Spinal tuberculosis in children: Retrospective analysis of 124 patients.
There is a paucity of report on spinal tuberculosis in children. We report a retrospective analysis of 124 children with TB spine treated over 30 years. We retrospectively reviewed 124 children; of cervical (n=36), cervicothoracic (n=4), thoracic (n=53), and lumbar and lumbosacral tuberculosis (n=31) with no skip or multifocal lesions treated between 1971-2004. The age ranged from 2 to 15 years of age with 28 children less than 5 years of age, 58 were between 6 and 10 years, and 38 were over 10 years, 18 had paraplegia of various degrees. Ninety-one children were treated conservatively, while 33 children were subjected to surgery for focal debridement (n=23), posterior interspinous wiring and cementation (n=4), and posterior instrumentation with rods and segmental wiring (n=14). Triple chemotherapy (isoniazid, streptomycin, and PAS) was given for 18 months (3HSPa, 15Hpa) between 1971 and 1975, and triple or quadruple chemotherapy (isoniazid, rifampicin, ethambutol, or pyrazinamide) after 1976 to 2004 for 12 months (12RHZ or 12 RHZE). Some of the children in the current series belonged to the British MRC conservative study patients. The average duration of followup was 5 years and 8 months (range 1.6-20 years). All children attained healed status and showed neural recovery (n=18). The patients attained healed status at 18 months in the first series and at 12 months in the second series after chemotherapy. Spontaneous intercorporal fusion occurred only in 10 (8.06%) of 124 children. Sagittal curve during growth showed three different patterns: Unchanged, decreased, and increased curves. The residual kyphosis was unavoidable in cases with growth plate damage. Kyphosis increased in cases with wedged monovertebra and fused wedged block vertebra, though it was different at different level. The vertebral reformation and curve correction were possible only through the growth plates. The posterior instrumented stabilization alone could correct and/or prevent progress of the kyphosis. However, for active tuberculosis, posterior instrumented stabilization combined with anterior radical surgery should be reserved only for the advanced tuberculosis with instability, rapid progress of kyphosis, and/or unacceptable pre-existing kyphosis, though there is a new trend of prophylactic posterior instrumentation even for the early tuberculosis.


Effects of Compound Feed Attractants on Growth Performance, Feed Utilization, Intestinal Histology, Protein Synthesis, and Immune Response of White Shrimp (Litopenaeus Vannamei).
To investigate the effects of compound attractants on the growth performance, feed utilization, intestinal morphology, protein synthesis, and immune response of Litopenaeus vannamei, the following seven diets were formulated: a positive control (P), a negative control (N), and five diets with compound attractants which were labeled as A, B, C, D, and E, each with four of five tested attractants (yeast extract, squid visceral powder, fish soluble, and squid paste, shrimp paste), respectively. Shrimp (0.71 ± 0.00 g) were distributed to seven groups of four replicates and fed for 7 weeks. Results showed that the final body weight, feed intake, specific growth rate, and weight gain of shrimp in the B and D groups were the greatest. Hemolymph total antioxidant capacity of shrimp in the B, D, and E groups reached the highest level. In the hepatopancreas, the activity of total nitric oxide synthase, malondialdehyde content, the expression levels of sod, myd88, eif4e2, and raptor in shrimp fed the B diet were the highest, and the highest levels of dorsal and relish were observed in the C group. In the intestine, intestinal muscle thickness and expression levels of toll and eif2α in the C group were the highest, while the highest expression level of sod and relish occurred in the B group. In summary, the B and E diets promoted the feed intake, growth performance and the antioxidant enzyme activity of L. vannamei. The C diet enhanced the protein synthesis of shrimp. Regression analysis indicated that the WG and FI of shrimp were increased as the dietary inclusion levels of squid paste and shrimp paste increased, while they were decreased as the dietary inclusion levels of yeast extract and fish soluble increased.


The hepatitis B carrier state.
Acute hepatitis B virus infection resolves in 95 percent of patients within one year. The remaining 5 percent have persistent infection and become chronic carriers. In the United States, there are nearly one million carriers, who are at increased risk of developing immune-complex disorders and liver diseases. Treatment is available to reduce vertical transmission, and ongoing trials of immunosuppressive and antiviral agents are aimed at decreasing or resolving viral replication.


Research Trend of Women's Health in Korean Nursing Journals (2010~2015).
To explore trends of women's health in nursing research by analyzing articles on women aged 13 years or older that were published in Korean Journal for Women Health Nursing from 2010 to 2015. Seven focus areas were identified and modified to reflect integrative conceptual models of women's health: maternity care, menstrual concerns, health problems in women, gender influences on health risks, social influences on women's health, women and health care policy, and sexual health and violence against women. A total of 383 studies were analyzed according to these seven focus areas. Health problems in women, maternity care, and societal influences on women's health were the most widely studied topics in Korean women's health. There was increased attention to societal influences on women's health and gender influences on health risk. However, these areas are still limited in nursing research. Only 1% of these studies were in area of women's health policy. More studies in area of sexual health and violence against women are needed. Studies in area of women and health care policy are also needed to improve women's health in Korea.


Trends in Cardiovascular Complications and Mortality among Patients with Diabetes in South Korea.
We investigated the cardiovascular complications and mortality rates of patients with diabetes in South Korea. The rates of hospitalization due to cardiovascular complications and mortality were analyzed using the Korean National Health Insurance Service-National Sample Cohort. From 2006 to 2015, the rates of hospitalization due to major cardiovascular complications decreased, while those due to heart failure (from 72 to 146 and 124 to 161 per 10,000 men and women, respectively) and peripheral artery disease (from 39 to 55 and 19 to 35 per 10,000 men and women, respectively) increased. In the period 2007 to 2015, the mortality rates for cancer, cerebrovascular disease, diabetes, heart disease, and hypertensive disease all decreased. However, the mortality rate for pneumonia increased. We observed a continuous reduction in cardiovascular complications and mortality in adults with diabetes. However, with the increase in some diabetes complications, more efforts are needed to prevent diabetes complications.


Development and evaluation of a colorimetric LAMP-based biosensor for rapid detection of a nosocomial infection agent, Citrobacter freundii.
Simple and fast diagnosis of Citrobacter freundii which is an important cause of nosocomial infection in human is crucial to achieve early treatment. We have developed and evaluated an optical LAMP-based biosensor for the visual detection of C. freundii for the first time. The efficiency of the assay was investigated and compared to PCR method. The selectivity and specificity of the biosensor were analyzed using Morganella morganii, Enterobacter aerogenes, Pseudomonas aeruginosa, Yersinia enterocolitica, Shigella sonnei, Serratia marcescens, Burkholderia cepacia and Klebsiella pneumoniae and a mixed-culture medium. Endpoint analysis using hydroxy naphthol blue was applied, and the color change to sky blue and no color change from violet indicated positive and negative results, respectively. The absorption at 650 nm was measured 0.39 for the positive sample, while the mean absorption of the test samples, including water, was 0.23. The specificity of the method was equal to that of PCR. However, the sensitivity was determined as 12.24 fg/µL of the genomic content of C. freundii, higher than PCR assay. The developed LAMP-based method provided a rapid and accurate technique for molecular diagnostics of C. freundii, making it a suitable technique for point-of-care diagnostics in cases of urgent situations.


Studies in porphyria. II. Evidence for a deficiency of steroid delta-4-5-alpha-reductase activity in acute intermittent porphyria.
Patients with the genetic liver disease, acute intermittent porphyria (AIP), have a defect in the reductive transformation of steroid hormones that is manifest by the disproportionate generation of 5beta-steroid metabolites from precursor hormones. 5beta-steroid metabolites were earlier shown to be potent inducers experimentally of delta-aminolevulinate synthetase (ALAS), the mitochondrial enzyme that is rate-limiting in porphyrin synthesis, and that is found at high levels of activity in the livers of AIP patients. In this report, the basis for the defective steroid metabolism in AIP has been shown, through studies with the (14)C-labeled adrenal hormone 11beta-hydroxy-Delta(4)-androstenedione, to reside in a substantial deficiency of hepatic steroid Delta(4)-5alpha-reductase activity. This enzymic deficiency was found in all seven AIP patients studied, and ranged from 34% to as much as 70% below the mean enzyme activity characterizing normal subjects. The functional consequence of the low levels of 5alpha-reductase activity in AIP is to divert the reductive transformation of certain natural hormones from the 5alpha- to the 5beta-pathway; the latter is the metabolic route through which endogenous steroids having the potential for inducing hepatic ALAS are generated. It is not presently known whether the 5alpha-reductase deficiency in AIP is acquired in some fashion or whether it has partial genetic determinants. It seems probable, however, that this enzymatic abnormality, coupled with the dramatic increase in hormone synthesis that occurs at puberty, may be of major importance in determining clinical expression of the latent gene defect for AIP in many individuals. The 5alpha-reductases for steroid hormones are known to be localized in the endoplasmic reticulum of hepatic cells and the present findings in AIP thus represent the first demonstration that an enzymic component of these membranous structures is functionally abnormal in this hereditary liver disease.


Decline in serum hemoglobin in the 7 days after cardiac catheterization.
Bleeding is an established complication following cardiac catheterization and lower preoperative hemoglobin concentration is a potentially modifiable risk factor for adverse outcomes after cardiac surgery. However, typical changes in serum hemoglobin concentration after cardiac catheterization are poorly defined. The authors sought to identify the pattern of change in serum hemoglobin concentration within 7 days after cardiovascular catheterization, factors associated with this change and any association with adverse outcomes. Retrospective observational study over a 1-year period. U.S. academic medical institution. Participants were 284 adult patients with baseline hemoglobin concentration≥12 g/dL undergoing nonemergent cardiac surgery after cardiovascular catheterization via the femoral arterial route. None. Lowest daily hemoglobin concentration was recorded where available for up to 7 days after catheterization and before surgery. Generalized estimating equations identified the pattern of change in serum hemoglobin while regression models identified factors associated with hemoglobin decline. Following cardiovascular catheterization average serum hemoglobin declined over time, reaching a nadir 1.4 g/dL (95% CI 1.0-1.8) below baseline 6 days after catheterization. A higher baseline hemoglobin concentration and lower body mass index were associated with greater maximal decline in hemoglobin concentration after catheterization. Acute preoperative hemoglobin decline was not associated with acute kidney injury (AKI) or a composite adverse outcome that may reflect organ ischemia. In a cohort of patients before cardiac surgery serum hemoglobin declines during the week after cardiac catheterization, with maximal average decline observed 5 to 7 days after catheterization.


Identification and characterization of novel rat and human gonad-specific organic anion transporters.
We have isolated three novel organic anion transporter cDNAs designated rat GST-1 (gonad-specific transporter), rat GST-2, and human GST, expressed at high levels in the testis. Rat GST-1, GST-2, and human GST consist of 748, 702, and 719 amino acids, respectively, and all molecules possess the 12 predicted transmembrane domains, which is a common structure of organic anion transporters. Northern blot analyses and in situ hybridization revealed that both of the rat molecules are highly expressed in the testis, especially in Sertoli cells, spermatogonia, and Leydig cells. Weak signals are also detected in the epididymis and ovary in adult rat. The exclusive expression of human GST mRNA in the testis was confirmed by RT-PCR. The pharmacological experiments of Xenopus laevis oocytes injected with the respective rat GST-1- and GST-2-cRNAs revealed that both rat GST-1 and GST-2 transport taurocholic acid, dehydroepiandrosterone sulfate, and T4 with Michaelis-Menten kinetics (taurocholic acid, Km = 8.9 and 2.5 microm, dehydroepiandrosterone sulfate, Km = 25.5 and 21.microm, and T4, Km = 6.4 and 5.8 for rat GST-1 and GST-2, respectively). T3 was also transported by rat GST-1 and GST-2. These data suggest that rat GST-1 and GST-2 might be one of the molecular entities responsible for transporting dehydroepiandrosterone sulfate and thyroid hormones involved in the regulation of sex steroid transportation and spermatogenesis in the gonad.


Abortion, euthanasia, and the limits of principlism.
Principlism is an ethical framework that has dominated bioethical discourse for the past 50 years. There are differing perspectives on its proper scope and limits. In this article, we consider to what extent principlism provides guidance for the abortion and euthanasia debates. We argue that whilst principlism may be considered a useful framework for structuring bioethical discourse, it does not in itself allow for the resolution of these neuralgic policy discussions. Scholars have attempted to use principlism to analyse the ethics and legality of abortion and euthanasia; but such efforts are methodologically problematic. We close with a consideration of the proper scope of principlism in bioethics-a vision that is more modest than the manner in which principlism is often deployed in contemporary academic bioethics and medical education.


The effect of marathon cycling on renal function.
The stress of strenuous long-term exercise may alter renal function. Whether this is also true for marathon cycling is unknown so far. The purpose of this study was to evaluate renal function following competitive marathon cycling. We investigated 38-male, well-trained recreational cyclists credibly not taking any kind of doping who participated in the Otztal Radmarathon. Blood and urine specimens were taken the day before, immediately after and one day after competition. Baseline renal functional parameters--normal before competition--increased significantly afterwards and remained elevated during 24 hours of recovery. The rises in serum creatinine, urea and uric acid were 20, 54 and 42 % (p < 0.001 respectively). The corresponding decline in estimated creatinine clearance was 18 %. In all athletes the serum urea/creatinine ratio rose above 40, fractional sodium excretion and fractional uric acid excretion fell below 0.4 % and 15 %, indicating reduced renal perfusion. The observed effects lasted for at least 24 h despite a stable fluid balance during the race and an expanding plasma volume (PV) in the recovery period. Levels of haematocrit remained unchanged immediately post-race but significantly declined from 0.44 to 0.41 on the following day (p < 0.001). The calculated rise in PV was + 10.8 %. Electrolyte homeostasis was preserved throughout the observation period. Post-exercise proteinuria was small and of the mixed glomerular-tubular type. There was neither evidence for exercise-induced haemolysis, nor for significant skeletal muscle damage. The finding obtained from well-hydrated recreational athletes reveals that the extraordinary strains of marathon cycling influence renal function only on a minimal scale. Though minor, the physiological effects were long-lasting. The results obtained suggest that a reduced renal perfusion is the mechanism responsible for the slight impairment of renal function following exhaustive marathon cycling.


Studies on the animal model of traumatic pseudoaneurysm.
Sixty-nine cases of pseudoaneurysm were made in 72 femoral arteries of 54 Japanese white rabbits, with a successful rate of 95.8%. Colored Doppler's ultrasonic imaging, CT, MRI, arterial angiography, anatomic dissection, and histologic observation were carried out at different times after the operation. The mechanism for the formation of pseudoaneurysm was discussed and the effects of colored Doppler's ultrasonic imaging, CT, MRI, and arterial angiography in the diagnosis of pseudoaneurysm were evaluated.


Physical activity and annual medical outlay in U.S. colorectal, breast and prostate cancer survivors.
Multiple chronic conditions in cancer survivors are highly prevalent and may increase health care costs for both patients and the health care system. Studies of cancer survivors reveal positive effects of physical activity (PA) on reducing risk of cancer recurrence, other chronic conditions, and secondary cancer. Few nationally representative studies have examined how physical activity levels have affected survivors' annual economic burden in the United States. Leisure-time physical activity data from the National Health Interview Survey was linked to health care expenditure data from the Medical Expenditure Panel Survey data (2008-2012). We calculated per-person annual total medical expenditures for identified colorectal, breast, and prostate cancer survivors. We conducted multivariable analyses controlled for survival years and other sociodemographic variables. Generalized linear models were performed to measure correlation between medical expenditure and PA level using STATA 14. All analyses considered the complex survey design and were conducted in 2017. Of 1015 cancer survivors sampled, 30% (n = 305) adhered to physical activity recommendation, while the other 70% (n = 710) did not. Multivariable-adjusted expenditure in adherence group was $9108.8 (95% CI 7410.9-10,806.7) versus 12,899.1 (95% CI 11,450.2-14,348) in non-adherence group. Stratified analyses revealed cancer survivors who adhered to their PA recommendation saved $4686.1 (1-5 years' survival time) and $2874.5 (11 or more years' survival time) on average for total health care expenditure, respectively. Analyses of the national representative sample revealed that the economic burden of survivors from the three most prevalent cancers is substantial. Increasing survivor's PA to guidelines may reduce U.S. health care expenditure.


Styles of coping with stress of cancer in patients treated with radiotherapy and expectations towards medical staff - Practical implications.
It is essential to adjust oncological treatment to medical procedures but also to the expectations of patients themselves. Expectations of patients may depend on the way of coping with the stress of cancer. Many researchers have dealt with this issue. However, it is difficult to find studies concerning relations between the styles of coping and expectations of patients towards medical staff. To demonstrate the relationship between the style of coping with stress of cancer shown by patients undergoing radiotherapy at the Greater Poland Cancer Centre and the nature of their expectations towards the medical staff, and to present work of the Clinical Psychology Unit in response to the expectations of patients. Questionnaire survey. The respondents filled in a questionnaire consisting of a patient request form (PRF), the mini-mental adjustment to cancer scale (Mini-MAC), and personal data. Obtained results were subjected to statistical analysis. SIGNIFICANT ASSOCIATIONS: the expectation to have the disease explained is associated with anxious preoccupation, fighting spirit, helplessness-hopelessness; the expectation of emotional support is associated with anxious preoccupation and helplessness-hopelessness; and the expectation of information on examinations and treatment is associated with anxious preoccupation and helplessness-hopelessness. Expectations of patients undergoing radiotherapy in the Greater Poland Cancer Centre towards the medical staff depend on their styles of coping with the stress of cancer.


What Does It Take to Get Somebody Back to Work after Severe Acquired Brain Injury? Service Actions within the Vocational Intervention Program (VIP 2.0).
Little is known about service actions delivered in the complex intervention of vocational rehabilitation (VR) for people with severe acquired brain injury (ABI). Scale-up of the Vocational Intervention Program (VIP) across the 12 Community teams of the NSW Brain Injury Rehabilitation Program provided an opportunity to analyse the intensity and profile of actions delivered in providing VR programs. Seventy-two participants with severe TBI were supported in returning to either pre-injury employment (FastTrack, FT, n = 27) or new employment (NewTrack, NT, n = 50), delivered by two types of VR providers (Disability Employment Service DES; private providers). VR providers documented their service actions in hours and minutes, using the Case Management Taxonomy, adapted to VR. The NT pathway required significantly higher levels of intervention in comparison to FT (25 h, five minutes vs. 35 h, 30 min, p = 0.048, W = 446). Case coordination was the most frequent service action overall (41.7% of total time for FT, 42.3% for NT). DES providers recorded significantly greater amounts of time undertaking engagement, assessment and planning, and emotional/motivational support actions compared to private providers. Overall duration of the programs were a median of 46 weeks (NT) and 36 weeks (FT), respectively. This study helps illuminate the profile of VR interventions for people with severe TBI.


[New questionnaire to assess self-efficacy toward physical activity in children].
To design a questionnaire for assessment of self-efficacy toward physical activity in school children, as well as to measure its construct validity, test-retest reliability, and internal consistency. A four-stage multimethod approach was used: (1) bibliographic research followed by exploratory study and the formulation of questions and responses based on a dichotomous scale of 14 items; (2) validation of the content by a panel of experts; (3) application of the preliminary version of the questionnaire to a sample of 900 school-aged children in Mexico City; and (4) determination of the construct validity, test-retest reliability, and internal consistency (Cronbach's alpha). Three factors were identified that explain 64.15% of the variance: the search for positive alternatives to physical activity, ability to deal with possible barriers to exercising, and expectations of skill or competence. The model was validated using the goodness of fit, and the result of 65% less than 0.05 indicated that the estimated factor model fit the data. Cronbach's consistency alpha was 0.733; test-retest reliability was 0.867. The scale designed has adequate reliability and validity. These results are a good indicator of self-efficacy toward physical activity in school children, which is important when developing programs intended to promote such behavior in this age group.


Synthetic European road freight transport flow data.
This data article describes a dataset on European road freight traffic. The dataset includes truck traffic flows between 1675 regions all over Europe. In addition to the road freight flows in tons as well as number of vehicles, the dataset also contains the shortest path between the respective regions on the European highway network (E-roads). Fifteen columns provide the following information for each pair of regions: (1) ID origin region, (2) name origin region, (3) ID destination region, (4) name destination region, (5) path in the E-road network, (6) distance from origin region to the E-road network, (7) distance within the E-road network, (8) distance from the E-road network to the destination region, (9) total distance, (10) road freight flow in tons for 2010, (11) road freight flow in tons for 2019, (12) road freight flow in tons for 2030, (13) truck traffic flow in number of vehicles for 2010, (14) truck traffic flow in number of vehicles for 2019, (15) truck traffic flow in number of vehicles for 2030. In addition, a table of nodes and a table of edges of the modelled E-road network is available. Finally, a list with supplementary information on the regions under consideration is given. In 2010, the ETISplus project collected Europe-wide freight volumes from various EU sources as well as from the EU countries and calibrated the resulting origin-destination matrices with measured traffic flows. For the dataset described here, the road freight volume was updated using Eurostat data and a forecast up to 2030 was added. The freight volume was converted into vehicles travelling. Subsequently, the highway network relevant for trucks was extracted from the ETISplus project and manually updated with the current E-road network. Finally, each origin-destination freight volume was allocated to the network using Dijkstra's algorithm. This provides a synthetically generated road freight traffic volume for each road section. The generated data provide an extremely relevant basis for the design of future road infrastructure in Europe, for example hydrogen refuelling stations or charging stations for electric trucks. Thus, the data are not only relevant for traffic science studies, but also of high importance for planners in practice.


Central insulin and leptin-mediated autonomic control of glucose homeostasis.
Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis.


Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
Cirrhotic patients frequently undergo screening endoscopy for the presence of oesophageal varices (OV). In the future, this social and medical burden will increase due to the greater number of patients with chronic liver disease and their improved survival. In this study, our aims were (1) to identify clinical, biochemical, and ultrasonographic parameters which might non-invasively predict the presence of OV in patients with liver cirrhosis; (2) to evaluate the reproducibility of the obtained results in a different, although related, further group of patients; and (3) to assess the predictiveness of the identified rules in patients with compensated cirrhosis. In the first part of the study we retrospectively evaluated the presence of OV in 145 cirrhotic patients, and in the second part we evaluated the reproducibility of the study results in a subsequent group of 121 patients. Finally, we evaluated these parameters in a subgroup of 145 patients with compensated disease. All 266 patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio was calculated for all patients. The prevalence rates of OV were 61% and 58% in the first and second groups of patients, respectively. In the first part of the study, we found that platelet count, spleen diameter, platelet count/spleen diameter ratio, and Child- Pugh class were significantly different among patients with or without OV, although the platelet count/spleen diameter ratio was the only parameter which was independently associated with the presence of OV in a multivariate analysis. A platelet count/spleen diameter ratio cut off value of 909 had 100% negative predictive value for a diagnosis of OV. This result was reproduced in the second group of patients as well as in patients with compensated disease. In a cost-benefit analysis, screening cirrhotic patients according to the "platelet count/spleen diameter ratio strategy" was far more cost effective compared with the "scope all strategy". The platelet count/spleen diameter ratio is the only parameter which is independently associated with the presence of OV, and its negative predictive value is reproducible. Its use is of value even in the subgroup of patients with compensated disease, and it is also cost effective.


LCA of management strategies for RDF incineration and gasification bottom ash based on experimental leaching data.
The main characteristics and environmental properties of the bottom ash (BA) generated from thermal treatment of waste may vary significantly depending on the type of waste and thermal technology employed. Thus, to ensure that the strategies selected for the management of these residues do not cause adverse environmental impacts, the specific properties of BA, in particular its leaching behavior, should be taken into account. This study focuses on the evaluation of potential environmental impacts associated with two different management options for BA from thermal treatment of Refuse Derived Fuel (RDF): landfilling and recycling as a filler for road sub bases. Two types of thermal treatment were considered: incineration and gasification. Potential environmental impacts were evaluated by life-cycle assessment (LCA) using the EASETECH model. Both non-toxicity related impact categories (i.e. global warming and mineral abiotic resource depletion) and toxic impact categories (i.e. human toxicity and ecotoxicity) were assessed. The system boundaries included BA transport from the incineration/gasification plants to the landfills and road construction sites, leaching of potentially toxic metals from the BA, the avoided extraction, crushing, transport and leaching of virgin raw materials for the road scenarios, and material and energy consumption for the construction of the landfills. To provide a quantitative assessment of the leaching properties of the two types of BA, experimental leaching data were used to estimate the potential release from each of the two types of residues. Specific attention was placed on the sensitivity of leaching properties and the determination of emissions by leaching, including: leaching data selection, material properties and assumptions related to emission modeling. The LCA results showed that for both types of BA, landfilling was associated with the highest environmental impacts in the non-toxicity related categories. For the toxicity related categories, the two types of residues behaved differently. For incineration BA the contribution of metal leaching to the total impacts had a dominant role, with the highest environmental loads resulting for the road scenario. For the gasification BA, the opposite result was obtained, due to the lower release of contaminants observed for this material compared to incineration BA. Based on the results of this study, it may be concluded that, depending on the type of BA considered, its leaching behavior may significantly affect the results of a LCA regarding its management strategies.


Preparation and properties of creatine kinase from the breast muscle of normal and dystrophic chicken (Gallus domesticus).
1. The purification of creatine kinase from normal and genetically dystrophic chicken breast muscle is described. Enzyme recovery was significantly lower from dystrophic muscle. 2. Both enzymes had the same number of reactive and total thiol groups and had similar specific activities and similar amino acid compositions. 3. No significant differences were observed in sedimentation, electrophoretic or kinetic properties. 4. Peptide ;maps' showed no significant differences, and electrophoresis of partial acid hydrolysates of the labelled enzymes suggested that corresponding amino acid sequences around all the thiol groups were very similar. 5. The enzymes showed identical temperature stabilities. 6. No significant differences between the enzymes from normal and dystrophic muscle were observed.


Reinvestigating the Preferential Enrichment of DL-Arginine Fumarate: New Thoughts on the Mechanism of This Far from Equilibrium Crystallization Phenomenon.
Preferential enrichment (PE) is a crystallization process, starting from either a racemic of slightly enantio-enriched solution (ca. +5%) that results in a high enantiomeric excess in the liquid phase (>+90%ee) and a slight opposite excess in the deposited crystals (−2 to −5%ee). The mechanism(s) of this symmetry-breaking phenomenon is (are) still a matter of debate since it eludes rationalization by phase diagram formalism. In this publication, we thoroughly reinvestigate the PE phenomenon of arginine fumarate by using a new approach: the process is monitored by introducing isotopically labeled arginine enantiomers into the crystallization medium to better understand the mass exchanges during crystallization. These experiments are supported by chiral HPLC-MS/MS. This study permits re-evaluating the criteria that were thought mandatory to perform PE. In particular, we show that PE occurs by a continuous exchange between the solution and the crystals and does not require the occurrence of a solvent-mediated solid−solid phase transition.


Quality of Psychoeducational Apps for Military Members With Mild Traumatic Brain Injury: An Evaluation Utilizing the Mobile Application Rating Scale.
Military personnel have an elevated risk of sustaining mild traumatic brain injuries (mTBI) and postconcussion symptoms (PCS). Smartphone apps that provide psychoeducation may assist those with mTBI or PCS to overcome unique barriers that military personnel experience with stigma and access to health care resources. This study aims to (1) use the Mobile Application Rating Scale (MARS) to evaluate smartphone apps purporting to provide psychoeducation for those who have sustained an mTBI or a PCS; (2) explore the relevance, utility, and effectiveness of these apps in facilitating symptom management and overall recovery from mTBI and PCS among military personnel; and (3) discuss considerations pertinent to health care professionals and patients with mTBI when considering the use of mobile health (mHealth), including apps for mTBI psychoeducation. A five-step systematic search for smartphone apps for military members with mTBI or PCS was conducted on January 31, 2020. Cost-free apps meeting the inclusion criteria were evaluated using the MARS and compared with evidence-based best practice management protocols for mTBI and PCS. The search yielded a total of 347 smartphone apps. After applying the inclusion and exclusion criteria, 13 apps were subjected to evaluation. Two apps were endorsed by the US Department of Veterans Affairs and the US Department of Defense; all the others (n=11) were developed for civilians. When compared with evidence-based best practice resources, the apps provided various levels of psychoeducational content. There are multiple considerations that health care professionals and those who sustain an mTBI or a PCS have to consider when choosing to use mHealth and selecting a specific app for mTBI psychoeducation. These may include factors such as the app platform, developer, internet requirement, cost, frequency of updates, language, additional features, acknowledgment of mental health, accessibility, military specificity, and privacy and security of data. Psychoeducational interventions have a good evidence base as a treatment for mTBI and PCS. The use of apps for this purpose may be clinically effective, cost-effective, confidential, user friendly, and accessible. However, more research is needed to explore the effectiveness, usability, safety, security, and accessibility of apps designed for mTBI management.


Comparison of methods used for estimating pharmacist counseling behaviors.
To compare the rates reported for provision of types of information conveyed by pharmacists among studies for which different methods of estimation were used and different dispensing situations were studied. Empiric studies conducted in the US, reported from 1982 through 1992, were selected from International Pharmaceutical Abstracts, MEDLINE, and noncomputerized sources. Empiric studies were selected for review if they reported the provision of at least three types of counseling information. Four components of methods used for estimating pharmacist counseling behaviors were extracted and summarized in a table: (1) sample type and area, (2) sampling unit, (3) sample size, and (4) data collection method. In addition, situations that were investigated in each study were compiled. Twelve studies met our inclusion criteria. Patients were interviewed via telephone in four studies and were surveyed via mail in two studies. Pharmacists were interviewed via telephone in one study and surveyed via mail in two studies. For three studies, researchers visited pharmacy sites for data collection using the shopper method or observation method. Studies with similar methods and situations provided similar results. Data collected by using patient surveys, pharmacist surveys, and observation methods can provide useful estimations of pharmacist counseling behaviors if researchers measure counseling for specific, well-defined dispensing situations.


Current efforts in medical education to incorporate national health priorities.
As a reflection on the Edinburgh Declaration, this conceptual synthesis presents six important challenges in relation to the role of medical education in meeting current national health priorities. This paper presents a conceptual synthesis of current efforts in medical education to incorporate national health priorities as a reflection on how the field has evolved since the Edinburgh Declaration. Considering that health needs vary from country to country, our paper focuses on three broad and cross-cutting themes: health equity, health systems strengthening, and changing patterns of disease. Considering the complexity of this topic, we conducted a targeted search to broadly sample and critically review the literature in two phases. Phase 1: within each theme, we assessed the current challenges in the field of medical education to meet the health priority. Phase 2: a search for various strategies in undergraduate and postgraduate education that have been tested in an effort to address the identified challenges. We conducted a qualitative synthesis of the literature followed by mapping of the identified challenges within each of the three themes with targeted efforts. We identified six important challenges: (i) mismatch between the need for generalist models of health care and medical education curricula's specialist focus; (ii) attitudes of health care providers contributing to disparities in health care; (iii) the lack of a universal approach in preparing medical students for 21st century health systems; (iv) the inability of medical education to keep up with the abundance of new health care technologies; (v) a mismatch between educational requirements for integrated care and poorly integrated, specialised health care systems; and (vi) development of a globally interdependent education system to meet global health challenges. Examples of efforts being made to address these challenges are offered. Although strategies for combatting these challenges exist, the effectiveness of educational models depends on them being locally adaptable and applicable. Curricular reform must go hand-in-hand with research and evaluation to develop comprehensive futuristic models of teaching and learning that will adequately prepare health professionals to address the challenges.


Cluster structures influenced by interaction with a surface.
Clusters on surfaces are vitally important for nanotechnological applications. Clearly, cluster-surface interactions heavily influence the preferred cluster structures, compared to clusters in vacuum. Nevertheless, systematic explorations and an in-depth understanding of these interactions and how they determine the cluster structures are still lacking. Here we present an extension of our well-established non-deterministic global optimization package OGOLEM from isolated clusters to clusters on surfaces. Applying this approach to intentionally simple Lennard-Jones test systems, we produce a first systematic exploration that relates changes in cluster-surface interactions to resulting changes in adsorbed cluster structures.


A bibliometric analysis: what do we know about metals(loids) accumulation in wild birds?
Metals and metalloids pollution is an important worldwide problem due to the social and ecological effects and therefore has been the subject of many disciplines and the adverse impacts have been documented. In this study, content analysis and trends of studies focused on heavy metal accumulation in birds were presented. For this purpose, a bibliometric network analysis of the studies that use the concepts of "pollution," "heavy metal," and "birds" together in the abstract, keywords, and titles of the papers was carried out. The purpose of choosing this research method was summarizing the relation between birds and environmental pollution in an understandable manner to determine metals(loids) pollution, which become an important environmental problem. Bibliometric data consisting of approximately 971 papers were evaluated with VOSviewer program using the network analysis method to answer the research questions. The results revealed that birds act as bioindicators in the determination of environmental pollution and that the contaminant metals deposited in the various tissues of birds provide preliminary information about environmental pollution. The most of bird studies emphasized that the metal accumulation was mostly in the liver, kidneys, and feathers and the accumulation caused serious problems in most of the vital activities of the birds. The USA is in the leading country in birds-heavy metal studies followed by Spain, Canada, and China. In addition, the mercury (Hg) was the most extensively studied heavy metal in these studies.


An Update on the Pathophysiology and Treatment of Cardiorenal Syndrome.
Cardiorenal syndrome (CRS) encompasses various disorders of the heart and kidneys; dysfunction of one organ leads to acute or chronic dysfunction of the other. It incorporates the intersection of heart-kidney interactions across several mediums, hemodynamically, through the alterations in neurohormonal markers, and increased venous and renal pressure, all of which are hallmarks of its clinical phenotypes. This article explores the epidemiology, pathology, classification and treatment of each type of CRS.


Prevalence and parasite load of nematodes and trematodes in an invasive slug and its susceptibility to a slug parasitic nematode compared to native gastropods.
The invasive slug Arion vulgaris (Gastropoda: Arionidae) is an agricultural pest and serious nuisance in gardens of Central and Northern Europe. To investigate if the success of A.vulgaris in Norway can be attributed to a release from parasites, we compared the prevalence and parasite load of nematodes and trematodes in A. vulgaris to that of three native gastropod species, A. circumscriptus, A. fasciatus and Arianta arbustorum, in SE Norway. We found A. vulgaris to have the highest prevalence of both parasite groups (49% nematodes, 76% trematodes), which does not support the parasite release hypothesis, but rather points to A. vulgaris as a potentially important intermediate host of these parasites. For trematodes the number of individuals (parasite load) did not differ among host species; for nematodes it was higher in A. vulgaris than A. fasciatus. To further compare the parasite susceptibility of the surveyed gastropods, we exposed A. vulgaris, A. fasciatus, and A. arbustorum to a slug parasitic nematode, Phasmarhabditis hermaphrodita, in the laboratory. This nematode is commercially available and widely used to control A. vulgaris. The non-target species A. fasciatus was most affected, with 100% infection, 60% mortality and significant feeding inhibition. A. vulgaris was also 100% infected, but suffered only 20% mortality and little feeding inhibition. The load of P. hermaphrodita in infected specimens was not significantly different for the two Arion species (median: 22.5 and 45, respectively). Only 35% of A. arbustorum snails were infected, none died, and parasite load was very low (median: 2). However, they showed a near complete feeding inhibition at highest nematode dose, and avoided nematode-infested soil. Our results indicate that A. vulgaris may be less susceptible to P. hermaphrodita than the native A. fasciatus, and that non-target effects of applying this nematode in fields and gardens should be further investigated.


Circulating 25-hydroxyvitamin D and the risk of rarer cancers: Design and methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.
The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974-2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50-<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations.


A new metric for quantifying performance impairment on the psychomotor vigilance test.
We have developed a new psychomotor vigilance test (PVT) metric for quantifying the effects of sleep loss on performance impairment. The new metric quantifies performance impairment by estimating the probability density of response times (RTs) in a PVT session, and then considering deviations of the density relative to that of a baseline-session density. Results from a controlled laboratory study involving 12 healthy adults subjected to 85 h of extended wakefulness, followed by 12 h of recovery sleep, revealed that the group performance variability based on the new metric remained relatively uniform throughout wakefulness. In contrast, the variability of PVT lapses, mean RT, median RT and (to a lesser extent) mean speed showed strong time-of-day effects, with the PVT lapse variability changing with time of day depending on the selected threshold. Our analysis suggests that the new metric captures more effectively the homeostatic and circadian process underlying sleep regulation than the other metrics, both directly in terms of larger effect sizes (4-61% larger) and indirectly through improved fits to the two-process model (9-67% larger coefficient of determination). Although the trend of the mean speed results followed those of the new metric, we found that mean speed yields significantly smaller (∼50%) intersubject performance variance than the other metrics. Based on these findings, and that the new metric considers performance changes based on the entire set of responses relative to a baseline, we conclude that it provides a number of potential advantages over the traditional PVT metrics.


[Use of synthetic materials for plasty of postoperative incisional hernias in interventions on the "open" colon].
Single-stage plasty of ventral hernias was performed in 40 patients with the use of synthetic materials and closure of colostomy (in 35 of them), resection of the sigmoid gut (in 3) or anterior resection of the rectum (in 2). Postoperative complications in the wound of the abdominal wall were found in 7 patients.There were no recurrences in the long-term (within 3-34 months) periods. Such single-stage interventions are thought to be possible.


Outcome After Ruptured AAA Repair in Octo- and Nonagenarians in Sweden 1994-2014.
To report the outcome after ruptured abdominal aortic aneurysm (rAAA) repair in octo- and nonagenarians from the Swedish Vascular Registry 1994-2014. 2335 intact AAA (iAAA) and 1538 rAAA were identified in patients aged 80 years and older. Crude, long-term, and relative survival data were analysed using the Kaplan-Meier method. Crude survival was calculated including all deaths. Long-term survival was analysed excluding AAA repair related mortality, defined as death within 90 days of surgery. Relative survival was assessed by comparing the observed long-term survival after AAA repair with the expected survival of a Swedish population adjusted for age, gender, and operation year. Differences were compared using log-rank tests. The multivariate Cox model was used for adjusting for confounding factors between open repair (OR) and endovascular aneurysm repair (EVAR). Crude survival after rAAA repair was 30 days (55%), 90 days (50%), 1 year (45%), 5 years (26%), and 10 years (9%). Long-term survival was 1 year (90%), 5 years (53%), and 10 years (18%). When individuals with rAAA were categorized into males and females, crude and long-term survival showed no significant differences (p = .204 and p = .134). When rAAA patients were categorized into age groups (80-84 years, 85-89 years, 90+) crude survival diminished with increasing age, but long-term survival was not (p = .009 and p = .368). Compared with the general population, rAAA patients showed only a minor decrease in relative survival. Crude survival after rAAA was better for EVAR compared with OR (p = .007), hazard ratio 1.3 (95% CI 1.1-1.6, p < .012). There is a high (50%) peri-operative mortality after surgery for rAAA in octo- and nonagenarians, with no significant differences between the sexes and worse survival with increasing age. However, if a patient has survived the initial 90 days, long-term survival in this very old cohort is surprisingly good at more than 50% after 5 years, only slightly less than the general population.


Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague-Dawley rats.
Methylglyoxal, a metabolite of the glycolysis pathway, may play an important role in the development of diabetes and hypertension, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether methylglyoxal could directly induce insulin resistance and salt sensitivity in Sprague-Dawley rats. Rats were allocated to four groups: control (normal drinking water), 1% methylglyoxal in drinking water, 1% methylglyoxal plus N-acetyl cysteine (NAC) (800 mg/kg per day), a methylglyoxal scavenger, or TM2002 (100 mg/kg per day), an advanced glycation endproducts (AGEs) inhibitor. After 4-week treatment insulin resistance was evaluated by an euglycemic hyperinsulinemic glucose clamp technique. In another set of rats, either a high-salt diet (4%) alone, standard rat chow with 1% methylglyoxal in drinking water or high-salt diet plus methylglyoxal was given for 4 weeks. Immunohistochemistry was performed to measure nitrotyrosine and methylglyoxal-induced AGEs, N-carboxyethyl-lysine (CEL) in the kidney. Four-week treatment with NAC or TM2002 completely improved methylglyoxal-induced insulin resistance. Co-administration of methylglyoxal and high-salt diet significantly increased systolic blood pressure, urinary albumin excretion, urinary thiobarbituric acid-reactive substances excretion and the renal nitrotyrosine expression in the kidney (markers of oxidative stress) compared with methylglyoxal or high-salt diet alone. Renal CEL was significantly increased in methylglyoxal-treated rats compared with nonmethylglyoxal-treated rats. These results indicate that methylglyoxal-induced insulin resistance and salt sensitivity at least in part by increasing oxidative stress and/or AGEs formation in Sprague-Dawley rats. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of insulin resistance and salt-sensitive hypertension.


Hyperglycemia Induces Meibomian Gland Dysfunction.
Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model. Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1β, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change. Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention. Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.


The proprotein convertase furin in tumour progression.
Proprotein convertases are proteases that have been implicated in the activation of a wide variety of proteins. These proteins are generally synthesised as precursor proteins and require limited proteolysis for conversion into their mature bioactive counterparts. Many of these proteins, including metalloproteases, growth factors and their receptors or adhesion molecules, have been shown to facilitate tumour formation and progression. Hence, this review will focus on the proprotein convertase furin and its role in cancer. The expression of furin has been confirmed in a large spectrum of cancers such as head and neck squamous cell carcinoma, breast cancer and rhabdomyosarcoma. Functional studies modulating furin activity uncovered its importance for the processing of many cancer-related substrates and strongly indicate that high furin activity promotes the malignant phenotype of cancer cells. In this review, we summarise the expression and function of furin in different cancer types, discuss its role in processing cancer-related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity of furin in cancer cells.


Phytochemical and Biological Characteristics of Mexican Chia Seed Oil.
The purpose of this research was to investigate the chemical profile, nutritional quality, antioxidant and hypolipidemic effects of Mexican chia seed oil (CSO) in vitro. Chemical characterization of CSO indicated the content of α-linolenic acid (63.64% of total fatty acids) to be the highest, followed by linoleic acid (19.84%), and saturated fatty acid (less than 11%). Trilinolenin content (53.44% of total triacylglycerols (TAGs)) was found to be the highest among seven TAGs in CSO. The antioxidant capacity of CSO, evaluated with ABTS•+ and DPPH• methods, showed mild antioxidant capacity when compared with Tocopherol and Catechin. In addition, CSO was found to lower triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels by 25.8% and 72.9%respectively in a HepG2 lipid accumulation model. As CSO exhibits these chemical and biological characteristics, it is a potential resource of essential fatty acids for human use.


Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing.
Microneedles are an efficient and minimally invasive approach to transdermal drug delivery and extraction of skin interstitial fluid. Compared to solid microneedles made of silicon, metals and ceramics, polymeric microneedles have attracted extensive attention due to their excellent biocompatibility, biodegradability and nontoxicity. They are easy to fabricate in large scale and can load drugs in high amounts. More importantly, polymers with different degradation profiles, swelling properties, and responses to biological/physical stimuli can be employed to fabricate polymeric microneedles with different mechanical properties and performance. This review provides a guideline for the selection of polymers and the corresponding fabrication methods for polymeric microneedles while summarizing their recent application in drug delivery and fluid extraction. It should be noted that although polymeric microneedles can achieve efficient transdermal delivery of drugs, their wide applications were limited by their unsatisfactory transdermal therapeutic efficiency. Delivery of nanomedicines that incorporate drugs into functional nanoparticles/capsules can address this problem and thus may be an interesting direction in the future.


Streptococcus didelphis sp. nov., a streptococcus with marked catalase activity isolated from opossums (Didelphis virginiana) with suppurative dermatitis and liver fibrosis.
beta-Haemolytic, catalase-positive, Gram-positive cocci that formed chains in broth media but did not react with Lancefield group antisera were isolated from skin lesions, spleen, liver and lungs of nine opossums, including eight from a research colony and one from a wildlife rehabilitation organization. The isolates had vigorous catalase activity that was retained on initial passage on non-blood-containing media, but this activity was lost in subsequent passages. The use of standard phenotypic tests did not lead to satisfactory identification of these organisms beyond the genus level, even if the aberrant catalase reaction was not considered. The 16S rRNA gene sequence of the isolates was most similar (96%) to Streptococcus dysgalactiae, but distinct from that species as 16S rRNA gene similarity of different strains of S. dysgalactiae was > 99%. Characterization of biochemical reactions and cell-wall fatty acid profiles also revealed significant differences between the opossum isolates and all other known Streptococcus spp., thus it is proposed as a new species with the name Streptococcus didelphis, sp. nov. The type strain is ATCC 700828T.


Alternative splicing of the guanylyl cyclase-A receptor modulates atrial natriuretic peptide signaling.
Atrial (ANP) and B-type natriuretic peptides (BNP) modulate blood pressure and volume through the stimulation of cyclic GMP production by their guanylyl cyclase-A (GC-A) receptor. A novel isoform of GC-A has been identified that is the result of differential splicing of exon 4. The deletion of a 51-bp sequence is predicted to delete 17 amino acids (Lys314-Gln330) in the membrane-distal part of the extracellular domain. Reverse transcription-PCR analyses demonstrated low messenger RNA expression levels of spliced GC-A in all tissues. Homology modeling suggested that the alterations in the protein structure could interfere with ANP binding or signaling. Indeed, functional studies in transfected HEK 293 cells demonstrated that binding of ANP and ANP-induced cyclic GMP formation by GC-ADelta(Lys314-Gln330) were totally abolished. Furthermore, cotransfection studies showed that this GC-A variant forms heterodimers with the wild type receptor and inhibits ligand-inducible cGMP generation. Finally, treatment of mice with angiotensin II (300 ng/kg/min during 7 days) resulted in enhanced pulmonary mRNA expression of spliced GC-A, which was concomitant to diminished GC-A/cGMP responses to ANP. We conclude that alternative splicing can regulate endogenous ANP/GC-A signaling. Angiotensin II-induced alternative splicing of GC-A may represent a novel mechanism for reducing the sensitivity to ANP.


Influence of carvacrol and 1,8-cineole on cell viability, membrane integrity, and morphology of Aeromonas hydrophila cultivated in a vegetable-based broth.
This study investigated the effects of carvacrol (CAR) and 1,8-cineole (CIN) alone (at the MIC) or in combination at subinhibitory amounts (both at 1/8 MIC) on the cell viability, membrane permeability, and morphology of Aeromonas hydrophila INCQS 7966 (A. hydrophila) cultivated in a vegetable-based broth. CAR and CIN alone or in combination severely affected the viability of the bacteria and caused dramatic changes in the cell membrane permeability, leading to cell death, as observed by confocal laser microscopy. Scanning and transmission electron microscopy images of bacterial cells exposed to CAR or CIN or the mixture of both compounds revealed severe changes in cell wall structure, rupture of the plasma membrane, shrinking of cells, condensation of cytoplasmic content, leakage of intracellular material, and cell collapse. These findings suggest that CAR and CIN alone or in combination at subinhibitory amounts could be applied to inhibit the growth of A. hydrophila in foods, particularly as sanitizing agents in vegetables.


On the front line: quantitative virus dynamics in honeybee (Apis mellifera L.) colonies along a new expansion front of the parasite Varroa destructor.
Over the past fifty years, annual honeybee (Apis mellifera) colony losses have been steadily increasing worldwide. These losses have occurred in parallel with the global spread of the honeybee parasite Varroa destructor. Indeed, Varroa mite infestations are considered to be a key explanatory factor for the widespread increase in annual honeybee colony mortality. The host-parasite relationship between honeybees and Varroa is complicated by the mite's close association with a range of honeybee viral pathogens. The 10-year history of the expanding front of Varroa infestation in New Zealand offered a rare opportunity to assess the dynamic quantitative and qualitative changes in honeybee viral landscapes in response to the arrival, spread and level of Varroa infestation. We studied the impact of de novo infestation of bee colonies by Varroa on the prevalence and titres of seven well-characterised honeybee viruses in both bees and mites, using a large-scale molecular ecology approach. We also examined the effect of the number of years since Varroa arrival on honeybee and mite viral titres. The dynamic shifts in the viral titres of black queen cell virus and Kashmir bee virus mirrored the patterns of change in Varroa infestation rates along the Varroa expansion front. The deformed wing virus (DWV) titres in bees continued to increase with Varroa infestation history, despite dropping infestation rates, which could be linked to increasing DWV titres in the mites. This suggests that the DWV titres in mites, perhaps boosted by virus replication, may be a major factor in maintaining the DWV epidemic after initial establishment. Both positive and negative associations were identified for several pairs of viruses, in response to the arrival of Varroa. These findings provide important new insights into the role of the parasitic mite Varroa destructor in influencing the viral landscape that affects honeybee colonies.


Generation and Characterization of a CRISPR/Cas9 -Induced 3-mst Deficient Zebrafish.
3-mercaptopyruvate sulfurtransferase (3-MST) is an enzyme capable of synthesizing hydrogen sulfide (H2S) and polysulfides. In spite of its ubiquitous presence in mammalian cells, very few studies have investigated its contribution to homeostasis and disease development, thus the role of 3-MST remains largely unexplored. Here, we present a clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) induced 3-mst mutant zebrafish line, which will allow the study of 3-MST's role in several biological processes. The 3-mst zebrafish orthologue was identified using a bioinformatic approach and verified by its ability to produce H2S in the presence of 3-mercaptopyruvate (3-MP). Its expression pattern was analyzed during zebrafish early development, indicating predominantly an expression in the heart and central nervous system. As expected, no detectable levels of 3-Mst protein were observed in homozygous mutant larvae. In line with this, H2S levels were reduced in 3-mst-/- zebrafish. Although the mutants showed no obvious morphological deficiencies, they exhibited increased lethality under oxidative stress conditions. The elevated levels of reactive oxygen species, detected following 3-mst deletion, are likely to drive this phenotype. In line with the increased ROS, we observed accelerated fin regenerative capacity in 3-mst deficient zebrafish. Overall, we provide evidence for the expression of 3-mst in zebrafish, confirm its important role in redox homeostasis and indicate the enzyme's possible involvement in the regeneration processes.


Screening dietary biochanin A, daidzein, equol and genistein for their potential to increase DHA biosynthesis in rainbow trout (Oncorhynchus mykiss).
Plant oil utilization in aquafeeds is still the most practical option, although it decreases the content of the nutritionally highly valuable omega-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) in fish. Phytoestrogens and their metabolites are putatively able to affect genes encoding proteins centrally involved in the biosynthesis of EPA and DHA due to their estrogenic potential. Thus, the aim of the study was to screen the potential of the phytoestrogens to stimulate the biosynthesis of EPA and DHA in rainbow trout (Oncorhynchus mykiss). Additionally, the potential effects on growth performance, nutrient composition and hepatic lipid metabolism in rainbow trout were investigated. For that, a vegetable oil based diet served as a control diet (C) and was supplemented with 15 g/kg dry matter of biochanin A (BA), daidzein (DA), genistein (G) and equol (EQ), respectively. These five diets were fed to rainbow trout (initial body weight 83.3 ± 0.4 g) for 52 days. Growth performance and nutrient composition of whole body homogenates were not affected by the dietary treatments. Furthermore, feeding EQ to rainbow trout significantly increased DHA levels by +8% in whole body homogenates compared to samples of fish fed the diet C. A tendency towards increased DHA levels in whole body homogenates was found for fish fed the diet G. Fish fed diets BA and DA lacked these effects. Moreover, EQ and G fed fish showed significantly decreased hepatic mRNA steady state levels for fatty acyl desaturase 2a (delta-6) (fads2a(d6)). In contrast, carnitine palmitoyl transferases 1 (cpt1) hepatic mRNA steady state levels and hepatic Fads2a(d6) protein contents were not affected by the dietary treatment. In conclusion, when combined with dietary vegetable oils, equol and genistein seem to stimulate the biosynthesis of DHA and thereby increase tissue DHA levels in rainbow trout, however, only to a moderate extent.


Glutathione adducts on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic function as well as promote ischemic blood flow recovery.
The sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) is key to Ca(2+) homeostasis and is redox-regulated by reversible glutathione (GSH) adducts on the cysteine (C) 674 thiol that stimulate Ca(2+) uptake activity and endothelial cell angiogenic responses in vitro. We found that mouse hind limb muscle ischemia induced S-glutathione adducts on SERCA in both whole muscle tissue and endothelial cells. To determine the role of S-glutathiolation, we used a SERCA 2 C674S heterozygote knock-in (SKI) mouse lacking half the key thiol. Following hind limb ischemia, SKI animals had decreased SERCA S-glutathione adducts and impaired blood flow recovery. We studied SKI microvascular endothelial cells in which total SERCA 2 expression was unchanged. Cultured SKI microvascular endothelial cells showed impaired migration and network formation compared with wild type (WT). Ca(2+) studies showed decreased nitric oxide (·NO)-induced (45)Ca(2+) uptake into the endoplasmic reticulum (ER) of SKI cells, while Fura-2 studies revealed lower Ca(2+) stores and decreased vascular endothelial growth factor (VEGF)- and ·NO-induced Ca(2+) influx. Adenoviral overexpression of calreticulin, an ER Ca(2+) binding protein, increased ionomycin-releasable stores, VEGF-induced Ca(2+) influx and endothelial cell migration. Taken together, these data indicate that the redox-sensitive Cys-674 thiol on SERCA 2 is required for normal endothelial cell Ca(2+) homeostasis and ischemia-induced angiogenic responses, revealing a novel redox control of angiogenesis via Ca(2+) stores.


Preventive effects of multiple domain interventions on lifestyle and risk factor changes in stroke survivors: Evidence from a two-year randomized trial.
Background and aim Behavioral and lifestyle interventions in stroke patients need to be intense enough to result in sustainable treatment differences among groups of a randomized trial. Therefore, we report the effects of multidomain interventions on lifestyle and laboratory parameters after 12 and 24 months from a trial that examined whether intensive risk factor management can prevent cognitive decline in ischemic stroke patients. Methods This prospective randomized, open-label, blinded endpoint trial recruited patients within three months after acute stroke in five Austrian neurological clinics during June 2010 and November 2012. One hundred and one patients were randomized into multidomain intervention and 101 into standard care. Lifestyle interventions were individualized to match predefined targets of regular physical activity, healthy diet, and adequate physiological risk factor control. Results A total of 167 participants (80 intervention, 87 control) completed the 12-month visit and 155 (76 intervention, 79 control) the 24-month visit. During the first 12 months, adherence to healthy lifestyle and adequately controlled physiological parameters (measured by summary scores) improved significantly in the intervention group compared to controls (p < 0.01). The consumption of reduced-fat milk (p = 0.031), reduced-fat spreads (p = 0.007), and fish (p = 0.021) increased in the intervention group from baseline to 12 months but not in controls. After 24 months, the group difference was significant for the lifestyle summary score but no longer for the combined laboratory lifestyle score. Conclusions These results demonstrate that intensified individualized multidomain lifestyle interventions in stroke patients are effective in promoting healthy lifestyle in stroke care.


Macrophage-specific chemokines induced via innate immunity by amino acid copolymers and their role in EAE.
The random amino acid copolymer poly(Y,E,A,K)(n) (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)(n) with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II -/- mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment.


Crystallization of FLINC4, an intramolecular LMO4-ldb1 complex.
LMO4 is the most recently discovered member of a small family of nuclear transcriptional regulators that are important for both normal development and disease processes. LMO4 is comprised primarily of two tandemly repeated LIM domains and interacts with the ubiquitous nuclear adaptor protein ldb1. This interaction is mediated via the LIM domains of LMO4 and the LIM-interaction domain (LID) of ldb1. An intramolecular complex, termed FLINC4, consisting of the two LIM domains from LMO4 linked to the LID domain of ldb1 via a flexible linker has been engineered, purified and crystallized. The trigonal crystals, which belong to space group P312 with unit-cell parameters a = 61.3, c = 93.2 A, diffract to 1.3 A resolution and contain one molecule of FLINC4 per asymmetric unit. Native and multiple-wavelength anomalous dispersion (MAD) data collected at the Zn X-ray absorption edge have been recorded to 1.3 and 1.7 A resolution, respectively. Anomalous Patterson maps calculated with data collected at the peak wavelength show strong peaks sufficient to determine the positions of four Zn atoms per asymmetric unit.


Molecular pathogenesis of neuroinflammation.
The past few years have seen significant progress towards understanding the mechanisms of immune surveillance and inflammation in the nervous system. In this review, the milestones of scientific discovery in this field are discussed, and the strengths and limitations of the different ways of examining the molecular pathogenesis of neuro-inflammation examined. The review is limited to the inflammatory reactions of the central nervous system that occur in multiple sclerosis and experimental autoimmune encephalomyelitis.


Sensorimotor Integration and GABA-ergic Activity in Embouchure Dystonia: An Assessment with Magnetoencephalography.
Embouchure dystonia (ED) is a task-specific dystonia affecting musicians thought to be related to alteration in sensorimotor processing and loss of cortical inhibition. Magnetoencephalography-coherence source imaging (MEG-CSI) was used to map connectivity between brain regions by imaging neuronal oscillations that are coherent across the brain in patient with ED at rest and while using the index finger to evoke dystonia normally triggered by playing the flute. During rest, there was increased coherence in the bilateral frontal and parietal regions that became more focal during dystonia. Diffuse hyperexcitability and increased coherence persisted in bilateral parietal regions as well as the bilateral frontal regions.


Hypothyroidism, the main thyroid dysfunction in Iranian patients with myasthenia gravis: A case serie.
Several concomitant disorders especially thyroid abnormalities have been reported in patients with myasthenia gravis (MG). We aimed to estimate the frequency and pattern of thyroid disorders in Iranian patients with MG. All consecutive patients with MG referred to neurology clinic of Rasool-e-Akram Hospital during 2006-2007 were enrolled. All patients underwent clinical assessment of thyroid gland as well as thyroid function test. AChR Ab titer was measured as well. Nerve conduction study (NCS), Electromyography (EMG), and Repetitive Nerve Stimulation (RNS) was done by a same neurologist. The diagnosis of MG was made on the basis of clinical examinations, an edrophonium chloride test and electrophysiological studies. The diagnosis of thyroid disorders were based on clinical presentation as well as thyroid function tests. FIFTY EIGHT PATIENTS (MEAN AGE [SD]: 37.1 [16.9], range: 10-80; female: 65.5%) were enrolled in this 12-month study. Four patients (6.9%) had abnormal thyroid function tests (Hypothyroidism: 3 [5.2%]; 4 females; 3 with hypothyroidism and 1 with hyperthyroidism). The mean age (SD) in men and women were 41.4 (21.3) and 34.9 (13.8) years (P: N.S.), respectively. In addition, once the MG patients are younger than 50, female gender is dominant while they are more than fifty, male is the dominant gender. Our results show that Iranian patients with MG tend to be female and young. Before sixth decade of life, women are the most presenting patients thereafter, men are the predominant gender. About 7 percent of them may suffer from concomitant thyroid problem especially hypothyroidism.


Treatment optimization with concurrent SBRT and intracavitary brachytherapy for locally advanced cervical cancer.
This work is aimed at investigating treatment planning strategies to optimally com-bine stereotactic body radiation therapy (SBRT) with intracavitary brachytherapy (ICBT) for the treatment of locally advanced cervical cancer. Forty patients (stage IIB - IIIB) previously treated with combined SBRT and ICBT were randomly selected for this retrospective study. All patients were CT- and MR-scanned with a ring applicator in situ. HR-CTV and OARs were contoured according to fused CT and MR images. Several ICBT plans were generated for each patient based on different dose prescription points, and then a matching SBRT plan was generated for each ICBT plan. The dose distribution of each composite plan was analyzed with a focus on the doses received by 90% and 100% of the target volume (D90 and D100), the target volume receiving 100% of the prescription dose (V100%), and the doses received by 2 cc and 40% of the OARs (D2 cc and D40). As the distance, d, between the prescription point and the tandem varied within 1.0 and 1.9 cm, the D90, D100 and V100% for the target, as well as D2 cc and D40 for the bladder and rectum approached their optimal values for d value between 1.0 and 1.4 cm. When design-ing a combined ICBT + SBRT plan, one should measure the size of the cervix and set the prescription isodose line 1.0 to 1.4 cm away from the tandem for the ICBT plan first and then optimize the SBRT plan based on the ICBT dose distribution to achieve the best target coverage and critical structures sparing.


Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey.
To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries. Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire. Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients. The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries.


An expanded halogen bonding scale using astatine.
As a non-covalent interaction, halogen bonding is now acknowledged to be useful in all fields where the control of intermolecular recognition plays a pivotal role. Halogen-bond basicity scales allow quantification of the halogen bonding of referential donors with organic functional groups from a thermodynamic point of view. Herein we present the pK BAtI basicity scale to provide the community an overview of halogen-bond acceptor strength towards astatine, the most potent halogen-bond donor element. This experimental scale is erected on the basis of complexation constants measured between astatine monoiodide (AtI) and sixteen selected Lewis bases. It spans over 6 log units and culminates with a value of 5.69 ± 0.32 for N,N,N',N'-tetramethylthiourea. On this scale, the carbon π-bases are the weakest acceptors, the oxygen derivatives cover almost two-thirds of the scale, and sulphur bases exhibit the highest AtI basicity. Regarding the applications of 211At in targeted radionuclide therapy, stronger labelling of carrier agents could be envisaged on the basis of the pK BAtI scale.


Effects of Ketogenic Diets on Cardiovascular Risk Factors: Evidence from Animal and Human Studies.
The treatment of obesity and cardiovascular diseases is one of the most difficult and important challenges nowadays. Weight loss is frequently offered as a therapy and is aimed at improving some of the components of the metabolic syndrome. Among various diets, ketogenic diets, which are very low in carbohydrates and usually high in fats and/or proteins, have gained in popularity. Results regarding the impact of such diets on cardiovascular risk factors are controversial, both in animals and humans, but some improvements notably in obesity and type 2 diabetes have been described. Unfortunately, these effects seem to be limited in time. Moreover, these diets are not totally safe and can be associated with some adverse events. Notably, in rodents, development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance have been described. The aim of this review is to discuss the role of ketogenic diets on different cardiovascular risk factors in both animals and humans based on available evidence.


Radiation proctitis: a decade's experience.
Pelvic radiotherapy is an essential component of potentially curative therapy for many pelvic malignancies; however, the rectum consequently often sustains collateral injury. The researchers retrieved patient data that was prospectively gathered over a ten-year period between January 1995 and December 2004. The relevant details, including gender, age, pelvic pathology for which radiotherapy was administered, the presenting symptoms, the interval between radiotherapy and the onset of symptoms, the mode of diagnosis, treatments received, length of hospital stay and duration of follow-up, were analysed. During the period under review, 77 patients were admitted for the treatment of radiation proctitis, with a median follow-up period of 14 (range 1-61) months. There were 23 male and 54 female patients, with a median age of 63.9 (range 37-89) years. The most common underlying cancers were gynaecological (63.6 percent), prostate (18.2 percent) and colorectal (15.6 percent) cancer. The most common presenting symptom was bleeding per rectum (89.6 percent), with a change in bowel habits a distant second (10.4 percent). The median latent period between the completion of radiotherapy and the onset of symptoms was 24 (range 3-68) months. The majority of the patients (72.5 percent) received non-surgical treatment, most commonly using topical 4 percent formalin solution to arrest the bleeding, with more than half the patients requiring repeat treatments. 14 (18.2 percent) patients required colorectal resections for intractable bleeding, intestinal obstruction or intra-abdominal sepsis. Radiation proctitis can be a therapeutic challenge, even in the most experienced hands. The majority of patients who present with per rectal bleeding can be treated using topical modalities, while surgery may offer the only chance of relief from life-threatening symptoms.


Examining the efficiency of home care.
This article focuses on the "efficiency" or cost-effectiveness of home care. Because home care encompasses a range of services targeted to many populations, it is necessary to take cognizance of case mix and clarify its goals to assess effectiveness. Goals for home care can be thought of as meeting and/or compensating for client dependency needs or making a difference in the client's clinical trajectory. The latter implies comparing actual to expected outcomes, where outcomes can cover a wide range of domains addressing quality of care and quality of life. Inferring the effect of treatment (i.e., home care) on various outcomes will likely rely heavily on epidemiological techniques that, in turn, rely on sophisticated statistical techniques. Problems measuring the costs of care include how to handle the costs of informal care and deciding whose costs should be of primary concern. Better data about the costs, and experimentation with different forms of caregiving, need to be pursued.


Treatment of non-small-cell lung cancer after progression on nivolumab or pembrolizumab.
Although PD-1 antibodies (PD1 Ab) are the standard of care for advanced non-small-cell lung cancer (ansclc), most patients will progress. We compared survival outcomes for patients with ansclc who received systemic therapy (st) after progression and for those who did not. Additionally, clinical characteristics that predicted receipt of st after PD1 Ab failure were evaluated. All patients with ansclc in British Columbia initiated on nivolumab or pembrolizumab between June 2015 and November 2017, with subsequent progression, were identified. Eligibility criteria for additional st included an Eastern Cooperative Oncology Group (ecog) performance status (ps) of 3 or less and survival for more than 30 days from the last PD1 Ab treatment. Post-progression survival (pps) was assessed by landmark analysis. Baseline characteristics associated with pps were identified by multivariable analysis. Of 94 patients meeting the eligibility criteria, 33 received st after progression. In 75.6%, a PD1 Ab was received as first- or second-line treatment. The most common sts were erlotinib (36.4%) and docetaxel (27.3%). No statistically significant difference in median pps was observed between patients who did and did not receive st within 30 days of their last PD1 Ab treatment (6.9 months vs. 3.6 months, log-rank p = 0.15.) In multivariable analysis, factors associated with increased pps included an ecog ps of 0 or 1 compared with 2 or 3 [hazard ratio (hr): 0.42; 95% confidence interval (ci): 0.24 to 0.73; p = 0.002] and any response compared with no response to PD1 Ab (hr: 0.54; 95% ci: 0.33 to 0.90; p = 0.02). In this cohort, only 35.1% of patients eligible for post-PD1 Ab therapy received st. Post-progression survival was not significantly affected by receipt of post-progression therapy. Prospective trials are needed to clarify the benefit of post-PD1 Ab treatments.


The ABC transporter structure and mechanism: perspectives on recent research.
ATP-binding cassette (ABC) transporters are multidomain integral membrane proteins that utilise the energy of ATP hydrolysis to translocate solutes across cellular membranes in all phyla. ABC transporters form one of the largest of all protein families and are central to many important biomedical phenomena, including resistance of cancers and pathogenic microbes to drugs. Elucidation of the structure and mechanism of ABC transporters is essential to the rational design of agents to control their function. While a wealth of high-resolution structures of ABC proteins have been produced in recent years, many fundamental questions regarding the protein's mechanism remain unanswered. In this review, we examine the recent structural data concerning ABC transporters and related proteins in the light of other experimental and theoretical data, and discuss these data in relation to current ideas concerning the transporters' molecular mechanism.


Antioxidant status and lipid peroxidation activity in evaluating hepatocellular damage in children.
Serum levels of glutathione reductase (GR), glutathione S-transferase-alpha (GST-alpha) and malondialdehyde (MDA) were determined to evaluate their use in diagnosing hepatocellular damage in 75 children with liver disease. Except for level of GR in patients with HBV, GR, GST-alpha and MDA were raised significantly in patients compared with controls. At 100% specificity, the sensitivity of the 3 markers for detecting hepatitis B virus, hepatitis C virus and schistosomiasis infection respectively were: 16.7%, 100.0% and 17.7% for GR; 33.3%, 62.1% and 38.2% for GST-alpha; and 25.0%, 10.3% and 29.4% for MDA. GR was more sensitive in hepatitis C infection, while MDA reflected changes in liver ultrasound and GST-alpha was the best indicator for histopathological changes.


Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.
Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.


Higher Expression of Linc00152 Promotes Bladder Cancer Proliferation and Metastasis by Activating the Wnt/β-Catenin Signaling Pathway.
BACKGROUND Recent studies have demonstrated that Linc00152 is highly expressed in multiple cancer types and its genes show tumor-promoting characteristics. However, the efficacy and biological mechanism of Linc00152 in bladder cancer remains unclear. MATERIAL AND METHODS We study investigated the relative expression and promoter methylation of Linc00152 in 126 cases of bladder cancer tissues by qRT-PCR and Bisulfite sequencing PCR. qRT-PCR was used to assess the relative expression of Linc00152 in 4 human bladder cancer cell lines. To explore the biological properties of Linc00152, we performed cell growth and soft-agar colony-formation assays, flow cytometry analyses, wound-healing assay, and Transwell assay. Western blot analysis was used to detect the underlying mechanisms of Linc00152 in bladder cancer. RESULTS We found that Linc00152 was highly expressed in 126 cases of bladder carcinoma tissues (p<0.001) and 4 cell lines (p<0.01), and Linc00152 is more commonly expressed in patients with advanced-stage cancer (p=0.021). Knockdown of Linc00152 by using siRNAs in bladder cancer cell lines (T24 and HT-1197) suppressed cell viability and growth by causing cell cycle arrest and apoptosis (p<0.001), as well as inhibiting cell migration and invasion (p<0.001). In addition, the quantitative RT-PCR and Western blot results suggest that knockdown of Linc00152 reduced Wnt/ß-Catenin signaling (p<0.001). CONCLUSIONS This research shows that Linc00152 is highly expressed in patients with bladder cancer and the possible carcinogenic effect of Linc00152 in bladder cancer occurs through activating the Wnt/ß-Catenin signaling pathway, and could be a new biomarker for diagnosis and prevention of this cancer.


Sleep medicine training across the spectrum.
There is now a new pathway and examination for sleep medicine, sponsored by the American Board of Internal Medicine, and a number of accredited sleep medicine fellowship programs through the Accreditation Council for Graduate Medical Education. This review takes an historical approach to discuss the process of education for sleep physiology and disorders not only in the postgraduate period but also at all levels of instruction. In reality, there is a continuum of knowledge that needs to be reinforced up and down the educational system, of which Sleep Medicine subspecialty training is just one part. Although progress has been made at all educational levels up to this point, the future of training and education will depend on a sustained effort at several levels from undergraduate to postgraduate continuing medical education and will be facilitated by professional societies and other specialties who will collectively promote the value of and outcomes for clinical sleep medicine.


Rapid flow cytometric susceptibility testing of Candida albicans.
A rapid flow cytometric assay for in vitro antifungal drug susceptibility testing was developed by adapting the proposed reference method for broth macrodilution testing of yeasts. Membrane permeability changes caused by the antifungal agent were measured by flow cytometry using propidium iodide, a nucleic acid-binding fluorochrome largely excluded by the intact cell membrane. We determined the in vitro susceptibility of 31 Candida albicans isolates and two quality control strains (Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258) to amphotericin B and fluconazole. Amphotericin B MICs ranged from 0.03 to 2.0 microg/ml, while fluconazole MICs ranged from 0.125 to 128 microg/ml. This method results in clear-cut endpoints that were reproducible. Four-hour incubation was required for fluconazole, whereas a 2-h incubation was sufficient for amphotericin B to provide MICs comparable to the reference macrodilution method developed by the National Committee for Clinical Laboratory Standards Subcommittee on Antifungal Susceptibility Tests. Results of these studies show that flow cytometry provides a rapid and sensitive in vitro method for antifungal susceptibility testing of C. albicans.


Cryptococcal meningitis in the acquired immunodeficiency syndrome.
Cryptococcosis is the most common, deep-seated fungal infection in AIDS patients, and cryptococcal meningitis is the most frequently observed syndrome. AIDS patients with cryptococcal meningitis usually have an indolent presentation and nonspecific findings on physical examination. Routine laboratory tests are of little assistance in diagnosing cryptococcal meningitis. Cerebrospinal fluid (CSF) white blood cell counts tend to be low, and glucose and protein levels are nonspecific. Serum cryptococcal antigen (CRAG) is a sensitive test for cryptococcal meningitis, and CSF CRAG is usually also positive. Definitive diagnosis is made by culture of the CSF. Therapy of cryptococcal meningitis is changing to antifungal agents that are easy to administer as outpatient therapy. Amphotericin B continues to be the primary antifungal used in initial treatment of cryptococcal meningitis; addition of flucytosine is of no benefit. Recent data suggest oral fluconazole is effective as primary therapy, and may be superior to amphotericin B as maintenance therapy. Maintenance therapy decreases the incidence of relapse and increases survival.


The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells.
We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.