Physical inactivity and associated factors in Iranian children and adolescents: the Weight Disorders Survey of the CASPIAN-IV study.
Introduction: This study aims to assess the associated factors of physical inactivity among Iranian children and adolescents at national level. The second objective is to assess the relationship of physical inactivity with anthropometric measures. Methods: Along with a national surveillance program, this survey on weight disorders was conducted among a nationally-representative sample of Iranian children and adolescents, aged 6-18 years. Students were selected by multi-stage cluster sampling from rural and urban areas of 30 provinces of Iran. The Physical Activity Questionnaire for Adolescents (PAQ-A) was used to assess physical activity (PA). Using PAQ-A instrument, PA of past week categorized as; low PA level, that included those who scored between 1 to 1.9 on the PAQ-A instrument and high PA level that included participants with estimated scores between 2-5 PAQ-A. Results: Participants were 23183 school students (50.8% boys) with a mean age of 12.55 ± 3.3 years, without significant difference in terms of gender. Totally, 23.48% of participants (13.84% of boys and 33.42% of girls) were physically inactive. In multivariate logistic regression model, with increased age in children and adolescence, the odds of a physically inactivity increased (OR: 1.08; 95% CI: 1.07-1.10). The odds of prevalence of both obesity and underweight were high in children and adolescents with low PA. There was a decreasing trend in PA in higher school grades. Conclusion: We found a considerably high prevalence of physical inactivity in Iranian children and adolescents, with higher rates among girls and older ages. However, we did not find correlation between PA and socioeconomic status (SES). Because of the positive relationship between PA and ST, future studies should consider the complex interaction of these two items. Multidisciplinary policies should be considered in increasing PA programs among children and adolescents.


Influence of glycerol on the cooling effect of pair hydrophobicity in water: relevance to proteins' stabilization at low temperature.
Glycerol, as a cosolvent of water, stabilizes proteins under extreme conditions (both at high and low temperatures). However, the mechanism of stabilization of proteins by glycerol at low temperature is still elusive. Because the decrease of hydrophobic interactions at a lower temperature is one of the crucial factors for the cold denaturation, we ask here whether glycerol protects the hydrophobic interactions upon cooling and thereby acts against cold denaturation. Here, we have performed potential of mean force (PMF) calculations, using the umbrella sampling technique, between a pair of methane hydrophobic solute molecules either in pure water or in binary mixtures of water and glycerol for two different compositions and each of them at four different temperatures. We have found that glycerol increases the pair hydrophobic interaction at all the temperatures studied and that the enhancement is more prominent at the lower temperatures studied here. Decomposition of the PMF into the enthalpic and the entropic components and detailed molecular structural analyses give insight into the above observation. We have found that the enhancement of the hydrophobic interaction with increasing glycerol concentration occurs primarily due to the strengthening of the glycerol-water interaction near the associated methane solute molecule pair and the tetrahedral ordering of the H-bonding network being made uniform around the solute by the added glycerol molecules. These results indirectly justify the efficacy of glycerol for the preservation of proteins against cold denaturation at low temperature.


Fatty acid and amino acid compositions of selected wild-edible mushrooms consumed in Turkey.
The fatty acid and amino acid compositions of 11 mushroom species commonly consumed were collected from the East Black Sea region of Turkey and analyzed. All species were characterized by a high content of linoleic acid (C18:2n-6) and glutamic acid. The highest content of linoleic acid (78.0%) and glutamic acid (29.4 μg/mg dry weight [d.w.]) was found in Agaricus arvensis and the lowest in Cantharellus tubaeformis, 19.8% and 10.9 μg/mg d.w., respectively. The average content of amino acids for all species was 148 μg/mg d.w. Overall, these results demonstrate that the 11 different kinds of wild edible mushrooms gathered from the region represent substantial sources of fatty acids and amino acids that are essential in the diet of humans. Quality of the mushroom protein compares favorably with the FAO/WHO Standard. The present study demonstrates that macrofungi from the East Black Sea region (Turkey) are a good source of many nutrients essential to human well-being.


Radiation schedules in relation to obliteration and complications in hypofractionated conformal stereotactic radiotherapy of arteriovenous malformations.
The purpose of this investigation was to assess the obliteration rate and complications following different radiation schedules of hypofractionated conformal stereotactic radiotherapy for cerebral arteriovenous malformations (AVMs). Twenty-five patients were treated with 35 Gy in 5 fractions, whereas 31 patients were treated with 30-32.5 Gy (mean: 31.6 +/- 0.23 Gy) in 5 fractions. A complete angiographic follow-up is available for 40 patients. Thirty-seven out of 40 patients (92.5%) have so far shown obliteration of their AVMs after a mean time of 3.2 +/- 0.26 years (range: 2-8 years). The mean AVM volume in these patients was 8.2 +/- 1.0 cm(3) (range: 1.5-29 cm(3)). There was a higher rate of obliteration (88%) in patients treated with 35 Gy compared to those treated with < 35 Gy (78%), even if this was not statistically significant. There was a significantly shorter time to obliteration in patients treated with 35 Gy. All patients who experienced symptomatic radionecrosis belonged to the group treated with 35 Gy. A radiation schedule of 35 Gy in 5 fractions may be more effective than a radiation schedule of <35 (30-32.5) Gy in obliterating AVMs. This may, however, be at the price of an increased risk of symptomatic radionecrosis.


In vivo confocal microscopy of Fuchs endothelial dystrophy before and after endothelial keratoplasty.
This study reveals significant changes of the anterior cornea in Fuchs endothelial dystrophy that probably affect the visual outcomes of endothelial keratoplasty for the disease. To determine whether abnormalities of corneal stromal and subepithelial cells in Fuchs endothelial dystrophy resolve after Descemet stripping endothelial keratoplasty (DSEK). Prospective observational study of 49 corneas of 42 patients with Fuchs dystrophy before DSEK and during 3 years of postoperative follow-up. None of the preoperative corneas were vascularized or had pronounced subepithelial fibrosis on results of slitlamp examination. Corneas were examined using in vivo confocal microscopy to determine stromal cell density and the presence of abnormal subepithelial cells (presumed fibroblasts). The cornea service at Mayo Clinic, Rochester, Minnesota. Forty-nine corneas of 42 patients. Descemet stripping endothelial keratoplasty. Stromal cell density and presence of subepithelial cells. Subnormal cell density in the most anterior 10% of the host stroma in Fuchs dystrophy before DSEK (mean [SD], 22 030 [6479] cells/mm(3) [n = 41]) remained unchanged at 2 (20 433 [4993] cells/mm(3) [n = 35]; P = .36) and 3 years (20 925 [5433] cells/mm(3) [n = 23]; P = .99) after DSEK. Abnormal subepithelial cells, which formed reticular networks deep to the basal epithelial cells, were visible in 33 eyes (67%) and remained present at 3 years after DSEK. Mean preoperative central corneal thicknesses when these subepithelial cells were and were not visible were 652 (45) and 668 (56) μm, respectively (P = .75). The reduced cellularity of the anterior stroma in Fuchs dystrophy does not recover 3 years after restoring endothelial function. Abnormal subepithelial cells, presumably fibroblasts, are present in most corneas with Fuchs dystrophy requiring DSEK, even in cases with mild edema and in the absence of clinically obvious preoperative subepithelial fibrosis. Anterior corneal structural abnormalities might be related to visual outcomes after DSEK.


Polypyrrole-para-phenolsulfonic acid/tape artificial muscle as a tool to clarify biomimetic driven reactions and ionic exchanges.
Thick films of the polypyrrole-para-phenolsulfonic acid (PPy-HpPS) blend were electrogenerated on stainless steel plates. The self-supported films, once peeled off from the metal, were electrochemically characterized in aqueous solutions of NaCl and NaPF6. The Na, Cl, P, S and F content of films, after attaining a different oxidation state, were determined by EDX. The bending movements of the bilayer (PPy-HpPS)/tape artificial muscle were video recorded during potential sweeps in both solutions allowing the translation of the prevalent ionic exchanges driven by the biomimetic reactions into macroscopic movements. Ionic exchanges between the film and the solution, biomimetic structural processes in the film, driving prevalent electrochemical reactions and film compositions related to each of the different structural potential domains defined by coulovoltammetric results were clarified. In NaPF6 solutions a prevalent exchange of anions exists: the film swells by oxidation and shrinks by reduction. In NaCl solutions prevailing exchange of cations or anions occurs in different potential ranges. Reactions related to the HpPS content play important roles at the more cathodic and more anodic overpotentials. The described methodology could be translated to biological reactions including reactive biopolymers.


Non-H3 CDR template selection in antibody modeling through machine learning.
Antibodies are proteins generated by the adaptive immune system to recognize and counteract a plethora of pathogens through specific binding. This adaptive binding is mediated by structural diversity in the six complementary determining region (CDR) loops (H1, H2, H3, L1, L2 and L3), which also makes accurate structural modeling of CDRs challenging. Both homology and de novo modeling approaches have been used; to date, the former has achieved greater accuracy for the non-H3 loops. The homology modeling of non-H3 CDRs is more accurate because non-H3 CDR loops of the same length and type can be grouped into a few structural clusters. Most antibody-modeling suites utilize homology modeling for the non-H3 CDRs, differing only in the alignment algorithm and how/if they utilize structural clusters. While RosettaAntibody and SAbPred do not explicitly assign query CDR sequences to clusters, two other approaches, PIGS and Kotai Antibody Builder, utilize sequence-based rules to assign CDR sequences to clusters. While the manually curated sequence rules can identify better structural templates, because their curation requires extensive literature search and human effort, they lag behind the deposition of new antibody structures and are infrequently updated. In this study, we propose a machine learning approach (Gradient Boosting Machine [GBM]) to learn the structural clusters of non-H3 CDRs from sequence alone. The GBM method simplifies feature selection and can easily integrate new data, compared to manual sequence rule curation. We compare the classification results using the GBM method to that of RosettaAntibody in a 3-repeat 10-fold cross-validation (CV) scheme on the cluster-annotated antibody database PyIgClassify and we observe an improvement in the classification accuracy of the concerned loops from 84.5% ± 0.24% to 88.16% ± 0.056%. The GBM models reduce the errors in specific cluster membership misclassifications when the involved clusters have relatively abundant data. Based on the factors identified, we suggest methods that can enrich structural classes with sparse data to further improve prediction accuracy in future studies.


Vascular retention of Tc-99m pertechnetate simulating ectopic or metastatic thyroid tissue.
A Tc-99m pertechnetate thyroid scan performed post-operatively in a patient with Hashimoto's disease demonstrated an area of uptake that simulated either ectopic or metastatic thyroid tissue. Radionuclide angiography showed vascular retention of the tracer.


Flashlamp-pumped pulsed dye laser (585nm) for the treatment of portwine stains--a study of treatment outcome in 94 Asian patients in Singapore.
This is a report of a prospective study on the treatment outcome of 94 Asian skin Types III and IV patients with port-wine stains with the 585 nm flashlamp-pumped pulsed dye laser in Singapore. All patients had completed at least 1 year of follow-up post treatment and had received treatment at 8-12 weekly intervals under topical lodocaine-prilocaine anaesthesia. Our patients received an average of 4 treatments sessions. At the end of each treatment (8-12 weeks after the last laser treatment/before the next laser treatment) and on completion of the last treatment (8-12 weeks after the final laser treatment), patients were assessed for response based on a subjective scoring system where excellent = > 75% improvement, good = 50% to 75% improvement, fair = 25% to 49% improvement and poor = < 25% improvement and the same = no observable improvement. The dermatologist also recorded scores after each treatment in a similar way. On completion of the final treatment, patients were asked to score (8-12 weeks after the final laser treatment) the overall response to the treatment themselves using the same scoring system. The mean age was 26.4 years (range 1 year to 58 years). The mean initial treatment energy density dose was 6.24 J/cm2. Eighty percent of our patients experienced excellent or good response to treatment after the initial treatment and further improvements were observed with each subsequent treatment. The author scored 86% of our patients having "excellent" or "good" response while 83% of our patients scored "excellent" or "good" response upon completion of their treatment. The dermatologist generally recorded better improvement scores than the patients. The dermatologist scored 36% and 50% of our patients having "excellent" and "good" response respectively. The corresponding treatment response scores by our patients were 22% ("excellent") and 61% ("good"). Macular lesions appear to respond better than papular/nodular lesions, but the difference was not statistically significant probably due to the small study cohort. Light coloured port-wine stains tended to respond better to treatment than darker lesions (not statistically significant), but overall, all colour lesions responded well to treatment. Patients' expectation of improvements was generally higher than the dermatologist's.


Mood volatility with rumination but neither attentional nor interpretation biases in chronic fatigue syndrome.
This study tested whether (1) chronic fatigue syndrome (CFS) individuals have a bias in the initial orientation of attention to illness-related information, which is enhanced by rumination. (2) CFS individuals have an illness interpretation bias (IB) in their early automatic processing of ambiguous information. (3) CFS individuals experience a greater degree of mood fluctuation following rumination and distraction inductions. Thirty-three CFS participants who had received a medical practitioner's diagnosis of CFS were compared to 33 healthy matched controls on an exogenous cueing task and a lexical decision task. All participants underwent either a rumination or distraction induction. They then completed an exogenous cueing task to assess bias to illness and social threat compared with neutral stimuli, as well as a lexical decision task to assess their interpretation of ambiguous words having illness, social threat, or neutral interpretations. Reaction time data revealed that CFS individuals did not have an attentional bias (AB) in the initial orientation of attention to illness-related material. Nor was there an IB towards illness in CFS individual's automatic response to ambiguous information. However, as hypothesized, CFS individuals showed a greater degree of mood fluctuation following the rumination/distraction induction. Rumination and distraction lead to greater mood volatility in CFS individuals than in controls, but not to attentional nor interpretation biases in the early automatic stages of information processing in CFS individuals.


Where does the current flow in two-dimensional layered systems?
In this Letter, we map for the first time the current distribution among the individual layers of multilayer two-dimensional systems. Our findings suggest that in a multilayer MoS2 field-effect transistor the "HOT-SPOT" of the current flow migrates dynamically between the layers as a function of the applied back gate bias and manifests itself in a rather unusual "contact resistance" that cannot be explained using the conventional models for metal-to-semiconductor contacts. To interpret this unique contact resistance, extracted from a channel length scaling study, we employed a resistor network model based on Thomas-Fermi charge screening and interlayer coupling. By modeling our experimental data we have found that the charge screening length for MoS2 is rather large (λMoS2 = 7 nm) and translates into a current distribution in multilayer MoS2 systems, which is distinctly different from the current distribution in multilayer graphene (λgraphene = 0.6 nm). In particular, our experimental results allow us to retrieve for the first time fundamental information about the carrier transport in two-dimensional layered systems that will likely play an important role in the implementation of future electronics components but that have not been evaluated in the past.


Outbreak of ciguatera fish poisoning on a cargo ship in the port of hamburg.
Ciguatera fish poisoning is a travel-related illness characterized by a combination of gastrointestinal and neurological symptoms in persons who eat ciguatoxic seafood in endemic areas. In 2009, an outbreak of the disease on a refrigerator vessel in the port of Hamburg was investigated. The ship's crew fell ill after they ate fish from a catch in the Caribbean 2 weeks earlier. All 15 sailors on board were examined by port medical officers. Samples of blood and stool specimens were taken from symptomatic sailors. The frozen fish was secured for the prevention of further disease spreading and additional diagnostic tests. All but one sailor ate the fish. The intoxication resulted in gastrointestinal or neurological symptoms in all 14 sailors who consumed the fish and persisted in varying degrees in 93% of sailors over at least 14 days. No fatality occurred, but two seamen were "unfit for duty" on the ship due to severity of symptoms. The diagnosis was supported by the fact that all seafarers who consumed the same reef fish, experienced typical signs, symptoms, and time course consistent with ciguatera fish poisoning. The fish from the catch in the Caribbean was identified as Caranx sexfasciatus (Bigeye Trevally) and Cephalopholis miniata (Red Grouper). An experimental assay later confirmed presence of the ciguatoxin in the fish. Sailors are an occupational group at risk for ciguatera fish poisoning due to potentially unsafe food sources during international travel. Even if no fatality occurred, the disease affected marine operations due to high attack rates and chronicity of symptoms. Medical doctors must be aware that ciguatera fish poisoning is a risk for seafarers traveling in tropical and subtropical areas. Stocking of food in affected ports from safe sources, adequate training of ship cooks, and informing sailors about the risk of fishing are needed to prevent disease occurrence in seafarers in international trade and traffic.


Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration.
Doripenem is a newer carbapenem with little data available to guide effective dosing during renal replacement therapy in critically ill patients. The objective of this study was to determine the population pharmacokinetics of doripenem in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF) for acute kidney injury (AKI). This was an observational pharmacokinetic study in 12 infected critically ill adult patients with AKI undergoing CVVHDF and receiving 500 mg of doripenem intravenously every 8 h as a 60 min infusion. Serial blood samples were taken on 2 days of treatment and used for population pharmacokinetic analysis with S-ADAPT. The median (IQR) age was 62 (53-71) years, the median (IQR) weight was 77 (67-96) kg and the median (IQR) APACHE II score was 29 (19-32). The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. A two-compartment linear model with doripenem clearance described by CVVHDF, renal or non-renal mechanisms was most appropriate. The mean value for total doripenem clearance was 4.46 L/h and volume of distribution was 38.0 L. Doripenem clearance by CVVHDF was significantly correlated with the replacement fluid flow rate and accounted for ∼30%-37% of total clearance. A dose of 500 mg intravenously every 8 h achieved favourable pharmacokinetic/pharmacodynamics for all patients up to an MIC of 4 mg/L. This is the first paper describing the pharmacokinetics/pharmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.


The impact of Earth system feedbacks on carbon budgets and climate response.
A number of studies have examined the size of the allowable global cumulative carbon budget compatible with limiting twenty-first century global average temperature rise to below 2°C and below 1.5°C relative to pre-industrial levels. These estimates of cumulative emissions have a number of uncertainties including those associated with the climate sensitivity and the global carbon cycle. Although the IPCC fifth assessment report contained information on a range of Earth system feedbacks, such as carbon released by thawing of permafrost or methane production by wetlands as a result of climate change, the impact of many of these Earth system processes on the allowable carbon budgets remains to be quantified. Here, we make initial estimates to show that the combined impact from typically unrepresented Earth system processes may be important for the achievability of limiting warming to 1.5°C or 2°C above pre-industrial levels. The size of the effects range up to around a 350 GtCO2 budget reduction for a 1.5°C warming limit and around a 500 GtCO2 reduction for achieving a warming limit of 2°C. Median estimates for the extra Earth system forcing lead to around 100 GtCO2 and 150 GtCO2, respectively, for the two warming limits. Our estimates are equivalent to several years of anthropogenic carbon dioxide emissions at present rates. In addition to the likely reduction of the allowable global carbon budgets, the extra feedbacks also bring forward the date at which a given warming threshold is likely to be exceeded for a particular emission pathway.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.


Pulmonary arterial stiffness assessed by cardiovascular magnetic resonance imaging is a predictor of mild pulmonary arterial hypertension.
Early detection of mild pulmonary arterial hypertension (PAH) based on clinical evaluation and echocardiography remains quite challenging. In addition to enhanced right ventricular (RV) assessment, cardiac magnetic resonance (CMR) imaging may accurately reflect deleterious remodeling and increased stiffness of the central pulmonary arteries based on pulsatility, or percent change of the PA during the cardiac cycle. The purpose of this study is to assess the utility of measuring PA pulsatility by CMR as a potential early maker in PAH. We hypothesize that pulsatility may help discriminate mild PAH from normal control subjects. Consecutive patients with PAH (n = 51) were prospectively enrolled to receive same day CMR and right heart catheterization (RHC). PA stiffness indices including pulsatility, distensibility, compliance, and capacitance were calculated. Comparisons were made between patients with varying severities of PAH and normal controls (n = 18). Of the 51 subjects, 20 had mild PAH, and 31 moderate-severe based on hemodynamic criteria. PA pulsatility demonstrated a progressive decline from normal controls (53%), mild PAH (22%), to moderate-severe PAH (17%; p < 0.001). There was no difference in RV size, function or mass between mild PAH and normal controls. PA pulsatility below 40% had an excellent ability to discriminate between mild PAH and normal controls with a sensitivity of 95% and specificity of 94%. CMR assessment of PA stiffness may noninvasively detect adverse pulmonary vascular remodeling and mild PAH, and thus be a valuable tool for early detection of PAH. Trial Registration: ClinicalTrials.gov Identifier: NCT01451255; https://clinicaltrials.gov/ct2/show/NCT01451255 .


Factors and interventions influencing health-related quality of life in patients with heart failure: a review of the literature.
Because of the lack of a cure for patients with chronic heart failure (HF), there has been a progressive interest in the use of health-related quality of life (Hr-QoL) as complementary end-point to mortality and morbidity. The aim of this review was from a nursing perspective to describe Hr-QoL and the influencing factors of Hr-QoL, as well as to identify interventions aimed at influencing Hr-QoL in HF patients. Medline, Cinahl and PsycInfo databases were searched from 1995 to 2004. A total of 58 papers were included. HF symptoms and activity status influence Hr-QoL negatively. However, several individual characteristics such as personality, gender and age must also be taken into consideration because different values might exist regarding what constitutes a good Hr-QoL. Nurse led interventions based on education, support and exercise can influence Hr-QoL positively. There is also a need of more studies about the effects of depression, sleep disturbances, support as well as education on Hr-QoL. There is also a need of exercise studies with larger sample sizes and older patients in higher NYHA classes. Several individual factors impact Hr-QoL, therefore, must nursing interventions are individually adapted to the patient's resources.


[Initial clinical experience with radiofrequency-guided percutaneous vertebral augmentation in the treatment of vertebral compression fractures].
Percutaenous Vertebroplasty (PVP) is effective in alleviating pain and facilitating early mobilization following vertebral compression fractures. The relatively high risk of extravertebral leakage due to uncontrolled delivery of low viscosity bone cement is an inherent limitation of the technique. The aim of this research is to investigate the ability of controlled cement delivery in decreasing the rate of such complications by applying radiofrequency heating to regulate cement viscosity. Thirty two vetebrae were treated in 28 patients as part of an Ethics Committee approved multicenter clinical trial using RadioFreqency assisted Percutaenous Vertebral Augmentation (RF-PVA) technique. This technique is injecting low viscosity polymethylmethacrylate (PMMA) bone cement using a pressure controlled hydraulic pump and applying radiofrequency heating to increase cement viscosity prior to entering the vertebral body. All patients were screened for any cement leakage by X-ray and CT scan. The intensity of pain was recorded on a Visual Analog Scale (VAS) and the level of physical activity on the Oswestry Disability Index (ODI) prior to, one day, one month and three months following procedure. All procedures were technically successful. There were no clinical complication, intraspinal or intraforaminal cement leakage. In nine cases (29%) a small amount of PMMA entered the intervertebral space through the broken end plate. Intensity of pain by VAS was reduced from a mean of 7.0 to 2.5 and physical inactivity dropped on the ODI from 52% to 23% three months following treatment. In this small series controlled cement injection using RF-PVA was capable of preventing clinically hazardous extravertebral cement leakage while achieving outcomes similar to that of conventional vertebroplasty.


Ultraviolet Light (UV) Inactivation of Porcine Parvovirus in Liquid Plasma and Effect of UV Irradiated Spray Dried Porcine Plasma on Performance of Weaned Pigs.
A novel ultraviolet light irradiation (UV-C, 254 nm) process was designed as an additional safety feature for manufacturing of spray dried porcine plasma (SDPP). In Exp. 1, three 10-L batches of bovine plasma were inoculated with 10(5.2 ± 0.12) tissue culture infectious dose 50 (TCID50) of porcine parvovirus (PPV) per mL of plasma and subjected to UV-C ranging from 0 to 9180 J/L. No viable PPV was detected in bovine plasma by micro-titer assay in SK6 cell culture after UV-C at 2295 J/L. In Exp. 2, porcine plasma was subjected to UV-C (3672 J/L), then spray dried and mixed in complete mash diets. Diets were a control without SDPP (Control), UV-C SDPP either at 3% (UVSDPP3) or 6% (UVSDPP6) and non-UV-C SDPP at 3% (SDPP3) or 6% (SDPP6). Diets were fed ad libitum to 320 weaned pigs (26 d of age; 16 pens/diet; 4 pigs/pen) for 14 d after weaning and a common diet was fed d 15 to 28. During d 0 to 14, pigs fed UVSDPP3, UVSDPP6, or SDPP6 had higher (P < 0.05) weight gain and feed intake than control. During d 0 to 28, pigs fed UVSDPP3 and UVSDPP6 had higher (P < 0.05) weight gain and feed intake than control and SDPP3, and SDPP6 had higher (P < 0.05) feed intake than control. Also, pigs fed UVSDPP had higher (P < 0.05) weight gain than pigs fed SDPP. In conclusion, UV-C inactivated PPV in liquid plasma and UVSDPP used in pig feed had no detrimental effects on pig performance.


Spontaneous resting-state BOLD fluctuations reveal persistent domain-specific neural networks.
Resting-state functional connectivity MRI (rs-fcMRI) analyses have identified intrinsic neural networks supporting domain-general cognitive functions including language, attention, executive control and memory. The brain, however, also has a domain-specific organization, including regions that contribute to perceiving and knowing about others (the 'social' system) or manipulable objects designed to perform specific functions (the 'tool' system). These 'social' and 'tool' systems, however, might not constitute intrinsic neural networks per se, but rather only come online as needed to support retrieval of domain-specific information during social- or tool-related cognitive tasks. To address this issue, we functionally localized two regions in lateral temporal cortex activated when subjects perform social- and tool conceptual tasks. We then compared the strength of the correlations with these seed regions during rs-fcMRI. Here, we show that the 'social' and 'tool' neural networks are maintained even when subjects are not engaged in social- and tool-related information processing, and so constitute intrinsic domain-specific neural networks.


Early, Computer-Aided Design/Computer-Aided Modeling Planned, Le Fort I Advancement With Internal Distractors to Treat Severe Maxillary Hypoplasia in Cleft Lip and Palate.
Traditionally, maxillary hypoplasia in the setting of cleft lip and palate is treated via orthognathic surgery at skeletal maturity, which condemns these patients to abnormal facial proportions during adolescence. The authors sought to determine the safety profile of computer-aided design/computer-aided modeling (CAD/CAM) planned, Le Fort I distraction osteogenesis with internal distractors in select patients presenting at a young age with severe maxillary retrusion. The authors retrospectively reviewed our "early" Le Fort I distraction osteogenesis experience-patients performed for severe maxillary retrusion (≥12 mm underjet), after canine eruption but prior to skeletal maturity-at a single institution. Patient demographics, cleft characteristics, CAD/CAM operative plans, surgical complications, postoperative imaging, and outcomes were analyzed. Four patients were reviewed, with a median age of 12.8 years at surgery (range 8.6-16.1 years). Overall mean advancement was 17.95 + 2.9 mm (range 13.7-19.9 mm) with mean SNA improved 18.4° to 87.4 ± 5.7°. Similarly, ANB improved 17.7° to a postoperative mean of 2.4 ± 3.1°. Mean follow-up was 100.7 weeks, with 3 of 4 patients in a Class I occlusion with moderate-term follow-up; 1 of 4 will need an additional maxillary advancement due to pseudo-relapse. In conclusion, Le Fort I distraction osteogenesis with internal distractors is a safe procedure to treat severe maxillary hypoplasia after canine eruption but before skeletal maturity. Short-term follow-up demonstrates safety of the procedure and relative stability of the advancement. Pseudo-relapse is a risk of the procedure that must be discussed at length with patients and families.


Rapid detection and structural characterization of verapamil metabolites in rats by UPLC-MSE and UNIFI platform.
High-resolution mass spectrometry (HRMS) is an important technology for studying biotransformations of drugs in biological systems. In order to process complex HRMS data, bioinformatics, including data-mining techniques for identifying drug metabolites from liquid chromatography/high-resolution mass spectrometry (LC/HRMS) or multistage mass spectrometry (MSn ) datasets as well as elucidating the detected metabolites' structure by spectral interpretation software, are important tools. Data-mining technologies have widely been used in drug metabolite identification, including mass defect filters, product ion filters, neutral-loss filters, control sample comparisons and extracted ion chromatographic analysis. However, the metabolites identified by current different technologies are not the same, indicating the importance of technique integration for efficient and complete identification of metabolic products. In this study, a universal, high-throughput workflow for identifying and verifying metabolites by applying the drug metabolite identification software UNIFI is reported, to study the biotransformation of verapamil in rats. A total of 71 verapamil metabolites were found in rat plasma, urine and faeces, including two metabolites that have not been reported in the literature. Phase I metabolites of verapamil were identified as N-demethylation, O-demethylation, N-dealkylation and oxidation and dehydrogenation metabolites; phase II metabolites were mainly glucuronidation and sulfate conjugates, indicating that UNIFI software could be effective and valuable in identifying drug metabolites.


Systemic treatments for advanced cutaneous melanoma.
The treatment of advanced cutaneous melanoma remains disappointing. Single-agent cytotoxic drugs usually produce response rates of less than 20%, though newer agents, particularly fotemustine and temozolomide, show some promise, especially in patients with brain metastases. Combination chemotherapy regimens yield response rates of 20% to 40%, but durable complete remissions are uncommon. Interferon-alfa and interleukin-2 alone produce response rates of 10% to 20%, 3% to 5% of which are durable. Vaccines and monoclonal antibodies have low level activity in advanced disease but may play a role in the adjuvant setting. The combinations of cisplatin-based regimens plus IFN-alfa and IL-2 have produced overall response rates of 50% to 60% and complete responses in 20% of patients, about half of which are durable. The toxicity of these regimens is severe, however, and their impact on survival remains to be established.


Repurposing of medications for pulmonary arterial hypertension.
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.


Chiral Cp-rhodium(III)-catalyzed asymmetric hydroarylations of 1,1-disubstituted alkenes.
Metal-catalyzed functionalizations at the ortho position of a directing group have become an efficient bond-forming strategy. A wide range of transformations that employ Cp*Rh(III) catalysts have been described, but despite their synthetic potential, enantioselective variants that use chiral versions of the Cp* ligand remain scarce (Cp*=pentamethyl cyclopentadienyl). Cyclopentadienyl compounds with an atropchiral biaryl backbone are shown to be suitable ligands for the efficient intramolecular enantioselective hydroarylation of aryl hydroxamates. Dihydrofurans that bear methyl-substituted quaternary stereocenters are thus obtained by CH functionalization under mild conditions.


Medial impingement lesions of the tibial plafond.
This paper presents a newly recognized post-traumatic lesion of the ankle resulting from the impingement of the medial aspect of the talar dome against the adjacent area of the tibial plafond secondary to dorsiflexory and plantarflexory inversion injuries. Subsequently, a transchondral fracture is produced, resulting in a medial impingement lesion. This lesion is usually associated with ankle trauma, such as lateral ankle sprains, ruptures of the fibular collateral ligaments, and transchondral fractures of the talar dome. It may also be associated with a fracture, but may be present as a specific pathologic entity causing chronic ankle pain. This presentation reviews the etiology, incidence, and prognosis of such lesions.


Severe liver injury associated with simeprevir plus pegylated interferon/ribavirin therapy in a patient with treatment-naïve genotype 1b hepatitis C virus: a case report.
A second-generation direct-acting antiviral agent, simeprevir, now provides a new treatment option for hepatitis C virus (HCV) infection with good safety profile in combination with pegylated interferon and ribavirin. We herein report a rare case of severe liver injury under simeprevir plus pegylated interferon/ribavirin therapy. We initiated this therapy in a 65-year-old male with treatment-naïve genotype 1b HCV. On day 28, the patient's HCV-RNA was successfully eliminated, and his liver function was fully restored. However, on day 49, the serum alanine aminotransferase level was elevated at 700 IU/L. The HCV-RNA titer was still undetectable and the involvement of other possible viruses was negligible. A liver biopsy performed on day 60 showed an acute hepatitis pattern. The discontinuation of therapy alone successfully improved his liver damage on day 84. No other treatments such as steroids were required. According to the diagnostic criteria for drug-induced liver injury in Japan (DDW-J2004), the liver injury observed in this case can be associated with the administration of simeprevir plus pegylated interferon/ribavirin therapy. In conclusion, simeprevir plus pegylated interferon/ribavirin should be used with caution, as these agents may cause unreported serious adverse events including severe liver injury, despite their clinical safety profile.


A study of nucleolar vacuoles in cultured tobacco cells using radioautography, actinomycin D, and electron microscopy.
Previously it has been found that in tobacco callus cells nucleolar vacuoles repeatedly form and contract. In this study, nucleolar vacuoles were investigated by using radioautography, actinomycin D, and electron microscopy. It was found, from grain counts of nucleoli labeled with uridine-(3)H, that nucleoli containing vacuoles had more than three times as many grains/micro(2) of nucleolar substance as did nucleolei without vacuoles. Treatment of tobacco callus cells with various concentrations of actinomycin D caused the percentage of cells containing nucleolar vacuoles to decrease; with the highest concentration the percentage of these cells dropped from the normal level of about 70% to less than 10%. However, after removal of actinomycin D the cells regained nucleolar vacuoles up to the control level. When radioautography was used with actinomycin D, it was found that the actinomycin D inhibited the uptake of uridine-(3)H, i.e. inhibited RNA synthesis, in those nucleoli which lost their nucleolar vacuoles. In addition, after removal of the cells from actinomycin D, it was found that as the cells regained nucleolar vacuoles the nucleoli also began to incorporate uridine-(3)H. Electron micrographs showed the nucleoli to be composed of a compact, finely fibrous central portion surrounded by a layer of dense particles 100-150 A in diameter. Nucleolar vacuoles occurred in the fibrous central portion. Dense particles similar to those in the outer layer of the nucleoli were found scattered throughout the vacuoles and in a dense layer at their outer edge. These data suggest that in cultured tobacco callus cells the formation and contraction of nucleolar vacuoles is closely related to RNA synthesis in the nucleolus.


Rhazes' (865-925 CE) contribution to surgery in Liber Almansoris.
Surgery has deep historical roots. Rhazes (865-925 CE), a Persian physician, made a significant contribution to the development of medical sciences in the medieval era. Liber Almansoris is one of his significant works on medicine. This book is a medical textbook for medical students. It covers every aspect of the medical sciences. This article discusses Rhazes' contribution to surgery, based on Liber Almansoris. This study examines Rhazes' contribution to surgery, based on his book, Liber Almansoris. Rhazes's Liber Almansoris contains a chapter (seventh chapter) on orthopedics, which includes surgical approaches. This chapter also describes surgical procedures for traumas and skull fractures. In other chapters, he also recommends surgical options for treating certain complications when discussing different treatment methods. Although Rhazes mentioned surgical procedures as a medical treatment method, he did not include a separate chapter on surgery. This strategy can be found in his other medical works, such as Liber Continens or Al-Hawi. It appears that Rhazes adheres to the Galenic (Greek) perspective on surgery. In this context, surgery is not an independent major but a method that a physician can employ as needed. It differs from an alternative approach in that era that adheres to ancient Persian perspectives, which identified surgery as a major like other medical sciences disciplines.


[Embryology, anatomy and rare pathologies of the popliteal artery: Peculiarities of surgical treatment].
Knowledge of anatomical variations of the division of the popliteal artery and specific lesions of the arterial segment involved is necessary for the surgeon, traumatologist-orthopaedist, vascular surgeon. The article contains a review of recent literature data on the prevalence of different variants of branching patterns of the arteries of the crus, also providing a detailed discussion of embryological development of the arterial system of the lower extremities, in many ways explaining the appearance of rare pathologies of the popliteal artery, such as for example popliteal artery entrapment syndrome. Particular attention is paid to cystic damage of the popliteal artery, describing currently known theories of the development of this rare pathology, this is accompanied by sharing own experience in surgical treatment of the patients involved. Awareness of anatomical variants and peculiarities of embryonic development contributes to decreasing the possibility of iatrogenic damage of the popliteal artery during orthopaedic operations and to appropriate decision-making as to the method of revascularization.


Efficient high-order harmonic generation boosted by below-threshold harmonics.
High-order harmonic generation (HHG) in gases has been established as an important technique for the generation of coherent extreme ultraviolet (XUV) pulses at ultrashort time scales. Its main drawback, however, is the low conversion efficiency, setting limits for many applications, such as ultrafast coherent imaging, nonlinear processes in the XUV range, or seeded free electron lasers. Here we introduce a novel scheme based on using below-threshold harmonics, generated in a "seeding cell", to boost the HHG process in a "generation cell", placed further downstream in the focused laser beam. By modifying the fundamental driving field, these low-order harmonics alter the ionization step of the nonlinear HHG process. Our dual-cell scheme enhances the conversion efficiency of HHG, opening the path for the realization of robust intense attosecond XUV sources.


Multimodal Human and Environmental Sensing for Longitudinal Behavioral Studies in Naturalistic Settings: Framework for Sensor Selection, Deployment, and Management.
Recent advances in mobile technologies for sensing human biosignals are empowering researchers to collect real-world data outside of the laboratory, in natural settings where participants can perform their daily activities with minimal disruption. These new sensing opportunities usher a host of challenges and constraints for both researchers and participants. This viewpoint paper aims to provide a comprehensive guide to aid research teams in the selection and management of sensors before beginning and while conducting human behavior studies in the wild. The guide aims to help researchers achieve satisfactory participant compliance and minimize the number of unexpected procedural outcomes. This paper presents a collection of challenges, consideration criteria, and potential solutions for enabling researchers to select and manage appropriate sensors for their research studies. It explains a general data collection framework suitable for use with modern consumer sensors, enabling researchers to address many of the described challenges. In addition, it provides a description of the criteria affecting sensor selection, management, and integration that researchers should consider before beginning human behavior studies involving sensors. On the basis of a survey conducted in mid-2018, this paper further illustrates an organized snapshot of consumer-grade human sensing technologies that can be used for human behavior research in natural settings. The research team applied the collection of methods and criteria to a case study aimed at predicting the well-being of nurses and other staff in a hospital. Average daily compliance for sensor usage measured by the presence of data exceeding half the total possible hours each day was about 65%, yielding over 355,000 hours of usable sensor data across 212 participants. A total of 6 notable unexpected events occurred during the data collection period, all of which had minimal impact on the research project. The satisfactory compliance rates and minimal impact of unexpected events during the case study suggest that the challenges, criteria, methods, and mitigation strategies presented as a guide for researchers are helpful for sensor selection and management in longitudinal human behavior studies in the wild.


[Radiological determination of femoral rotation deformity--computerized tomography, optimized measurement accuracy and exposure dosage].
58 Patients, suspicious to have rotation deformity of the femur, were examined. To compare the value of diagnostic methods in measuring the degree of malrotation we estimated this degree using clinical examination and calculated the anteversion of the femoral neck, taking radiographs in the technique of Dunn and Rippstein, and a modified method of computed tomography. Only in twelve cases the direction of malrotation was corresponding in all three methods, although considerable variations in quantitative results were noted. Maintaining the exact position of the patient, necessary to get reproducible results using conventional X-ray technique, was impossible in most cases of patients with posttraumatic joint-stiffness and malalignment. Determination of femoral neck anteversion using this modified method of CT is a quick, reproducible technique to calculate the degree of malrotation, insensitive to the position of the patient. By means of this CT method it was possible to approach the highest accuracy in precise preoperative planing. Furthermore the radiation exposure could be reduced in a range of 20%-40%.


Zone-specific inducibility of cytochrome P450 2B1/2 is retained in isolated perivenous hepatocytes.
The expression and induction of the cytochrome P450 2B1/2 isoenzyme is heterogeneous, exhibiting a regional pattern in the intact liver and a varied response to phenobarbital in isolated cultured hepatocytes. We report that P450 2B1/2 immunostaining of hepatocytes isolated from the perivenous liver region and cultured in the presence of phenobarbital is much stronger than that of cells identically treated but isolated from the periportal region. P450 2B1 mRNA, quantified by a sensitive and specific RNAase protection assay, is also preferentially induced in perivenous hepatocytes, demonstrating that the difference in induced expression is at the pretranslational level. Our results suggest that perivenous and periportal hepatocytes are differentially imprinted to retain regiospecific factors governing their inducibility after isolation.


[Obstructive sleep-apnoea syndrome: good results with maxillo-mandibular osteotomy after failure of conservative therapy].
A 36-year-old woman and a 49-year-old man with symptoms of an obstructive sleep-apnoea syndrome benefited insufficiently from the therapy of choice, i.e. treatment with continuous positive airway pressure. Minor surgical procedures to improve the upper airways did not have the desired effect. Subsequently, maxillo-mandibular osteotomy was performed. Thereafter, both the daytime somnolence and the snoring during sleep disappeared. Indications for osteotomy of the maxilla and mandible are: failure of conservative therapy or other forms of treatment with a lower morbidity, severe mandibular hypoplasia, extreme respiratory distress and morbid obesity. Ventral displacement of the maxilla or mandible eliminates the obstruction at the level of the base of the tongue. The operation is successful for the first year in 95% of the patients. A disadvantage is the temporary post-operative morbidity.


Monitoring outcomes during long-term opioid therapy for noncancer pain: results with the Pain Assessment and Documentation Tool.
The increasingly common practice of long-term opioid therapy for chronic noncancer pain must be guided by ongoing assessment of four types of outcomes: pain relief, function, side effects, and drug-related behaviors. Our objective was to gather initial pilot data on the clinical application of a specialized chart note, the Pain Assessment and Documentation Tool (PADT), which was developed and tested with 27 physicians. This pilot test provided the means to collect cross-sectional outcome data on a large sample of opioid-treated chronic pain patients. Each of the physician volunteers (located in a variety of settings across the United States) completed the PADT for a convenience sample of personally treated chronic pain patients who had received at least three months of opioid therapy. Completion of the PADT required a clinical interview, review of the medical chart, and direct clinical observation. Data from the PADTs were collated and analyzed. The results suggested that the majority of patients with chronic pain achieve relatively positive outcomes in the eyes of their prescribing physicians in all four relevant domains with opioid therapy. Analgesia was modest but meaningful, functionality was generally stabilized or improved, and side effects were tolerable. Potentially aberrant behaviors were common but viewed as an indicator of a problem (i.e., addiction or diversion) in only approximately 10 percent of cases. Using the PADT physician ratings can be developed in four domains. In this sample, outcomes suggested that opioid therapy provided meaningful analgesia.


Medical insurance claims associated with international business travel.
Preliminary investigations of whether 10,884 staff and consultants of the World Bank experience disease due to work related travel. Medical insurance claims filed by 4738 travellers during 1993 were compared with claims of non-travellers. Specific diagnoses obtained from claims were analysed overall (one or more v no missions) and by frequency of international mission (1, 2-3, or > or = 4). Standardised rate of claims ratios (SSRs) for each diagnostic category were obtained by dividing the age adjusted rate of claims for travellers by the age adjusted rate of claims for non-travellers, and were calculated for men and women travellers separately. Overall, rates of insurance claims were 80% higher for men and 18% higher for women travellers than their non-travelling counterparts. Several associations with frequency of travel were found. SRRs for infectious disease were 1.28, 1.54, and 1.97 among men who had completed one, two or three, and four or more missions, and 1.16, 1.28, and 1.61, respectively, among women. The greatest excess related to travel was found for psychological disorders. For men SRRs were 2.11, 3.13, and 3.06 and for women, SRRs were 1.47, 1.96, and 2.59. International business travel may pose health risks beyond exposure to infectious diseases. Because travellers file medical claims at a greater rate than non-travellers, and for many categories of disease, the rate of claims increases with frequency of travel. The reasons for higher rates of claims among travellers are not well understood. Additional research on psychosocial factors, health practices, time zones crossed, and temporal relation between travel and onset of disease is planned.


Research notes: Prevalence of selected microbial pathogens in processed poultry waste used as dairy cattle feed.
Processed poultry litter intended for dairy cattle feed was collected on 13 dairy ranches in the San Joaquin Valley of California and analyzed for the presence of significant bacterial pathogens associated with clinical disease in cattle or foodborne disease in humans. Litter samples were collected from the surface and interior of the litter piles upon arrival on the dairies and 2 to 4 wk later. Litter samples were cultured for Salmonella, Escherichia coli, Campylobacter, and other bacteria. The temperature of the litter piles was obtained on the surface and interior at each sampling. Dry matter was determined for each sample. No Salmonella, E. coli O157, or Campylobacter was identified (n = 104). Other E. coli strains were found in 8 out of 52 samples on arrival and 4 out of 52 samples at 2 to 4 wk after arrival. Although the surface and interior temperatures of the litter pile were different (23 C vs 50 C, respectively), the mean temperatures did not significantly change with time on the ranches. Average dry matter content did not differ between samples. In conclusion, the pathogens under investigation were not detected in processed poultry litter on these California dairy ranches upon arrival at the dairy or 2 to 4 wk later.


Racial differences in glycemic markers: a cross-sectional analysis of community-based data.
Although differences between black and white persons in hemoglobin A(1c) (HbA(1c)) values are well established, recent studies suggest that this might not reflect differences in glycemia. To investigate racial disparities in glycemic markers, including those that reflect biological processes independent of hemoglobin glycation and erythrocyte turnover. Cross-sectional. Community-based. 1376 nondiabetic and 343 diabetic adults in a substudy of the Atherosclerosis Risk in Communities Study. Hemoglobin A(1c), fasting glucose, glycated albumin, fructosamine, and 1,5-anhydroglucitol levels. Among persons with and without diabetes, black persons had significantly higher HbA(1c), glycated albumin, and fructosamine levels than white persons before and after adjustment for covariates and fasting glucose concentration. Serum 1,5-anhydroglucitol levels, which are reduced in the setting of hyperglycemia-induced glycosuria, were lower in black persons than in white persons, although this difference was statistically significant only in nondiabetic adults. The design was cross-sectional, a limited number of participants with a history of diabetes was included, and the study did not include integrated measures of circulating nonfasting glycemia. Differences between black and white persons in glycated albumin, fructosamine, and 1,5-anhydroglucitol levels parallel differences between these groups in HbA(1c) values. Racial differences in hemoglobin glycation and erythrocyte turnover cannot explain racial disparities in these serum markers. The possibility that black persons have systematically higher levels of nonfasting glycemia warrants further study. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.


Experimental Klebsiella pneumoniae burn wound sepsis: role of capsular polysaccharide.
The role of Klebsiella pneumoniae capsular polysaccharide in relation to virulence in a murine burn wound sepsis model was investigated. Burn trauma markedly predisposed mice to lethal K. pneumoniae sepsis. A highly encapsulated variant (KP1-O) derived from K. pneumoniae KP1 was found to be extremely virulent for burned mice (50% lethal dose less than 10 organisms), whereas another variant (KP1-T), which possessed a much smaller capsule, was comparatively nonvirulent (50% lethal dose greater than 10(6) organisms). Production of large quantities of capsular material by KP1-O allowed for its rapid growth in vivo and persistence in the blood and liver. These traits were not demonstrated by KP1-T, which was effectively cleared after challenge.


Ferastral treatment of three healthy phlebotomized males.
Iron deficiency anaemia was produced by repeated phlebotomies in three healthy males. The storage iron was estimated as 666, 522 and 750 mg. After treatment with 1 000 mg of Ferastral the blood haemoglobin concentration rose at an average daily rate of 0.1 g/100 ml/day. Ninety per cent of the injected iron could be accounted for, and the utilization was estimated to about 70-80%. Side effects comprised pain and discolouration at the injection site.


Disruption of Phthorimaea operculella (Lepidoptera: Gelechiidae) oviposition by the application of host plant volatiles.
Phthorimaea operculella is a key pest of potato. The authors characterised the P. operculella olfactory system, selected the most bioactive host plant volatiles and evaluated their potential application in pest management. The electrophysiological responses of olfactory receptor neurons (ORNs) housed in long sensilla trichodea of P. operculella to plant volatiles and the two main sex pheromone components were evaluated by the single-cell recording (SCR) technique. The four most SCR-active volatiles were tested in a laboratory oviposition bioassay and under storage warehouse conditions. The sensitivity of sensilla trichodea to short-chained aldehydes and alcohols and the existence of ORNs tuned to pheromones in females were characterised. Male recordings revealed at least two types of ORN, each of which typically responded to one of the two pheromone components. Hexanal, octanal, nonanal and 1-octen-3-ol significantly disrupted the egg-laying behaviour in a dose-dependent manner. Octanal reduced the P. operculella infestation rate when used under storage conditions. This work provides new information on the perception of plant volatiles and sex pheromones by P. operculella. Laboratory and warehouse experiments show that the use of hexanal, octanal, nonanal and 1-octen-3-ol as host recognition disruptants and/or oviposition deterrents for P. operculella control appears to be a promising strategy.


Effects of Serelaxin in Patients with Acute Heart Failure.
Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).


Influence of Alveolar Bone Loss and Cement Layer Thickness on the Biomechanical Behavior of Endodontically Treated Maxillary Incisors: A 3-dimensional Finite Element Analysis.
In order to understand the mechanical behavior of a weakened incisor, this study aimed to evaluate the stress distribution caused by different alveolar bone heights and cement layer thickness. A finite element analysis was conducted for this investigation. An intact maxillary central incisor was initially modeled, and the bone of the models was modified in order to simulate 4 levels of bone height: BL0 (no bone loss), BL1 (1/3 bone loss), BL2 (1/2 bone loss), and BL3 (2/3 bone loss). These teeth models were remodeled with a fiber post at 2 different cement thicknesses and restored with a ceramic crown; "A" refers to the well-adapted fiber post (0.3 mm) and "B" to the nonadapted fiber post (1 mm), resulting in 12 models. RelyX ARC (3M ESPE, St Paul, MN) cement was simulated for the cementation of the crowns and fiber posts for all groups. Numeric models received a load of 100 N on the lingual surface. All materials and structures were considered linear elastic, homogeneous, and isotropic. Numeric models were plotted and meshed with isoparametric elements, and results were expressed in maximum principal stress. For fiberglass posts, cement, and dentin, the highest stress concentration occurred in the groups with increased bone loss. For cortical bone, the highest values were for the groups with 1/3 bone loss. A greater thickness of cement layer concentrates more stress. More bone loss and greater CLT were the influential factors in concentrating the stress.


Perspective: Transient postparturient hypocalcemia: a lactation-induced phenomenon of high-producing dairy cows.
Milk fever is one of the most historically relevant diseases of dairy cows. It is caused by tremendous calcium (Ca) expenditure at the initiation of lactation, so severe that cows can no longer stand and, if left untreated, die. Fortunately, through prepartum nutritional improvements, this version of clinical hypocalcemia is rare in the United States. Nonetheless, the opinion that all versions of postpartum hypocalcemia are detrimental remains pervasive, which is particularly significant given that 50% of cows are subclinically hypocalcemic after calving. This has led to a variety of available management and treatment strategies, ranging from prepartum dietary programs to postpartum Ca gels and boluses, targeted at preventing hypocalcemia in dairy cows. Recent research has determined that postpartum dairy cows can experience different types of subclinical hypocalcemia: transient, persistent, or delayed. We now know cows experiencing transient hypocalcemia as part of the homeorhetic adaptation to lactation are the highest milk producers in modern dairy herds, whereas cows with hypocalcemia several days after calving experience disease and losses in milk production. Therefore, it is wrong to assume all postpartum hypocalcemia is detrimental and that treatment of all cases is considered necessary and beneficial. Research indicates that milk synthesis at the onset of lactation contributes to immediate postpartum hypocalcemia, and that the mammary gland is a critical factor in management of Ca homeostasis. However, cows differ in their ability to manage this phenomenon, and it is possible that immediate postpartum influences such as dry matter intake, inflammation, and immune activation impact appropriate Ca regulation in the days following calving.


Dietary lycopene downregulates carotenoid 15,15'-monooxygenase and PPAR-gamma in selected rat tissues.
In vitro studies have suggested that lycopene is an efficient substrate for carotenoid 9'10'-monooxygenase II (CMO2) but an inhibitor of carotenoid 15,15'-monooxygenase I (CMO1). The objectives of this study were to clone the rat CMO2 gene, determine whether feeding lycopene for different lengths of time (3-37 d) altered the expression of genes related to carotenoid cleavage [CMO1, CMO2 and peroxisomal proliferator-activated receptor gamma (PPAR-gamma)] or increased the activity of selected phase I and phase II detoxification enzymes in rat tissues. The cloned rat CMO2 gene was 92 and 82% homologous to the mouse and human CMO2 nucleotide sequence, respectively. The relative abundance of CMO1, CMO2, and PPAR-gamma were differentially expressed among rat tissues. CMO1 and PPAR-gamma expression were decreased in the kidney and adrenal with lycopene intake (P < 0.05), whereas CMO2 expression was reduced only in the kidney. Lycopene did not alter hepatic phase I activity, but hepatic quinone reductase activity increased after 3 and 7 d of lycopene feeding (P < 0.05). Lycopene intake decreased a PPAR-gamma target gene, fatty acid binding protein 3 (FABP3), in the kidney and adrenal (P < 0.05). Thus, these data show that although the intake of 0.25 g lycopene/kg diet does not induce hepatic P450 detoxification enzymes, lycopene feeding alters CMO1, PPAR-gamma, and FABP3 mRNA expression in selected rat tissues with a moderate effect on kidney CMO2 expression. These data suggest that lycopene may play an important role in the modulation of beta-carotene, retinoid, and/or lipid metabolism.


Engineering of Bacteriophages Y2::dpoL1-C and Y2::luxAB for Efficient Control and Rapid Detection of the Fire Blight Pathogen, Erwinia amylovora.
Erwinia amylovora is the causative agent of fire blight, a devastating plant disease affecting members of the Rosaceae Alternatives to antibiotics for control of fire blight symptoms and outbreaks are highly desirable, due to increasing drug resistance and tight regulatory restrictions. Moreover, the available diagnostic methods either lack sensitivity, lack speed, or are unable to discriminate between live and dead bacteria. Owing to their extreme biological specificity, bacteriophages are promising alternatives for both aims. In this study, the virulent broad-host-range E. amylovora virus Y2 was engineered to enhance its killing activity and for use as a luciferase reporter phage, respectively. Toward these aims, a depolymerase gene of E. amylovora virus L1 (dpoL1-C) or a bacterial luxAB fusion was introduced into the genome of Y2 by homologous recombination. The genes were placed downstream of the major capsid protein orf68, under the control of the native promoter. The modifications did not affect viability of infectivity of the recombinant viruses. Phage Y2::dpoL1-C demonstrated synergistic activity between the depolymerase degrading the exopolysaccharide capsule and phage infection, which greatly enhanced bacterial killing. It also significantly reduced the ability of E. amylovora to colonize the surface of detached flowers. The reporter phage Y2::luxAB transduced bacterial luciferase into host cells and induced synthesis of large amounts of a LuxAB luciferase fusion. After the addition of aldehyde substrate, bioluminescence could be readily monitored, and this enabled rapid and specific detection of low numbers of viable bacteria, without enrichment, both in vitro and in plant material.IMPORTANCE Fire blight, caused by Erwinia amylovora, is the major threat to global pome fruit production, with high economic losses every year. Bacteriophages represent promising alternatives to not only control the disease, but also for rapid diagnostics. To enhance biocontrol efficacy, we combined the desired properties of two phages, Y2 (broad host range) and L1 (depolymerase for capsule degradation) in a single recombinant phage. This phage showed enhanced biocontrol and could reduce E. amylovora on flowers. Phage Y2 was also genetically engineered into a luciferase reporter phage, which transduces bacterial bioluminescence into infected cells and allows detection of low numbers of viable target bacteria. The combination of speed, sensitivity, and specificity is superior to previously used diagnostic methods. In conclusion, genetic engineering could improve the properties of phage Y2 toward better killing efficacy and sensitive detection of E. amylovora cells.


The effects of disaster on women's reproductive health in developing countries.
The objective of this study is to empirically test the effects of disasters which include natural as well as human made disasters such as armed conflict on women's reproductive health in developing countries. Data from 128 developing countries are used. It was found that average number of deaths from natural disasters and armed conflict in the East Asia and Pacific region was not significantly different from the rest of the developing world. The data are examined using structural equation analysis. This study finds that 'armed conflict' in developing countries presents significant reproductive health risks. The implications are discussed.


Non-cardiomyocyte microRNAs in heart failure.
Multiple structural changes are known to occur in a failing heart. Myocyte hypertrophy, cardiomyocyte apoptosis, interstitial fibrosis, reduced capillary density, and activation of the immune system are all involved in the pathogenesis and progression of heart failure (HF). The molecular mechanisms underlying these changes of the myocardium have been extensively studied, and many pathways involved in these processes have been uncovered. Recently, it has become evident that a novel class of small non-coding RNAs, called miRNAs, also plays a key role in these structural changes of the heart. This review summarizes the current insights on the role of miRNAs outside myocytes in the heart. Specifically, we will discuss miRNA function in fibroblasts, endothelial cells and immune cells in response to myocardial stress as occurs after myocardial infarction and in the pathogenesis of HF.


Human trophoblast-derived hydrogen sulfide stimulates placental artery endothelial cell angiogenesis.
Endogenous hydrogen sulfide (H2S), mainly synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), has been implicated in regulating placental angiogenesis; however, the underlying mechanisms are unknown. This study was to test a hypothesis that trophoblasts synthesize H2S to promote placental angiogenesis. Human choriocarcinoma-derived BeWo cells expressed both CBS and CTH proteins, while the first trimester villous trophoblast-originated HTR-8/SVneo cells expressed CTH protein only. The H2S producing ability of BeWo cells was significantly inhibited by either inhibitors of CBS (carboxymethyl hydroxylamine hemihydrochloride, CHH) or CTH (β-cyano-L-alanine, BCA) and that in HTR-8/SVneo cells was inhibited by CHH only. H2S donors stimulated cell proliferation, migration, and tube formation in ovine placental artery endothelial cells (oFPAECs) as effectively as vascular endothelial growth factor. Co-culture with BeWo and HTR-8/SVneo cells stimulated oFPAEC migration, which was inhibited by CHH or BCA in BeWo but CHH only in HTR-8/SVneo cells. Primary human villous trophoblasts (HVT) were more potent than trophoblast cell lines in stimulating oFPAEC migration that was inhibited by CHH and CHH/BCA combination in accordance with its H2S synthesizing activity linked to CBS and CTH expression patterns. H2S donors activated endothelial nitric oxide synthase (NOS3), v-AKT murine thymoma viral oncogene homolog 1 (AKT1), and extracellular signal-activated kinase 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) in oFPAECs. H2S donor-induced NOS3 activation was blocked by AKT1 but not MAPK3/1 inhibition. In keeping with our previous studies showing a crucial role of AKT1, MAPK3/1, and NOS3/NO in placental angiogenesis, these data show that trophoblast-derived endogenous H2S stimulates placental angiogenesis, involving activation of AKT1, NOS3/NO, and MAPK3/1.


Physiologically Relevant, Humanized Intestinal Systems to Study Metabolism and Transport of Small Molecule Therapeutics.
Intestinal disposition of small molecules involves interplay of drug metabolizing enzymes (DMEs), transporters, and host-microbiome interactions, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bioengineered from intestinal crypts, mucosal extracts, induced pluripotent stem cell (iPSC)-derived organoids, and human intestinal tissue. This minireview discusses the utility and limitations of these human-derived models in support of small molecule drug metabolism and disposition. Enteroids from human intestinal crypts, organoids derived from iPSCs using growth factors or small molecule compounds, and enterocytes extracted from mucosal scrapings show key absorptive cell morphology while are limited in quantitative applications due to the lack of accessibility to the apical compartment, the lack of monolayers, or low expression of key DMEs, transporters, and nuclear hormone receptors. Despite morphogenesis to epithelial cells, similar challenges have been reported by more advanced technologies that have explored the impact of flow and mechanical stretch on proliferation and differentiation of Caco-2 cells. Most recently, bioengineered human intestinal epithelial or ileal cells have overcome many of the challenges, as the DME and transporter expression pattern resembles that of native intestinal tissue. Engineering advances may improve such models to support longer-term applications and meet end-user needs. Biochemical characterization and transcriptomic, proteomic, and functional endpoints of emerging novel intestinal models, when referenced to native human tissue, can provide greater confidence and increased utility in drug discovery and development.


Synthesis of fibronectin, laminin, and several collagens by a liver-derived epithelial line.
We have investigated the ability of ARL-6 cells, a cell line derived from rat liver, to synthesize various collagens and two glycoproteins of the extracellular matrix, fibronectin, and laminin. Using immunofluorescence, we detected types I, II, and IV collagen plus laminin and fibronectin. Antibodies to types I and III collagen and to fibronectin were associated with most cells and showed a similar distribution. Type IV collagen and laminin were found in thin filaments associated with a small proportion of the cells. Chemical studies showed that ARL-6 cells synthesize predominantly types I and III collagens. The level of collagen synthesis was greatly affected by the presence of exogenous fibronectin added to the cells in the media. Cells maintained in fibronectin-free serum synthesized much less collagen. These studies indicate that liver-derived cells can synthesize a variety of connective tissue proteins and that collagen synthesis by these cells is enhanced by the presence of fibronectin.


Physicochemical and Structural Studies on Shaping of β-hairpin in Proteins as a First Stage of Amyloid Formation.
The aggregation of proteins or their digested fragments through β-sheet structures has a great significance because it leads to neurodegenerative diseases, which are a problem of the aging societies of the developed countries. Short peptides are typically used as models to study the formation of specific structures. However, while the formation of α-helical structure was investigated thoroughly, until recently, there have been much fewer studies on the formation of β-structure. In this review, recent experimental and theoretical studies of β-hairpin-forming peptides, both model alaninebased systems, and those based on the fragments of real proteins, are summarized with regard to the role of hydrophobic, local, and Coulombic interactions. It is demonstrated that the presence of charged residues can induce a bent structure not only owing to the formation of salt bridges if oppositely- charged residues present at the ends of a sequence but also through shielding the hydrophobic interior by like-charged residues at the end of the sequence.


Structural and functional analyses of a yeast mitochondrial ribosomal protein homologous to ribosomal protein S15 of Escherichia coli.
We have purified a small subunit mitochondrial ribosomal protein, MRPS28p, from the yeast, Saccharomyces cerevisiae. Sequence from the amino terminus of MRPS28p was used to design a degenerate oligonucleotide that was complementary to the MRPS28 gene. The MRPS28 gene was isolated and its sequence determined. The MRPS28 sequence encodes a 28 kDa protein that has a region of homology with ribosomal protein S15 of E. coli. This region spans the entire length of the E. coli protein, but as MRPS28p is larger, includes only the portion of the MRPS28p sequence from amino acids 150 to 238. Based on this homology, we predict that MRPS28p, like E. coli S15, interacts directly with small subunit rRNA and functions as an early protein in ribosome assembly. Cells carrying a disrupted chromosomal copy of MRPS28 are unable to respire and spontaneously lose portions of their mitochondrial genomes at a high frequency. These phenotypes are consistent with an essential role for MRPS28p in the assembly and/or function of the mitochondrial ribosome.


Effect of saliva composition on growth of Candida albicans and Torulopsis glabrata.
Candida albicans and Torulopsis glabrata are the most prevalent yeasts in humans. The majority harbor C. albicans in the oral cavity, but only a few develop oral candidiasis. We have sought a possible relationship between indigenous salivary constituents, including antimicrobial and nutritive factors, and the growth rate and/or viability of inoculated fungi in glucose-supplemented sterilized saliva. Stimulated whole saliva was collected from 30 healthy donors. Saliva samples were sterilized, supplemented with glucose and inoculated with C. albicans or T glabrata. After incubation of the inoculates for 20 h, the number of viable cells were counted. All saliva samples were analyzed for different indigenous salivary components and Candida before as well as after sterilization. Besides a 4% reduction in calcium (Ca2+) and thiocyanate (SCN-) concentrations, sterilization did not affect the concentrations of saliva electrolytes, but the proteins were significantly reduced (19-85%). Indigenous candidal carriage (n=19) correlated with neither the growth of inoculated fungi nor any of the analyzed components in saliva. The growth of C. albicans and T. glabrata was similar at pH 5 but, at pH 6, C. albicans had a remarkably slower growth rate than T. glabrata. Statistical analysis showed that the 5-h growth of C. albicans at pH 5 was associated with water and electrolyte secretion, whereas the growth after 20 h was associated with variations in protein-glycoprotein content. The growth of T. glabrata was not related to variations in the salivary variables analyzed.


Genomic and Transcriptomic Investigation of the Physiological Response of the Methylotroph Bacillus methanolicus to 5-Aminovalerate.
The methylotrophic thermophile Bacillus methanolicus can utilize the non-food substrate methanol as its sole carbon and energy source. Metabolism of L-lysine, in particular its biosynthesis, has been studied to some detail, and methanol-based L-lysine production has been achieved. However, little is known about L-lysine degradation, which may proceed via 5-aminovalerate (5AVA), a non-proteinogenic ω-amino acid with applications in bioplastics. The physiological role of 5AVA and related compounds in the native methylotroph was unknown. Here, we showed that B. methanolicus exhibits low tolerance to 5AVA, but not to related short-chain (C4-C6) amino acids, diamines, and dicarboxylic acids. In order to gain insight into the physiological response of B. methanolicus to 5AVA, transcriptomic analyses by differential RNA-Seq in the presence and absence of 5AVA were performed. Besides genes of the general stress response, RNA levels of genes of histidine biosynthesis, and iron acquisition were increased in the presence of 5AVA, while an Rrf2 family transcriptional regulator gene showed reduced RNA levels. In order to test if mutations can overcome growth inhibition by 5AVA, adaptive laboratory evolution (ALE) was performed and two mutants-AVA6 and AVA10-with higher tolerance to 5AVA were selected. Genome sequencing revealed mutations in genes related to iron homeostasis, including the gene for an iron siderophore-binding protein. Overexpression of this mutant gene in the wild-type (WT) strain MGA3 improved 5AVA tolerance significantly at high Fe2+ supplementation. The combined ALE, omics, and genetics approach helped elucidate the physiological response of thermophilic B. methanolicus to 5AVA and will guide future strain development for 5AVA production from methanol.


Experimental infection with Toxoplasma gondii in broiler chickens (Gallus domesticus): seroconversion, tissue cyst distribution, and prophylaxis.
Toxoplasma gondii is a widespread zoonotic protozoan that infects most species of mammals and birds, including poultry. This study aimed to investigate the course of T. gondii infection and the efficacy of diclazuril and Artemisia annua in preventing infection in experimentally infected chickens. Seventy-five 1-month-old chickens, female and male, were randomly divided into five groups (n = 15 each) as follows: (1) uninfected untreated (negative control, NC); (2) infected with T. gondii genotype II/III isolated from a wild cat (group WC); (3) infected with T. gondii genotype II isolated from a domestic cat (group DC); (4) infected with T. gondii domestic cat strain and treated with the anticoccidial diclazuril (group DC-D); and (5) infected with T. gondii domestic cat strain and treated with the medicinal plant Artemisia annua (group DC-A). Clinical signs, body temperature, mortality rate, weight gain, feed conversion ratio, hematological parameters, and the presence of T. gondii-specific IgY antibodies were recorded in all groups. Five chickens per group were euthanized 28 days post-infection (p.i.) and their brains, hearts, and breast muscle tested for T. gondii by mouse bioassay and polymerase chain reaction (PCR). No clinical signs related to the experimental infection were observed throughout the study period. T. gondii-specific antibodies were detected by day 28 p.i., but not in all infected chickens. Overall, T. gondii DNA was detected (bioassay or tissue digests) in all infected and untreated chickens (10/10), while viable parasite (bioassay) was isolated from 7 out of 10 chickens. The parasite was most frequently identified in the brain (7/10). There were no differences in the T. gondii strains regarding clinical infection and the rate of T. gondii detection in tissues. However, higher antibody titers were obtained in chickens infected with T. gondii WC strain (1:192) comparing with T. gondii DC strain (1:48). A. annua reduced replication of the parasite in 3 out of 5 chickens, while diclazuril did not. In conclusion, broiler chickens were resistant to clinical toxoplasmosis, irrespective of the strain (domestic or wild cat strain). The herb A. annua presented prophylactic efficacy by reduced parasite replication. However, further studies are required aiming at the efficacy of diclazuril and A. annua for the prevention of T. gondii infection in chickens using quantitative analysis methods.


One-year follow-up effects of two obesity treatments on psychological well-being and weight.
The effectiveness of a cognitive and a behavioural treatment for obese binge eaters and obese non-binge eaters was evaluated at 1-year follow-up. Furthermore, we examined the role of weight changes on psychological well-being at 1-year follow-up. Participants were reassessed 6 months and 1 year after they had finished a group cognitive treatment or a group behavioural treatment. The outcome measures were; psychological well-being (concerns about shape, weight and eating, self-esteem and depression), binge eating, and weight. Analyses on the completers' sample revealed that both treatments had a markedly positive and lasting impact on shape concern, weight concern and eating concern, binge eating, self-esteem, and depression at 1-year follow-up. Cognitive treatment was not superior to behavioural treatment on most outcome measures. This might be due to selective drop-out. Analyses including non-responders showed that the cognitive treatment was superior on shape, weight and eating concern, and binge eating. The 1-year follow-up results for weight-loss were disappointing. Between pre-treatment and 1-year follow-up participants in the behaviour treatment lost 3.0 kg, while participants in the cognitive treatment lost 0.3 kg. However, participants who gained weight were as successful on changes in psychological well-being changes as participants who lost weight.


Injury-coupled induction of endothelial eNOS and COX-2 genes: a paradigm for thromboresistant gene therapy.
Nitric oxide (NO) and prostacyclin (PGI2) are potent molecules produced by endothelial cells that act synergistically to maintain normal vascular functions. Recent studies indicate that key enzymes that catalyze the synthesis of these two molecules are induced by chemical and physical factors. Because NO and PGI2 and their synthetic enzymes have short half-lives, transcriptional induction by injurious agents, such as lysophosphatidylcholine (lysoPC), represents an important defense mechanism. LysoPC is capable of inducing constitutive endothelial NO synthase (eNOS) and cyclooxygenase-2 (COX-2), an immediate early gene, with distinct kinetics and possibly distinct transcriptional mechanisms. The importance of injury-coupled eNOS and COX overexpression in vasoprotection is supported by powerful effects of virus-mediated transfer of COX and eNOS genes on defense against thrombosis and intimal hyperplasia in angioplasty-injured carotid arteries in animal models.


Patented in vitro blood-brain barrier models in CNS drug discovery.
The blood-brain barrier (BBB) is a regulatory interface between the circulation and the central nervous system (CNS). Therapy of neurological diseases is limited due to restricted penetration of pharmacons across the BBB. Models for screening the brain penetration of drug candidates are needed early in drug discovery. Culture-based models are useful tools for both basic research on BBB, and testing the permeability of new therapeutical molecules. This review focuses on patented in vitro BBB models and their potential application in CNS drug discovery. Cell culture models using primary and immortalized brain endothelial cells of non-human and human origin, in co-culture or mono-culture setting, in static or dynamic conditions are discussed, as well as methods to induce BBB properties in such in vitro models. The aim of these models is to reproduce as many aspects as possible of the in vivo BBB. All models should show some elements of general endothelial and specific BBB properties, like physiologically realistic cell architecture, restrictive paracellular pathway, and functional expression of transport mechanisms. Though no "ideal in vitro BBB model" has been constructed yet, the currently available models provide valuable information on BBB permeability and are useful tools in CNS drug discovery.


Cruciate-retaining vs posterior-substituting inserts in total knee arthroplasty: functional outcome comparison.
Despite clinical success, it is unclear which one, posterior-substituting (PS) or cruciate-retaining (CR) insert, has superior functional outcomes or longevity. We compared the collected results from 2 institutional review board-approved, multicenter, prospective observational studies following CR (412) and PS inserts (328). Participants were evaluated preoperatively, at 6 weeks, at 3 months, and at 1 and 2 years regarding pain, motion, function (Knee Society Score, Krackow Activity Score, Short Form-36), and procedure variables such as anesthesia and preoperative/perioperative/postoperative complications. Implant longevity was recorded at the 2-year follow-up. Improvement was observed within each group; however, there was no difference between groups in terms of pain, motion, or function at any end point. Two-year survival rate was higher than 95%. A higher incidence of wound hematoma was observed in the PS group. Both inserts can be used expecting satisfactory outcomes and high survival rates at 2 years.


[Modification of spectrophotometric method for determination of protein carbonyl groups].
Based on detailed study of optical absorption spectra of protein-hydrazones a modification of the spectrophotometric method determination of the protein carbonyl groups has been proposed. For the hydrazone adduct determination we proposed to measure the optical absorption at three wavelengths (320, 370 and 420 nm) instead of only one (at 370 nm). Two additional wavelengths are used for the linear approximation of the background optical spectrum. This modification improves the specificity and reduces the error when determining the content of CO groups in proteins.


Rituximab for the treatment of multiple sclerosis: a review.
In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated. The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing-remitting MS (RRMS). Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile.Despite these encouraging results, RTX is currently approved for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness aspects of RTX for the treatment of MS. Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.


Generalized Multilevel Functional Regression.
We introduce Generalized Multilevel Functional Linear Models (GMFLMs), a novel statistical framework for regression models where exposure has a multilevel functional structure. We show that GMFLMs are, in fact, generalized multilevel mixed models (GLMMs). Thus, GMFLMs can be analyzed using the mixed effects inferential machinery and can be generalized within a well researched statistical framework. We propose and compare two methods for inference: 1) a two-stage frequentist approach; and 2) a joint Bayesian analysis. Our methods are motivated by and applied to the Sleep Heart Health Study (SHHS), the largest community cohort study of sleep. However, our methods are general and easy to apply to a wide spectrum of emerging biological and medical data sets. Supplemental materials for this article are available online.


Working and Reference Memory Tasks Trigger Opposed Long-Term Synaptic Changes in the Rat Dentate Gyrus.
Long-term storage of information into memory is supposed to rely on long-term synaptic plasticity processes. The detection of such synaptic changes after training in long-term/reference memory (RM) tasks has yet been scarce, variable and only studied on a short time scale. Short-term or working memory (WM) is largely known to depend on persistent neuronal activity or short-term plasticity. However, processing information into WM could also involve long-term synaptic changes that could be responsible for the erasure/forgetting of items previously stored in WM and acting as proactive interference. In order to study long-term synaptic changes associated with RM or WM, we trained chronically implanted rats in 3 different radial maze tasks: a classical RM task and 2 WM tasks involving different levels of proactive interference. Synaptic responses in the dentate gyrus were recorded during 2 × 24 h in freely moving rats after training. We found that consolidation of long-term information leads first to a delayed synaptic potentiation, occurring 9 h after RM training that is replaced by a synaptic depression once the RM rule is fully acquired. In contrast, optimal information processing into WM triggers a synaptic depression immediately after training and lasting 3 h that could act as a mechanism for interference erasure/forgetting.


Synthesis of odd generation triazine dendrimers using a divergent, macromonomer approach.
Using a macromonomer, first, third, and fifth generation triazine dendrimers can be prepared using a divergent approach. The nine-step process to the fifth generation target relies on an iterative two-reactions-per-generation strategy to yield the desired material in approximately 48% overall yield. This target displays 96 surface groups. NMR spectroscopy and mass spectrometry show that exceptionally narrow polydispersity is achieved using this strategy.


Results of a double-blind, placebo-controlled pharmacotherapy trial in alcoholism conducted in Germany and comparison with the US COMBINE study.
The results of placebo-controlled trials (RCTs) with acamprosate or naltrexone vary substantially. Those differences have been attributed to differing patient characteristics, recruitment strategies, treatment settings and remuneration systems. We tested these assumptions by comparing a new double-blind, placebo-controlled randomized trial conducted in Germany (called PREDICT Study) with data from the US COMBINE Study. PREDICT was designed according to the protocol of the COMBINE Study. A total of 426 alcohol-dependent patients were compared to 459 COMBINE Study patients corresponding to the treatment cells in PREDICT. All patients received acamprosate, naltrexone or placebo for 3 months (PREDICT) or 4 months (COMBINE). Biweekly manualized 'medical management' to enhance compliance was delivered in both studies. Time until the first occurrence of heavy drinking was the main outcome measure. PREDICT found neither acamprosate nor naltrexone to supply any additional benefit compared with placebo, which is at variance with a positive naltrexone effect being reported in the COMBINE Study. A secondary comparison between both studies showed better overall treatment outcomes in PREDICT, although these patients had been more severely affected than their COMBINE counterparts. The divergence in results may be attributable to basic differences in the treatment environments (such as in-patient pre-treatment versus primary outpatient care). We suggest that identically designed RCTs conducted in different parts of the world may help improve the external validity of RCTs. This approach could be called 'comparative efficacy research'.