Progesterone and 5 alpha-pregnane-3,20-dione in human amniotic fluid.
Progesterone and 5 alpha-pregnane-3,20-dione (5 alpha-DHP) were determined by radioimmunoassay in 242 amniotic fluid samples from 16-19 weeks of gestation. 165 samples fulfilled the criteria of the normal collective. There is a positive correlation (r = 0.359, p less than 0.001) between progesterone and 5 alpha-DHP. The mean concentration (+/- SD) of progesterone for normal pregnancies was 68.04 +/- 35.56 ng/ml, the mean for 5 alpha-DHP was 6.6 +/- 4.76 ng/ml. A slight decrease of the hormone concentrations with increase of the week of gestation was observed. 7 cases, who later developed EPH-gestosis showed a significant higher progesterone concentration (p less than 0.05). 16 women with premature labor had a significant higher 5 alpha-DHP concentration (p less than 0.05). Significantly elevated progesterone and 5 alpha-DHP values were found in 36 cases of bleedings in early pregnancy. Pregnant women older than 35 years proved to have a significant higher 5 alpha-DHP concentration (p less than 0.05). Also women, who delivered a child weighing less than 2,500 g (n = 8), showed a significant higher progesterone concentration (p less than 0.01). There was no difference in amniotic fluid progesterone and 5 alpha-DHP concentration depending on the sex of the child. The hormone concentrations of 3 cases with Morbus Langdon-Down were slightly below the mean concentration for progesterone and 5 alpha-DHP. Progesterone and 5 alpha-DHP concentrations were found to be normal in one case each of open Ductus Botalli, esophagial atresia, conjunctival bleeding with eyelid edema, teleangiectasia, Morbus Gaucher, sicklefoot, omphalocele, clubfoot, and stillbirth respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling.
The ability of the tubercle bacillus to arrest phagosome maturation is considered one major mechanism that allows its survival within host macrophages. To identify mycobacterial genes involved in this process, we developed a high throughput phenotypic cell-based assay enabling individual sub-cellular analysis of over 11,000 Mycobacterium tuberculosis mutants. This very stringent assay makes use of fluorescent staining for intracellular acidic compartments, and automated confocal microscopy to quantitatively determine the intracellular localization of M. tuberculosis. We characterised the ten mutants that traffic most frequently into acidified compartments early after phagocytosis, suggesting that they had lost their ability to arrest phagosomal maturation. Molecular analysis of these mutants revealed mainly disruptions in genes involved in cell envelope biogenesis (fadD28), the ESX-1 secretion system (espL/Rv3880), molybdopterin biosynthesis (moaC1 and moaD1), as well as in genes from a novel locus, Rv1503c-Rv1506c. Most interestingly, the mutants in Rv1503c and Rv1506c were perturbed in the biosynthesis of acyltrehalose-containing glycolipids. Our results suggest that such glycolipids indeed play a critical role in the early intracellular fate of the tubercle bacillus. The unbiased approach developed here can be easily adapted for functional genomics study of intracellular pathogens, together with focused discovery of new anti-microbials.


Oxygen consumption and ventilation during simulated escape from an offshore oil platform.
Twenty-six male workers from the North Sea offshore oil industry took part in a simulated escape exercise at the Offshore Fire Training Centre. The course was 370 m long and had 19.4 m of vertical ascent and descent using the stairs on simulated offshore structures. Inspired ventilation and oxygen consumption were measured using the P. K. Morgan "Oxylog' and subjects breathed through the apparatus by mouthpiece and one-way valve assembly while wearing a nose clip. On comparison with anthropometric data from larger studies, this sample of the offshore work-force was thought to be representative. The mean duration of the exercise period was 371 s (SD = 24 s, range = 325-424 s). Mean oxygen consumption standing still at the start of the trial was 0.421 min-1 (SD = 0.101 min-1, max. = 0.611 min-1) and mean ventilation 12.351 min-1 (SD = 4.251 min-1, max. = 22.271 min-1). During exercise, the mean oxygen consumption rose to 2.711 min-1 (SD = 0.641 min-1, max = 4.051 min-1) and mean ventilation reached 46.341 min-1 (SD = 15.831 min-1, max = 87.361 min-1) during the fifth minute of exercise. At the end of the exercise period, oxygen consumption returned to resting values after 2 min and ventilation after 3 min. There was no indication of an oxygen debt. Oxygen consumption and ventilation were related to body weight and the maximum figures for ventilation and oxygen consumption were seen in individuals of over the 95th centile for weight who completed the exercise more quickly than other subjects. Draft standards for respiratory protective equipment for use during escape from fire do not specify the breathing volumes identified in this study, and which are considerably higher than those being currently considered. Additionally, the atmospheric conditions near a fire are likely to stimulate ventilation to considerably higher levels than those identified here. Accordingly, such equipment is likely to limit physical performance if a similar intensity of exercise is necessary during an escape. The architecture of offshore installations and protocols for escape from them should be structured to minimize exercise, and stair climbing should be avoided if emergency respirators are to be used. Workers should be trained in the use of escape breathing equipment and instruction should include information regarding its limitations and the need to limit exercise to an appropriate level.


Spectral CT reconstruction via low-rank representation and structure preserving regularization.
Objective:With the development of computed tomography (CT) imaging technology, it is possible to acquire multi-energy data by spectral CT. Being different from conventional CT, the X-ray energy spectrum of spectral CT is cut into several narrow bins which leads to the result that only a part of photon can be collected in each individual energy channel.This can severely degrade the image qualities. To address this problem, we propose a spectral CT reconstruction algorithm based on low-rank representation and structure preserving regularization in this paper.Approach:To make full use of the prior knowledge about both the inter-channel correlation and the sparsity in gradient domain of inner-channel data, this paper combines a low-rank correlation descriptor with a structure extraction operator as priori regularization terms for spectral CT reconstruction. Furthermore, a split-Bregman based iterative algorithm is developed to solve the reconstruction model. Finally, we propose a multi-channel adaptive parameters generation strategy according to CT values of each individual energy channel.Main results: Experimental results on numerical simulations and real mouse data indicate that the proposed algorithm achieves higher accuracy on both reconstruction and material decomposition than the methods based on simultaneous algebraic reconstruction technique (SART), total variation minimization (TVM), total variation with low-rank (LRTV), and spatial-spectral cube matching frame (SSCMF). Compared with SART, our algorithm improves the feature similarity (FSIM) by 40.4% on average for numerical simulation reconstruction, whereas TVM, LRTV, and SSCMF correspond to 26.1%, 28.2%, and 29.5%, respectively.Significance: We outline a multi-channel reconstruction algorithm tailored for spectral CT. The qualitative and quantitative comparisons present a significant improvement of image quality, indicating its promising potential in spectral CT imaging.


Effects of stretching on muscle activation in gas cylinder handling.
Previously, a stretching regimen was designed for manual material handling (MMH) of gas cylinders as a potential ergonomic solution for reducing occupational injury. No studies have made use of objective process measures, such as muscle activation levels, for evaluation of effects of stretching programs. Examine acute effects of stretching on muscle activation levels and driver perceived level of exertion in gas cylinder handling during simulated delivery operations. A within-subject experiment was conducted with eight male participants being subjected randomly to two conditions over a two-day period: stretching before delivery trials and no stretching. Surface electromyography and the Borg CR-10 scale for perceived exertion were used. Generally, results were variable among muscle responses. The extensor muscle bundle in the forearm was found to show a significant decrease (p = 0.0464) in activation level because of stretching. The anterior deltoid and trapezius significantly increased (p < .0001) the EMG activation level with stretching. Also counter to expectations, participants rated perceived exertion significantly higher (p = 0.0423) for trials preceded by stretching. This research indicates a muscle stretching regimen in advance of MMH activities has mixed effects on activation levels across muscles. It is possible that effects are attributable to body posture positions, or manner of muscle use, during actual work activities. Findings indicate that stretching prior to work activity does have an impact on specific muscle activation.


Microscopic Mechanism and Kinetics of Ice Formation at Complex Interfaces: Zooming in on Kaolinite.
Most ice in nature forms because of impurities which boost the exceedingly low nucleation rate of pure supercooled water. However, the microscopic details of ice nucleation on these substances remain largely unknown. Here, we have unraveled the molecular mechanism and the kinetics of ice formation on kaolinite, a clay mineral playing a key role in climate science. We find that the formation of ice at strong supercooling in the presence of this clay is about 20 orders of magnitude faster than homogeneous freezing. The critical nucleus is substantially smaller than that found for homogeneous nucleation and, in contrast to the predictions of classical nucleation theory (CNT), it has a strong two-dimensional character. Nonetheless, we show that CNT describes correctly the formation of ice at this complex interface. Kaolinite also promotes the exclusive nucleation of hexagonal ice, as opposed to homogeneous freezing where a mixture of cubic and hexagonal polytypes is observed.


Functional analysis of mouse kinesin motor Kif3C.
Members of the kinesin II family are thought to play essential roles in many types of intracellular transport. One distinguishing feature of kinesin II is that it generally contains two different motor subunits from the Kif3 family. Three Kif3 family members (Kif3A, Kif3B, and Kif3C) have been identified and characterized in mice. Intracellular localization and biochemical studies previously suggested that Kif3C is an anterograde motor involved in anterograde axonal transport. To understand the in vivo function of the Kif3C gene, we used homologous recombination in embryonic stem cells to construct two different knockout mouse strains for the Kif3C gene. Both homozygous Kif3C mutants are viable, reproduce normally, and apparently develop normally. These results suggest that Kif3C is dispensable for normal neural development and behavior in the mouse.


Floral traits mediate the vulnerability of aloes to pollen theft and inefficient pollination by bees.
Pollen-collecting bees are among the most important pollinators globally, but are also the most common pollen thieves and can significantly reduce plant reproduction. The pollination efficiency of pollen collectors depends on the frequency of their visits to female(-phase) flowers, contact with stigmas and deposition of pollen of sufficient quantity and quality to fertilize ovules. Here we investigate the relative importance of these components, and the hypothesis that floral and inflorescence characteristics mediate the pollination role of pollen collection by bees. For ten Aloe species that differ extensively in floral and inflorescence traits, we experimentally excluded potential bird pollinators to quantify the contributions of insect visitors to pollen removal, pollen deposition and seed production. We measured corolla width and depth to determine nectar accessibility, and the phenology of anther dehiscence and stigma receptivity to quantify herkogamy and dichogamy. Further, we compiled all published bird-exclusion studies of aloes, and compared insect pollination success with floral morphology. Species varied from exclusively insect pollinated, to exclusively bird pollinated but subject to extensive pollen theft by insects. Nectar inaccessibility and strong dichogamy inhibited pollination by pollen-collecting bees by discouraging visits to female-phase (i.e. pollenless) flowers. For species with large inflorescences of pollen-rich flowers, pollen collectors successfully deposited pollen, but of such low quality (probably self-pollen) that they made almost no contribution to seed set. Indeed, considering all published bird-exclusion studies (17 species in total), insect pollination efficiency varied significantly with floral shape. Species-specific floral and inflorescence characteristics, especially nectar accessibility and dichogamy, control the efficiency of pollen-collecting bees as pollinators of aloes.


Influence of demographic factors on outcome of collecting duct carcinoma: a Surveillance, Epidemiology, and End Results (SEER) database analysis.
Collecting duct carcinoma (CDC) is a rare tumor that is difficult to analyze in a single-institution setting. The Surveillance, Epidemiology, and End Results (SEER) database was used to examine demographics and outcomes of CDC. The SEER registry was queried for patients diagnosed with CDC from 1973 to 2004 who also had available demographic, stage, and survival information (n = 98). Stage at presentation as a function of gender and as a function of race were compared using the chi2 test. Relative survival (RS) curves were computed and were compared using the log-rank test; stage-specific relative survival rates were compared across subgroups using the chi2 test. Stage at presentation was not influenced by race (P = .5) or by gender (P = .488). Three-year relative survival rates for localized, regional, and distant disease were 93%, 45%, and 6%, respectively (P < .001). Three-year RS were 58% and 33% for White and Black patients, respectively (P = .354), and for males and females, RS was 58% and 45%, respectively (P = .475). Furthermore, there were no significant differences in 3-year stage-specific relative survival rates by race (P = .425) or gender (P = .245). this study is the largest analysis of CDC and the first to explore the influence of demographic factors on outcomes. Within stated limitations, there appear to be no significant differences in patterns of disease presentation or relative survival rates based on race or sex. Further work is needed to improve outcomes, particularly for patients with regional or distant disease at presentation.


Update on Extensively Drug-Resistant Salmonella Serotype Typhi Infections Among Travelers to or from Pakistan and Report of Ceftriaxone-Resistant Salmonella Serotype Typhi Infections Among Travelers to Iraq - United States, 2018-2019.
Ceftriaxone-resistant Salmonella enterica serotype Typhi (Typhi), the bacterium that causes typhoid fever, is a growing public health threat. Extensively drug-resistant (XDR) Typhi is resistant to ceftriaxone and other antibiotics used for treatment, including ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole (1). In March 2018, CDC began enhanced surveillance for ceftriaxone-resistant Typhi in response to an ongoing outbreak of XDR typhoid fever in Pakistan. CDC had previously reported the first five cases of XDR Typhi in the United States among patients who had spent time in Pakistan (2). These illnesses represented the first cases of ceftriaxone-resistant Typhi documented in the United States (3). This report provides an update on U.S. cases of XDR typhoid fever linked to Pakistan and describes a new, unrelated cluster of ceftriaxone-resistant Typhi infections linked to Iraq. Travelers to areas with endemic Typhi should receive typhoid vaccination before traveling and adhere to safe food and water precautions (4). Treatment of patients with typhoid fever should be guided by antimicrobial susceptibility testing whenever possible (5), and clinicians should consider travel history when selecting empiric therapy.


Efficacy and Safety of Alpha-Blockers for Kidney Stones in Adults.
Objective: To review the literature for α-blocker treatment of kidney stones. Data Sources: PubMed search performed November 15, 2017, using the following search terms: alpha-blocker, alfuzosin, silodosin, or tamsulosin AND kidney or ureteral stones. Additional studies found through references of primary and tertiary literature. Inclusion criteria included English language, randomized controlled trials (not included in meta-analyses), and meta-analyses evaluating US available alpha-blockers as medical expulsive therapy with or without lithotripsy in adults with renal or ureteral stones, and no date limits. Study Selection and Data Extraction: Seven randomized controlled trials (RCTs), 1 case-control trial, and 6 meta-analyses were found and included in this review. Two RCTs and 4 meta-analyses evaluated alpha-blockers without lithotripsy. Five RCTs, 1 case-control trial, and 2 meta-analyses evaluated their use post-lithotripsy. The primary endpoint was stone clearance rate in most studies. Data Synthesis: For ureteral stones ≤10 mm treated without lithotripsy, alpha-blockers increased clearance in all meta-analyses and one RCT versus control. For ureteral or renal stones treated with lithotripsy, 4 RCTs and all meta-analyses found benefit with alpha-blockers compared with control. When results were stratified by stone size, alpha-blockers performed better for stones 10 to 20 mm, while there was no difference for stones <10 mm. Conclusion: Alpha-blockers are beneficial without lithotripsy for ureteral stones 5 to 10 mm. They are beneficial post-lithotripsy for renal or ureteral stones >10 mm. They can be considered post-lithotripsy for stones 5 to 10 mm, but little benefit may be seen. Although all uroselective alpha-blockers have been found to be effective, most data are with tamsulosin 0.4 mg daily.


The impact of nutritional status on pancreatic cancer therapy.
Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive disease with poor outcomes. One of the reasons for the dismal prognosis resides in its impressive ability to alter the nutritional status of patients who develop malnutrition, cachexia, anorexia, and sarcopenia in most cases. The ideal way to measure such changes in PDAC patients, in order to readily identify them and avoid complications or discontinuations of treatment is a relatively unexplored area. In addition, most PDAC patients experience pancreatic exocrine insufficiency (PEI) that contributes to the complex puzzle of malnutrition and that can be treated with Pancreatic Enzyme Replacement Therapy (PERT). We review current knowledge on the impact of nutritional status on both surgical and medical treatments for PDAC, reporting available data on the causes of malnutrition, characteristics, and advantages of different tools to investigate nutritional status and possible strategies to improve patient outcomes. All PDAC patients should receive a careful nutritional assessment at diagnosis, and this should be repeated alongside their treatment path. Screening tools and biochemical variables or scores are associated with prognosis, but bioimpedance vector analysis (BIVA) and radiological assessment of body composition seem more accurate in predicting clinical outcomes and postoperative complications.


Association between milk yield and milk anti-Fasciola hepatica antibody levels, and the utility of bulk tank milk samples for assessing within-herd prevalence on organic dairy farms.
Fasciola hepatica is an important disease of livestock that is responsible for substantial economic losses worldwide. Estimates of the impact of infection on milk yield vary, likely reflecting different geographical locations, farm-level management, and diagnostic methods. Measuring anti-Fasciola antibodies on bulk tank milk (BTM) by ELISA provides a convenient herd-level diagnosis, but the utility of this test remains unclear. Therefore, we evaluated the utility of BTM ELISA test results in Danish organic dairy farms, including estimating the association between 305 day energy corrected milk yield (305d ECM) and F. hepatica infection both at individual and herd level. BTM samples from 218 organic farms were analysed using IDEXX ELISA and subsequently the farmers were interviewed during spring 2016 with the aim of characterising their management practices. The corresponding farm-level production data covering the period 2014-2017 were collected from the Danish national cattle registry. In the following year, 284 individual milk samples (4-7 per herd) along with BTM samples were collected from a subset of the same herds (n = 55). Linear mixed models were used to estimate the association between milk production and ELISA value at both individual and farm levels, and a generalised additive model was used to assess the relationship between within-herd prevalence and BTM ELISA. A dichotomised BTM result with positive outcome was associated with a reduction of 580.5 kg in average 305d ECM, and a positive outcome on individual-level ELISA was associated with a 919.5 kg reduction in milk yield for cows in their third or later lactations. A strong relationship between quantitative BTM ELISA sample to positive percentage (S/P%) and apparent within-herd prevalence based on dichotomised individual-level milk ELISA was also observed, although this relationship was non-linear in nature. We conclude that a useful indication of the within-herd prevalence of infection can be obtained from BTM ELISA following categorisation as negative, low, medium or high according to S/P% cut-offs of approximately 30, 80, and 150. This approach represents a cheap and useful diagnostic tool for monitoring the long-term success of control strategies for F. hepatica infections on a dairy farm.


Functional analysis of a point mutation in the ryanodine receptor of Plutella xylostella (L.) associated with resistance to chlorantraniliprole.
The diamondback moth, Plutella xylostella (L.) has developed extremely high resistance to chlorantraniliprole and other diamide insecticides in the field. A glycine to glutamic acid substitution (G4946E) in the P. xylostella ryanodine receptor (PxRyR) has been found in two resistant populations collected in Thailand and Philippines and was considered associated with the diamide insecticides resistance but no experimental evidence was provided. The present study aimed to clarify the function of the reported mutation in chlorantraniliprole resistance in P. xylostella. We identified the same mutation (G4946E) in PxRyR from four field collected chlorantraniliprole resistant populations of Plutella xylostella in China. Most importantly, we found that the frequency of the G4946E mutation is significantly correlated to the chlorantraniliprole resistance ratios in P. xylostella (R(2) = 0.82, P = 0.0003). Ligand binding assays showed that the binding affinities of the PxRyR to the chlorantraniliprole in three field resistant populations were 2.41-, 2.54- and 2.60-times lower than that in the susceptible one. For the first time we experimentally proved that the G4946E mutation in PxRyR confers resistance to chlorantraniliprole in Plutella xylostella. These findings pave the way for the complete understanding of the mechanisms of diamide insecticides resistance in insects.


Molecular and clinical patterns of local progression in the pancreatic remnant following resection of pancreatic intraductal papillary mucinous neoplasm (IPMN).
Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can progress to invasive carcinoma. Consensus guidelines indicate surgery for IPMN at high risk of malignant progression, as assessed by specific radiological and clinical criteria, whereas an active radiological surveillance is recommended for IPMN at low risk of malignancy. The management of IPMN is further complicated by the risk of developing a distinct new cyst or a ductal adenocarcinoma in the remnant pancreas, either synchronously or metachronously. Several studies therefore investigated local progression in the remnant pancreas following partial pancreatic resection for IPMN and whether an unstable epithelium at risk for malignant degeneration may exist. Understanding the biological mechanisms behind progression of IPMN will help in identifying patients that would benefit from the resection of the entire pancreas.


Behavioral Intention to Receive a COVID-19 Vaccination Among Chinese Factory Workers: Cross-sectional Online Survey.
COVID-19 vaccines will become available in China soon. Understanding communities' responses to the forthcoming COVID-19 vaccines is important. We applied the theory of planned behavior as the theoretical framework. This study investigates the prevalence of and factors associated with behavioral intention to receive self-financed or free COVID-19 vaccinations among Chinese factory workers who resumed work during the pandemic. We examined the effects of factors including sociodemographics, perceptions related to COVID-19 vaccination, exposure to information about COVID-19 vaccination through social media, and COVID-19 preventive measures implemented by individuals and factories. Participants were full-time employees 18 years or older who worked in factories in Shenzhen. Factory workers in Shenzhen are required to receive a physical examination annually. Eligible workers attending six physical examination sites were invited to complete a survey on September 1-7, 2020. Out of 2653 eligible factory workers, 2053 (77.4%) completed the online survey. Multivariate two-level logistic regression models and ordinal logistic regression models were fitted. The prevalence of behavioral intention to receive a COVID-19 vaccination was 66.6% (n=1368, conditional on 80% vaccine efficacy and market rate) and 80.6% (n=1655, conditional on 80% vaccine efficacy and free vaccines). After adjusting for significant background characteristics, positive attitudes toward COVID-19 vaccination (adjusted odds ratio [AOR] 1.20, 95% CI 1.15-1.25 and AOR 1.24, 95% CI 1.19-1.30), perceived support from significant others for getting a COVID-19 vaccination (AOR 1.43, 95% CI 1.32-1.55 and AOR 1.37, 95% CI 1.25-1.50), and perceived behavioral control to get a COVID-19 vaccination (AOR 1.51, 95% CI 1.32-1.73 and AOR 1.28, 95% CI 1.09-1.51) were positively associated with both dependent variables (conditional on 80% vaccine efficacy and market rate or free vaccines, respectively). Regarding social media influence, higher frequency of exposure to positive information related to COVID-19 vaccination was associated with a higher intention to receive a COVID-19 vaccination at market rate (AOR 1.53, 95% CI 1.39-1.70) or a free vaccination (AOR 1.52, 95% CI 1.35-1.71). Higher self-reported compliance with wearing a face mask in the workplace (AOR 1.27, 95% CI 1.02-1.58 and AOR 1.67, 95% CI 1.24-2.27) and other public spaces (AOR 1.80, 95% CI 1.42-2.29 and AOR 1.34, 95% CI 1.01-1.77), hand hygiene (AOR 1.21, 95% CI 1.00-1.47 and AOR 1.52, 95% CI 1.19-1.93), and avoiding social gatherings (AOR 1.22, 95% CI 1.01-1.47 and AOR 1.55, 95% CI 1.23-1.95) and crowded places (AOR 1.24, 95% CI 1.02-1.51 and AOR 1.73, 95% CI 1.37-2.18) were also positively associated with both dependent variables. The number of COVID-19 preventive measures implemented by the factory was positively associated with the intention to receive a COVID-19 vaccination under both scenarios (AOR 1.08, 95% CI 1.04-1.12 and AOR 1.06, 95% CI 1.01-1.11). Factory workers in China reported a high behavioral intention to receive a COVID-19 vaccination. The theory of planned behavior is a useful framework to guide the development of future campaigns promoting COVID-19 vaccination.


An Early Cretaceous heterodontosaurid dinosaur with filamentous integumentary structures.
Ornithischia is one of the two major groups of dinosaurs, with heterodontosauridae as one of its major clades. Heterodontosauridae is characterized by small, gracile bodies and a problematic phylogenetic position. Recent phylogenetic work indicates that it represents the most basal group of all well-known ornithischians. Previous heterodontosaurid records are mainly from the Early Jurassic period (205-190 million years ago) of Africa. Here we report a new heterodontosaurid, Tianyulong confuciusi gen. et sp. nov., from the Early Cretaceous period (144-99 million years ago) of western Liaoning Province, China. Tianyulong extends the geographical distribution of heterodontosaurids to Asia and confirms the clade's previously questionable temporal range extension into the Early Cretaceous period. More surprisingly, Tianyulong bears long, singular and unbranched filamentous integumentary (outer skin) structures. This represents the first confirmed report, to our knowledge, of filamentous integumentary structures in an ornithischian dinosaur.


Integrating digital pathology with transcriptomic and epigenomic tools for predicting metastatic uterine tumor aggressiveness.
The incidence of new cancer cases is expected to increase significantly in the future, posing a worldwide problem. In this regard, precision oncology and its diagnostic tools are essential for developing personalized cancer treatments. Digital pathology (DP) is a particularly key strategy to study the interactions of tumor cells and the tumor microenvironment (TME), which play a crucial role in tumor initiation, progression and metastasis. The purpose of this study was to integrate data on the digital patterns of reticulin fiber scaffolding and the immune cell infiltrate, transcriptomic and epigenetic profiles in aggressive uterine adenocarcinoma (uADC), uterine leiomyosarcoma (uLMS) and their respective lung metastases, with the aim of obtaining key TME biomarkers that can help improve metastatic prediction and shed light on potential therapeutic targets. Automatized algorithms were used to analyze reticulin fiber architecture and immune infiltration in colocalized regions of interest (ROIs) of 133 invasive tumor front (ITF), 89 tumor niches and 70 target tissues in a total of six paired samples of uADC and nine of uLMS. Microdissected tissue from the ITF was employed for transcriptomic and epigenetic studies in primary and metastatic tumors. Reticulin fiber scaffolding was characterized by a large and loose reticular fiber network in uADC, while dense bundles were found in uLMS. Notably, more similarities between reticulin fibers were observed in paired uLMS then paired uADCs. Transcriptomic and multiplex immunofluorescence-based immune profiling showed a higher abundance of T and B cells in primary tumor and in metastatic uADC than uLMS. Moreover, the epigenetic signature of paired samples in uADCs showed more differences than paired samples in uLMS. Some epigenetic variation was also found between the ITF of metastatic uADC and uLMS. Altogether, our data suggest a correlation between morphological and molecular changes at the ITF and the degree of aggressiveness. The use of DP tools for characterizing reticulin scaffolding and immune cell infiltration at the ITF in paired samples together with information provided by omics analyses in a large cohort will hopefully help validate novel biomarkers of tumor aggressiveness, develop new drugs and improve patient quality of life in a much more efficient way.


Diagnosis of portal vein thrombosis: value of color Doppler imaging.
This study was undertaken to determine the accuracy of color Doppler imaging in the diagnosis of portal vein thrombosis. Two hundred fifteen patients were studied with color Doppler imaging to determine patency of the main portal vein. Sonographic findings were confirmed in 75 patients, aged 19 to 66 years. Correlation with angiography was obtained in 13 patients, and surgical correlation was obtained in the remaining 62. Nine patients had portal vein thrombosis on the basis of these gold standards. Sonograms were classified as showing either patency or thrombosis, depending on the ability to show color flow within the main portal vein. Agreement between sonography and angiography or surgery was found in 69 patients (61 patent, eight thrombosed). One patient with a patent portal vein at sonography was found to have a thrombosed vessel at surgery, whereas five patients without portal venous flow at sonography had patent vessels at angiography (one patient) or surgery (four patients). Overall sensitivity and specificity for detection of portal vein thrombosis were 89% and 92%, with an accuracy of 92%, a false-negative rate of 0.11, a negative predictive value of 0.98, and a positive predictive value of 0.62. We postulate that the majority of errors in our study occurred in vessels that, although patent, had only sluggish flow, which could not be resolved because of technical limitations. We conclude that color Doppler imaging is a valuable screening procedure for the assessment of portal vein patency. If the sonogram shows a patent portal vein, no further studies are required. However, a lack of demonstrable flow does not always indicate thrombosis, and other imaging studies should be performed for confirmation.


Perspectives on suicide prevention among American Indian and Alaska native children and adolescents: a call for help.
Suicide rates among American Indian Alaska Native (AIAN) children and adolescents are the highest in the United States. Risk factors for suicide among AIAN youth include: strained interpersonal relationships, family instability, depression, low self-esteem, and alcohol use or substance abuse. Protective factors include: caring family relationships, supportive tribal leaders, and positive school experiences. Carefully planned, culturally sensitive, comprehensive programs that address the social determinants of health outcomes such as poverty, school failure, familial conflicts, and limited access to health care, should be the focus of blueprints for change for these vulnerable children. Moreover, culturally competent providers are key elements associated with reducing the suicide rates among AIAN children and adolescents.


Intracorporeal versus extracorporeal anastomosis in right hemicolectomy: a systematic review and meta-analysis.
Laparoscopic right hemicolectomy for colon cancer is associated with substantial morbidity despite the introduction of enhanced recovery protocols and laparoscopic surgery. Laparoscopic right hemicolectomy with an intracorporeal anastomosis (IA) is less invasive than laparoscopic assisted hemicolectomy, possibly leading to further decrease in post-operative morbidity and faster recovery. The current standard technique includes an extracorporeal anastomosis with mobilization of the colon, mesenteric traction and a extraction wound located in the mid/upper abdomen with relative more post-operative morbidity compared to extraction wounds located in the lower abdomen. A systematic review of PubMed and Embase databases was performed on studies comparing the intracorporeal versus the extracorporeal performed anastomosis in laparoscopic right hemicolectomy. Primary outcomes were mortality, short-term morbidity and length of stay. For quality assessment, the MINORS checklist was used. Meta-analysis was performed using a random-effects model, and a subgroup analysis was performed for data regarding short-term morbidity and length of stay in studies published in 2012≥. A total of 2692 papers were identified, 12 non-randomized comparative studies were included in the analysis with a total number of 1492 patients. No significant change in mortality was found (OR 0.36, 95 % CI 0.09-1.46; I 2 = 0 %). Short-term morbidity decreased significantly in favour of IA (OR 0.68, 95 % CI 0.49-0.93; I 2 = 20 %). Length of stay was decreased, but with serious risk of heterogeneity (MD -0.77 days, 95 % CI -1.46 to -0.07; I 2 = 81 %). Subgroup analysis for papers published in 2012≥ resulted in an even larger decrease in short-term morbidity (OR 0.65, 95 % CI 0.50-0.85; I 2 = 0 %) and a significant decrease in length of stay with low risk of heterogeneity (MD -0.77 days, 95 % CI -1.17 to -0.37; I 2 = 4 %). Intracorporeal anastomosis in laparoscopic right hemicolectomy is associated with reduced short-term morbidity and decreased length of hospital stay suggesting faster recovery as shown in this meta-analysis.


Sport Education and Direct Instruction Units: Comparison of Student Knowledge Development in Athletics.
This study conducted a comparative analysis of students' knowledge development on athletics in Sport Education and in a Direct Instruction unit taking into account sex and initial skill level. The participants were an experienced Physical Education teacher and two sixth-grade classes totaling 47 students (25 boys and 22 girls). Each class was randomly placed in either Sport Education or Direct Instruction classes and participated in 20, 45-minutes lessons focused on shot put, hurdles and triple jump. Knowledge on athletics was assessed through a 25-items written and video-based test. The inter-group differences and improvements across time in the knowledge test were analyzed through the Mann-Whitney and Wilcoxon tests, respectively. There were significant knowledge improvements in both instructional approaches irrespective of students' gender and skill level. In Direct Instruction, the type of task organization, the high rates of repetition of movement patterns and feedback by the teacher were beneficial to student learning. In Sport Education, the autonomy granted to students in the control of the pace of task transitions by making on-going judgments on achievement of performance criteria, implicated students affectively and cognitively with the learning content. It was further supported that several models and teaching strategies should be taken into consideration when teaching Physical Education. Different approaches should be perceived as alternatives and teachers should retain the best in each according with the moment in the unit, student developmental stage, and the specific learning objectives in the task.


Promoting plant-based eating in meat-centric meal contexts: a field study.
Shifting from meat-centric to plant-rich diets may help to enable healthier and more sustainable food systems. Here we present the results of a 1-week intervention to promote plant-based eating in a meat-centric food context (i.e. canteen). The intervention included environmental restructuring strategies (e.g. promotional materials and menu redevelopment) and improvements to the offer of plant-based meals. The evaluation (sales data; pre-registered) spanned 3 weeks prior to the intervention (baseline), 1 week during the intervention (immediate/short-term impact) and 3 weeks after the intervention (follow-up). Opinion surveys were also used to collect data with customers during the intervention. Canteen unit of a university campus in Portugal (Lisbon metropolitan area). In addition to sales data (baseline: 7965 meals; immediate/short-term: 2635 meals; follow-up: 7135 meals), we used opinion surveys to assess customers' meal appraisals during the intervention (n = 370). The odds of a sold meal being vegetarian were 24 % higher in the intervention week compared with the pre-intervention period [OR = 1·24, 95 % CI (1·10, 1·40)] and 9 % higher in the post-intervention period compared with the pre-intervention period [OR = 1·09, (95 % CI (1·00, 1·19)]. Survey data showed that vegetarian meals compared favourably to meat and fish alternatives in liking, sustainability and satiety. A short-term, theory-driven, operationally feasible intervention was effective in promoting increased plant-based meal choices in a collective meal context. Nevertheless, these changes were not entirely sustained over time. Future studies could test whether prolonged or more transformative interventions are necessary to unlock entrenched food practices more effectively in meat-centric collective meal contexts.


HVEM Promotes the Osteogenesis of allo-MSCs by Inhibiting the Secretion of IL-17 and IFN-γ in Vγ4T Cells.
Bone defects are a common orthopaedic concern, and an increasing number of tissue-engineered bones (TEBs) are used to repair bone defects. Allogeneic mesenchymal stem cells (allo-MSCs) are used as seed cells in many approaches to develop TEB constructs, but the immune response caused by allogeneic transplantation may lead to transplant failure. V gamma 4 T (Vγ4T) cells play an important role in mediating the immune response in the early stage after transplantation; therefore, we wanted to verify whether suppressing Vγ4T cells by herpesvirus entry mediator (HVEM)/B and T lymphocyte attenuator (BTLA) signalling can promote MSCs osteogenesis in the transplanted area. In vitro experiments showed that the osteogenic differentiation of MSCs and Vγ4T cells was weakened after co-culture, and an increase in interleukin-17 (IL-17) and interferon-γ (IFN-γ) levels was detected in the culture supernatant. HVEM-transfected MSCs (MSCs-HVEM) still exhibited osteogenic differentiation activity after co-culture with Vγ4T cells, and the levels of IL-17 and IFN-γ in the co-culture supernatant were significantly reduced. In vivo experiments revealed that inflammation in the transplanted area was reduced and osteogenic repair was enhanced after Vγ4T cells were removed. MSCs-HVEM can also consistently contribute to reduced inflammation in the transplanted area and enhanced bone repair in wild-type (WT) mice. Therefore, our experiments verified that HVEM can promote the osteogenesis of allo-MSCs by inhibiting IL-17 and IFN-γ secretion from Vγ4T cells.


Metabolomic profiling of wild-type and mutant soybean root nodules using laser-ablation electrospray ionization mass spectrometry reveals altered metabolism.
The establishment of the nitrogen-fixing symbiosis between soybean and Bradyrhizobium japonicum is a complex process. To document the changes in plant metabolism as a result of symbiosis, we utilized laser ablation electrospray ionization-mass spectrometry (LAESI-MS) for in situ metabolic profiling of wild-type nodules, nodules infected with a B. japonicum nifH mutant unable to fix nitrogen, nodules doubly infected by both strains, and nodules formed on plants mutated in the stearoyl-acyl carrier protein desaturase (sacpd-c) gene, which were previously shown to have an altered nodule ultrastructure. The results showed that the relative abundance of fatty acids, purines, and lipids was significantly changed in response to the symbiosis. The nifH mutant nodules had elevated levels of jasmonic acid, correlating with signs of nitrogen deprivation. Nodules resulting from the mixed inoculant displayed similar, overlapping metabolic distributions within the sectors of effective (fix+ ) and ineffective (nifH mutant, fix- ) endosymbionts. These data are inconsistent with the notion that plant sanctioning is cell autonomous. Nodules lacking sacpd-c displayed an elevation of soyasaponins and organic acids in the central necrotic regions. The present study demonstrates the utility of LAESI-MS for high-throughput screening of plant phenotypes. Overall, nodules disrupted in the symbiosis were elevated in metabolites related to plant defense.


Funding: grants or contracts? A survey of cancer scientists.
The members of the American Association for Cancer Research (AACR) were polled for their reactions to the current controversy of funding by research grant versus that by the research contract and to the nature of the scientific review appropriate for the evaluation of both types of applications. About 50% of the members responded; 97% of these felt that additional basic knowledge was absolutely essential or probably essential for the successful pursuit of the goals of the National Cancer Program. Eighty % of the respondents concluded that the funding of such research programs should be derived largely from grants rather than contracts. Most of the participants agreed that there should be a major rather than a minor redistribution of funds toward grants and away from contracts. About 50% of the respondent AACR members currently are being supported by research grants, about 10% receive contracts only, and another 25% of the members have both types of funds at their disposal. The group of contract-supported scientists felt less critical of contracts, but about one-half of that group also wished to see more funds going into the grant rather than into the contract programs for the additional support of basic research. There was considerable agreement among all groups of respondents that the review process for contracts should make much more active use of extramural peer evaluation to eliminate scientific inequities now existing between the two instruments for funding of work in cancer research.


Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure.
To study the role of glutamate in cocaine-conditioned responses, we developed a rat model in which conditioned locomotion is produced by repeated pairing of cocaine with discrete stimuli (flashing light and metronome). "Paired" subjects received cocaine (15 mg/kg) prior to six exposures to stimuli for 30 min in the test environment. "Unpaired" subjects received equivalent presentations of the stimuli yet received cocaine in home cages. Tests with the stimuli alone demonstrated that the conditioned locomotion displayed by Paired subjects was evident at 3 or 10 days post-training and resistant to two sessions of testing. The degree of conditioned locomotion was not correlated with the subjects' response to novelty or cocaine. Administration of the noncompetitive AMPA receptor antagonist GYKI 52466 (2.5 mg/kg, a dose without effect on spontaneous activity) attenuated the expression of conditioned activity. In vivo microdialysis revealed that Paired subjects had significantly lower basal glutamate levels in the nucleus accumbens (NAc) than did Unpaired subjects when no stimuli were presented. Presentation of the conditioned stimuli resulted in significant increases in glutamate levels in the NAc in the Paired group whilst glutamate levels in the Unpaired group remained unchanged. The associative control of glutamate levels in the NAc by stimuli formerly paired with a drug of abuse is an unprecedented finding. It is likely to reflect the convergence of excitatory inputs that the NAc receives from limbic structures.


Neurodevelopmental profile of a new dysmorphic syndrome associated with submicroscopic partial deletion of 1p36.3.
We describe four children with dysmorphic syndrome with severe learning disability (SLD). Their chromosomes had been normal on conventional cytogenetic examination. However, screening using a multiprobe fluorescence in situ hybridisation (FISH) technique for subtelomeric abnormalities revealed a deletion of the p arm of chromosome 1. The physical features include body asymmetry, microcephaly, distinctive facies with deep-set eyes, sharply defined eye sockets, and mid-face hypoplasia; the neurodevelopmental profile was characterised by SLD, motor delay with hypotonia, markedly delayed visual maturation, and postural asymmetry together with epilepsy. This phenotype is consistent with that described for partial monosomy for 1p36.3.


[Neuropsychological disorders in multiple sclerosis].
In multiple sclerosis (MS) neuropsychological disorders such as cognitive dysfunctions, depression, and fatigue are common and have a significant impact on everyday live. The three symptoms interact in different ways which has to be bore in mind in diagnostic and therapeutic proceedings. The clinical management of the three symptoms should include an assessment of overlapping cofactors and primary causes as well as a step-wise treatment approach that encompasses non-pharmacological and pharmacological interventions.


T cell immunity in autoimmune hepatitis.
T cells play a central role in the immunopathogenesis of AIH. Until recently CD4+ T cells were thought to be critical for disease development, increasing evidence has shown that CD8+ T and gammadelta T cells also play a significant role. The predisposition of certain HLA genotypes to AIH as well as the clonal expansion of a limited number of T cell receptors suggests that the presentation of a self-antigen or a molecular mimic may be responsible for the initiation of the immune response. Given the association of AIH with viral hepatitis, it is thought that the loss of tolerance begins with an infection of hepatocytes and subsequent cytolysis by CD8+ T cells. The presentation of self-antigens or molecular mimics leads to activation and clonal expansion of T cells; this process may be increased by impaired regulatory T cells and a defect in apoptosis. Ultimately T cells initiate B cell production of autoantibodies, proinflammatory cytokines and finally hepatocyte cytotoxicity.


Joubert syndrome co-existing with partial Xp trisomy: review of the literature.
We report a five-year-old girl who has been clinically diagnosed as Joubert syndrome. Her cytogenetic analysis showed 46,XX,der(2)add(2q37) karyotype. Cytogenetic analysis of her mother and maternal grandmother revealed a karyogram designated as 46,X,t (X;2)(p11.2;q37). The proband's derivative chromosome was further confirmed to be a translocation chromosome 2 carrying segments from chromosome X, which originated from a segregation event of the maternal grandmother's balanced translocation passed on as a balanced translocation to the proband's mother either. So far, a number of candidate genes including EN1 on 2q were analyzed for Joubert syndrome. Based on our proband's abnormal karyotype, we suggest that further mapping studies for the syndrome should also be directed towards the chromosome X segments present on the derivative chromosome 2 of our proband.


Enabling glucose/xylose co-transport in yeast through the directed evolution of a sugar transporter.
The capacity to co-transport glucose and xylose into yeast has remained a technical challenge in the field. While significant efforts have been made in transporter engineering to increase xylose transport rates, glucose-based inhibition still limit most of these transporters. To address this issue, we further engineer sugar transporter proteins to remove glucose inhibition and enable glucose/xylose co-transport. Specifically, we start with our previously derived CiGXS1 FIM mutant strain and subjugate it to several rounds of mutagenesis and selection in a hexose metabolism null strain. Through this effort, we identify several mutations including N326H, a truncation in the C-terminal tail, I171F, and M40V as additionally dominant for reducing glucose inhibition. The resulting transporter shows substantially improved xylose transport rates in the presence of high quantities of glucose including up to 70 g/L glucose. Moreover, the resulting transporter enables co-utilization of glucose and xylose with glucose rates on par with a wild-type transporter and xylose rates exceeding that of glucose. These results demonstrate that major facilitator superfamily hexose transporters can be rewired into glucose-xylose co-transporters without functional inhibition by either substrate. These results enhance the potential of using lignocellulosic biomass as a feedstock for yeast.


Splenic abscess. Imaging and intervention.
We reviewed the imaging findings of 14 splenic abscesses in 13 patients. All patients underwent chest radiography, 12 ultrasonography (US), 9 CT, 4 plain abdominal radiography, 2 99mTc-HMPAO leukocyte scan and 2 99mTc-HIG scan. Three patients were treated with percutaneous catheter drainage, and 5 with diagnostic or therapeutic fine-needle aspiration (FNA). At US the abscess was hypoechoic (n = 9), anechoic (n = 2), or anechoic with gas-bubbles (n = 1), or the entire spleen was inhomogeneous with gas-bubbles (n = 1). At CT the abscesses appeared as low density (18-30 HU) lesions with (n = 2) or without (n = 7) gas. In 2 cases 99mTc-HMPAO leukocyte scan, and in one case 99mTc-HIG scan showed an intrasplenic defect, and in one case 99mTc-HIG scan was considered normal. At plain abdominal radiography extraintestinal gas was suggested in 2 patients, and the findings were normal in 2. US-guided FNA confirmed infectious etiology of the lesion in 4 patients, and a necrotic specimen suggested infection in one. One patient was cured with repeated aspirations. Catheter drainage was successful in all 3 patients who underwent the procedure. We conclude that US and CT are accurate in detecting splenic abscesses. Our results in splenic interventions advocate wider use of the procedures.


[Chemotherapy of pulmonary tuberculosis. Sputum culture conversion in 8 weeks in 84% of patients].
Conversion rate to negativity of sputum culture and microscopy in 50 patients, previously untreated, with open cavernous pulmonary tuberculosis was analysed. Treatment consisted of isoniazid, rifampicin and pyrazinamide for three months, followed by administration of isoniazid and rifampicin. Conversion to a negative sputum culture had occurred after four weeks in 30% of patients, after eight weeks in 84%, and after 14 weeks in all patients. In 76% of patients the cultural conversion preceded the microscopic one. Treatment was well tolerated; only one patient had side effects requiring a short interruption of drug administration. The results confirm that this regimen is effective against pulmonary tuberculosis without significant side effects.


In-vitro, in-vivo and ex-vivo studies with oral beta-lactams against Streptococcus pneumoniae.
In-vitro killing curves, a protection model in immunocompetent mice and an ex-vivo model in volunteers were used to evaluate the efficacy of amoxycillin, cefuroxime axetil and cefpodoxime proxetil against a penicillin-intermediate-resistant Streptococcus pneumoniae (MIC = 1 mg/L) (PRP) and a penicillin-susceptible S. pneumoniae (MIC = 0.01 mg/L) (PSP). In vitro, the maximal bactericidal activity was obtained with amoxycillin (1 x MIC versus 2 x MIC cefpodoxime and 4 x MIC cefuroxime). Mice were challenged by intraperitoneal inoculation and treated orally every 8 h for 48 h with 2.5, 5, 7.5 and 10 mg/kg doses of these three beta-lactams. The rate of survival for the PSP strain was 100% with any dose of the three tested antibiotics. For the PRP strain only amoxycillin showed 100% survival with 5, 7.5 or 10 mg/kg doses. Twelve healthy volunteers were randomized in three groups and each received two doses of the oral antibiotic. Blood samples were collected from each subject 0.5 h and 2 h after drug administration and serum inhibitory and bactericidal titres were measured. Similar values were obtained with the three beta-lactams against PSP but against PRP only the serum of volunteers that had taken amoxycillin exhibited serum bactericidal titres of > or = 8. This study suggests a more predictable therapeutic efficacy against pneumococcal infection with amoxycillin than with available oral cephalosporins.


A Pilot Randomized Controlled Trial Using Prophylactic Dressings to Minimize Sacral Pressure Injuries in High-Risk Hospitalized Patients.
This pilot randomized controlled trial examined the effect of prophylactic dressings to minimize sacral pressure injuries (PIs) in high-risk hospitalized patients and assessed feasibility criteria to inform a larger study. Eighty patients were recruited at admission points (the emergency department and surgical care unit) or directly from participating wards in the general medical-surgical setting following the assessment of high risk of sacral PI. Participants were randomized into either the routine care or routine care and silicone foam border dressing group. Outcome assessment comprised digital photographs of each participant's sacrum every 72 hr for evaluation by a blind-to-intervention assessor. Sixty-seven participants had at least one sacral photograph taken and assessed by a blind-to-intervention assessor. Three participants were assessed as having a Stage I PI. Although the use of photography was effective, feasibility criteria identified challenges related to bias, blinding, weight assessment, preparation of nursing staff, and sample size estimation.


Tension pleural effusion. A delayed complication of pneumothorax therapy in tuberculosis.
Three cases of delayed development of pleural effusion under tension, 20 to 30 years after therapeutic pneumothorax, are described. A sudden increase in dyspnea and the radiographic findings of increasing opacity, a change from hypovolemia to hypervolemia of the hemithorax, and mediastinal shift should alert one to this delayed complication. Careful thoracentesis to decompress intrapleural tension effusion can relieve the dyspnea and improve hypoxemia. The potential risks of creating excessive negative intrapleural pressure are presented.


Characterization of human recombinant alpha(2A)-adrenoceptors expressed in Chinese hamster lung cells using intracellular Ca(2+) changes: evidence for cross-talk between recombinant alpha(2A)- and native alpha(1)-adrenoceptors.
1. Human alpha(2A)-adrenoceptors expressed in Chinese hamster lung (CHL) fibroblasts have been pharmacologically characterized by measuring intracellular calcium (Ca(2+)(i)) changes using the Ca(2+)-sensitive dye Fluo3-AM, in conjunction with a fluorometric imaging plate reader (FLIPR). 2. Several alpha-adrenoceptor agonists were examined including the alpha(2)-adrenoceptor agonists UK-14304, B-HT 920, dexmedetomidine and A-54741, the selective alpha(1)-adrenoceptor agonist phenylephrine and the non-selective adrenergic agonist noradrenaline. Of these only noradrenaline (mean pEC(50)=6.49) and A-54741 (6.90) evoked changes in Ca(2+)(i); A-54741 was a partial agonist relative to noradrenaline, achieving only 33% of the noradrenaline maximum. 3. Ca(2+)(i) changes induced by noradrenaline and A-54741 were antagonized by the alpha(2)-selective antagonist rauwolscine (10 nM) and by the alpha(1)-selective antagonists prazosin (0.1 nM) and doxazosin (1.0 nM). 4. Phenylephrine (100 microM) and UK-14304 (10 microM) alone were ineffective in causing Ca(2+)(i) increase. In the presence of a fixed concentration of UK-14304 (3.0 microM), phenylephrine induced concentration-dependent increases in Ca(2+)(i) (mean pEC(50)=5.33). In the presence of phenylephrine (30.0 microM) UK-14304 induced Ca(2+)(i) release (pEC(50)=6.92). The effects of phenylephrine were abolished by prazosin (1.0 nM) or rauwolscine (100 nM). 5. In saturation radioligand binding experiments using membranes of parental (non-transfected) CHL cells there was a small, specific binding of [(3)H]-prazosin (B(max)=24 fmol mg protein(-1); pK(D)=10. 24). 6. Collectively, these data suggest that alpha-adrenoceptor agonist-induced Ca(2+)(i) release in CHL fibroblasts transfected with the human alpha(2A)-adrenoceptor is dependent upon co-activation of the recombinant receptor and a native alpha(1)-adrenoceptor.


Allergic and Immunologic Perspectives of Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory condition primarily involving the gastrointestinal tract. It includes Crohn's disease (CD), ulcerative colitis (UC), and a less common phenotype-indeterminate colitis. It is thought to result from a complex interplay of environmental, microbial, and host factors including genetic factors, although the exact mechanism is not known. Dietary factors have been shown to play a role in the pathogenesis of IBD and can potentially alter the intestinal microbiota as well as disrupt the immune function in the gut. CD is characterized by transmural inflammation, sometimes associated with granulomatous lesions, and involves the entire gastrointestinal tract but often spares the rectum. UC is characterized by mucosal inflammation typically confined to the colon and rectum. Although IBD is mostly seen in western world, recent data suggests that the incidence and prevalence are increasing worldwide. Enteral nutrition has been shown to be effective in inducing remission in pediatric population with CD; however, there is mixed data in adult population. Nutritional deficiencies such as vitamin D and zinc deficiency are often noted in IBD patients. Several extraintestinal manifestations are noted in patients with IBD. Some of them parallel with the disease activity and others are independent of the disease course. Assessment of IBD disease activity clinically, radiologically, if indicated, biochemically and endoscopically is important to guide therapy in IBD. To ensure comprehensive care, it is important to assess associated conditions such as nutritional and psychological well-being, as well as age appropriate health maintenance status prior to starting treatment for IBD. Several biologic agents including anti-tumor necrosis factor alpha (anti-TNF-α) drugs, anti-integrins, and antibodies to the p40 subunit of IL12/23 are approved for induction and maintenance of remission of IBD. Steroids are also often used for induction. Anti-metabolites and thiopurines are also useful either as monotherapy or in combination regimens. Potential side effects of anti-TNF-α drugs such as serious infections, malignancy, worsening of heart failure, and infusion-related reactions should be considered prior to starting these drugs. Anti-TNF-α drugs with or without immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) are often used for the induction and maintenance of remission. Treating to target of endoscopic and clinical remission provides the best long-term outcomes. Our knowledge and understanding of IBD has grown significantly. However, there are several unanswered questions on pathogenesis, disease behavior, and drivers of inflammation in various patient subgroups which require further research.


Degradation of poly(ether sulfone)/polyvinylpyrrolidone membranes by sodium hypochlorite: insight from advanced electrokinetic characterizations.
Poly(ether sulfone) (PES)/polyvinylpyrrolidone (PVP) membranes are widely used in various industrial fields such as drinking water production and in the dairy industry. However, the use of oxidants to sanitize the processing equipment is known to impair the integrity and lifespan of polymer membranes. In this work we showed how thorough electrokinetic measurements can provide essential information regarding the mechanism of degradation of PES/PVP membranes by sodium hypochlorite. Tangential streaming current measurements were performed with ultrafiltration and nanofiltration PES/PVP membranes for various aging times. The electrokinetic characterization of membranes was complemented by FTIR-ATR spectroscopy. Results confirmed that sodium hypochlorite induces the degradation of both PES and PVP. This latter is easily oxidized by sodium hypochlorite, which leads to an increase in the negative charge density of the membrane due to the formation of carboxylic acid groups. The PVP was also found to be partly released from the membrane with aging time. Thanks to the advanced electrokinetic characterization implemented in this work it was possible for the first time to demonstrate that two different mechanisms are involved in the degradation of PES. Phenol groups were first formed as a result of the oxidation of PES aromatic rings by substitution of hydrogen by hydroxyl radicals. For more severe aging conditions, this membrane degradation mechanism was followed by the formation of sulfonic acid functions, thus indicating a second degradation process through scission of PES chains.


Non-histone Methylation of SET7/9 and its Biological Functions.
(su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9 (SET7/9) is a member of the protein lysine methyltransferases (PLMTs or PKMTs) family. It contains a SET domain. Recent studies demonstrate that SET7/9 methylates both lysine 4 of histone 3 (H3-K4) and lysine(s) of non-histone proteins, including transcription factors, tumor suppressors, and membrane-associated receptors. This article mainly reviews the non-histone methylation effects of SET7/9 and its functions in tumorigenesis and development. PubMed was screened for this information. SET7/9 plays a key regulatory role in various biological processes such as cell proliferation, transcription regulation, cell cycle, protein stability, cardiac morphogenesis, and development. In addition, SET7/9 is involved in the pathogenesis of hair loss, breast cancer progression, human carotid plaque atherosclerosis, chronic kidney disease, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. SET7/9 is an important methyltransferase, which can catalyze the methylation of a variety of proteins. Its substrates are closely related to the occurrence and development of tumors.


The effects of a single dose of concentrated beetroot juice on performance in trained flatwater kayakers.
The aim of the current study was to determine the effects of dietary nitrate ingestion on parameters of submaximal and supramaximal exercise and time trial (TT) performance in trained kayakers. Eight male kayakers completed four exercise trials consisting of an initial discontinuous graded exercise test to exhaustion and three performance trials using a kayak ergometer. The performance trials were composed of 15 min of paddling at 60% of maximum work rate, five 10-s all-out sprints, and a 1 km TT. The second and third trials were preceded by ingestion of either 70 ml nitrate-rich concentrated beetroot juice (BR) or tomato juice (placebo [PLA]) 3 hr before exercise using a randomized crossover design. Plasma nitrate (PLA: 33.8 ± 1.9 μM, BR: 152 ± 3.5 μM) and nitrite (PLA: 519.8 ± 25.8, BR: 687.9 ± 20 nM) were higher following ingestion of BR compared with PLA (both p < .001). VO2 during steady-state exercise was lower in the BR trial than in the PLA trial (p = .010). There was no difference in either peak power in the sprints (p = .590) or TT performance between conditions (PLA: 277 ± 5 s, BR: 276 ± 5 s, p = .539). Despite a reduction in VO2, BR ingestion appears to have no effect on repeated supramaximal sprint or 1 km TT kayaking performance. A smaller elevation in plasma nitrite following a single dose of nitrate and the individual variability in this response may partly account for these findings.


Under-reporting of venous and arterial thrombotic events in randomized clinical trials: a meta-analysis.
For the detection of unwanted outcomes of new interventions, physicians rely on adverse event reporting. We attempt to quantify the reported incidence of venous thromboembolism (VTE) and arterial thrombosis (AT) in randomized clinical trials (RCTs), and evaluate the extent of under-reporting. We selected all therapeutic RCTs published in the four highest-impact general medicine journals between January 2011 and July 2011. Patients were categorized according to VTE risk. The occurrences of VTE and AT, either as predefined outcome or adverse event, were assessed. We identified 131 RCTs. VTE and AT were not reported in 89 and 70 % of these studies, respectively. The raw-unweighted reported incidence in the 3 studies with predefined outcomes for VTE was 8.4 (7.8-9.1) per 1,000 person-years. In the 128 studies without predefined outcomes for VTE, (consisting of 322,029 individuals, including patients with cancer, inflammatory disease, cardiovascular disease, surgery, adding up to a follow-up >500,000 person-years), an incidence of 0.4 (0.4-0.5) per 1,000 person-years was found. The reported incidence of AT in 18 studies in which AT was part of predefined outcomes was 25.6 (24.9-26.3) per 1,000 person-years. In 92 studies without predefined outcomes for AT (231,638 individuals, follow-up >200,000 person-years,), the incidence was 2.5 (2.3-2.7) per 1,000 person-years. The incidence of VTE and AT in RCTs is highly under-reported. Uniform registration of adverse events, even when unlikely to be related to the intervention, is necessary to be able to inform physicians about the potential toxicities of new therapeutic strategies.


Treatment of refractory thrombocytopenic purpura with cyclophosphamine.
Cyclophosphamide, an immunosuppressive agent, was administered as an additional mode of therapy to 30 patients with idiopathic thrombocytopenic purpura (ITP) refractory to conventional management. Of 22 previously tested by splenectomy an excellent response was achieved in 12, who remained in complete hematologic remission for 14-96 months after therapy was discontinued; a fair response in 3, with definite increase in platelets, but not to normal levels; and a poor response in 7 who failed to improve. Of 8 nonsplenectomized patients who failed to respond to steroids or maintain a response after steroids were discontinued, 4 were considered excellent, 1 required continued therapy to remain in remission (good response), 2 were fair, and 1 was poor. Remission was observed in 2-10 weeks in both groups and appeared to be related to duration of disease; presence of disease for less than 1 year was associated with a much better response to treatment (11 of 15) when compared with disorders lasting over 2 years (6 of 15). Cyclophosphamide therapy offers additional means of treating patients with ITP who fail to respond to conventional therapy and may serve as an alternative to splenectomy when surgery is contraindicated.


Development of a measure of genome sequencing knowledge for young people: The kids-KOGS.
Genome sequencing (GS) is increasingly being used to diagnose rare diseases in paediatric patients; however, no measures exist to evaluate their knowledge of this technology. We aimed to develop a robust measure of knowledge of GS (the kids-KOGS') suitable for use in the paediatric setting as well as for general public education. The target age was 11 to 15 year olds. An iterative process involving six sequential stages was conducted to develop a set of draft true/false items. These were then administered to 539 target-age school pupils (mean 12.8; SD ± 1.3), from the United Kingdom. Item-response theory was used to confirm the psychometric suitability of the candidate items. None of the Items was identified as misfits. All 10 items performed well under the two-parameter logistic model. The internal consistency of the test was 0.84 (Cronbach alpha value) indicating excellent reliability. The mean kids-KOGS score in the sample overall was 4.24 (SD; 2.49), where 0 = low knowledge and 10 = high knowledge. Age was positively associated with score in a multivariate linear regression. The kids-KOGS is a short and reliable tool that can be used by researchers and healthcare professionals offering GS to paediatric patients. Further validation in a clinical setting is required.


Predicting Flowering Behavior and Exploring Its Genetic Determinism in an Apple Multi-family Population Based on Statistical Indices and Simplified Phenotyping.
Irregular flowering over years is commonly observed in fruit trees. The early prediction of tree behavior is highly desirable in breeding programmes. This study aims at performing such predictions, combining simplified phenotyping and statistics methods. Sequences of vegetative vs. floral annual shoots (AS) were observed along axes in trees belonging to five apple related full-sib families. Sequences were analyzed using Markovian and linear mixed models including year and site effects. Indices of flowering irregularity, periodicity and synchronicity were estimated, at tree and axis scales. They were used to predict tree behavior and detect QTL with a Bayesian pedigree-based analysis, using an integrated genetic map containing 6,849 SNPs. The combination of a Biennial Bearing Index (BBI) with an autoregressive coefficient (γ g ) efficiently predicted and classified the genotype behaviors, despite few misclassifications. Four QTLs common to BBIs and γ g and one for synchronicity were highlighted and revealed the complex genetic architecture of the traits. Irregularity resulted from high AS synchronism, whereas regularity resulted from either asynchronous locally alternating or continual regular AS flowering. A relevant and time-saving method, based on a posteriori sampling of axes and statistical indices is proposed, which is efficient to evaluate the tree breeding values for flowering regularity and could be transferred to other species.


Failures of inverse folding and threading with gapped alignment.
To calculate the tertiary structure of a protein from its amino acid sequence, the thermodynamic approach requires a potential function of sequence and conformation that has its global minimum at the native conformation for many different proteins. Here we study the behavior of such functions for the simplest model system that still has some of the features of the protein folding problem, namely two-dimensional square lattice chain configurations involving two residue types. First we show that even the given contact potential, which by definition is used to identify the folding sequences and their unique native conformations, cannot always correctly select which sequences will fold to a given structure. Second, we demonstrate that the given contact potential is not always able to favor the native alignment of a native sequence on its own native conformation over other gapped alignments of different folding sequences onto that same conformation. Because of these shortcomings, even in this simple model system in which all conformations and all native sequences are known and determined directly by the given potential, we must reexamine our expectations for empirical potentials used for inverse folding and gapped alignment on more realistic representations of proteins.


Analytical energy gradients for second-order multireference perturbation theory using density fitting.
We present algorithms for computing analytical energy gradients for multi-configuration self-consistent field methods and partially internally contracted complete active space second-order perturbation theory (CASPT2) using density fitting (DF). Our implementation is applicable to both single-state and multi-state CASPT2 analytical gradients. The accuracy of the new methods is demonstrated for structures and excitation energies of valence and Rydberg states of pyrrole, as well as for structures and adiabatic singlet-triplet energy splittings for the hydro-, the O,O(')-formato-, and the N,N(')-diiminato-copper-dioxygen complexes. It is shown that the effects of density fitting on optimized structures and relative energies are negligible. For cases in which the total cost is dominated by the integral evaluations and transformations, the DF-CASPT2 gradient calculations are found to be faster than the corresponding conventional calculations by typically a factor of three to five using triple-ζ basis sets, and by about a factor of ten using quadruple-ζ basis sets.


Human mycoses and current antifungal therapy.
The Focus on Fungal Infections meeting has become a popular conference for specialists in medical mycology and antifungal chemotherapy. Highlights of the 8th meeting are reported, with a focus on infection and therapy. Although the incidence of mycoses has increased, the identification of these fungal etiologic agents remains difficult. Mucosal candidiasis caused by endogenous Candida albicans and Candida species remains the most common fungal manifestation in HIV-infected patients, while systemic infection by Aspergillus species also has increased in HIV patients. Two presenters at the meeting debated whether fungal infections in AIDS patients are becoming less common and less important. Various strategies for antifungal therapy in AIDS or HIV-positive patients were presented. Most fungal infections in solid organ transplant patients are due to Candida species or Aspergillus species; however, dematiaceous (dark-pigmented) fungi are becoming more common fungal pathogens in these patients. Antifungal therapy remains difficult in this patient group. The meeting included an overview of the current status of diagnosing fungal infections through serodiagnostic techniques. If properly validated, serology can be useful in fungal diagnosis since antigens and antibodies are easier to detect than the invading organism. Premature infants are at high risk for developing invasive fungal infections. Antifungal drugs have not been tested in controlled clinical trials in these patients, thus therapy is accomplished using adult treatment regimens and anecdotal experience. As regards the new lipid-based formulations of amphotericin B, published clinical studies are only now appearing in the literature and these reports suggest that the new formulations have reduced toxicity and comparable efficacy compared to conventional amphotericin B under various clinical conditions. Correlation of minimum inhibitory concentration (MIC) values with clinical response to therapy is beginning to emerge. Two fungal cell wall-active compounds have recently entered clinical trials: an echinocandin and the chitin-synthesis inhibitor nikkomycin Z. Pradimycin and analogues have been studied through experimental animal models with good success; however, phase I clinical trials suggested drug-related toxicities and development was stopped. New molecular targets also are being investigated in antifungal therapy.


Effect of treatment with and subsequent withdrawal of exogenous porcine somatotropin on growth and reproductive characteristics of gilts.
Two experiments were conducted to examine responses of gilts to treatment with and withdrawal of exogenous porcine somatotropin (PST). In Exp. 1, 36 prepubertal gilts (79.7 +/- .9 kg; 159.1 +/- .7 d) were allotted randomly to receive daily either 0 micrograms PST (C) or 70 micrograms PST/kg initial BW for either 21 (PST-3) or 42 d (PST-6). Gilts were examined for estrus daily by a mature boar starting on d 22 and continuing for up to 50 d. Gilts that expressed estrus were mated and removed from treatment. PST-treated gilts had higher ADG (P less than .01) and lower feed/gain (P less than .02) than C gilts. Following initiation of boar exposure, C gilts (mean interval to estrus = 2.0 d) exhibited estrus earlier than PST-3 (24.8 d) and PST-6 (24.0 d) gilts (P less than .07); however, only two C gilts were observed in estrus compared with six PST-3 and six PST-6 gilts. In Exp. 2, 40 prepubertal gilts (72.6 +/- 1.0 kg; 141.1 +/- .7 d) were allotted randomly to receive daily either 0 mg PST (C) or 5 mg PST for 30 d. On d 31, half the gilts were comingled with unfamiliar penmates and examined for estrus daily by a mature boar for up to 45 d. Estrual gilts were removed from treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Editor's Highlight: Off-Target Effects of Neuroleptics and Antidepressants on Saccharomyces cerevisiae.
Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation of many pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses, microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins.


Neuropathogenesis of SARS-CoV-2 infection.
The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.


Distribution of sickness absence risk across different levels and patterns of drinking: findings from the Stockholm Public Health Cohort.
This study estimated (i) the risk function between different indicators of alcohol use and long-term sickness absence, adjusting for possible confounding factors, (ii) whether the risk function between average volume of consumption and sickness absence is modified by heavy episodic drinking (HED), and (iii) to what extent the risk for sickness absence among abstainers is due to health selection bias. The study was based on data from the Stockholm Public Health Cohort 2006, with an analytical sample of 16,477 respondents aged 18-64 years. The outcome included register-based long-term (> 14 days) sickness absence. Negative binominal regression was used to estimate the association between sickness absence and average weekly volume of consumption, frequency of HED, and both in interaction. Abstainers, chronic heavy drinkers and respondents with the highest frequency of HED had approximately two-fold higher rates of sickness absence relative to the reference groups, i.e., moderate drinkers and those with HED one to 6 times per year. Adjustment for confounding factors did not materially affect the shape of the risk function. After exclusion of abstainers with alcohol-related problems, or poor health, the estimates for abstainers became non-significant. Moderate drinkers with HED did not have significantly higher rates of sickness absence than moderate drinkers without HED. Our results suggest a significant association between alcohol use and sickness absence. There were indications that the U-shaped risk function may largely be due to health selection bias among abstainers. We found no indication of effect modification of HED on moderate drinking.


The effect of weaner diet protein content and diet quality on the long-term performance of pigs to slaughter.
Short and long-term effects of manipulating dietary CP content and diet quality in weaner diets on health and performance of pigs were investigated in a 2 x 2 factorial combination of CP inclusion (high-CP, 230 g of CP/kg vs. low-CP, 170 g of CP/kg) and diet quality (high-quality, cooked cereals, and animal protein vs. low-quality, raw cereals, and plant protein). Diets were fed ad libitum for 14 d postweaning to pigs weaned at 29.4+/-3.1 d of age and 9.9+/-1.0 kg of BW. From d 14 to slaughter at 104+/-3 kg, all pigs were fed the same series of standard commercial diets. There were 15 replicates per treatment in the weaner phase (<30 kg) and 5 replicates per treatment in the grower-finisher phase (>30 kg). High-quality diets promoted gut health as indicated by improved fecal lactobacilli to coliform ratio (P=0.002) and decreased fecal enterotoxigenic Escherichia coli counts on d 11 postweaning (P=0.028), reducing the risk of postweaning diarrhea and improving pig health from weaning to the end of the weaner phase. Reducing CP content had no effect on gut health. High-CP (P=0.053) and high-quality (P=0.025) diets independently increased ADG during the first 14 d postweaning compared with low-CP and low-quality diets, respectively. There were no interactions between dietary CP content and quality on any of the response criteria investigated. Despite differences in the immediate postweaning period, there was no effect of manipulating diet quality or CP content for 2 wk postweaning on lifetime performance with pigs reaching slaughter weight in 128+/-7 d. These results indicate that high-quality diets may protect pig gut health during the immediate postweaning period. However, it may be possible to use less expensive, decreased quality weaner diets without any adverse effects on long-term performance when weaning older, heavier pigs and where health status, environmental control, and stock management are all maintained to a high standard.


Eudragit S-100 entrapped chitosan microspheres of valdecoxib for colon cancer.
COX-2 inhibitors have demonstrated beneficial effects in colorectal cancer. The purpose of this study was to prepare and evaluate the colon specific microspheres of COX-2 inhibitors using valdecoxib as a model drug. Mucoadhesive core microspheres were prepared using chitosan as polymer and entrapped within Eudragit S 100 for colon targeting. FTIR spectrum of selected, coated microspheres showed peaks of valdecoxib at 3377, 3250, 1334 and 1155 cm(-1). XRD showed amorphous character and DSC showed depressed broad endotherm of valdecoxib at 169.07 degrees C, which may be attributed to dilution effect by the amorphous polymer. The coated microspheres were spherical with an average size of 90 mum. Storage of the microspheres at 40 degrees C/75% relative humidity for 6 months indicated no significant drug degradation. The coated microspheres did neither release the drug in acidic pH of stomach (pH 1.2) nor in small intestinal pH between 5 to 6.8, and the release started at pH 7.4, indicting perfect colonic delivery. The coated microspheres pretreated with phosphate buffer pH 7.4 for 30 min, when applied to mucosal surface of freshly excised goat colon, showed good mucoadhesion. The drug release at pH 7.4 and good mucoadhesive property of the microspheres make the system ideal for colonic delivery.


Immune-based therapies for childhood cancer.
After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in B-ALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms.


Metal-Based Green Synthesized Nanoparticles: Boon for Sustainable Agriculture and Food Security.
The applications of metal-based nanoparticles (MNPs) in the sustainable development of agriculture and food security have received greater attention in recent years in the science community. Different biological resources have been employed to replace harmful chemicals to reduce metal salts and stabilize MNPs, i.e., green methods for the synthesis have paid attention to the nanobiotechnological advances. This review mainly focused on the applications of green synthesized MNPs for the agriculture sector and food security. Because of the novel domains, the green synthesized MNPs could be helpful in the different areas of agriculture like plant growth promotion, plant disease, and insect/pest management, fungicidal agent, in food security for food packaging, for increasing the shelf life and protection from spoilage, and other purposes. The global scenario of the recent studies on the applications of green synthesized MNPs, particularly in sustainable agriculture and food security, is comprehensively discussed.


Conservative Management after Intraoperative Over-Release of the Medial Collateral Ligament from its Tibial Insertion Site in Patients Undergoing Total Knee Arthroplasty.
During varus deformity correction in a patient undergoing total knee arthroplasty (TKA), the medial collateral ligament (MCL) could get completely detached from its distal insertion site. Our aim was to evaluate the (1) mid-term clinical outcome and implant survival after conservative treatment in patients with intraoperatively over-released MCL and (2) preoperative risk factors for MCL over-release. A retrospective study was conducted on patients who had undergone a primary TKA between 2001 and 2006. The number of knees with intraoperative MCL over-release (over-released group) was 47 (40 patients); we compared these with the knees that had intact MCL (intact group, 502 knees). Simple anchoring of MCL was performed with no additional protection. The postoperative clinical outcome and implant survival were compared. Risk factors for MCL over-release were identified using multivariate analysis. The average follow-up period was 7.5 years. The mean Knee Society score of the over-released group improved from 23.3 to 92.7 and it was not significantly different from the intact group. Three cases of aseptic loosening occurred in the over-released group and 19 in the intact group (p = 0.423). The survival rates of the implant were 94.4% and 96.1%, respectively, at 13 years postoperatively. Multivariate analysis showed preoperative femoral-tibial angle as the only risk factor for over-release. This study showed that even MCL was over-released inadvertently, but it did not affect the clinical outcome. Preoperative femoral-tibial angle was the only predictable risk factor for MCL over-release.


Efficacy of Autologous Microfat Graft on Facial Handicap in Systemic Sclerosis Patients.
Autologous adipose tissue injection is used in plastic surgery for correction of localized tissue atrophy and has also been successfully offered for treatment of localized scleroderma. We aimed to evaluate whether patients with systemic sclerosis (SSc) and facial handicap could also benefit from this therapy. We included 14 patients (mean age of 53.8 ± 9.6 years) suffering from SSc with facial handicap defined by Mouth Handicap in Systemic Sclerosis Scale (MHISS) score more than or equal to 20, a Rodnan skin score on the face more than or equal to 1, and maximal mouth opening of less than 55 mm. Autologous adipose tissue injection was performed under local anesthesia using the technique of subcutaneous microinjection. The main objective of this study was an improvement of the MHISS score 6 months after the surgical treatment. The procedure was well tolerated. We observed a mean decrease in the MHISS score of 10.7 points (±5.1; P < 0.0001) at 6 months (35% improvement). Secondary efficacy parameters assessing perioral skin sclerosis, maximum mouth opening, sicca syndrome, and facial pain significantly improved at 3 and 6 months postsurgery. At a 6-month follow-up, 75% of patients were satisfied or very satisfied of the adipose tissue microinjection therapy. Our study suggests that subcutaneous perioral microfat injection in patients with SSc is beneficial in the treatment of facial handicap, skin sclerosis, mouth opening limitation, sicca syndrome, and facial pain. Thus, this minimally invasive approach offers a new hope for face therapy for patients with SSc.


The standard of healthcare accreditation standards: a review of empirical research underpinning their development and impact.
Healthcare accreditation standards are advocated as an important means of improving clinical practice and organisational performance. Standard development agencies have documented methodologies to promote open, transparent, inclusive development processes where standards are developed by members. They assert that their methodologies are effective and efficient at producing standards appropriate for the health industry. However, the evidence to support these claims requires scrutiny. The study's purpose was to examine the empirical research that grounds the development methods and application of healthcare accreditation standards. A multi-method strategy was employed over the period March 2010 to August 2011. Five academic health research databases (Medline, Psych INFO, Embase, Social work abstracts, and CINAHL) were interrogated, the websites of 36 agencies associated with the study topic were investigated, and a snowball search was undertaken. Search criteria included accreditation research studies, in English, addressing standards and their impact. Searching in stage 1 initially selected 9386 abstracts. In stage 2, this selection was refined against the inclusion criteria; empirical studies (n = 2111) were identified and refined to a selection of 140 papers with the exclusion of clinical or biomedical and commentary pieces. These were independently reviewed by two researchers and reduced to 13 articles that met the study criteria. The 13 articles were analysed according to four categories: overall findings; standards development; implementation issues; and impact of standards. Studies have only occurred in the acute care setting, predominately in 2003 (n = 5) and 2009 (n = 4), and in the United States (n = 8). A multidisciplinary focus (n = 9) and mixed method approach (n = 11) are common characteristics. Three interventional studies were identified, with the remaining 10 studies having research designs to investigate clinical or organisational impacts. No study directly examined standards development or other issues associated with their progression. Only one study noted implementation issues, identifying several enablers and barriers. Standards were reported to improve organisational efficiency and staff circumstances. However, the impact on clinical quality was mixed, with both improvements and a lack of measurable effects recorded. Standards are ubiquitous within healthcare and are generally considered to be an important means by which to improve clinical practice and organisational performance. However, there is a lack of robust empirical evidence examining the development, writing, implementation and impacts of healthcare accreditation standards.


[Correlation of space-time ranges in ecological hierarchies of various nature].
Relations between characteristic scales of time and space are analyzed for the hierarchical systems of a various nature. The available data fit well to the power relation: [T] = a[L]b, where [T] and [L] are characteristic ranges of time and space, b--scaling exponent, a--conversion coefficient. The spatio-temporal scales of ocean physical and biological (pelagic) processes are closely overlapped. Contrastingly, the scale for terrestrial and benthic ecosystems and their environments differ noticeably. For terrestrial and benthic ecological systems, and also for atmospheric phenomena, the b values significantly less than 1, that indicates a significant coherence of structure-generating processes integrating lower-level hierarchical units to a higher-level entity. For geomorphological structures, both terrestrial and oceanic, the scaling parameters has appeared close to 1 (a "direct transfer" type of generating processes). For plankton systems, which are related with water masses, the b values vary from 1 (processes of direct transfer) up to 2 (random dispersal or diffusion processes). The author attributes this difference to the principle distinctions in dynamic properties of the physical environments for terrestrial (and probably, benthic) and plankton organisms. Finally, for the units (structures or processes) of one and the same organization level, scaling exponents are significantly higher and close to 2 (diffusive dynamics) or more (rigid spatial limitation). Thus, the development of many ecological structures looks dynamically like diffusion or gradual growth, but their putting in the higher-level order (integrity) is a qualitative leap forward and demands appropriate cooperative organizational processes.