependently bound to solid phase LPS via the N- and C-domain globular head region of CRT and the C-domain alone. The specific interaction of CRT with LPS may be important in PAMP innate immunity.


Application and usefulness of enzyme immunoassay for diagnosis of Salmonella typhimurium infection.
An enzyme immunoassay for serogroup specific immunological diagnosis of salmonella infections has been developed. Antigens representing salmonella O-antigens 4 (serogroup B) and 9 (serogroup D) were prepared by periodate oxidation of phenol-water extracted lipopolysaccharides from S. typhimurium and S. enteritidis respectively. Applied for seroepidemiological studies of S. typhimurium infections such chemically modified antigens showed a superior specificity compared to native lipopolysaccharides. The antibody titres against O-antigen 4 measured by the enzyme-linked immunosorbent assay (ELISA) were detectable during the second week and increased during the first 3--4 weeks of S. typhimurium infection. High titres persisted for at least 2--3 months and in some cases for more than 3 years. For reliable serodiagnosis a significant increase of the titre between acute and convalescent samples is necessary . Determination of ratio between IgG and IgM antibody titres against the pathogen may, however, be used on single serum samples to indicate whether the observed antibody titre is of recent or longstanding origin.


Dynamic Systems Approach in Sensorimotor Synchronization: Adaptation to Tempo Step-Change.
This paper presents a dynamic systems model of a sensorimotor synchronization (SMS) task. An SMS task typically gives temporally discrete human responses to some temporally discrete stimuli. Here, a dynamic systems modeling approach is applied after converting the discrete events to regularly sampled time signals. To collect data for model parameter fitting, a previously published pilot study was expanded. Three human participants took part in an experiment: to tap a finger on a keyboard, following a metronome which changed tempo in steps. System identification was used to estimate the transfer function that represented the relationship between the stimulus and the step response signals, assuming a separate linear, time-invariant system for each tempo step. Different versions of model complexity were investigated. As a minimum, a second-order linear system with delay, two poles, and one zero was needed to model the most important features of the tempo step response by humans, while an additional third pole could give a somewhat better fit to the response data. The modeling results revealed the behavior of the system in two distinct regimes: tempo steps below and above the conscious awareness of tempo change, i.e., around 12% of the base tempo. For the tempo steps above this value, model parameters were derived as linear functions of step size for the group of three participants. The results were interpreted in the light of known facts from other fields like SMS, psychoacoustics and behavioral neuroscience.


How RNA modifications regulate the antiviral response.
Induction of the antiviral innate immune response is highly regulated at the RNA level, particularly by RNA modifications. Recent discoveries have revealed how RNA modifications play key roles in cellular surveillance of nucleic acids and in controlling gene expression in response to viral infection. These modifications have emerged as being essential for a functional antiviral response and maintaining cellular homeostasis. In this review, we will highlight these and other discoveries that describe how the antiviral response is controlled by modifications to both viral and cellular RNA, focusing on how mRNA cap modifications, N6-methyladenosine, and RNA editing all contribute to coordinating an efficient response that properly controls viral infection.


Pharmacologic studies on anti-inflammatory activity of di- and triketopiperidine derivatives.
A number of derivatives of piperidine-2,4,6-trione and oxazine-2,4-dione with cyclohexyl and allyl substituents at their ring were evaluated pharmacologically. Piperidine-2,4,6-trione compounds, regardless of type of substituent, were readily absorbed from the site of their introduction and displayed similar biological activity. Introduction of the N-cyclohexylcarboxamide substituent diminished general toxicity of the derivative and increased anti-inflammatory activity in all tests. The oxazine-4,6-dione derivatives were poorly absorbed. The bis-(1-cyclohexyl-5,5-diallyl-piperidine-2,4,6-trione) derivative, product of condensation of two molecules of a simpler compound, was very well absorbed, strongly toxic, and showed distinct anti-inflammatory activity. Limited correlation between chemical structure and biological activity was noted, supporting the concept that introduction of cyclohexyl and allyl radicals imparts anti-inflammatory and immunosuppressive activity to derivatives of this type.


'Capital ideas' for health care in 2015.
Key factors in planning for healthcare financing in 2015 include: New rules related to municipal advisors. Long-term interest rates and the cost of traditional versus synthetic fixed-rate debt. Ways to use interest-rate swaps to take advantage of synthetic fixed-rate debt. Lesser-known structures that may make variable-rate financing advantageous.


Occurrence of pathogens in raw and ready-to-eat meat and poultry products collected from the retail marketplace in Edmonton, Alberta, Canada.
A total of 800 meat and poultry products were purchased from the retail marketplace in Edmonton, Alberta, Canada. The products consisted of raw ground beef, chicken legs, pork chops, and ready-to-eat fermented sausage, roast beef, processed turkey breast, chicken wieners, and beef wieners. The samples were analyzed to determine the prevalence of Shiga toxin-producing Escherichia coli, Salmonella, Campylobacter spp., and Listeria monocytogenes. Shiga toxin-producing E. coli 022: H8 was found in one raw ground beef sample. Salmonella and Campylobacter were found in 30 and 62% of raw chicken legs, respectively. L. monocytogenes was found in 52% of raw ground beef, 34% of raw chicken legs, 24% of raw pork chops, 4% of fermented sausages, 3% of processed turkey breast, 5% of beef wieners, and 3% of chicken wieners. The occurrence of pathogens in this study is similar to that in retail products in many other international locales.


Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer.
A patient-derived xenograft (PDX) approach, which relies on direct transplantation of tumor specimens into an immunocompromised animal, is a commonly used method for investigating tumor therapy predictions in vivo. This study evaluated influencing factors, including clinical, oncological, and genetic variables, for a pancreatic PDX model in mice. Tumor specimens were obtained from 121 patients with pancreatic ductal adenocarcinoma who underwent surgical resection at the Changhai Pancreatic Surgery Medical Center (Shanghai, China) between April 2016 and February 2017. Pancreatic cancer (PC) samples <3 mm3 were subcutaneously implanted into the NOD/Shi-scid/IL-2Rγnull (NSG) mice. Once the xenograft reached 300-500 mm3 or reached 180 d after cell inoculation, the tumor was excised. Part of the tumor was subsequently transplanted to next-generation mice, and another part was analyzed by using immunohistochemistry. Among the 121 patients with PC, tumor xenograft was successfully generated in 86 patients (71.1%). Primary tumor >3.5 cm in size was independently associated with xenograft formation rate. In addition, several enriched mutated genes within the VEGF pathway and higher microvessel density were found in the positive group (with xenograft) compared with the negative group (without xenograft). We concluded that tumor size and mutated VEGF pathway in PC are important factors affecting PDX model construction with NSG mice.-Guo, S., Gao, S., Liu, R., Shen, J., Shi, X., Bai, S., Wang, H., Zheng, K., Shao, Z., Liang, C., Peng, S., Jin, G. Oncological and genetic factors impacting PDX model construction with NSG mice in pancreatic cancer.


'I can do the child no good': Dr Sims and the enslaved infants of Montgomery, Alabama.
This article examines the influence of slavery and race on medical education, practice and research in the American South. Drawing on the published autobiography, case-histories, and correspondence of American slave surgeon and 'pioneer' gynaecologist, James Marion Sims, the contribution highlights a lesser known episode from his early career, namely his surgical treatment of enslaved infants suffering from trismus nascentium (neonatal tetanus). Sims became a highly prestigious figure in his later medical career, but the foundations of his success relied on the use of slave bodies and enslaved patients. These were typically distinctive features of the life of an ambitious medical professional in the slave South, where the profession profited from the institution of slavery, and human experimentation and medical research were advanced specifically through the exploitation of the region's enslaved population.


Prophylactic treatment of asthma by an ozone scavenger in a mouse model.
Our hypothesis that inflammation in asthma involves production of ozone by white blood cells and that ozone could be an inflammatory mediator suggests that scavengers of reactive oxygen species (ROS), for example, electron-rich olefins, could serve for prophylactic treatment of asthma. Olefins could provide chemical protection against either exogenous or endogenous ozone and other ROS. BALB/c mice pretreated by inhalation of d-limonene before an ovalbumin challenge exhibited significant attenuation of the allergic asthma symptoms. Diminution of the inflammatory process was evident by reduced levels of aldehydes, reduced counts of neutrophils in the BAL fluid and by histological tests. A surprising systemic effect was observed by decreased levels of aldehydes in the spleen, suggesting that the examination of tissues and organs that are remote from the inflammation foci could provide valuable information on the distribution of the oxidative stress and may serve as guide for targeted treatment.


Investigating the Opposing Effect of Two Different Green Tea Supplements on Oxidative Stress, Mitochondrial Function and Cell Viability in HepG2 Cells.
Green tea extract (GTE) improves exercise outcomes and reduces obesity. However, case studies indicate contradictory physiology regarding liver function and toxicity. We studied the effect of two different decaffeinated GTE (dGTE) products, from a non-commercial (dGTE1) and commercial (dGTE2) supplier, on hepatocyte function using the human cell model, HepG2. dGTE1 was protective against hydrogen peroxide (H2O2)-induced apoptosis and cell death by attenuating oxidative stress pathways. Conversely, dGTE2 increased cellular and mitochondrial oxidative stress and apoptosis. A bioavailability study with dGTE showed the major catechin in GTE, EGCG, reached 0.263 µg·ml-1. In vitro, at this concentration, EGCG mimicked the protective effect of dGTE1. GC/MS analysis identified steric acid and higher levels of palmitic acid in dGTE2 versus dGTE1 supplements. We demonstrate the significant biological differences between two GTE supplements which may have potential implications for manufacturers and consumers to be aware of the biological effects of supplementation.


Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes.
Pemphigoid (Pg) diseases are a group of potentially fatal autoimmune mucocutaneous diseases. They have different clinical phenotypes, involving only the skin or multiple mucous membranes. They occur globally and frequently affect the elderly. The common marker among all variants is the presence of autoantibodies targeting the dermal-epidermal or mucosal-submucosal junctions, or basement membrane zone (BMZ). Four target antigens in the BMZ were studied. These included BPAG1, BPAG2 and subunits of α6 and β4 human integrins. Our objective was to find a molecular basis for the global incidence of Pg diseases and a mechanism that will explain the vast differences in clinical phenotypes and outcomes. All the variants of Pg that were analyzed had a statistically significant association with HLA-DQβ1*03:01 in ten countries on four continents. This explains the reason for global incidence. Prediction models discovered multiple peptides in each of the four antigens that serve as T cell epitopes. These T cell epitopes were shown to bind to HLA-DQβ1*03:01. In addition, structure modelling demonstrated the peptide-HLA complex bound to the T cell receptor. These autoreactive T cells would stimulate B cells to produce specific anti-BMZ autoantibodies. Anti-BMZ autoantibodies with different specificities will produce different phenotypes, which will account for involvement of different tissues and organs in different molecules. The contribution this study makes is that it provides a molecular basis of why a similar disease occurs in different racial groups. Furthermore, it provides the basis for the production of autoantibodies with different specificities, which resultantly produces different phenotypes.


Coexistence of Low Damping and Strong Magnetoelastic Coupling in Epitaxial Spinel Ferrite Thin Films.
Low-loss magnetization dynamics and strong magnetoelastic coupling are generally mutually exclusive properties due to opposing dependencies on spin-orbit interactions. So far, the lack of low-damping, magnetostrictive ferrite films has hindered the development of power-efficient magnetoelectric and acoustic spintronic devices. Here, magnetically soft epitaxial spinel NiZnAl-ferrite thin films with an unusually low Gilbert damping parameter (<3 × 10-3 ), as well as strong magnetoelastic coupling evidenced by a giant strain-induced anisotropy field (≈1 T) and a sizable magnetostriction coefficient (≈10 ppm), are reported. This exceptional combination of low intrinsic damping and substantial magnetostriction arises from the cation chemistry of NiZnAl-ferrite. At the same time, the coherently strained film structure suppresses extrinsic damping, enables soft magnetic behavior, and generates large easy-plane magnetoelastic anisotropy. These findings provide a foundation for a new class of low-loss, magnetoelastic thin film materials that are promising for spin-mechanical devices.


Ultrasound Guidance Superiority in Pediatric Sialorrhea Treatment With Intraglandular Botulinum Toxin Application: A Four-Year Retrospective Study.
Introduction The management of sialorrhea in children with multiple disabilities is extremely important not only for aesthetic/psychosocial reasons but also for functional and clinical ones. There are several recommended management methods with strong evidence of the effectiveness of intraglandular application of botulinum toxin A. Materials and methods In this four-year retrospective report, we compare two populations who received intraglandular type A botulinum toxin injections in the pediatric unit of the Physical Medicine and Rehabilitation (PM&R) Department at a central hospital. The injections were administered using either ultrasound guidance (US) or anatomical landmarks. Results Out of a total of 29 patients with neurological conditions, 16 met the eligibility criteria for this study. The study group comprised seven females (44%) and nine males (56%), with a median age of 9 years. The average pre-procedure sialorrhea staging was four. A total of 23 procedures were performed, with 16 conducted under ultrasound guidance (US) and seven via anatomical landmarks (non-US). In the US group, a statistically significant difference in sialorrhea staging was observed at one and three months post-procedure (p<0.05), but not at six months post-procedure. Conversely, no statistically significant difference in sialorrhea staging was found at any time point in the non-US group. The comparison between the two groups supports the use of ultrasound guidance, showing superior outcomes at one and three months post-procedure (p<0.05). Conclusion The results of this study align with global trends seen in medical publications and guidelines advocating for the use of ultrasound in this procedure. Future prospective and larger-scale studies are essential to validate these findings.


Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse.
Since transitional cell carcinoma (TCC) of the upper urinary tract is a relatively uncommon malignancy, the role of adjuvant radiotherapy is unknown. We treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008. The 67 patients who received external beam radiotherapy (EBRT) following surgery were assigned to the radiation group (RT). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy. The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT). The overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198). However, there was a significant difference between the survival rates for these groups based on patients with T3/T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated and non-irradiated bladder groups (p = 0.004). Multivariate analysis indicated that improved overall survival was associated with age < 60 years, T1 or T2 stage, absence of synchronous LN metastases, and EBRT. Acute gastrointestinal and bladder reactions were the most common symptoms, but mild non-severe (> grade 3) hematologic symptoms also occurred. EBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and delay bladder tumour recurrence in all patients.


Genetic polymorphism of high-molecular-weight glutenin subunit loci in bread wheat varieties in the Pre-Ural steppe zone.
High-molecular-weight glutenins play an important role in providing high baking qualities of bread wheat grain. However, breeding bread wheat for this trait is very laborious and, therefore, the genotyping of variety samples according to the allelic composition of high-molecular-weight glutenin genes is of great interest. The aim of the study was to determine the composition of high-molecular-weight glutenin subunits based on the identification of the allelic composition of the Glu-1 genes, as well as to identify the frequency of the Glu-1 alleles in bread wheat cultivars that are in breeding work under the conditions of the Pre-Ural steppe zone (PSZ). We analyzed 26 winter and 22 spring bread wheat varieties from the PSZ and 27 winter and 20 spring varieties from the VIR collection. Genotyping at the Glu-A1 locus showed that the Ax1 subunits are most common in winter varieties, while the predominance of the Ax2* subunits was typical of spring varieties and lines. In the Glu-B1 locus, the predominance of alleles associated with the production of the Bx7 and By9 subunits was revealed for both winter and spring varieties. In the case of the Glu-D1 gene, for all the wheat groups studied, the composition of the Dx5+Dy10 subunits was the most common: in 92.3 % of winter and 68.2 % of spring PSZ accessions and in 80 % of winter and 55 % of spring VIR accessions. The analysis of genotypes showed the presence of 13 different allelic combinations of the Glu-A1, Glu-B1, Glu-D1 genes in the PSZ varieties, and 19 combinations in the VIR varieties. The b b/al/с d allelic combination (Ax2* Вх7+Ву8/8*/9 Dx5+Dy10) turned out to be the most common for the PSZ spring varieties and lines, while for the PSZ winter accessions it was a с d (Ax1 Вх7+By9 Dx5+Dy10); the b с a and b с d genotypes (Ax2* Вх7+Ву9 Dx2+Dy12 and Ax2* Вх7+Ву9 Dx5+Dy10, respectively) occur with equal frequency among the VIR spring accessions; in the group of VIR winter varieties, the combination of the a b/ al d alleles (Ax1 Вх7+Ву8/8* Dx5+Dy10) prevails. The most preferred combination of alleles for baking qualities was found in the spring variety 'Ekaterina' and winter varieties 'Tarasovskaya 97', 'Volzhskaya S3', as well as in lines k-58164, L43510, L43709, L-67, L-83, which are recommended for further breeding programs to improve and preserve baking qualities in the conditions of the Pre-Ural steppe zone.


Spin-spiral states in undoped manganites: role of finite Hund's rule coupling.
The experimental observation of multiferroic behavior in perovskite manganites with a spiral spin structure requires a clarification of the origin of these magnetic states and their relation to ferroelectricity. We show that spin-spiral phases with a diagonal wave vector and also an E-type phase exist for intermediate value of Hund's rule and the Jahn-Teller coupling in the orbitally ordered and insulating state of the standard two-band model Hamiltonian for manganites. Our results support the spin-current mechanism for ferroelectricity and present an alternative view to earlier conclusions where frustrating superexchange couplings were crucial to obtaining spin-spiral states.


Carbohydrate digestion and absorption in the equine small intestine.
Dietary carbohydrates, which constitute a most important source of equine nutrition, are digested and absorbed by a series of complex processes principally in the small intestine, beginning with intraluminal starch hydrolysis by the action of pancreatic amylase. The continuous secretion of a copious volume of pancreatic juice, low in enzyme activity, presumably releases sufficient oligosaccharides for further hydrolysis at the intestinal cell surface by brush border enzymes. Active carrier mediated mechanisms then transport the final hexose products across the intestinal cell for uptake in the hepatic portal system. Brush border disaccharidase activities in the equine small intestine are of the same order of magnitude, and have a similar distribution pattern, to those reported in omnivorous and carnivorous species. The disaccharidase development patterns are characteristic and reflect the ability of the horse to digest the major nutrient sources adequately at various stages of life. The efficiency of the mucosal disaccharidases and the monosaccharide transport systems in the equine small intestine have been established by a series of oral disaccharide and monosaccharide tolerance tests. Horses older than three years of age are unable to hydrolyse lactose, but young and adult horses are fully capable of rapidly hydrolysing sucrose and maltose loads. Several tests have clinical application for assessing small intestinal dysfunction in the investigation of diarrhoea and malabsorption. The deficient digestion or absorption of carbohydrate, whether primary or secondary, can almost always be localized to a defect in the enzymic or transport capacity of the small intestinal surface cell. The continued ingestion of lactose could be detrimental in severely diarrhoeic foals.


Synthesis and Photobiological Activity of Ru(II) Dyads Derived from Pyrrole-2-carboxylate Thionoesters.
The synthesis and characterization of a series of heteroleptic ruthenium(II) dyads derived from pyrrole-2-carboxylate thionoesters are reported. Ligands bearing a conjugated thiocarbonyl group were found to be more reactive toward Ru(II) complexation compared to analogous all-oxygen pyrrole-2-carboxylate esters, and salient features of the resulting complexes were determined using X-ray crystallography, electronic absorption, and NMR spectroscopy. Selected complexes were evaluated for their potential in photobiological applications, whereupon all compounds demonstrated in vitro photodynamic therapy effects in HL-60 and SK-MEL-28 cells, with low nanomolar activities observed, and exhibited some of the largest photocytotoxicity indices to date (>2000). Importantly, the Ru(II) dyads could be activated by relatively soft doses of visible (100 J cm-2, 29 mW cm-2) or red light (100 J cm-2, 34 mW cm-2), which is compatible with therapeutic applications. Some compounds even demonstrated up to five-fold selectivity for malignant cells over noncancerous cells. These complexes were also shown to photocleave, and in some cases unwind, DNA in cell-free experiments. Thus, this new class of Ru(II) dyads has the capacity to interact with and damage biological macromolecules in the cell, making them attractive agents for photodynamic therapy.


[Thrombosis of intracraneal sinuses in homocystinuria (author's transl)].
The case of a child affected with piridoxinresistant homocystinuria who developed early on the disease an aseptic thrombosis of intracraneal sinuses, of chronic evolution is presented. Pathogenesis and therapy of the thrombosis are discussed emphasizing the value of measures directed to avoid the aggregation of platelets.


Mean lung pressure during adult high-frequency oscillatory ventilation: an experimental study using a lung model.
In adult high-frequency oscillatory ventilation (HFOV), stroke volume (SV) and mean lung pressure (PLung) are important for lung protection. We measured the airway pressure at the Y-piece and the lung pressure during HFOV using a lung model and HFOV ventilators for adults (R100 and 3100B). The lung model was made of a 20-liter, airtight rigid plastic container (adiabatic compliance: 19.3 ml/cmH2O) with or without a resistor (20 cmH2O/l/sec). The ventilator settings were as follows: mean airway pressure (MAP), 30 cmH2O; frequency, 5-15 Hz (every 1 Hz); airway pressure amplitude (AMP), maximum;and % of inspiratory time (IT), 50% for R100, 33% or 50% for 3100B. The measurements were also performed with an AMP of 2/3 or 1/3 maximum at 5, 10 and 15 Hz. The PLung and the measured MAP were not consistently identical to the setting MAP in either ventilator, and decreasing IT decreased the PLung in 3100B. In conclusion, we must pay attention to the possible discrepancy between the PLung and the setting MAP during adult HFOV.


[The prophylactic oophorectomy. An unsolved problem].
The ovarian cancer is the second cancer of the female genital organs and it is the first cause of death for gynecological oncology and the sixth cause of death in women. Prevention and early detection may reduce the mortality of ovarian cancer. Potential screening tests include pelvic exams, sonography and tumor markers measurements, although they do not guarantee a positive effect on the survival rate. In the last century, the role of prophylactic oophorectomy during benign pelvic operation has been discussed. The choice of this preventive measure raises the question of the advantages and disadvantages that a surgical menopause could cause. Finally, the role of laparoscopy in the performance of the oophorectomy versus the vaginal approach is discussed.


Enhancing mHealth Technology in the Patient-Centered Medical Home Environment to Activate Patients With Type 2 Diabetes: A Multisite Feasibility Study Protocol.
The potential of mHealth technologies in the care of patients with diabetes and other chronic conditions has captured the attention of clinicians and researchers. Efforts to date have incorporated a variety of tools and techniques, including Web-based portals, short message service (SMS) text messaging, remote collection of biometric data, electronic coaching, electronic-based health education, secure email communication between visits, and electronic collection of lifestyle and quality-of-life surveys. Each of these tools, used alone or in combination, have demonstrated varying degrees of effectiveness. Some of the more promising results have been demonstrated using regular collection of biometric devices, SMS text messaging, secure email communication with clinical teams, and regular reporting of quality-of-life variables. In this study, we seek to incorporate several of the most promising mHealth capabilities in a patient-centered medical home (PCMH) workflow. We aim to address underlying technology needs and gaps related to the use of mHealth technology and the activation of patients living with type 2 diabetes. Stated differently, we enable supporting technologies while seeking to influence patient activation and self-care activities. This is a multisite phased study, conducted within the US Military Health System, that includes a user-centered design phase and a PCMH-based feasibility trial. In phase 1, we will assess both patient and provider preferences regarding the enhancement of the enabling technology capabilities for type 2 diabetes chronic care management. Phase 2 research will be a single-blinded 12-month feasibility study that incorporates randomization principles. Phase 2 research will seek to improve patient activation and self-care activities through the use of the Mobile Health Care Environment with tailored behavioral messaging. The primary outcome measure is the Patient Activation Measure scores. Secondary outcome measures are Summary of Diabetes Self-care Activities Measure scores, clinical measures, comorbid conditions, health services resource consumption, and technology system usage statistics. We have completed phase 1 data collection. Formal analysis of phase 1 data has not been completed. We have obtained institutional review board approval and began phase 1 research in late fall 2016. The study hypotheses suggest that patients can, and will, improve their activation in chronic care management. Improved activation should translate into improved diabetes self-care. Expected benefits of this research to the scientific community and health care services include improved understanding of how to leverage mHealth technology to activate patients living with type 2 diabetes in self-management behaviors. The research will shed light on implementation strategies in integrating mHealth into the clinical workflow of the PCMH setting. ClinicalTrials.gov NCT02949037. https://clinicaltrials.gov/ct2/show/NCT02949037. (Archived by WebCite at http://www.webcitation.org/6oRyDzqei).


Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis.
The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.


JNK/MAPK pathway regulation by BEX2 gene silencing in alcoholic hepatitis mice: Effects on oxidative stress.
Alcoholic hepatitis (AH) is a severe alcoholic-related liver disease that is a leading cause of morbidity and mortality, for which effective treatments are lacking. Brain-expressed X-linked gene 2 (BEX2) has been implicated in various diseases, but its association with AH has received limited attention. Thus, this study investigated BEX2's impact on the progression of AH by affecting the c-Jun NH2-terminal kinase/mitogen-activated protein kinase (JNK/MAPK) pathway. Microarray dataset GSE28619 from the Gene Expression Omnibus database was used to identify differentially expressed genes in AH. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), Western blot analysis, and flow cytometry were used to measure various factors in the liver tissue of AH mice. BEX2 expression was significantly upregulated in the model. BEX2 gene silencing increased the levels of glutathione peroxidase and superoxide dismutase while decreasing malondialdehyde content; phosphorylation of JNK, c-JUN, and p38MAPK; apoptosis rate; and the extent of JNK/MAPK pathway activation. These findings provide valuable insights into the mechanisms underlying AH development and highlight the potential role of BEX2 gene expression as a promising therapeutic target for AH.


[Law and educational components of patient's safety in surgery].
To evaluate law and educational components of patient's safety (PS) in surgery. In order to analyze complex causes of adverse outcomes in surgery we performed an interviewing of 110 surgeons, 42 emergency physicians and 25 health care managers. The main keynote consisted in assessing law and educational components of PS. The study revealed significant professional shortcomings in law PS level and low educational and motivational activity of physicians of all specialties. Multi-faceted nature of PS problem requires multidisciplinary training of modern surgeons not only in the knowledge of key risk factors for adverse outcomes, but also in satisfaction of non-medical expectations of patients. Due to numerous objective reasons Russian surgical school should have the opportunity not to blindly copy the experience of our foreign colleagues, but to scientifically substantiate the development of own national security system both for surgical patients and medical workers themselves.


Effects of random motion in traveling and grazing herds.
We examine the role that randomness or noise in individual motion may play in forming effective grazing strategies for herd members as they collectively move toward a destination. Through a model where animals are attracted to Voronoi neighbors as well as a destination endpoint, we show that including a significant random motion component can speed up the movement of a herd toward this destination, increase the efficiency that food is acquired during the travel, and facilitate a natural herd shape that mitigates predation risk. Specifically, if the influence of the Voronoi neighbors on individual motion is equal to the pull toward the destination, we find that optimal travel time and food consumption efficiency occurs for noise approximately twice as strong as the influence of herd members to each other, in a range of herd sizes from 10 to 100. We find that reducing the destination influence lowers this optimal noise only slightly, with random motion still exceeding the influence of neighbors. For a destination influence exceeding that of the Voronoi neighbors, an additional travel mode appears with minimal noise and aligned velocities in which the herd marches directly toward the endpoint. Our results are consistent with observational evidence of random motion in several animal groups, and motivate its generalization to traveling and grazing herds.


[Percutaneous balloon dilatation of pulmonary valve stenosis].
Balloon valvuloplasty was carried out on five children with isolated valvular pulmonary stenosis. One child had a residual stenosis following a Brock's transventricular valvotomy. The systolic gradient between the right ventricle and the pulmonary artery fell from 60.4 +/- 18.7 mmHg to 21.8 +/- 12.0 mmHg. Right ventricular pressure fell from 76.2 +/- 20.7 mmHg to 43.0 +/- 16.4 mmHg. Percutaneous balloon valvuloplasty has proved to be an effective method for the treatment of isolated valvular pulmonary stenosis.


A randomized pilot trial of brief family-involved treatment for alcohol use disorder: Treatment engagement and outcomes.
Involving family members in a patient's treatment for alcohol use disorder (AUD) leads to more positive outcomes, but evidence-based family-involved treatments have not been adopted widely in AUD treatment programs. Study aims the following: (a) modify an empirically supported 12-session AUD treatment, alcohol behavioral couple therapy (ABCT) to make it shorter and appropriate for any concerned family member and (b) conduct a small clinical trial to obtain feasibility data and effect size estimates of treatment efficacy. ABCT content was adapted to three-sessions following input from clinicians, patients, and family members. Patient and family member dyads were recruited from an inpatient treatment program and randomized to the new treatment, brief family-involved treatment (B-FIT), or treatment-as-usual (TAU). Drinking was assessed using the Form-90; family support and family functioning were assessed using the Family Environment Scale Conflict and Cohesion subscales and the Family Adaptability and Cohesion Evaluation Scale-IV, Communication scale. Dyads (n = 35) were assessed at baseline and 4-month follow-up. On average, dyads received one of three B-FIT sessions with 6 dyads receiving no sessions due to scheduling conflicts or patient discharge. At follow-up, there was a large-to-medium effect size estimate favoring B-FIT for proportion drinking days (patient report, n = 22; Hedges' g = 1.01; patient or family report, n = 28; Hedges' g = .48). Results for family support or family functioning measures favored TAU. Implementation of brief family-involved treatment in inpatient AUD treatment was challenging, but preliminary data suggest the potential value of B-FIT in impacting drinking outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Loss of Gspt1l disturbs the patterning of the brain central arteries in zebrafish.
The cranial vasculature is crucial for the survival and development of the central nervous system and is closely related to brain pathologies. Characterizations of the underlying mechanisms by which cranial vessels acquire their stereotypic patterning remain to be the key interest in the cerebrovascular research. In this report, we show an interesting zebrafish cq37 mutant displaying aberrant patterning of the central arteries. Genetic mapping results indicate that the gene responsible for cq37 encodes G1 to S phase transition 1, like (Gspt1l) with a nonsense mutation. Complementation studies with a CRISPR-generated allele, as well as mRNA rescues, together strongly demonstrate that gspt1l is the cq37 gene. Zebrafish gspt1l is broadly expressed in the brain with enhanced expression in hindbrain during central artery sprouting. Further studies reveal that vascular endothelial growth factor (VEGF) signaling and unfolded protein response (UPR) pathway are activated in gspt1lcq37 mutants. In addition, expression analysis shows that vegfa and activating transcription factor-4 (atf4) are strongly upregulated in regions of gspt1l expression. Our results suggest that loss of Gspt1l activates the UPR pathway, which in turn induces ectopic expression of vegfa via Atf4, thus disturbing the patterning of the central arteries.


[Myoclonus as a side effect to citalopram treatment in a patient with liver cirrhosis].
Side effects such as myoclonus and tremor are rare when treating with selective serotonin reuptake inhibitors (SSRIs). We present a case where a patient with known liver cirrho-sis and in treatment with citalopram developed myoclonus, tremor and gait difficulties. The symptoms were reduced when the SSRI dose was decreased. In patients with unexplained movement disorders the usage of SSRIs should be considered as a cause. Furthermore, treatment with SSRIs should be carefully assessed in patients with reduced liver function.


Accidental detection of a giant right atrial aneurysm in an asymptomatic infant.
We present a 4-month old infant boy accidentally detected to have cardiomegaly on a chest radiograph, and on further investigation discovered to have a giant right atrial aneurysm and a secundum atrial septal defect. Congenital right atrial aneurysm or diverticulum is a rare anomaly, usually presenting with atrial or supraventricular tachycardia. Previously reported patients did not have any associated congenital heart defect. Although asymptomatic our patient needs close follow-up, and surgical resettion of the aneurysm and closure of the atrial septal defect in view of potential complications.


Coronary CT Angiography for In-Stent Restenosis: Diagnosis and Therapeutic Planning.
A 64-year-old man presented with previous non-ST elevation myocardial infarction and cardiogenic shock. Due to hemodynamic instability, percutaneous coronary intervention (PCI) was performed with implantation of two everolimus-eluting stents by V-stenting technique to LM-LAD and LM-LCX. After 9 months without symptoms, he developed progressive angina. Non-selective LM coronary angiography was performed due to stents protrusion in the aortic root. A 128-slice dual-source coronary CT angiography showed severe LM-LAD stent underexpansion with critical in-stent restenosis at the proximal third. Two days later, selective angiography and optical coherence tomography depicted stent underexpansion and confirmed the in-stent restenosis. This case is illustrative of the potential role of the complementary use of invasive and non-invasive imaging techniques. The coronary CT angiography was very useful to identify the severity and mechanism of restenosis, and thus guiding the PCI procedure in a case of especially difficult catheterization.


An update on multiple sclerosis in children: diagnosis, therapies, and prospects for the future.
Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, is increasingly being recognized in children and adolescents. Pediatric MS follows a relapsing-remitting course at onset, with a risk for early cognitive impairment. Areas covered: In this review, we discuss the clinical features of acute demyelinating syndromes in children and risk factors that increase the likelihood of a diagnosis of MS. We also address the application of diagnostic criteria for MS in children, immunological features, therapeutic options and psychosocial considerations for children and adolescents with MS. Expert commentary: Collaborative multicenter clinical trials and research efforts are key to the advancement in understanding the pathophysiology and therapeutic strategies for multiple sclerosis across the lifespan.


Effect of Surface Treatment with CO2 Laser on Bond Strength in Composite Resin Restorations.
Objective: Evaluate the bond strength of repairs made on composite resin following the treatment of the surface of the flaw with different bonding agents and/or CO2 laser. Background: The influence of CO2 laser and its interaction with other bonding agents on the surface of the flaw is not yet known. In this study, CO2 laser was chosen to treat the surface of the flaw due to its capacity to promote irregularities on the surface that enhance mechanical micro-retention. Methods: A block was created with Vitra APS nanohybrid composite resin (color: A3; FGM, Joinville, Brazil) measuring 5 mm in width, length, and depth (volume: 125 mm3). The surface of the flaw was treated before the repair with an adhesive, silane bonding agent, and/or CO2 laser. Six specimens were created in composite resin for each group (total: n = 36): G1: resin+resin; G2: adhesive+resin; G3: laser+adhesive; G4: laser+silane+adhesive; G5: silane+adhesive; G6: laser+silane. After the repair, the surfaces of the fracture of all specimens, which were submitted to the microtraction test, were analyzed under an optical microscope. Bond strength values obtained according to the type of surface treatment were tabulated and submitted to the Kruskal-Wallis test. Dunn's test was used to compare means. Results: G3 and G4 had significantly higher bond strength values compared to all other groups tested. Adhesive fractures predominated in all groups. However, G3 and G4 had a higher percentage of cohesive fractures compared to the other groups. Conclusions: The application of CO2 laser as a surface treatment led to greater bond strength of composite resin repairs in comparison with the groups that only received treatment with a burr and silanization. The groups submitted to CO2 laser also had a significantly lower number of adhesive failures when submitted to the microtraction test.


Latency of pupillary reflex dilation during general anesthesia.
Areas of insensibility produced by neuraxial anesthesia or peripheral nerve blocks can be detected during general anesthesia by failure of noxious stimulation to trigger pupillary reflex dilation. We examined the latency of pupillary reflex dilation and the effect of fentanyl on the latency of reflex dilation during anesthesia in nine volunteers. We hypothesized that the reflex was generated by slowly conducting C nociceptive fibers and would be significantly delayed if a distal dermatome (L(4)) was stimulated compared with a proximal dermatome (C(5)). We also hypothesized that fentanyl would prolong the latency and alter the shape of the reflex. After induction of general anesthesia, pupillary reflex dilation was measured with an infrared pupillometer every 5 min after stimulations of the L(4) and C(5) dermatomes. Fentanyl (3 microg/kg) was then given intravenously. Pupillary reflex dilation latencies were calculated by examining each individual measurement. After 3 h, naloxone (400 microg) was given intravenously; anesthesia was then discontinued. Pupillary reflex dilation had a long latency and consisted of distinct early and late phases. No differences were found between latencies of reflex dilation after simulation of L(4) and C(5) dermatomes either before or after fentanyl administration. Fentanyl at high concentrations essentially eliminated pupillary reflex dilation; but over the 180-min observation period, first early and then late dilation returned. Fentanyl produced a small increase in the latency of the initial early dilation. We conclude that pupillary reflex dilation during anesthesia is not initiated by slowly conducting C fibers and that fentanyl depresses the reflex in a stereotypical manner.


Safety and adverse effects of the coronavirus disease 2019 vaccine among the general Japanese adult population.
We aimed to identify and explore the association between the characteristics of coronavirus disease 2019 (COVID-19) vaccine recipients and the types of vaccine-related adverse effects in the general Japanese adult population. An anonymous self-report questionnaire was distributed to 4393 students and 1657 white and blue-collar workers (N = 6050). Data on vaccine-related adverse effects were collected twice, once after each vaccination. The data collection was performed daily from the day of injection (D0) until the sixth day after injection (D6). The list of adverse effects comprised local reactions at the injection site (pain, redness, and swelling) and systemic symptoms (fever, fatigue, headache, myalgia, joint pain, chills, and nausea or vomiting). The Student's t-test and Mann-Whitney U test were used to analyze parametric and non-parametric data, respectively. The incidence of adverse reactions to the COVID-19 vaccination was higher after the second dose (e.g., redness: 47.1%; swelling: 60.6%; fever: 80.6%) of vaccination than after the first dose (e.g., redness: 16.4%; swelling: 37.2%; fever: 11.9%). Women reported adverse reactions to the vaccination more frequently. Some adverse reactions included more symptoms in younger participants, and participants with a lower body mass index were more at risk for these symptoms. Some adverse reactions to the COVID-19 vaccination are a greater risk of symptoms in the younger group, women, and participants with lower BMI. Care should be taken to monitor women, younger people, and individuals with a low body mass index for adverse effects after receiving the COVID-19 vaccination.


The influence of progestins on receptor levels in breast cancer metastasis.
The influence of oral high-dose (HD) medroxyprogesterone acetate (MPA) and megestrol acetate (MA) treatment on steroid hormone receptor levels in metastatic breast tumor tissue was investigated. In ten postmenopausal women with advanced breast cancer, receptor biopsies were obtained from the same tumor before the start, and one and eight weeks after the start of oral HD progestin treatment. Endocrine treatment had been stopped in all patients at least five weeks before the start of progestin treatment. Estradiol receptor (ER) levels were reduced by 26.9% and 20.0% respectively after one and eight weeks of treatment. Progesterone receptors (PgR) were significantly reduced to undetectable levels, possibly due to MPA and MA binding to PgR. A stepwise decrease in androgen receptors (AR) was observed, indicating that the two progestins (MPA and MA) may also act through AR, and/or interfere with the replenishment of AR.


Giardia duodenalis and Cryptosporidium spp. in the intestinal contents of ringed seals (Phoca hispida) and bearded seals (Erignathus barbatus) in Nunavik, Quebec, Canada.
The prevalence of Giardia duodenalis and Cryptosporidium spp. was determined for ringed and bearded seals harvested for food in the Nunavik region in northern Quebec, Canada. Flow cytometric results demonstrated that G. duodenalis was present in the intestinal contents of 80% of the ringed seals and 75% of the bearded seals tested, while Cryptosporidium spp. were present in 9% of the ringed seals and none of the bearded seals. Prevalence of both parasites was highest in animals less than 1 yr of age. Giardia sp. isolates from ringed seals were identified as G. duodenalis Assemblage B, which is commonly identified in human infections. The high prevalence of G. duodenalis in ringed seals, and the presence of Assemblage B in these animals, highlights the potential for zoonotic transmission to the Inuit people, who consume dried seal intestines and uncooked seal meat.


Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction.
Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and maximizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment, such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea: barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD analysis uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information regarding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials.


Separation and analysis of pig pancreatic zymogen granules with free flow electrophoresis and lectins.
Purified pig pancreatic zymogen granules were subjected to free flow electrophoresis (FFE) in an acetate buffer system (acetic acid/NaOH, pH 5.5) to detect the presence or absence of more than one population or zymogen granules. Pig pancreatic zymogen granules were purified by differential and density gradient centrifugation and subjected to FFE. Fractions were analyzed for protein, alpha-amylase (EC 126.96.36.199) and 5'-nucleotidase (EC 220.127.116.11) as marker enzymes for zymogen granule content and membranes, respectively. Only one distinct peak, with coincident alpha-amylase and 5'-nucleotidase activity, and most protein was detected, which reflects the presence of a single population of intact zymogen granules. This was confirmed by electron microscopy. When the granules were incubated with different lectins before FFE, the one distinct peak representing intact zymogen granules was shifted towards the cathode in the case of concanavalin A (Con A) and Ricinus communis agglutinin 120 (RCA 120). No splitting of the peak occurred. Our results do not support the hypothesis of a coexistence of more than one distinct population of zymogen granules.


Chemical Emissions From Heated Vitamin E Acetate-Insights to Respiratory Risks From Electronic Cigarette Liquid Oil Diluents Used in the Aerosolization of Δ9-THC-Containing Products.
As of February 18, 2020, the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak caused the hospitalization of a total of 2,807 patients and claimed 68 lives in the United States. Though investigations have reported a strong association with vitamin E acetate (VEA), evidence from reported EVALI cases is not sufficient to rule out the contribution of other chemicals of concern, including chemicals in either THC or non-THC products. This study characterized chemicals evolved when diluent oils were heated to temperatures that mimic e-cigarette, or vaping, products (EVPs) to investigate production of potentially toxic chemicals that might have caused lung injury. VEA, vitamin E, coconut, and medium chain triglyceride (MCT) oil were each diluted with ethanol and then tested for constituents and impurities using a gas chromatograph mass spectrometer (GC/MS). Undiluted oils were heated at 25°C (control), 150°C, and 250°C in an inert chamber to mimic a range of temperatures indicative of aerosolization from EVPs. Volatilized chemicals were collected using thermal desorption tubes, analyzed using a GC/MS, and identified. Presence of identified chemicals was confirmed using retention time and ion spectra matching with analytic standards. Direct analysis of oils, as received, revealed that VEA and vitamin E were the main constituents of their oils, and coconut and MCT oils were nearly identical having two main constituents: glycerol tricaprylate and 2-(decanoyloxy) propane-1,3-diyl dioctanoate. More chemicals were measured and with greater intensities when diluent oils were heated at 250°C compared to 150°C and 25°C. Vitamin E and coconut/MCT oils produced different chemical emissions. The presence of some identified chemicals is of potential health consequence because many are known respiratory irritants and acute respiratory toxins. Exposure to a mixture of hazardous chemicals may be relevant to the development or exacerbation of EVALI, especially when in concert with physical damage caused by lung deposition of aerosols produced by aerosolizing diluent oils.


Two mutations in extracellular loop 2 of the human GnRH receptor convert an antagonist to an agonist.
GnRH regulates the reproductive system through cognate G protein-coupled receptors in vertebrates. Certain GnRH analogs that are antagonists at mammalian receptors behave as agonists at Xenopus laevis and chicken receptors. This phenomenon provides the opportunity to elucidate interactions and the mechanism underlying receptor activation. A D-Lys(iPr) in position 6 of the mammalian GnRH receptor antagonist is required for this agonist activity (inositol phosphate production) in the chicken and X. laevis GnRH receptors. Chimeric receptors, in which extracellular loop domains of the human GnRH receptor were substituted with the equivalent domains of the X. laevis GnRH receptor, identified extracellular loop 2 as the determinant for agonist activity of one of the mammalian antagonists: antagonist 135-18. Site-directed mutagenesis of nine nonconserved residues in the C-terminal domain of extracellular loop 2 of the human GnRH receptor showed that a minimum of two mutations (Val(5.24(197))Ala and Trp(5.32(205))His) is needed in this region for agonist activity of antagonist 135-18. Agonist activity of antagonist 135-18 was markedly decreased by low pH (<7.0) compared with GnRH agonists. These findings indicate that D-Lys(iPr)(6) forms a charge-supported hydrogen bond with His(5.32(205)) to stabilize the receptor in the active conformation. This discovery highlights the importance of EL-2 in ligand binding and receptor activation in G protein-coupled receptors.


[Surgical treatment outcome of hemorrhoidal in 475 patients].
Despite feared by patients and reserved for the minority of patients suffering from hemorrohoids, hemorrhoidectomy remains as the most effective approach to this condition. To analyse results from 475 hemorrhoidectomies performed at University of São Paulo Hospital das Clínicas between 1984 and 1995, a retrospective chart review regarding gender, age, associated anorectal conditions, surgical technique, complications and their management and follow-up was addressed. Two hundred and seven (43.6%) were male. Age between fourth and sixth decades were observed for 70.8%. Associated anorectal conditions were diagnosed in 18.9%. Chronic anal fissure was the commonest one. Milligan-Morgan operation was performed in the majority of patients (91.2%) and Ferguson technique in 6.7%. There were no intraoperative complications postoperative complications occurred in 38 (8%) patients regardless of employed surgical technique. Urinary retention was the commonest postoperative complication. Mean follow-up was 5.8 years for 70% of patients. Surgical hemorrhoidectomy remains as a treatment with excellent results in the management of hemorrhoid disease for selected patients. Produces erradications of the disease in all cases in spite of low morbidity.


Secondary data analysis of intertrigo in hospital and geriatric settings: a comparison of prevalence, anatomical locations, and interventions.
Skin conditions and dermatological diseases (eg, intertrigo) in older patients are common in clinical practice. In addition to the negative impact on the patient's health, diseases such as intertrigo place a financial burden on the health care system. The purpose of this secondary data analysis was to compare the prevalence, anatomical locations, and applied interventions of intertrigo in patients in hospitals and geriatric institutions. The authors report the outcome of a secondary data analysis of data collected from 2012 to 2016 from the Nursing Quality Measurement 2.0. This is an annually conducted cross-sectional multicenter study. Descriptive statistics and statistical tests were used to analyze the data. Of patients in the hospital, 2.4% (n = 15,152) had intertrigo compared with 3.4% (n = 3743) of patients in geriatric institutions. In general, expert consultation was the least used intervention for the treatment of intertrigo in hospitals (6.1%, n = 359) and geriatric institutions (9.8%, n = 122). Independent of the setting, considering the worldwide climate change, the authors expect that the number of patients with intertrigo will be increasing. Therefore, they highly recommend implementing standardized skin assessments for moisture-associated skin damage to identify intertrigo as early as possible. Moreover, as the consultation of experts was seldom used in both settings, advances in the interdisciplinary and interprofessional management of moisture-associated skin damages are needed.