Development of uridine diphosphate-glucuronyltransferase activity in cultures of chick-embryo liver.
1. The liver of the domestric fowl (Gallus gallus) remains capable of conjugating o-aminophenol with glucuronic acid after 8 days' culture. The pathway of o-aminophenyl glucuronide formation in cultured liver, as in fresh tissue, includes the enzyme UDP-glucuronyltransferase. 2. UDP-glucuronyltransferase activity in chick-embryo liver increases on culture from very low to adult values within 6-8 days. 3. The development of UDP-glucuronyltransferase activity in cultured chick-embryo liver requires certain serum factors in the medium. The requirements change with embryo age. Liver from embryos younger than 15 days develops enzyme activity equally well in media containing either foetal or adult serum; liver from embryos older than 16 days develops activity only with adult serum. The development of enzyme activity in liver from the older embryos appears to be stimulated by diffusible factors in adult serum and inhibited by diffusible factors in foetal serum. It is suggested that the stimulation and inhibition of enzyme formation by small, diffusible molecules may be part of the mechanism regulating UDP-glucuronyltransferase activity in vivo. 4. Liver from 19-day-old chick embryos cultured with foetal serum begins to develop UDP-glucuronyltransferase activity if transferred to an adult-serum medium. Its capacity to develop UDP-glucuronyltransferase activity in adult serum survives in a foetal-serum medium for at least 5 days, the longest period tested. 5. The activity of UDP-glucuronyltransferase reached in 19-day chick-embryo liver after 1 or 2 days with adult serum is maintained without further increase after transfer to a foetal-serum medium. After 3 days with adult serum UDP-glucuronyltransferase activity continues to increase when the tissue is transferred to a foetal-serum medium. Thus liver from 19-day-old embryos requires 3 days with adult serum before development of enzyme activity becomes independent of a continuous adult-serum environment.


Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats.
Notch signaling is a component of a wide variety of developmental processes in many organisms. Notch activity can be modulated by O-fucosylation (mediated by protein O-fucosyltransferase-1) and Fringe, a beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose in the context of epidermal growth factor-like (EGF) repeats. Fringe was initially described in Drosophila, and three mammalian homologues have been identified, Manic fringe, Lunatic fringe, and Radical fringe. Here for the first time we have demonstrated that, similar to Manic and Lunatic, Radical fringe is also a fucose-specific beta1,3-N-acetylglucosaminyltransferase. The fact that three Fringe homologues exist in mammals raises the question of whether and how these enzymes differ. Although Notch contains numerous EGF repeats that are predicted to be modified by O-fucose, previous studies in our laboratory have demonstrated that not all O-fucosylated EGF repeats of Notch are further modified by Fringe, suggesting that the Fringe enzymes can differentiate between them. In this work, we have sought to identify specificity determinants for the recognition of an individual O-fucosylated EGF repeat by the Fringe enzymes. We have also sought to determine differences in the biochemical behavior of the Fringes with regard to their in vitro enzymatic activities. Using both in vivo and in vitro experiments, we have found two amino acids that appear to be important for the recognition of an O-fucosylated EGF repeat by all three mammalian Fringes. These amino acids provide an initial step toward defining sequences that will allow us to predict which O-fucosylated EGF repeats are modified by the Fringes.


Ca-P spots modified zirconia by liquid precursor infiltration and the effect on osteoblast-like cell responses.
Ca-P spots modified zirconia by liquid precursor infiltration and the cell responses were investigated. Pre-sintered zirconia specimens were immersed in Ca-P precursor solution. After dense sintering, scanning electron microscopy showed Ca-P spots were formed on the zirconia and anchored with zirconia substrates. The distribution density was increased with the extension of immersion time. Energy dispersive spectrometer confirmed the stoichiometric Ca/P ratio was about 1.67. After hydrothermal treatment, Ca-P spots turned into rod crystals where diffraction peaks of tricalcium phosphate and hydroxyapatite were detected by X-ray diffraction, and Ca2+ and PO43- release decreased slightly (p>0.05). There was no significant decrease on three-point bending strength (p>0.05). Osteoblast-like MC3T3-E1 cells attached and spread well and showed higher proliferation on Ca-P spots modified zirconia (p<0.05), though its initial alkaline phosphatase activity was not significant high (p>0.05). In conclusion, Ca-P liquid precursor infiltration is a potential method to modify the zirconia ceramics for improving bioactivity.


[The planning of values of indices of quality of resource management in medical organizations of the Moscow state medical care system].
The article presents the results of planning the values of indices of resource management quality in medical organizations of the Moscow state health system, that participated i the project of implementation of the quality standard of resource management in 2016-2017. The approaches of medical organizations to assessment of resources and opportunities of increasing efficiency of management of financial and human resources are described.


Safety and Efficacy of Laparoscopic Versus Open Gastrectomy in Patients With Advanced Gastric Cancer Following Neoadjuvant Chemotherapy: A Meta-Analysis.
Given the expanding clinical applications of laparoscopic surgery and neoadjuvant chemotherapy in advanced gastric cancer treatment, there is an emerging need to summarize the few evidences that evaluated the safety and efficacy of laparoscopic versus open gastrectomy in patients with advanced gastric cancer (AGC) following neoadjuvant chemotherapy (NAC). From January 1 to 2, 2021, we searched Ovid Embase, PubMed, Cochrane central register Trials (Ovid), and web of science to find relevant studies published in English, and two authors independently performed literature screening, quality assessment of the included studies, data extraction, and data analysis. This study was registered with PROSPERO (CRD42021228845). The initial search retrieved 1567 articles, and 6 studies were finally included in the meta-analysis review, which comprised 2 randomized control trials and 4 observational studies involving 288 laparoscopic gastrectomy (LG) and 416 open gastrectomy (OG) AGC patients treated with NAC. For intraoperative conditions, R0 resection rate, blood transfusion, intraoperative blood loss, number of lymph nodes dissected, proximal margin, and distal margin were comparable between LG group and open OG group. For postoperative short-term clinical outcomes, LG has significantly less postoperative complications (OR = 0.65, 95%CI: 0.42-1.00, p = 0.05) and shorter postoperative time to first aerofluxus (WMD = -0.57d, 95%CI: -0.89-0.25, p = 0.0004) than OG, and anastomotic leakage, pulmonary infection, pleural effusion, surgical site infection, thrombosis, intestinal obstruction, peritoneal effusion or abscess formation, postoperative time to first defecation, postoperative time to first liquid diet, and postoperative length of stay were comparable between the two groups. For postoperative survival outcomes, there were no significant differences in disease-free survival (DFS) and overall survival (OS) between the two groups. The available evidences indicated that LG is an effective and feasible technology for the treatment of AGC patients treated with NAC, and LG patients have much less postoperative complications and faster bowel function recovery than OG patients. PROSPERO database (identifier, CRD42021228845).


High-energy inelastic-scattering beamline for electron momentum density study.
The advent of synchrotron radiation sources for well polarized and high-energy X-rays offers new opportunities for exploiting Compton scattering spectroscopy as a tool for investigating the electronic and magnetic structures of materials. Recent high-resolution Compton scattering experiments show the unique capability for the study of Fermiology-related issues and electron-electron correlation effects. Intense, high-energy and circularly polarized X-ray sources have improved magnetic Compton scattering spectroscopy from the point of statistical accuracy and momentum resolution. As a next advance, a high-energy inelastic scattering beamline dedicated to Compton scattering spectroscopies is being constructed at SPring-8. The light source is an elliptic multipole wiggler with a periodic length of 12 cm. The beamline includes two experimental stations: one is for high-resolution spectroscopy using 100-150 keV X-rays and the other is for magnetic Compton scattering experiments using circularly polarized 300 keV X-rays. The use of such high-energy X-rays makes it possible to carry out experiments efficiently on samples including heavier elements, such as high-T(c) superconductors and 4f and 5f magnetic materials.


[The standardization of near visual acuity].
The determination of close visual acuity is done accurately if the vision exam at a distance of 40 cm is standardized and if an exact estimation of the near visual acuity for professional activities of normal people and people with bad visual acuity can be made. The model of an optotype for near vision, Snellen metric type, using the Jaeger notation from 1 to 16 and also the standardized point system from 3 to 36, is presented. A professional selection of people with bad visual acuity after near visual exam is also presented.


ASSESSMENT OF SERUM 25-HYDROXYVITAMIN D CONCENTRATIONS IN TWO COLLECTIONS OF CAPTIVE GORILLAS (GORILLA GORILLA GORILLA).
Serum 25-hydroxyvitamin D concentrations were assessed in subadult to adult captive lowland gorillas ( Gorilla gorilla gorilla) (n = 26) at two institutions with different husbandry and management practices. Serum 25-hydroxyvitamin D (25[OH]D) concentrations for gorillas managed predominantly indoors was low (14.2 ± 5.9 ng/ml), despite consuming commercial biscuits fortified with vitamin D3. Concentrations of 25(OH)D in gorillas with near daily outdoor access were significantly higher than gorillas managed indoors, although many individuals still had serum values below concentrations recommended for adult humans. Consideration should be given to assessing 25(OH)D concentrations in all captive gorillas and providing specific supplementation, particularly to juveniles without access to direct sunlight.


The effects of exercise training on muscle atrophy in haemodialysis patients.
Patients with end-stage renal disease on haemodialysis (HD) have limited work capacity. Many structural and functional alterations in skeletal muscles contribute to this disability. To evaluate the effects of exercise training on uraemic myopathy, seven HD patients (mean age 44.1+/-17.2 years) were studied. Open muscle biopsies were taken from their vastus lateralis muscle before and after a 6-month exercise rehabilitation programme and examined by routine light- and transmission electron-microscopy. Histochemical stainings of frozen sections were performed and morphometric analysis was also applied to estimate the proportion of each fibre type and the muscle fibre area. Spiroergometric and neurophysiological testing and peak extension forces of the lower limbs were measured before and after exercise training. All patients showed impaired exercise capacity, which was associated with marked muscular atrophy (mean area 2548+/-463 microm2) and reduction in muscle strength and nerve conduction velocity. All types of fibres were atrophied, but type II were more affected. The ultrastructural study showed severe degenerative changes in skeletal muscle fibres, mitochondria, and capillaries. Exercise training had an impressive effect on muscular atrophy; in particular the proportion of type II fibres increased by 51% and mean muscle fibre area by 29%. Favourable changes were also seen on the structure and number of capillaries and mitochondria. These results were confirmed by a 48% increase in VO2 peak and a 29% in exercise time, as well as an improvement in the peak muscle strength of the lower limbs and in nerve conduction velocity. Skeletal muscle atrophy in HD patients contribute to their poor exercise tolerance. The application of an exercise training rehabilitation programme improved muscle atrophy markedly, and therefore had beneficial effects in overall work performance.


Dental caries prevalence and dental health care of Mexican-American workers' children.
The purpose of this study was to determine the prevalence of dental caries and the use of dental services in a pediatric population of Mexican-American migrant workers. The results were compared with the Mexican-American child population from the Hispanic Health and Nutrition Examination Survey (HHANES). One hundred thirty three-to-sixteen-year-old children participated in the study. The children who were born in Mexico and those who spoke Spanish had seen the dentist less often and had a higher incidence of decayed teeth than those who were born in the US and than those who spoke English (p < 0.05). The children from low-income families had visited the dentist less frequently and did so at an older age than those from high income families (p < 0.05). When compared with HHANES, the children in this study visited the dentist at an older age, had been to the dentist less often, were less likely to have dental insurance, and had a higher incidence of dental caries than the children from HHANES (p > 0.05). This study demonstrated a general lack of dental health knowledge, a disproportionate prevalence of decayed teeth and unmet dental need in the Mexican-American migrant workers' children.


The physician-patient relationship revisited: the patient's view.
The importance of the physician-patient relationship for the health care market is beyond controversy. Recent work emphasizes a two-sided asymmetric information relationship between physician and patient. In contrast to most work looking only at the physician's perspective, our paper concentrates on the patient's view. Estimation results support the hypotheses that physician consultation and health relevant behavior are not stochastically independent. In the recursive bivariate probit model, patient's health relevant behavior has a significant influence on the probability of a physician visit. This means that health care demand and not only the contact decision is determined by both, patient and physician.


Effect of high-impact aerobics and strength training on BMD in young women aged 20-35 years.
To evaluate the effects of a 12-month exercise intervention using either high-impact step aerobic exercise or moderate-intensity strength training on areal bone mineral density (aBMD) we studied 51 untrained women, aged 20-35 years, for this study. Whole body and heel and wrist aBMD were measured by dual-energy X-ray absorptiometry (DXA, Hologic or PIXI Lunar). Subjects were randomly assigned to: impact-loaded step aerobic exercise (SA, n=15), moderate-intensity lower body strength training (ST, n=16) or non-exercise control (CON, n=20). Data analysis only included those who completed 95% of each training routine and attended at least 80% of all sessions. Group differences in aBMD, leg press strength and urinary cross-link deoxypridinoline (μDPD) were analysed using analysis of variance. After a 12-month intervention, the SA elicited an increase in aBMD of the heel (4.4%, p<0.05) and leg press strength (15%, p<0.05), relative to baseline. Meanwhile, the ST showed an increase in leg press strength (48%, p<0.05) with no significant increase in aBMD at any measured site. Similar and unchanged μDPD was observed in all 3 groups at baseline, 6 and 12 months. In conclusion, a 12-month high-impact step aerobic exercise resulted in a significant increase in the heel aBMD in untrained young women, who complied with the exercise regimen. A moderate intensity strength training intervention of similar duration had no effect on aBMD although leg strength increased significantly.


Weather factors in the short-term forecasting of daily ambulance calls.
The daily ambulance demand for Hong Kong is rising, and it has been shown that weather factors (temperature and humidity) play a role in the demand for ambulance services. This study aimed at developing short-term forecasting models of daily ambulance calls using the 7-day weather forecast data as predictors. We employed the autoregressive integrated moving average (ARIMA) method to analyze over 1.3 million cases of emergency attendance in May 2006 through April 2009 and the 7-day weather forecast data for the same period. Our results showed that the ARIMA model could offer reasonably accurate forecasts of daily ambulance calls at 1-7 days ahead of time and with improved accuracy by including weather factors. Specifically, the inclusion of average temperature alone in our ARIMA model improved the predictability of the 1-day forecast when compared to that of a simple ARIMA model (8.8% decrease in the root mean square error, RMSE=53 vs 58). The improvement in the 7-day forecast with average temperature as a predictor was more pronounced, with a 10% drop in prediction error (RMSE=62 vs 69). These findings suggested that weather forecast data can improve the 1- to 7-day forecasts of daily ambulance demand. As weather forecast data are readily accessible from Hong Kong Observatory's official website, there is virtually no cost to including them in the ARIMA models, which yield better prediction for forward planning and deployment of ambulance manpower.


Flow cytometric analysis of virus-infected cells and its potential use for screening antiviral agents.
Virus-infected cells were analyzed using multiparameter flow cytometry. Two virus-cell systems were investigated: HSV-1-infected VF cells and influenza C virus JHB/1/66-infected MDCK cells. Analysis included the measurement of the appearance of virus specific antigens. On individual cells, with polyclonal antibodies, antigens were first detected at 12 h p.i., and the numbers of labeled cells were followed up to 96 h p.i. The efficacy of four antiviral agents was tested with this system. The results were in good agreement with those of plaque reduction tests and indicated that this new method may be extremely useful for the correlation of viral and cellular events with antiviral activity. Finally, it was demonstrated that infected cells in both systems have a considerably greater volume than non-infected cells.


Formulation of garlic oil-in-water nanoemulsion: antimicrobial and physicochemical aspects.
Despite the unique properties, application of garlic essential oil (GEO) is too limited in food and drugs, due to its low water solubility, very high volatility and unpleasant odour. In this work, a nanoemulsion containing GEO was formulated to cover and protect the volatile compounds of GEO. The encapsulation efficiency of formulated nanoemulsions was measured by gas chromatography and obtained encapsulation efficiency ranged from 91 to 77% for nanoemulsions containing 5-25% GEO, respectively. The 2,2-diphenyl-1-picrylhydrazyl method for antioxidant activity measurement showed that free radical scavenging capacity of nanoemulsions intensified during storage time. The electrical conductivity of the samples was constant over storage time while linearly increased by raising the temperature. Thermogravimetric analysis was used to determine the thermal resistance of nanoemulsions and their ingredients. Interestingly, microbial tests cleared that the control nanoemulsion with a particle size below 100 nm (nanoemulsion without GEO) also showed antimicrobial activity. Disk diffusion method showed that pure GEO and also formulated nanoemulsions had a stronger effect against Gram-positive bacterium (Staphylococcus aureus) than Gram-negative bacterium (Escherichia coli).


A fast tracking method for magnetic abnormalities using distributed Overhauser magnetometer system based on genetic algorithm.
Magnetic anomaly detection technologies have been widely used for tracking moving targets. In this paper, we present a fast-tracking method for magnetic abnormalities using a distributed Overhauser magnetometer system based on the genetic algorithm. Our proposed framework of the Overhauser magnetometer system employs multiple sensors to eliminate background interference, and the genetic algorithm efficiently solves magnetic anomaly data without requiring the derivation of the objective function. Test platforms were built to evaluate the distributed Overhauser magnetometer system and the genetic algorithm. Results from the natural outdoor magnetism laboratories showed that the noise of our presented magnetometers was below 0.134 nT. The optimal factors for solution precision and effectiveness in the genetic algorithm were obtained from the simulation. Moreover, the outdoor tracking experiments indicated that the proposed method could accurately and quickly detect the moving ferromagnetic object within 6.9% maximum positioning error in 0.55 m, and the tracking precision of the object velocity can get 5.88% maximum error in 4.33 km/h.


Stent Implantation for Effective Treatment of Refractory Chylothorax due to Superior Vena Cava Obstruction as a Complication of Congenital Cardiac Surgery.
Chylothorax is a serious complication of congenital cardiac surgery and is significantly associated with increased morbidity and mortality. Central venous obstruction, which is often related to the insertion of central venous catheters for postoperative management, is known to be an important risk factor for treatment failure and mortality associated with this condition. We present the case of a 6-month-old girl with refractory chylothorax after surgical repair of tetralogy of Fallot. The chylous drainage continued for more than 2 months despite maximal conservative therapy (water restriction, total parenteral nutrition, and infusion of somatostatin and steroid) and surgical ligation of the thoracic duct. Subsequently, we observed stenosis of the superior vena cava (SVC) caused by large thrombi possibly associated with the prolonged use of central venous catheter placed in the internal jugular vein. Because transcatheter balloon dilation failed to relieve the stenosis, we performed stent implantation for the SVC and innominate vein. After the procedure, chylous drainage dramatically reduced, and the patient was discharged from the hospital. In conclusion, central venous obstruction due to thrombosis should be routinely examined when chylothorax is diagnosed and is resistant to conservative therapy after congenital heart surgery. Stent implantation can effectively relieve the venous obstruction and thus be a life-saving treatment option for this difficult condition.


The role of prostaglandins as modulators of insulin-stimulated glucose metabolism in skeletal muscle.
Prostaglandins of the E series are known to increase the sensitivity of glucose uptake to insulin in isolated, incubated skeletal muscle of the rat. In the present study the relationships between changes in both insulin sensitivity and prostaglandins E2 metabolism were investigated. Chronic treatment of rats with the synthetic glucocorticoid dexamethasone causes an insulin resistant state in vivo. Also, the sensitivity of glucose metabolism to insulin from normal rats varies over a 24-h period. In both these rat models the sensitivity of glucose metabolism to insulin in isolated skeletal muscle was greatest when the content or rates of release of prostaglandin E2 were highest. These results strongly suggest that changes in PGE2 metabolism can influence the sensitivity of glucose metabolism to insulin in skeletal muscle.


Conscious updating is a rhythmic process.
As the visual world changes, its representation in our consciousness must be constantly updated. Given that the external changes are continuous, it appears plausible that conscious updating is continuous as well. Alternatively, this updating could be periodic, if, for example, its implementation at the neural level relies on oscillatory activity. The flash-lag illusion, where a briefly presented flash in the vicinity of a moving object is misperceived to lag behind the moving object, is a useful tool for studying the dynamics of conscious updating. Here, we show that the trial-by-trial variability in updating, measured by the flash-lag effect (FLE), is highly correlated with the phase of spontaneous EEG oscillations in occipital (5-10 Hz) and frontocentral (12-20 Hz) cortices just around the reference event (flash onset). Further, the periodicity in each region independently influences the updating process, suggesting a two-stage periodic mechanism. We conclude that conscious updating is not continuous; rather, it follows a rhythmic pattern.


Detection of Chili Foreign Objects Using Hyperspectral Imaging Combined with Chemometric and Target Detection Algorithms.
Chilies undergo multiple stages from field production to reaching consumers, making them susceptible to contamination with foreign materials. Visually similar foreign materials are difficult to detect manually or using color sorting machines, which increases the risk of their presence in the market, potentially affecting consumer health. This paper aims to enhance the detection of visually similar foreign materials in chilies using hyperspectral technology, employing object detection algorithms for fast and accurate identification and localization to ensure food safety. First, the samples were scanned using a hyperspectral camera to obtain hyperspectral image information. Next, a spectral pattern recognition algorithm was used to classify the pixels in the images. Pixels belonging to the same class were assigned the same color, enhancing the visibility of foreign object targets. Finally, an object detection algorithm was employed to recognize the enhanced images and identify the presence of foreign objects. Random forest (RF), support vector machine (SVM), and minimum distance classification algorithms were used to enhance the hyperspectral images of the samples. Among them, RF algorithm showed the best performance, achieving an overall recognition accuracy of up to 86% for randomly selected pixel samples. Subsequently, the enhanced targets were identified using object detection algorithms including R-CNN, Faster R-CNN, and YoloV5. YoloV5 exhibited a recognition rate of over 96% for foreign objects, with the shortest detection time of approximately 12 ms. This study demonstrates that the combination of hyperspectral imaging technology, spectral pattern recognition techniques, and object detection algorithms can accurately and rapidly detect challenging foreign objects in chili peppers, including red stones, red plastics, red fabrics, and red paper. It provides a theoretical reference for online batch detection of chili pepper products, which is of significant importance for enhancing the overall quality of chili pepper products. Furthermore, the detection of foreign objects in similar particulate food items also holds reference value.


Neurophysiological and nutritional considerations of pain control.
Pain is a phenomenon experienced by all forms of life. Many theories exist to explain how it is perceived. This paper examines several of those theories, particularly as they relate to nutritional and neurophysiological implications in the production and management of pain. An explanation of how certain chiropractic treatment modalities operate is provided.


PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.
During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.


Variations of AbaR4-type resistance islands in Acinetobacter baumannii isolates from South Korea.
AbaR resistance islands in Acinetobacter baumannii isolates from South Korea were investigated. AbaR4-type resistance islands, including bla(OXA-23)-containing Tn2006, interrupted the comM gene in A. baumannii ST75 isolates. However, Tn2006 was not identified within AbaR resistance islands of ST138 isolates, although the bla(OXA-23) gene was detected in them. The similar structures of resistance islands suggest that most carbapenem-resistant A. baumannii isolates in South Korea have originated from the same ancestor with a globally disseminated clone, GC II.


Diabetes and obesity: therapeutic targeting and risk reduction - a complex interplay.
Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off-target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non-pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co-morbid hypertension and dyslipidaemia. Additional long-term studies, including CVD end-point studies, will be necessary to determine the appropriate places for incretin-based therapies in treatment algorithms.


IL-2, TNF-alpha, and leptin: local versus systemic concentrations in NSCLC patients.
One recent line of cancer research shows increasing interest for biological factor such as IL-2, TNF-alpha, and leptin, which have been found to participate in the development and progression of non-small cell lung cancer (NSCLC). The aim of this study was to measure IL-2, TNF-alpha, and leptin concentrations in the airways and in the systemic circle of patients with NSCLC, investigating the role of these factors in the lung tumors. We enrolled 32 patients (17 men, 71 +/- 7 years) with a histological diagnosis of NSCLC and 20 healthy ex-smoker controls, negative for computed tomography of the chest (14 men, 69 +/- 8 years). IL-2, TNF-alpha, and leptin levels were measured in the serum, the urine, the bronchoalveolar lavage, the induced sputum, and exhaled breath condensate (EBC) of patients enrolled by means of a specific enzyme immunoassay kit. Higher concentrations of IL-2, TNF-alpha and leptin were found in NSCLC patients than in controls (p < 0.0001). A statistically significant increase of IL-2, TNF-alpha, and leptin concentrations was observed in patients from stage I to stage III of NSCLC. These findings suggest that IL-2, TNF-alpha, and the leptin play an important role in the cancerogenesis of NSCLC. Their measure in the EBC could be proposed as noninvasive markers for an early detection of NSCLC and in the follow-up of this tumor.


Hormone receptors in renal cancer: an overview.
The current literature concerning hormone receptors in renal cell cancer is reviewed. Our own results of histochemical determination of estrogen receptors by means of monoclonal antibodies are presented. Based on the studies that have been reviewed and the differing results of the receptor assays, we conclude that there is a very limited basis to apply hormone therapy in renal cell cancer. However, the new immunohisto-chemical methods should be used to resolve the question about the hormone dependency of renal carcinoma.


Exposure to air pollution and self-reported effects on Chinese students: A case study of 13 megacities.
Air pollution causes severe physical and psychological health complications. Considering China's continuously-deteriorating air quality, this study aimed to assess the self-reported effects of air pollution on the behavior and physical health of the students of 13 densely populated cities, and their awareness, practices, and perception of air pollution and its associated public health risks. A detailed, closed-ended questionnaire was administered to 2100 students from 54 universities and schools across China. The questionnaire, which had 24 questions, was categorized into four sections. The first two sections were focused on air pollution-associated behavior and psychology, and physical effects; while the final two sections focused on the subjects' awareness and perceptions, and practices and concerns about air pollution. The respondents reported that long-term exposure to air pollution had significantly affected their psychology and behavior, as well as their physical health. The respondents were aware of the different adverse impacts of air pollution (respiratory infections, allergies, and cardiovascular problems), and hence had adopted different preventive measures, such as the use of respiratory masks and glasses or goggles, regularly drinking water, and consuming rich foods. It was concluded that air pollution and haze had negative physical and psychological effects on the respondents, which led to severe changes in behavior. Proper management, future planning, and implementing strict environmental laws are suggested before this problem worsens and becomes life-threatening.


General Versus Nongeneral Anesthesia for Spinal Surgery: A Comparative National Analysis of Reimbursement Trends Over 10 Years.
Nongeneral anesthesia (non-GA) spine surgery is growing in popularity and has facilitated earlier postoperative recovery, reduced cost, and fewer complications compared with spine surgery under general anesthesia (GA). Changes in reimbursement policies have been demonstrated to correlate with clinical practice; however, they have yet to be studied for GA vs non-GA spine procedures. We aimed to investigate trends in physician reimbursement for GA vs non-GA spine surgery in the United States. We queried the ACS-NSQIP for GA and non-GA (regional, epidural, spinal, and anesthesia care/intravenous sedation) spine surgeries during 2011-2020. Work relative value units per operative hour (wRVUs/h) were retrieved for decompression or stabilization of the cervical, thoracic, and lumbar spine. Propensity score matching (1:1) was performed using all baseline variables. We included 474 706 patients who underwent spine decompression or stabilization procedures. GA was used in 472 248 operations, whereas 2458 operations were non-GA. The proportion of non-GA spine operations significantly increased during the study period. Operative times (P < .001) and length of stays (P < .001) were shorter in non-GA when compared with GA procedures. Non-GA lumbar procedures had significantly higher wRVUs/h when compared with the same procedures performed under GA (decompression; P < .001 and stabilization; P = .039). However, the same could not be said about cervicothoracic procedures. Lumbar decompression surgeries using non-GA witnessed significant yearly increase in wRVUs/h (P < .01) contrary to GA (P = .72). Physician reimbursement remained stable for procedures of the cervical or thoracic spine regardless of the anesthesia. Non-GA lumbar decompressions and stabilizations are associated with higher and increasing reimbursement trends (wRVUs/h) compared with those under GA. Reimbursement for cervical and thoracic surgeries was equal regardless of the type of anesthesia and being relatively stable during the study period. The adoption of a non-GA technique relative to the GA increased significantly during the study period.


[Influence of testicular microlithiasis on male fertility: An update].
With the increasing awareness of men's health, more and more clinical studies are reported on the relationship of testicular microlithiasis (TM) with male infertility. TM is a relatively rare disease characterized by multiple microcalcifications (<3 mm) in the seminiferous tubules of the testis. This review summarizes the findings in the studies of the diagnosis, epidemiology, correlation with male fertility, treatment, and follow-up of TM in recent years. Many researches show that TM has a certain correlation with the decline of male fertility, which, however, is not identically agreed on at home and abroad. As for the treatment of TM complicated with male infertility, there is still a lack of effective and reliable drugs and strategies and a need for many basic and clinical studies.


An integrated model of the younger generation's online shopping behavior based on empirical evidence gathered from an emerging economy.
The younger generation is the largest Internet user group in China. They are the first generation to grow up with computers, the Internet, smartphones, online social media, and online shopping. The individuals that belong to this generational cohort have one thing in common-their online shopping behavior. To understand the shopping behavior of the younger Chinese generation, this study draws on the theoretical foundation of generational cohort theory. This study proposes an integrated model that examines the effects of information adoption, personalized service, perceived switching risk, and habitual behavior on purchase intention in the online shopping environment. Survey data have been collected from 407 Chinese people that belong to the post-90s generation. Structural equation modeling is used to analyze the data. Empirical findings show that information adoption, personalized service, and perceived switching risk are the most important predictors of online purchase intention. However, habitual behavior is negatively related to online purchase intention.


The modified use of a proximal humeral locking plate for tibiotalocalcaneal arthrodesis.
Different types of fixation have been used to achieve a tibiotalocalcaneal (TTC) arthrodesis. The purpose of this study was to retrospectively examine the modified use of a 3.5-mm proximal humeral locking plate (PHILOS plate, Synthes, Paoli, PA) in obtaining a TTC fusion. Between April, 2003, and November, 2005, 17 patients had 18 TTC arthrodeses with a PHILOS plate through a transfibular approach. Preoperative diagnoses included Charcot arthropathy, neuromuscular disease, arthritis, and talar osteonecrosis. Patients were followed from 8 months to 3 years and 2 months (mean 20.6 months). Fusion was achieved in 16 of the 17 patients (94.1%) and 17 of the 18 arthrodeses (94.4%) with a mean time to fusion of 20.6 weeks. The mean American Orthopaedic Foot and Ankle Society (AOFAS) score increased from 14.6 of 100 preoperatively to 76.7 of 86 (equivocal to 89.2 of 100) at final followup. One patient who had brittle diabetes went on to develop a nonunion. The patients in this study had a wide variety of medical conditions that left their bone osteopenic or osteoporotic. This study demonstrated that using a modified locking plate for a TTC arthrodesis results in a high rate of bony union and alignment correction stability. The locking plate provides fixation by acting as a fixed angle device, with the locking screws providing multiplanar fixation. The use of a locking plate has not been previously reported, and it may hold promise as a means of achieving a TTC fusion.


Salicylic acid interferes with GFP fluorescence in vivo.
Fluorescent proteins have become essential tools for cell biologists. They are routinely used by plant biologists for protein and promoter fusions to infer protein localization, tissue-specific expression and protein abundance. When studying the effects of biotic stress on chromatin, we unexpectedly observed a decrease in GFP signal intensity upon salicylic acid (SA) treatment in Arabidopsis lines expressing histone H1-GFP fusions. This GFP signal decrease was dependent on SA concentration. The effect was not specific to the linker histone H1-GFP fusion but was also observed for the nucleosomal histone H2A-GFP fusion. This result prompted us to investigate a collection of fusion proteins, which included different promoters, subcellular localizations and fluorophores. In all cases, fluorescence signals declined strongly or disappeared after SA application. No changes were detected in GFP-fusion protein abundance when fluorescence signals were lost indicating that SA does not interfere with protein stability but GFP fluorescence. In vitro experiments showed that SA caused GFP fluorescence reduction only in vivo but not in vitro, suggesting that SA requires cellular components to cause fluorescence reduction. Together, we conclude that SA can interfere with the fluorescence of various GFP-derived reporter constructs in vivo. Assays that measure relocation or turnover of GFP-tagged proteins upon SA treatment should therefore be evaluated with caution.


Electrochemistry serving people and nature: high-energy ecocapacitors based on redox-active electrolytes.
Positive Poles: A new type of electrochemical capacitor with two different aqueous solutions, separated by a Nafion membrane is described. High capacitance values as well as excellent energy/power characteristics are reported and discussed. The neutral character of the applied electrolytes makes this capacitor an environmentally friendly, easy to assemble, and cost-effective device for energy storage.


Case Report: Remdesivir and Convalescent Plasma in a Newly Acute B Lymphoblastic Leukemia Diagnosis With Concomitant Sars-CoV-2 Infection.
Introduction: The spread of Covid-19 has worsened the prognosis of oncology patients, interrupting or delaying life-saving therapies and contextually increasing the risk of severe SARS-CoV-2 infections. Acute lymphoblastic leukemia (ALL) is the most frequent cancer in pediatric age and the management of this disease with concomitant SARS-COV-2 infection represents a challenging situation. Case presentation: We present the case of a 6-year-old female newly diagnosed with ALL during a documented SARS-CoV-2 infection. Our patient was admitted 20 days after SARS-CoV-2 detection for evening-rise fever. Laboratory testing showed severe neutropenia while chest x-ray detected moderate pulmonary involvement. Acute lymphoblastic leukemia diagnosis was made through morphological and molecular analysis on bone marrow aspirate. Given the stability of the blood count and clinical conditions, antiviral therapy with Remdesivir and Convalescent Plasma was started before antileukemic treatment, obtaining a rapid resolution of the infection. Conclusion: In our experience, the treatment with Remdesivir and Convalescent Plasma led to a rapid resolution of Sars-Cov-2 infection. Our case did not present any adverse event to the therapy. Thus, this treatment could be considered in patients with malignancies, in order to accelerate the resolution of the infection and begin immunosuppressive treatment safely. Further studies are required to confirm this hypothesis.


Charge recombination via intercolumnar electron tunneling through the lipid-like mantle of discotic hexa-alkyl-hexa-peri-hexabenzocoronenes.
The recombination of the mobile charge carriers formed in pulse-ionized hexa-alkyl-substituted hexa-peri-hexabenzocoronenes occurs mainly via intercolumnar electron tunneling through the intervening hydrocarbon mantle. This is evidenced as a dramatic increase in the time scale of the decay of the radiation-induced conductivity from a few hundred nanoseconds to close to a millisecond as the peripheral alkyl substituents increase in size from 8 to 24 carbon atoms with corresponding disk diameters, D, from 23.4 to 36.6 A. The decay kinetics are a function only of the total number of peripheral carbon atoms with no evidence for specific effects of chain branching. The 1/e decay time, tau(e), increases exponentially with D according to tau(e) = tau(e)(0) exp(betaD) with tau(e)(0) = 48 fs and beta = 0.63 A(-1). Taking into account the tilted columnar configuration of the molecules in the solid phase leads to a beta value of ca. 0.8 A(-1) for the distance dependence of intercolumnar electron tunneling. In contrast to the orders of magnitude changes in the time scale for intercolumnar charge recombination, the intracolumnar charge hopping times vary by only a factor of 4, between 40 and 160 fs, with no systematic dependence on the nature of the alkyl substituents. On the basis of the results, the time scale estimated for electron tunneling across a 40 A thick lipid membrane is estimated to be close to 1 ms.


The transcription elongation factor TFIIS is a component of RNA polymerase II preinitiation complexes.
In this article, we provide direct evidence that the evolutionarily conserved transcription elongation factor TFIIS functions during preinitiation complex assembly. First, we identified TFIIS in a mass spectrometric screen of RNA polymerase II (Pol II) preinitiation complexes (PICs). Second, we show that the association of TFIIS with a promoter depends on functional PIC components including Mediator and the SAGA complex. Third, we demonstrate that TFIIS is required for efficient formation of active PICs. Using truncation mutants of TFIIS, we find that the Pol II-binding domain is the minimal domain necessary to stimulate PIC assembly. However, efficient formation of active PICs requires both the Pol II-binding domain and the poorly understood N-terminal domain. Importantly, Domain III, which is required for the elongation function of TFIIS, is dispensable during PIC assembly. The results demonstrate that TFIIS is a PIC component that is required for efficient formation and/or stability of the complex.


Technetium-99m MDP demonstration of heterotopic ossification in fibrodysplasia ossificans progressiva.
The extensive heterotopic bone formation in patients with fibrodysplasia ossificans progressiva (FOP) has been documented previously with radiographs. A case in which a Tc-99m MDP bone scan showed increased uptake at sites well before ossification could be documented radiographically is described. This finding suggests that bone scans would likely be useful to monitor the extent of involvement with FOP and to detect areas of new activity.


Advancing a multivalent 'Pan-anthelmintic' vaccine against soil-transmitted nematode infections.
The Sabin Vaccine Institute Product Development Partnership is developing a Pan-anthelmintic vaccine that simultaneously targets the major soil-transmitted nematode infections, in other words, ascariasis, trichuriasis and hookworm infection. The approach builds off the current bivalent Human Hookworm Vaccine now in clinical development and would ultimately add both a larval Ascaris lumbricoides antigen and an adult-stage Trichuris trichiura antigen from the parasite stichosome. Each selected antigen would partially reproduce the protective immunity afforded by UV-attenuated Ascaris eggs and Trichuris stichosome extracts, respectively. Final antigen selection will apply a ranking system that includes the evaluation of expression yields and solubility, feasibility of process development and the absence of circulating antigen-specific IgE among populations living in helminth-endemic regions. Here we describe a five year roadmap for the antigen discovery, feasibility and antigen selection, which will ultimately lead to the scale-up expression, process development, manufacture, good laboratory practices toxicology and preclinical evaluation, ultimately leading to Phase 1 clinical testing.


Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism.
PPARγ (peroxisome proliferator activated receptor γ) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARγ include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARγ have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists.


Prenatal diagnosis by chorionic villus sampling.
The future of chorionic villus sampling can only be envisioned in the light of current knowledge. Amniocentesis will undoubtedly continue to hold an important place in prenatal diagnosis and has recently assumed greater importance in diagnosing neural tube defects and Down syndrome through widespread maternal serum alpha-fetoprotein screening. Patients now have a choice in prenatal diagnostic procedures for most genetic disorders. Many are already choosing chorionic villus sampling despite the questions that remain regarding risks and diagnostic accuracy. Risk figures for miscarriages due to the procedure and for intrauterine infection are especially needed. The issues of maternal contamination in laboratory analyses and chromosomal mosaicism that may not be present in the fetus are also of prime importance. Collaborative efforts continue to answer these and other questions so that in the future patients will be better able to make informed decisions regarding prenatal diagnosis.


Explaining Obesity- and Smoking-related Healthcare Costs through Unconditional Quantile Regression.
Background: This paper assesses obesity- and smoking-related incremental healthcare costs for the employees and dependents of a large U.S. employer. Objectives: Unlike previous studies, this study evaluates the distributional effects of obesity and smoking on healthcare cost distribution using a recently developed econometric framework: the unconditional quantile regression (UQR). Methods: Results were compared with the traditional conditional quantile regression (CQR), and the generalized linear modeling (GLM) framework that is commonly used for modeling healthcare cost. Results: The study found strong evidence of association of healthcare costs with obesity and smoking. More importantly, the study found that these effects are substantially higher in the upper quantiles of the healthcare cost distribution than in the lower quantiles. The insights on the heterogeneity of impacts of obesity and smoking on healthcare costs would not have been captured by traditional mean-based approaches. The study also found that UQR impact estimates were substantially different from CQR impact estimates in the upper quantiles of the cost distribution. Conclusions: These results suggest the potential role that smoking cessation and weight management programs can play in arresting the growth in healthcare costs. Specifically, given the finding that obesity and smoking have markedly higher impacts on high-cost patients, such programs appear to have significant cost saving potential if targeted toward high-cost patients.


Genomic analysis of a virulent and a less virulent strain of the entomopathogenic fungus Beauveria bassiana, using restriction fragment length polymorphisms.
The genomic DNA of two strains of the entomopathogenic fungus Beauveria bassiana, strain GK2016, a "wild type" (virulent), and strain GK2051, a less virulent mutant to grasshoppers, was digested with 12 restriction endonucleases. Gel electrophoresis conditions were established to show restriction fragment length patterns visually in the digested DNA stained with ethidium bromide. The less virulent mutant was generated by ultraviolet illumination of conidiospores at a 95% lethal dose. Both strains of the fungi were identical in morphology as well as in 16 of 22 API-ZYM kit enzyme assays. Differences in levels of total enzyme activity were observed for esterase, esterase-lipase, beta-galactosidase, chitinase, and protease. A Neurospora crassa beta-tubulin gene (heterologous gene) and two homologous DNA probes (pJK16 and pJK18) hybridized to several specific DNA bands in B. bassiana strain GK2016 but not in strain GK2051. Strain GK2051 gave different restriction fragment length pattern when compared with its parent strain. Taken together, the data show restriction fragment length differences between the genomic DNA of the two strains, including the loss of some DNA sequences from the mutant strain, which may be involved in pathogenicity. Finally, B. bassiana GK2016 contains a beta-tubulin gene with at least partial homology to that of N. crassa.


Selective estrogen receptor modulators to prevent treatment-related osteoporosis.
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.


Filamin B: The next hotspot in skeletal research?
Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Up to present, pathogenic mutations in FLNB are solely found to cause skeletal deformities, indicating the important role of FLNB in skeletal development. FLNB-related disorders are classified as spondylocarpotarsal synostosis (SCT), Larsen syndrome (LS), atelosteogenesis (AO), boomerang dysplasia (BD), and isolated congenital talipes equinovarus, presenting with scoliosis, short-limbed dwarfism, clubfoot, joint dislocation and other unique skeletal abnormalities. Several mechanisms of FLNB mutations causing skeletal malformations have been proposed, including delay of ossification in long bone growth plate, reduction of bone mineral density (BMD), dysregulation of muscle differentiation, ossification of intervertebral disc (IVD), disturbance of proliferation, differentiation and apoptosis in chondrocytes, impairment of angiogenesis, and hypomotility of osteoblast, chondrocyte and fibroblast. Interventions on FLNB-related diseases require prenatal surveillance by sonography, gene testing in high-risk carriers, and proper orthosis or orthopedic surgeries to correct malformations including scoliosis, cervical spine instability, large joint dislocation, and clubfoot. Gene and cell therapies for FLNB-related diseases are also promising but require further studies.


Palladium-Catalyzed ortho-C-H Methylation of Benzoic Acids.
A palladium-catalyzed methylation of C-H bonds of benzoic acids with di-tert-butyl peroxide as the methylating reagent under an external oxidant and ligand-free conditions has been achieved. The reaction is found to be directed by a weakly coordinating carboxyl group, offering a facile route for the synthesis of highly functionalized ortho-methyl benzoic acids.


Neuregulin-1 and schizophrenia in the genome-wide association study era.
Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1's relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1's role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia.


The adenovirus E1A transforming protein activates the proliferating cell nuclear antigen promoter via an activating transcription factor site.
The transforming region of adenovirus (E1) stimulates expression of a reporter construct linked to the promoter for the human proliferating cell nuclear antigen (PCNA) gene in a cotransfection assay (G. F. Morris and M. B. Mathews, J. Biol. Chem. 264:13856-13864, 1989). The major products of the E1 region were assessed individually for their contribution to transactivation of the PCNA promoter. The E1A 13S and 12S products and the E1B 19-kDa product elevated expression from the PCNA promoter, whereas the E1B 55-kDa product did not. Induction of the PCNA promoter by E1A differed from transcriptional activation of the adenovirus E3 promoter in that the PCNA promoter is activated by the E1A 12S product whereas the E3 promoter is repressed; furthermore, the PCNA promoter is activated upon E1A overexpression, whereas the E3 promoter responds less well to high amounts of E1A. A site for the activating transcription factor ATF located approximately 50 nucleotides upstream from the transcription initiation site in the PCNA promoter mediates a positive response to the E1A 12S and 13S products.


Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform.
A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, methodology was developed for measuring a suite of 10 different cytokines in human blood, exhaled breath condensate (EBC), and urine using an electrochemiluminescent multiplex Th1/Th2 cytokine immunoassay platform. Measurement distributions and correlations for eight interleukins (IL) (1β, 2, 4, 5, 8, 10, 12p70 and 13), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were evaluated using 90 blood plasma, 77 EBC, and 400 urine samples collected from nominally healthy adults subjects in North Carolina in 2008-2012. The in vivo results show that there is sufficient sensitivity for characterizing all 10 cytokines at levels of 0.05-0.10 ρg/ml with a dynamic range up to 100 ng/ml across all three of these biological media. The measured in vivo results also show that the duplicate analysis of blood, EBC and urine samples have average estimated fold ranges of 2.21, 3.49, and 2.50, respectively, which are similar to the mean estimated fold range (2.88) for the lowest concentration (0.610 ρg/ml) from a series of spiked control samples; the cytokine method can be used for all three biological media. Nine out of the 10 cytokines measured in EBC were highly correlated within one another with Spearman ρ coefficients ranging from 0.679 to 0.852, while the cytokines measured in blood had a mix of negative and positive correlations, ranging from -0.620 to 0.836. Almost all correlations between EBC and blood were positive. This work also represents the first successful within- and between-person evaluation of ultra trace-level inflammatory markers in blood, EBC, and urine.


Isolation and expression of the full-length cDNA encoding CD59 antigen of human lymphocytes.
To identify the primary structure of CD59 antigen and to elucidate its function, a full-length cDNA clone of CD59 was isolated. The cDNA sequence contained an open reading frame that encodes an 128-amino-acid peptide. The amino-terminal 25 amino acids represented a typical signal peptide sequence and the carboxy-terminal hydrophobic amino acids were characteristic for phosphatidylinositol-anchored proteins. The predicted mature protein sequence showed 35% homology with murine Ly-6C.1 and 31% with Ly-6A.2. The number and the distribution of cysteine residues were conserved, implying that the CD59 represented a human homologue of murine Ly-6. RNA blot hybridization analysis revealed the expression of CD59 mRNA in placental, lung, and pancreatic tissues. The mRNA was not only expressed in T-cell lines but in some of monocytic, myeloid, and B-cell lines. In all of these tissues and cell lines, at least four mRNA species were detected. DNA blot hybridization analysis revealed a rather simple genomic structure, which suggested a single gene as compared with the complex multigene family of murine Ly-6.


CD4-dependent signaling is required for a late checkpoint during Th2 development associated with resistance to activation-induced cell death.
Previous studies have found that class II-restricted T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene have a specific defect in the development of Th2 effector cells; however, the reason for this defect was not clear. Following stimulation with a high potency peptide and exogenous IL-4, CD4-dependent signaling is required for optimal generation of a Th2 effector population. However, initial IL-4 and GATA-3 transcription is appropriately induced, suggesting that the initial stages of Th2 development are intact and independent of CD4 after priming with a strong agonist peptide. In addition to the defect in Th2 development, CD4 mutant T cells are also relatively resistant to activation-induced cell death (AICD). Furthermore, inhibition of AICD in wild-type T cells causes a defect in Th2 development similar to that seen in the CD4 mutant T cells. These data support the hypothesis that CD4-dependent signaling pathways regulate a distinct checkpoint in the expansion and commitment phase of Th2 development, which is related to dysregulation of AICD.


The History and Future of Ablative Neurosurgery for Major Depressive Disorder.
There is an urgent need to develop safe and effective treatments for patients with treatment-resistant depression (TRD). Several neurosurgical procedures have been developed to treat the dysfunctional brain circuits implicated in major depression. This review describes the most common ablative procedures used to treat major depressive disorder: anterior cingulotomy, subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy. The efficacy and safety of each are discussed and compared with other current and emerging modalities, including deep brain stimulation (DBS) and MR-guided focused ultrasound (MRgFUS). The PubMed and MEDLINE electronic databases were used in this study, through July 2016. Keywords, including "treatment resistant depression," and "ablative neurosurgery," etc. were used to generate reference hits. Approximately a third to half of patients who underwent ablative procedures achieved a treatment response and/or remission. The efficacy and safety profiles corresponding to both ablative procedures and DBS were very similar. The longitudinal experience with ablative procedures shows that there remains an important role for accurate, discrete lesions in disrupting affective circuitry in the treatment of TRD. New modalities, such as MRgFUS, have the potential to further improve the accuracy of ablative procedures, while enhancing safety by obviating the need for open brain surgery.


Functional independence, diagnostic groups, hospital stay, and modality of payment in three Croatian seaside inpatient rehabilitation centers.
To determine patients' functional independence, diagnostic groups, duration of hospital stay, and modality of payment of rehabilitation in major special hospitals for rheumatology and medical rehabilitation on the Croatian seaside. In a cross-sectional study conducted from October 2006 until January 2009, we surveyed 400 patients treated at 3 special hospitals for medical rehabilitation. Their functional independence was assessed by modified Barthel index and they self-evaluated their health using the first item from the 36-Item Short-Form Health Survey questionnaire. On admission, almost half of the patients (46%) were fully functionally independent, 33% were slightly dependent, while 21% were moderately or severely dependent. At the end of the hospitalization, significant predictors for the increase in Barthel index were longer hospital stay (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.22), diagnosis of post-procedural musculoskeletal disorders (OR, 4.84; 95% CI, 1.90-10.57), diagnosis of conditions following acute ischemic heart disease (OR, 9.71; 95% CI, 3.40-27.75), and lower Barthel index at admission (OR, 0.96; 95% CI, 0.94-0.97). Of the 97 patients with dorsopathy, 73 (75%) were fully functionally independent and 57 (59%) paid for the treatment either themselves or contributed substantially to the total cost. Assessment of patients' functional status is important for the organization of inpatient rehabilitation. Patients with dorsopathy could be targeted as a population for medical tourism in rehabilitation medicine in order to maximize the use of rehabilitation hospitals.


Individual risk factors of the metabolic syndrome in adult patients with growth hormone deficiency--a cross-sectional case-control study.
Growth hormone deficiency in adults (GHDA) is considered to be associated with increased cardiovascular risk, most commonly reflected by the prevalence of the metabolic syndrome (MS). However, there are still a limited number of studies comparing directly the MS prevalence in GHD patients to that in general population. The aim of this study was to investigate the individual risk factors of the MS in a cohort of GHD patients and to compare its prevalence with an age- and sex-matched control group. A cross-sectional case-control study. In total, 54 adult patients with GHD (childhood onset GHD (COGHD): n=19, adult onset GHD (AOGHD): n=35) and 2 153 control subjects were studied. GHD was diagnosed according to the Endocrine Society Clinical Practice Guideline recommendations from 2011 and MS was scored by the NCEP-ATP III definition. The main metabolic abnormalities in GHD group were increased waist circumference (50.0%), low HDL-cholesterol (42.6%) and hypertriglyceridemia (40.7%) and their prevalence was significantly higher (p=0.013, p=0.019 and p=0.010, respectively) than in control group, where increased blood pressure prevailed (64.2%, p<0.0001). However, the difference in the MS prevalence between the 2 groups (29.6% vs. 24.9% in controls) failed to reach statistical significance (p=0.429). Patients with MS from both groups did not differ significantly in their metabolic profile (except for increased blood pressure), mean age and gender distribution. Although GHDA was associated with the development of visceral obesity and dyslipidemia, these adverse cardiovascular risk factors did not determine a higher prevalence of the MS in Bulgarian GHD patients compared to control subjects. Furthermore, the individual risk factors of the MS did not significantly differ between patients with MS from both groups.


Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer.
Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost the AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between the high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting a refinement of critical TFCGs in prostate cancer progression. We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent the development of CRPC following ADT.


The health of children looked after by local authorities.
There are some 40,000 children 'in care' in England and Wales, i.e. being 'looked after' by local authorities and living in foster and residential homes. These children come from highly disadvantaged social backgrounds and are likely to experience more serious health problems than the wider population. Despite this, there is evidence to suggest that their health needs are frequently neglected. This is reflected in the dearth of research information. Health professionals play a key role in combating child abuse and are particularly concerned about future mental health, self-injury and high levels of pregnancy in this group of children. Health promotion is therefore vital, but is complicated by the fact that this group of children often do not attend school. The Department of Health has introduced a major initiative which has a strong health dimension to help promote better care planning and monitoring for children who have been separated from their parents.


Vegetative and psychological symptoms associated with depressed mood over the first two years after stroke.
In patients with acute physical illness, symptoms used in the diagnosis of major depression such as sleep or appetite disturbance may be nonspecific for depression. This study was undertaken to examine the association of depressed mood with other depressive symptoms to determine which symptoms were most useful in the accurate diagnosis of major depression after stroke. Using a structured mental status examination, 142 patients with acute stroke were followed at three, six, twelve, and twenty-four months. The median number of vegetative and psychological symptoms among patients with depressed mood was more than three times the respective rates among nondepressed patients at all time points over two years. Autonomic anxiety, morning depression, subjective anergia, worrying, brooding, loss of interest, hopelessness, and lack of self-confidence were significantly more frequent among depressed patients than nondepressed patients throughout the entire two-year period. Some symptoms such as anxious foreboding and loss of libido, as well as self-depreciation, feelings of guilt, and irritability were no longer significantly more common among depressed compared with nondepressed patients after six months. Standard DSM-IV diagnostic criteria and modified DSM-IV diagnostic criteria which included only specific symptoms of depression (i.e., symptoms which were significantly more frequent among depressed than nondepressed mood patients) yielded similar frequencies of major depression diagnosis. There were only a few patients (i.e., 2% to 3%) with depressive symptoms without a depressed mood (perhaps "masked" depression). Vegetative and psychological depressive symptoms are significantly more common in depressed patients over the first two years after stroke and DSM-IV criteria do not overdiagnose major depression even in this population with chronic physical illness. The symptoms which characterize major depression appear to change between the subacute and chronic post-stroke periods.


[25 cases of gastric smooth muscle tumors and review of the literature].
25 gastric smooth muscle tumors (12 symptomatic leiomyomas, 9 fortuitously discovered leiomyomas and 4 leiomyosarcomas) are presented. Follow-up has lasted from 9 months to 9 years. We have correlated the epidemiology, symptoms and anatomopathology with the evolution of these cases, in an attempt to single out specific features of benign and malignant forms. The most relevant macroscopic criteria of malignity are: a tumor measuring over 5 cm in diameter, widespread intratumoral necrosis. The histologic degree of malignity depends on several criteria, of which the most important are: the number of mitoses per high power microscopic field, cellular pleomorphism. Barium meal detects all symptomatic gastric smooth muscle tumors, and echography has the advantage of objectivizing intratumoral necrosis. For benign as well as malignant tumors the excision should be minimal, leaving a 2 cm safety margin. Simple enucleation is ruled out. If possible, metastases should be removed with the same safety margin. There is a good correlation between histologic type and prognosis. One case in 4 is associated with another malignancy.


Immunoglobulin responses after rubella infection.
The indirect immunofluorescence technique has been used to study specific IgG, IgA, and IgM antibodies in adults with acute rubella, volunteers who receive attentuated rubella vaccine, and infants with suspected congenital infection. In acute rubella, IgA and IgM antibodies reached peak titers during the second week after the rash and then declined, but specific IgG persisted. A similar pattern of response occurred after rubella vaccination, but titers were lower. Occasionally, fluorescent staining failed to detect specific IgM in whole serum but demonstrated it clearly in sucrose density gradient fractions. The improvement in fluorescence obtained by staining serum fractions was particularly striking in samples obtained from congenitally infected infants. In these cases, IgM staining with whole serum was often poor, but when fractions were tested, specific IgM was demonstrated in nearly all samples obtained within 9 months of birth. IgM antibody was seldom detected after the first year of life, but IgG antibody persisted. IgA antibody was not detected in congenital rubella.


Evaluation of health related quality of life changes after initial orthodontic treatment.
To evaluate the changes of Oral Health Related Quality of Life (OHRQoL) in patients after the placement of a fixed orthodontic appliance. This prospective study consisted of 148 adolescents (97 girls and 51 boys) between the ages of 14 and 17 who were patients of an orthodontic clinic. OHRQoL was assessed by a modified questionnaire that evaluated four domains: oral symptoms, functional limitations as well as emotional and social well-being in three time frames: before bonding and banding (T(0)), two months after initiating orthodontic treatment (T(1)) and six months after initiating orthodontic treatment (T(2)). The repeated measures test was used to compare the relative changes of OHRQoL among the different time frames. There were no significant differences between the levels of OHRQoL and its domains for boys or girls at any time point. The overall level of OHRQoL decreased significantly at T(1) relative to T(0); however, the emotional well-being domain improved at T(1) in comparison to T(0). At T(2), the OHRQoL level increased significantly relative to T(0) in all domains. The patients' quality-of-life level decreased by initiating orthodontic treatment; however, during that period, emotional well-being increased. As orthodontic treatment progressed, the quality of life level increased.


Use of physician-specific data and flow sheets to improve compliance with preventive and screening health care measures.
The benefits of preventive and screening health-care measures have been well documented, but physician compliance with these measures has been imperfect. This investigation sought to measure and improve compliance of seven internists with a range of health-care measures. This study had two parts. Part 1: Office medical records of seven internists were scored on 36 measures. Physicians were given their individual and group scores to determine if such data would improve future compliance with these measures. A second record review was performed six months later, and the two compliance scores for both individual physician and the group were compared. Part 2: A flow sheet utilizing these 36 measures was custom designed for each physician to determine if this tool would increase compliance rates over those determined in Part 1. Part 1: Baseline compliance with health measures by these internists was approximately 75%. Providing individual and group scores to physicians had no significant effect on compliance with these health-care measures as measured by the second record review. Part 2: Custom designed flow sheets provided comparable compliance rates and were as effective as record review in assessing compliance, with some measures improving and some declining in comparison scores on Part 1. The flow sheet itself, however, did not increase overall compliance scores either for individual physicians or the group as a whole. Baseline compliance with health-care measures was higher in this investigation than reported elsewhere. Neither data feedback nor redesigned flow sheets increased overall compliance rates, but flow sheets were superior in documenting some frequently updated items, such as medication lists. Flow sheets were inexpensive and easy to implement. Additionally, flow sheets allowed for more rapid assessment of physician performance than time-consuming chart review. Until superior methods are widely available, the use of flow sheets in ambulatory care should be encouraged.


Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis.
The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.


In vitro characterization of two lineage-negative CD34+ cell-enriched hematopoietic cell populations from human UC blood.
During the last few years there has been increasing interest, from both biologic and clinical points of view, in the ex vivo expansion of umbilical cord blood (UCB)-derived hematopoietic cells. This has brought about the need to characterize different cell populations present in UCB, and to explore different ex vivo approaches for the culture, expansion and biologic manipulation of these cells. By using a negative-selection method, two UCB cell populations were obtained that were enriched for primitive lineage-negative (Lin-) cells, including those expressing the CD34 Ag (35-93% of the total cells in each fraction). Population I was enriched for CD34+ Lin- cells, whereas population II was enriched for CD34+ CD38- Lin- cells. Both populations were cultured in serum-free liquid cultures supplemented with different combinations of early and late-acting recombinant cytokines (all of them added at 10 ng/mL). Every 5-7 days proliferation, expansion and differentiation capacities of each population were determined, for a total period of 25-42 days. Both cell populations showed extensive proliferation and expansion capacities; however, population II [2300- and 232-fold increase in nucleated and colony-forming cell (CFC) numbers, respectively] was clearly superior in both parameters compared with population I (1120- and 20-fold increase in nucleated and CFC numbers, respectively). Depending on the cytokine combination used, granulocytes, macrophages and erythroblasts were preferentially produced. We also observed that both populations were highly sensitive to the inhibitory effects of tumor necrosis factor-alpha, even in the presence of stimulatory cytokines. This study demonstrates that the two progenitor cell-enriched populations obtained by negative selection possess extensive proliferation and expansion potentials in vitro, generating significant numbers of both primitive and mature cells. These cells may be a good alternative to purified CD34+ cells, obtained by positive selection, for pre-clinical and clinical protocols aimed at the ex vivo expansion of UCB cells.


Comparison of final heights of growth hormone-treated vs. untreated children with idiopathic growth failure.
We measured adult heights (Ht) of 94 healthy GH-sufficient children (peak GH > 10 ng/mL, polyclonal RIA) whose Ht at presentation were more than 2 SD below the mean for chronological age, with normal weight-to-Ht ratios, normal body proportions, and pathologic growth velocity for chronological age. Group 1 (n 36, 6 females) received standardized doses (0.3 mg/kg x week) of GH (mean duration = 41 months), while group 2 (n = 58, 17 females) received no treatment. Our conclusion was that the mean final Ht SD score in the GH-treated group (-1.5) was significantly greater than in the untreated group (-2.1); P < .001. Genetic predisposition to short stature was evident in both groups: the midparental Ht SD score was -1.1 in the treated and -1.0 in the untreated group. Midparental Ht was met or exceeded by 42% of the GH-treated group but only 15% of the untreated group. Final Ht was not significantly different from predicted Ht, except from GH-treated girls, who exceeded their predicted Ht. Although the mean Ht gains (6.8 cm in girls and 3 cm in boys) were modest and variable, GH treatment provided significantly better Ht outcomes for the majority of children with idiopathic growth failure.


Blood-brain barrier breakdown involves four distinct stages of vascular damage in various models of experimental focal cerebral ischemia.
Ischemic stroke not only impairs neuronal function but also affects the cerebral vasculature as indicated by loss of blood-brain barrier (BBB) integrity. Therefore, therapeutical recanalization includes an enhanced risk for hemorrhagic transformation and bleeding, traditionally attributed to a 'reperfusion injury'. To investigate the mechanisms underlying ischemia-/reperfusion-related BBB opening, we applied multiple immunofluorescence labeling and electron microscopy in a rat model of thromboembolic stroke as well as mouse models of permanent and transient focal cerebral ischemia. In these models, areas exhibiting BBB breakdown were identified by extravasation of intravenously administered fluorescein isothiocyanate (FITC)-albumin. After 24 hours, expression of markers for tight and adherens junctions in areas of FITC-albumin leakage consistently remained unaltered in the applied models. However, lectin staining with isolectin B4 indicated structural alterations in the endothelium, which were confirmed by electron microscopy. While ultrastructural alterations in endothelial cells did not differ between the applied models including the reperfusion scenario, we regularly identified vascular alterations, which we propose to reflect four distinct stages of BBB breakdown with ultimate loss of endothelial cells. Therefore, our data strongly suggest that ischemia-related BBB failure is predominantly caused by endothelial degeneration. Thus, protecting endothelial cells may represent a promising therapeutical approach in addition to the established recanalizing strategies.


Retrieval difficulty and retention of reactivated memories over the first year of life.
A newly acquired memory is remembered longer when its retrieval is more difficult (i.e., when the time since the last retrieval is longer). In two experiments using an operant conditioning task with 198 infants between 3 and 12 months of age, we presently asked if a reactivated memory also is remembered longer when its retrieval is more difficult. During their first year, infants remember a memory reactivated 1 week after forgetting and the newly acquired memory equally as long. After determining the upper limit (UL) of reactivation at all ages (Experiment 1), we reactivated the memory near the UL and then measured its subsequent persistence (Experiment 2). We found that increasing the training-reactivation interval enhanced retention at 6 months only. These data reveal that increasing retrieval difficulty affects infants' retention of newly acquired and reactivated memories differently. More generally, memory reactivation seems to disproportionately benefit retention in younger infants.


Formoterol attenuates neutrophilic airway inflammation in asthma.
Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison. We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.


Associations among physical activity, comorbidities, depressive symptoms and health-related quality of life in type 2 diabetes.
To investigate associations between physical activity, comorbidity severity, depressive symptoms, and health-related quality of life in type 2 diabetes mellitus. All individuals, 200 patients and 50 controls, aged from 40 to 60 years, were investigated by interview, and all variables were measured concurrently. Physical activity was evaluated by the International Physical Activity Questionnaire (IPAQ), Health-Related Quality of Life (HRQL) by the Short-Form Health Survey (SF-36), comorbidity severity by the Charlson Comorbidity Index (CCI), and depressive symptoms by the Beck Depression Inventory (BDI-II > 16). Single and multiple regression analysis evaluated the effects of independent variables on physical activity. The patients had more depressive symptoms and greater comorbidity severity (p < 0.005). Diabetic patients showed better activity levels (IPAQ) (p < 0.005). Functional Capacity, General State of Health, and Physical Limitation were the most affected subscales in the SF-36 evaluation of the HRQL. Sedentary diabetic patients had higher waist circumference, waist-to-hip ratios, more depressive symptoms, and worse HRQL. Functional capacity (p = 0.000), followed by General State of Health (p = 0.02), were the health status measure subscales independently associated with physical activity. The findings suggest that increasing patient independence and treating depressive symptoms can promote physical activity for type 2 diabetes mellitus patients. It is suggested that group activities and caregivers/family support might compensate for the patient dependence, and increase adherence to exercise programs in those that are less active.


Cholesterol impairment contributes to neuroserpin aggregation.
Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol reg-ulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.


Prenatal Maternal Distress: A Risk Factor for Child Anxiety?
The deleterious association between various types of prenatal maternal psychological distress (PNMS, anxiety, depression, psychological distress, stress) and childhood anxiety symptomatology (internalizing behaviors, anxiety symptoms) has been established using both retrospective and prospective longitudinal studies across varied demographic cohorts and throughout development. Yet, the existing literature cannot claim maternal distress during pregnancy to be a specific risk factor for anxiety symptomatology, as studies utilizing such observational designs are unable to adequately account for confounding of potential genetic factors and the postnatal environment. In this review, we examine studies that attempt to minimize such confounding and thus disentangle the unique intrauterine exposure effect of varying types of PNMS on childhood anxiety symptomatology. Such methodologies include paternal versus maternal comparison studies, sibling comparisons, prenatal cross-fostering designs and timing of exposure studies (including disaster studies). Of the identified studies, findings indicate that prenatal maternal distress is likely to constitute a risk factor for anxiety symptomatology, although more studies are needed to replicate current findings in order to determine whether there are clear differences in effects across specific types of PNMS and for specific subpopulations. We review the methodological limitations and strengths of the literature prior to exploring avenues of future research and implications for theory and clinical practice.


Feeling useful and engaged in daily life: exploring the experiences of people with young-onset dementia.
To explore the aspects of daily life that give people with young-onset dementia (YOD) a sense of usefulness. Eighteen people with YOD and 21 informal caregivers participated in this qualitative study. Participants were recruited from specialized day-care centers for people with YOD in the Netherlands. Four focus groups were conducted with people with YOD, and four with informal caregivers. Focus groups were audio-recorded, transcribed, and analyzed using inductive content analysis. Four themes emerged from the analysis: (1) staying engaged, (2) loss in daily life, (3) coping and adaptation, and (4) external support. Staying engaged in activities that provide a sense of usefulness or participating in leisure and recreational activities as much as possible in daily life emerged as the key theme. Retaining a sense of usefulness was considered both important and possible by having social roles or participating in functional activities. The importance of activities providing a sense of usefulness seemed to decrease over time, while the need for pleasant activities seemed to increase. Experienced loss, coping, adaptation, and available external support are important parts of the context in which the person with YOD tries to engage in daily life as much as possible. Active coping styles and external support appear to play a facilitating role in staying engaged. It is important for people with YOD to have the opportunity to feel useful; especially in the early stages of the condition. Caregivers should be educated in ways to enhance a sense of usefulness and engagement in daily life for people with YOD.