Rat thymectomy effects on leptin receptor and T-bet: erythroid hyperplasia with maturation arrest and suppressed T-cell-mediated hepatotoxicity.
Thymectomy is an inevitable therapy for thymoma. Therefore, determining hemato-immune changes post-thymectomy is important. Twenty-six normal LEW/Sea rats thymectomized (Tx) at the ages of 38 +/- 5 days were followed without any treatment for 4 months (experiments [Exp] A and B). In addition, 16 LEW/Sea rats Tx at the age of 42 days (Exp C and D) and 10 non-Tx control LEW/Sea rats (Exp E) were immunized with syngeneic male liver cells 2 to 3 times and followed 2.7 months after the first immunization. Flow cytometric (FCM) analysis of mesenteric lymph nodes (MLN) and peripheral blood (PB) showed as follows: among the 26 Tx rats (Exp A and B), MLN lymphocyte population at 4 months postthymectomy was characterized by decreased numbers of CD4+ cells (22%-36%) or alphabeta T-cell receptor (TCR)-positive cells (16%-54%) and increased numbers of interleukin 2 receptors (IL-2R) (>90%). In the 16 Tx-immunized rats (Exp C and D), both alphabeta TCR (MLN) and CD45R (PB) expression on lymphocytes was suppressed with rather high numbers of CD4. Bone marrow (BM) and PB hematological studies of the partially and totally Tx rats indicated the following: 8 BM of the 10 totally Tx males (Exp A) and the 7/10 male spleen showed erythroid hyperplasia with maturation arrest at the stage of basophilic erythroblasts and reticulocytopenia in the PB. One of the 10 males, which had both BM myeloid to erythroid (M/E) ratio of 4.3 and spleen myeopoiesis, was in a more advanced stage, a prestage of pure red cell aplasia (PRCA) with 22% of CD4+ MLN cells. Syngeneic liver cell immunization resulted in the Tx rats as follows: hepatotoxicity based on the immunization was weaker in the 16 Tx rats (Exp C and D) than in the 10 non-Tx rats (Exp E). Polymerase chain reaction (PCR) of PB and MLN showed compensatory activated leptin receptor (LR) and T-bet DNA in 19 Tx rats (Exp A and B) with abnormal FCM findings. The ineffective erythropoiesis at 4 months after thymectomy was explained by the erythroblast LR/erythropoietin receptor (EPOR) dysfunction. The low grade hepatotoxicity in the Tx rats (Exp C and D) was explained by the disturbed Th1 reactions (or the disturbed T-bet gene transcription) at postthymectomy.


A new humanized HLA transgenic mouse model of multiple sclerosis expressing class II on mouse CD4 T cells.
Among all the genetic factors associated with susceptibility to multiple sclerosis (MS), the strongest association has been seen with expression of certain major histocompatibility complex (MHC) class II molecules, although analysis of their exact function remains complicated. In general, the expression of class II is restricted to professional antigen-presenting cells; however, human but not mouse CD4+ T cells express class II on their surface. Functional studies of class II+ CD4+ T cells have been hampered due to lack of a proper animal model. Here, we describe development and characterization of a new humanized class II transgenic (tg) mouse expressing HLA-DR3 on mouse endogenous class II-negative background.


Inhibition of histone deacetylase activity promotes invasion of human cancer cells through activation of urokinase plasminogen activator.
Histone acetylation plays an important role in chromatin remodeling and gene expression. The molecular mechanisms involved in differential regulation of urokinase plasminogen activator (uPA) gene expression are not fully understood. In this study, we investigated whether histone deacetylation was involved in repression of uPA expression in human cancer cells. Induction of uPA expression by histone deacetylase (HDAC) inhibitors trichostatin A (TSA), sodium butyrate, and scriptaid was observed in all three different types of human cancer cells examined. Chromatin immunoprecipitation assays showed that the induction of uPA expression by TSA was accompanied by a remarkable increase of acetylation of histones H3 and H4, which are associated with the uPA promoter region in human cancer cells. These results were further substantiated by the findings of a restriction enzyme accessibility assay and TSA-stimulated uPA promoter activity through the inhibition of HDAC activity. In vitro Matrigel invasion assays showed that induction of uPA expression by HDAC inhibitors in human cancer cells resulted in a significant increase of cancer cell invasion. Furthermore, HDAC1 knockdown by small interference RNA stimulated uPA expression and cancer cell invasion. In conclusion, this study demonstrates the important role of histone modifications in regulating uPA gene expression and raises a possibility that the use of HDAC inhibitors in patients as cancer therapy may paradoxically establish metastasis through up-regulation or reactivation of uPA.


Prevalence of depression and its associated sociodemographic factors among Iranian female adolescents in secondary schools.
Across the globe, depression is a common psychiatric disorder and is the main cause of disability among adolescents. To this end, this study was conducted to screen for the prevalence of depression among secondary school female students in the city of Hamadan, in western Iran. In this cross-sectional study, a total of 670 secondary school female students, within the age range of 15-18 years were investigated using multistage random sampling method. Moreover, the Persian version of Center for Epidemiologic Studies Depression Scale (CES-D) and a researcher-designed questionnaire containing demographic variables were employed as research instruments. Analyses of the findings were made using SPSS version 16 software followed by stratified logistic regression model, which was performed for correlation analysis. The mean (standard deviation) age of students was 16.2 (0.68) years. The prevalence of severe depression in female students estimated by the Center for Epidemiologic Studies Depression Scale (CES-D) was equal to 52.6%. A statistically significant relationship was also observed to exist between prevalence of depression and type of school (P < 0.001), family income (P < 0.001), living in the suburbs (P < 0.001), and field of study at school (P < 0.001). However, no statistically significant correlation was found between depression among students and school grade, type of living with parents, father's education and occupation, mother's education and occupation, and family size. Depression was prevalent among the secondary school female students examined and it significantly correlated with socioeconomic status. Therefore, periodic screening, psychological training programs, proper diagnosis of high-risk individuals in secondary schools, and early intervention among secondary school female students are urgently needed.


Her-2 neu (Cerb-B2) expression in fine needle aspiration samples of breast carcinoma: A pilot study comparing FISH, CISH and immunocytochemistry.
Breast cancers with Her-2 neu gene amplification are recognized as important markers for aggressive disease and targets which respond to therapy with trastuzumab. Her-2 neu testing on histological sections is routinely performed to select patients who may benefit from anti- Her-2 neu therapy. Few reports are available which document Her-2 neu status on fine needle aspirates (FNA). This pilot study is to document expression of Her-2 neu (Cerb-B2) on cytospin smears from FNA of patients with breast carcinoma. Twenty samples of FNA already collected for diagnostic purposes from patients with primary breast carcinoma were studied for demonstration of Her-2 neu expression by immunohistochemistry (IHC), Fluorescent in-situ hybridization (FISH) and chromogenic in-situ hybridization (CISH) on cytospin smears from FNA. Their expression was compared with tissue sections where possible. Good correlation was observed between Her-2 neu protein expression and gene amplification in cytospin smears. Three of five (60%) breast carcinomas cases with 2+ and 3+ staining on IHC showed gene amplification by FISH and CISH. Three of 7 (43%) and 5 of 7 (71%) cases negative/1+ staining on IHC did not show gene amplification by FISH and CISH respectively. Tissue sections from 10 cases with 2+ and 3+ staining for Her2neu by IHC showed gene amplification in 8 cases. Demonstration of Her-2 neu by IHC, FISH or CISH in FNA is possible and may play a role in the management of patients with advanced breast cancer or those cases where surgical resection is not advisable.


A look into the small bowel in Crohn's disease.
Crohn's disease (CD) is an inflammatory bowel disease that can affect the entire gastrointestinal tract, with the small bowel (SB) being the most commonly affected site. In some patients, refractory inflammation or chronic strictures of the SB are responsible for a debilitating course of the disease that might lead to severely reduced quality of life. Therefore, SB imaging is a crucial element in diagnosing and/or managing SB CD, and continues to evolve because of technologic advances. SB endoscopy (capsule endoscopy and device-assisted enteroscopy) and cross-sectional radiologic imaging (computed tomography enterography and magnetic resonance enterography) have become key players to diagnose and/or manage CD. In everyday practice, the choice of the imaging modalities is based on the presence and availability of the techniques and of experienced operators in each institute, clinical usefulness, safety, and cost. Here, SB endoscopy and radiologic imaging in suspected or known CD patients will be addressed and discussed.


An essay on an authentic meaning of medicalization: the patient's perspective.
In this essay, the experiences of the author serve as a key to a critical understanding of medicalization in the treatment of cancer in American society. Forms of medicalization described are (a) giving useless treatments to keep the patient under medical care; (b) demeaning and undermining efforts at self-determination and self-care; and (c) keeping the patient's life suspended by continual reminders that death is just around the corner, and that all time and energy left must be devoted to ferreting out and killing the disease.


Childhood Obesity is Associated With Osteochondritis Dissecans of the Knee, Ankle, and Elbow in Children and Adolescents.
Osteochondritis dissecans (OCD) is a joint disorder of the subchondral bone and articular cartilage whose association with obesity in children is not clearly known. The purpose of this study was to assess the magnitude of the association between childhood obesity and the occurrence of OCD of the knee, ankle, and elbow in children. A retrospective chart review of an integrated health system was performed on OCD patients aged 2 to 19 from 2007 to 2011, with over 1 million patients in this cohort. Lesion location, laterality, and all patient demographics were recorded. The body mass index (BMI) for each patient in the cohort was used to stratify patients into 5 weight classes (underweight, normal weight, overweight, moderately obese, and extremely obese) based on BMI-for-age. The associations between the 5 weight classes and OCD of the ankle, knee, and elbow were assessed using multiple logistic regression models to estimate odds ratios (OR) and 95% confidence intervals using multivariate analysis to adjust for patient demographic variables. In total, 269 patients fit the inclusion criteria. Mean BMI, both absolute and percentile, was significantly higher for patients with OCD of the knee, elbow, and ankle than patients without OCD. In the multivariate analysis, extremely obese patients were found to have an increased OR of OCD for all patients, with an 86% increased risk of any OCD compared with normal weight patients. In addition, assessment by different types of OCD revealed that extremely obese patients had an increased OR of OCD of the elbow and ankle individually, with a 3.1 times increased OCD elbow risk and 3.0 times increased risk of ankle OCD in extremely obese patients. Although extremely obese patients did not have a statistically significant increased risk of knee OCD, moderately obese patients did have a 1.8 times increased risk of knee OCD as compared with normal weight children. There were no significantly different risks of any type of OCD seen in overweight or underweight patients as compared with normal weight patients. In this population-based cohort study, extreme obesity is strongly associated with an increased risk of OCD overall and OCD of the elbow and ankle specifically. In addition, moderate obesity is associated with an increased risk of knee OCD. All types of OCD were also found to have a significantly greater average BMI when compared with patients without OCD. Level IV-descriptive epidemiology study.


Environmental friendly crush-magnetic separation technology for recycling metal-plated plastics from end-of-life vehicles.
Metal-plated plastics (MPP), which are important from the standpoint of aesthetics or even performance, are increasingly employed in a wide variety of situations in the automotive industry. Serious environmental problems will be caused if they are not treated appropriately. Therefore, recycling of MPP is an important subject not only for resource recycling but also for environmental protection. This work represents a novel attempt to deal with the MPP. A self-designed hammer crusher was used to liberate coatings from the plastic substrate. The size distribution of particles was analyzed and described by the Rosin-Rammler function model. The optimum retaining time of materials in the crusher is 3 min. By this time, the liberation rate of the materials can reach 87.3%. When the density of the suspension is 31,250 g/m(3), the performance of liberation is the best. Two-step magnetic separation was adopted to avoid excessive crushing and to guarantee the quality of products. Concerning both the separation efficiency and grade of products, the optimum rotational speed of the magnetic separator is 50-70 rpm. On the basis of the above studies about the liberating and separating behavior of the materials, a continuous recycling system (the technology of crush-magnetic separation) is developed. This recycling system provides a feasible method for recycling MPP efficiently, economically, and environmentally.


Apigenin and tangeretin enhance gap junctional intercellular communication in rat liver epithelial cells.
Two flavones, apigenin and tangeretin, were studied for their ability to modulate gap junctional intercellular communication (GJIC) in the rat liver epithelial cell line REL. Their cytotoxicity was first determined by cell density and neutral red uptake assays: neither apigenin nor tangeretin are cytotoxic at 10 and 25 microM, the concentrations used in our experiments. We then studied GJIC using the dye transfer assay and we observed that both apigenin and tangeretin enhance it, the maximum stimulation (x 1.7-1.8) being achieved at 25 microM for 24 h. When the dye transfer was enhanced, the amount of connexin 43 increased, which was demonstrated by Western blot and immunofluorescence analysis. For apigenin only, Northern blot analysis showed an accumulation of connexin 43 mRNA. In addition, the incubation of REL cells with the two compounds, for 1 or 24 h, prevented the inhibition of dye transfer by 12-O-tetradecanoylphorbol-13-acetate (1 or 10 ng/ml). The enhancement of GJIC by apigenin could be one of the major mechanisms responsible for apigenin's anti-tumour promoting action in vivo. As for tangeretin, its capacity to enhance GJIC completes its potential protective properties towards the post-initiation process.


Free energy map for the co-oligomerization of formaldehyde and ammonia.
Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to construct a free energy map of formaldehyde and ammonia co-oligomerization in aqueous solution at pH 7. The stepwise route to forming hexamethylenetetramine (HMTA), the one clearly identified major product in a complex mixture, involves a series of addition reactions of formaldehyde and ammonia coupled with dehydration and cyclization reactions at key steps in the pathway. The free energy map also allows us to propose the possible identity of some major peaks observed by mass spectroscopy in the reaction mixture being the result of stable species not along the pathway to HMTA, in particular those formed by intramolecular condensation of hydroxyl groups to form six-membered rings with ether linkages. Our study complements a baseline free energy map previously worked out for the self-oligomerization of formaldehyde in solution at pH 7 using the same computational protocol and published in this journal (J. Phys. Chem. A 2013, 117, 12658).


[Effects of stabilized N fertilizer combined with straw returning on rice yield and emission of N2O and CH4 in a paddy field].
Based on a two-year field experiment located at Shenyang Applied Ecological Experiment Station of Chinese Academy of Sciences, we examined the effects of stabilized N fertilizer combined with straw returning on rice yield and emission of N2O and CH4 in aquic brown soil. Six treatments were set up, i.e. control (CK), urea(U), urea+urease inhibitor+nitrification inhibitor (U+I), straw (S), straw+urea (S+U), straw+urea+ urease inhibitor+nitrification inhibitor (S+U+I). The results showed that urea application increased rice yield, cumulative N2O and CH4 emission, and global warming potential. The treatment of U+I significantly mitigated cumulative N2O emission. Returning rice straw to the field significantly increased cumulative N2O emission, cumulative CH4 emission, global warming potential, and greenhouse gas emission intensity. The S+U+I treatment had the highest rice yield and greenhouse gas emission intensity. U+I treatment had the the second highest rice yield and the lowest greenhouse gas emission intensity. Rice yield in the S treatment showed no significant difference with CK. Our results indicated that S+U+I and U+I are relatively better agricultural strategies compared with other treatments in paddy fields on aquic soil.


Training elements at different levels in the strategies for control of schistosomiasis.
Recently acquired comprehensive knowledge concerning the epidemiology of schistosomiasis has provided the background for the establishment of schistosomiasis control strategies. However, the planning, implementation, and maintenance of such control programmes requires sufficient numbers of well trained personnel at the local, district and central levels. Training of health personnel as well as motivation of the community are fundamental and essential elements in any schistosomiasis control programme. The training elements and approaches are discussed.


[Local wound care: evidence-based treatments and dressings].
Patients with open wounds require specific local-wound care. There is huge variety in methods of local-wound care. This is due not only to the many different types of wounds but also to the widely varying preferences of doctors and nurses, and to the lack of strong evidence and relevant guidelines regarding the most appropriate form of local-wound care. In 19 systematic literature reviews from the Cochrane Collaboration on surgical and traumatic wounds and ulcers (venous, arterial and diabetic) information can be found on local-wound treatment. Eleven of these reviews were limited to strong evidence for the use of: tissue adhesives for surgical and traumatic wounds; foam dressings in surgical wounds healing by secondary intention; (intermittent) compression, bilayer artificial skin and lidocaine-prilocaine cream for venous ulcers; hydrogel and in-shoe orthotics for diabetic-foot ulcers; negative pressure for chronic wounds, and cleansing of acute wounds with clean tap water.


Pfizer-BioNTech COVID-19 Vaccine Tolerance in Allergic versus Non-Allergic Individuals.
Individuals with a history of allergy are potentially at risk of suffering from adverse effects after COVID-19 vaccination. We sought to assess the tolerance towards the Pfizer-BioNTech vaccine in allergic patients. To address this issue, we used a questionnaire conducted on-line in a group of medical professionals who were vaccinated with the Pfizer-BioNTech vaccine. A total of 1808 respondents, out of whom 1707 received two doses of the vaccine, returned the questionnaire. Local reactions after injection were more frequent in allergic individuals after both doses (swelling p = 0.0003). Systemic adverse events (AE-SYS) occurred more often after the second than the first dose in both groups (allergic persons: 77.29% vs. 41.06%); vomiting and arthralgia occurred more often in allergic subjects (p = 0.0009). AE-SYS in allergic individuals lasted longer than in non-allergic ones after the first (p = 0.01) and the second dose (p = 0.0009). Allergic reactions after vaccination were reported more frequently in allergic subjects: after the first dose (p = 0.00001) and after the second dose (p = 0.001). Rhinitis was the most frequent symptom observed more often in allergic patients. No severe allergic reactions occurred during the full cycle of vaccination. Although the Pfizer-BioNTech vaccine is tolerated worse by allergic than non-allergic individuals, the occurring adverse symptoms are mild and do not preclude a successful completion of the vaccination cycle. The presence of symptoms suggestive of allergy does not constitute a condition of increased risk of developing clinically significant adverse events following Pfizer COVID-19 vaccination.


The Expulsion of South Africa and Rhodesia from the Commonwealth Medical Association, 1947-70.
In 1970 the medical associations of South Africa and Rhodesia (now, Zimbabwe) were expelled from the Commonwealth Medical Association. The latter had been set up, as the British Medical Commonwealth Medical Conference, in the late 1940s by the British Medical Association (BMA). These expulsions, and the events leading up to them, are the central focus of this article. The BMA's original intention was to establish an organisation bringing together the medical associations of the constituent parts of the expanding Commonwealth. Among the new body's preoccupations was the relationship between the medical profession and the state in the associations' respective countries. It thus has to be seen as primarily a medico-political organisation rather than one concerned with medicine per se. Although, there were also tensions from the outset regarding the membership of the Southern African medical associations. Such stresses notwithstanding, these two organisations remained in the BMA-sponsored body even after South Africa and Rhodesia had left the Commonwealth. This was not, however, a situation which could outlast the growing number of African associations which joined in the wake of decolonisation; and hardening attitudes towards apartheid. The article therefore considers: why the BMA set up this Commonwealth body in the first place and what it hoped to achieve; the history of the problems associated with South African and Rhodesian membership; and how their associations came to be expelled.


Climate Change and Public Health through the Lens of Rural, Eastern North Carolina.
BACKGROUND Recognizing that health outcomes are associated with climate threats is important and requires increased attention by health care providers and policymakers. The primary goal of this report is to provide information related to the public health threats of climate change, while identifying climate-sensitive populations primarily in rural, Eastern North Carolina.METHODS Publicly available data was used to evaluate regional (eg, Eastern, Piedmont, and Western) and county level socio-vulnerability characteristics of population groups in North Carolina, including: percent of persons living in poverty, percent of non-white persons, percent of persons under 18 years living in poverty, percent of elderly people living in poverty, percent of persons with a disability, and number of primary care physicians. One-way ANOVA was used to calculate and compare mean value estimates of population socio-vulnerability variables in Eastern North Carolina with Piedmont and Western regions.RESULTS Across all regional categories, the eastern part of the state had considerably higher averages than the state for percent of persons living in poverty (17.2%), percent of non-white persons (13.3%), percent of persons under 18 years old living in poverty (24.9%), percent of elderly people living in poverty (10.0%), and percent of persons with a disability (13.3%). Overwhelmingly, more counties in Eastern North Carolina had fewer primary care physicians (per 10,000 persons) than the state average (8.6 per 10,000 persons).CONCLUSION Eastern North Carolina has a disproportionally higher percent of population groups that are vulnerable to the threats of climate change. The need for health care providers to understand and communicate the challenges faced by rural, vulnerable population groups is of great public health importance. Communicating these health risks to policy makers is of equal importance.


TMEM164 is a new determinant of autophagy-dependent ferroptosis.
Macroautophagy (hereafter "autophagy") is a membrane-mediated biological process that involves engulfing and delivering cytoplasmic components to lysosomes for degradation. In addition to autophagy's pro-survival effect during nutrient starvation, excessive activation of autophagy machinery can also cause regulated cell death, especially iron-dependent ferroptosis. Here, we report a key role of TMEM164 (transmembrane protein 164) in selectively mediating ATG5 (autophagy related 5)-dependent autophagosome formation during ferroptosis, rather than during starvation. In contrast, the membrane protein ATG9A (autophagy-related 9A) is dispensable for the formation of autophagosomes during ferroptosis. TMEM164-mediated autophagy degrades ferritin, GPX4 (glutathione peroxidase 4), and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death. Consequently, the loss of TMEM164 limits the anticancer activity of ferroptosis-mediated cytotoxicity in mice. High TMEM164 expression is associated with improved survival and increased immune cell infiltration in patients with pancreatic cancer. These findings establish a new mode of autophagy-dependent ferroptosis.


Preparation and Performance of a Low-Carbon Foam Material of Fly-Ash-Based Foamed Geopolymer for the Goaf Filling.
The treatment of goaf subsidence is important for sustainable development. Geopolymer is a new type of cementing material with excellent mechanical properties, durability, corrosion resistance, and other advantages owing to its unique three-dimensional spatial aggregation structure. Herein, a type of preparation technology of fly-ash-based foamed geopolymer suitable for goaf filling was developed by adding a chemical foaming agent to the matrix of fly-ash-based geopolymer. The mechanical properties, chemical composition, and pore structure characteristics of the samples were discussed. When the samples with different contents of fly ash, sodium metasilicate, sodium stearate, H2O2, and NaOH were prepared, a uniaxial compression test was performed to analyze the uniaxial compression failure characteristics and compression strength of the samples. The mineralogical composition of each sample was analyzed by X-ray diffraction (XRD) test, and the microstructure images of different samples were observed using scanning electron microscopy (SEM). The effects of the content of each component on the properties of the samples were discussed. Finally, the CO2 emission, energy consumption, and cost of producing fly-ash-based foamed geopolymer were analyzed. Overall, the material had the advantages of low energy consumption, low CO2 emission, environmental-protection ability, and waste utilization and thus has a broad application prospect in treating subsidence.


Direct acting antivirals are associated with more liver stiffness regression than pegylated interferon therapy in chronic hepatitis C patients.
Extent of post-treatment fibrosis change in patients with different stages of fibrosis not fully known. We aimed to study changes in liver fibrosis in chronic hepatitis C patients who were treated with pegylated interferon/ribavirin (PEG/RBV) or direct acting antivirals (DAAs). Retrospective evaluation of results of transient elastography (TE) was done before and 1 year after end of treatment for patients treated with PEG/RBV (n = 268) and DAAs (n = 245). The average age was 45.54 ± 10.64 years; mainly males. All patients in the DAAs group achieved sustained virological response (SVR), unlike 56.3% of the patients in the PEG/RBV group. F3-F4 fibrosis was predominant in the PEG/RBV nonresponder patients (51.3%) and DAAs responders (57.1%). TE decreased 1 year after end of treatment (p = 0.001) in the viral responders of the PEG/RBV group (7.44 ± 4.02 vs. 10.24 ± 7.29 kPa) and DAAs group (12.12 ± 9.21 vs. 16.81 ± 12.84 kPa) respectively. The delta TE change in the DAAs responders was higher than the PEG/RBV responders (p = 0.001) and PEG/RBV nonresponders (p = 0.001). The percentage of patients with liver fibrosis regression was higher in DAAs responders (52.5%) than in PEG/RBV responders (23.3%). Treatment with DAAs is associated with fibrosis improvement more than treatment with PEG/RBV in chronic hepatitis C patients.


A transient flow reactor for rapid gas switching at atmospheric pressure.
Herein, we present a design for a transient flow reactor system with high detection sensitivity and minimal dead volume, such that it is capable of sub-second switching of the gas stream flowing through a catalytic bed. We demonstrate the reactor's capabilities for step transient, pulse, and stream oscillation experiments using the model system of CO oxidation over Pd catalysts, and we find that we are able to precisely model step transients for CO oxidation using a pseudo-homogenous-packed bed reactor model. The design principles leading to minimal gas hold-up time and increased sensitivity that are described in this paper can be implemented into existing flow reactor designs with minimal cost, providing a readily accessible alternative to the existing transient instrumentation.


Interdependent Group Contingencies Decrease Adolescents' Disruptive Behaviors During Group Therapy: A Practitioner's Demonstration.
Adolescents who have been adjudicated for illegal sexual behavior may receive treatment that requires attending group therapy sessions and classes. For some adolescents, nonsexual problem behavior (e.g., verbal outbursts, noncompliance) interferes with their ability to participate in group treatment. Researchers used a multiple-baseline across groups design with an embedded changing criterion design to evaluate the effects of an interdependent group contingency for decreasing disruptive behavior in adolescents across two therapy groups. Results indicated that the procedure was effective in reducing disruptive behavior emitted by adolescents in group therapy. Measures of social validity indicated that both the therapists and students viewed the overall procedures and outcomes as acceptable. Implications for interdependent group contingencies across diverse populations are discussed.


[Is ethanol suitable as an energy carrier in infusion therapy?].
Using experimental animals and human volunteers the suitability of ethanol for parenteral nutrition was investigated. The most evident disadvantage is the relatively low metabolic capacity for intravenous ethanol. A steady state was attained in the animal experiment with the low dose of 0.2 g/kg bodyweight per hour. No indications were found, however, that intravenous ethanol would contribute to the development of a lactate acidosis. Merely a short time before death because of hyperalcoholemia (5-7% blood concentration) an increase in lactate concentration is found which might be caused by circulatory collaps. Additionally, the effect of intravenous ethanol seems to be of minor importance. Small effects were found only in the experimental animal as well as in volunteers. A very strong inhibition of galactose metabolism was found to be a significant effect of ethanol application. Despite of similar metabolic reactions neither the application of xylitol nor of sorbitol causes an inhibition of galactose metabolism. These results might be interpreted as signs for compartmentalisation of the different metabolic reactions in the cytoplasma of the hepatocytes. According to the results of these investigations ethanol merely evokes small acute metabolic effects. The low metabolic capacity and the established hepatotoxicity are indications for a restrained use of ethanol in parenteral nutrition.


Predictive power of 24-h ambulatory pulse pressure and its components for mortality and cardiovascular outcomes in 11 848 participants recruited from 13 populations.
The role of pulse pressure (PP) 'widening' at older and younger age as a cardiovascular risk factor is still controversial. Mean PP, as determined from repeated blood pressure (BP) readings, can be expressed as a sum of two components: 'elastic PP' (elPP) and 'stiffening PP' (stPP) associated, respectively, with stiffness at the diastole and its relative change during the systole. We investigated the association of 24-h ambulatory PP, elPP, and stPP ('PP variables') with mortality and composite cardiovascular events in different age classes. Longitudinal population-based cohort study of adults with baseline observations that included 24-h ambulatory BP. Age classes were age 40 or less, 40-50, 50-60, 60-70, and over 70 years. Co-primary endpoints were total mortality and composite cardiovascular events. The relative risk expressed by hazard ratio per 1SD increase for each of the PP variables was calculated from multivariable-adjusted Cox regression models. The 11 848 participants from 13 cohorts (age 53 ± 16 years, 50% men) were followed for up for 13.7 ± 6.7 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or nonfatal cardiovascular event (12.9 per 1000 person-years). Mean PP, elPP, and stPP were, respectively, 49.7, 43.5, and 6.2 mmHg, and elPP and stPP were uncorrelated ( r = -0.07). At age 50-60 years, all PP variables displayed association with risk for almost all outcomes. From age over 60 years to age over 70 years, hazard ratios of of PP and elPP were similar and decreased gradually but differently for pulse rate lower than or higher than 70 bpm, whereas stPP lacked predictive power in most cases. For age 40 years or less, elPP showed protective power for coronary events, whereas stPP and PP predicted stroke events. Adjusted and unadjusted hazard ratio variations were similar over the entire age range. This study provides a new basis for associating PP components with outcome and arterial properties in different age groups and at different pulse rates for both old and young age. The similarity between adjusted and unadjusted hazard ratios supports the clinical usefulness of PP components but further studies are needed to assess the prognostic significance of the PP components, especially at the young age.


Fracture in glassy polymers: a molecular modeling perspective.
Over the past 25 years, molecular modeling and simulations have provided important insights into the physics of deformation and fracture of glassy polymers. This review presents an overview of key results discussed in the context of experimentally observed polymer behavior. Both atomistic and coarse-grained polymer models have been used in different deformation protocols to study elastic properties, shear yielding, creep, physical aging, strain hardening and crazing. Simulations reproduce most of the macroscopic features of plasticity in polymer glasses such as stress-strain relations and creep response, and reveal information about the underlying atomistic processes. Trends of the shear yield stress with loading conditions, temperature and strain rate, and the atomistic dynamics under load have been systematically explored. Most polymers undergo physical aging, which leads to a history-dependent mechanical response. Simulations of strain hardening and crazing demonstrate the nature of polymer entanglements in the glassy state and the role of local plasticity and provide insight into the origin of fracture toughness of amorphous polymers.


Continuing Orthohantavirus Circulation in Deer Mice in Western Montana.
Hantavirus pulmonary syndrome (HPS) is an often-fatal disease caused by New World hantaviruses, such as Sin Nombre orthohantavirus (SNV). In the US, >800 cases of HPS have been confirmed since it was first discovered in 1993, of which 43 were reported from the state of Montana. The primary cause of HPS in the US is SNV, which is primarily found in the reservoir host Peromyscus maniculatus (deer mouse). The reservoir host covers most of the US, including Montana, where multiple studies found SNV in local deer mouse populations. This study aimed to check the prevalence of SNV in the deer mice at popular recreation sites throughout the Bitterroot Valley in Western Montana as compared to previous studies in western Montana. We found high prevalence (up to 20%) of deer mice positive for SNV RNA in the lungs. We were unable to obtain a SNV tissue culture isolate from the lungs but could passage SNV from lung tissue into naïve deer mice. Our findings demonstrate continuing circulation of SNV in western Montana.


Effects of calcium ion concentration on the degeneration of amputated axons in tissue culture.
Light and electron microscope studies were conducted on the nature of the degenerative changes in amputated nerve fibers of cultured rat sensory ganglia and on the effects of media with differing calcium concentrations upon these changes. With glucose-enriched Eagle's media (MEM) containing 1.6 mM calcium, the amputated myelinated and unmyelinated axons undergo a progressive granular disintegration of their axoplasm with collapse and fragmentation of myelin sheaths between 6 and 24 h after transection. With MEM containing only 25-50 microM calcium, the granular axoplasmic degeneration does not occur in transected fibers and they retain their longitudinal continuity and segmental myelin ensheathment for at least 48 h. Addition of 6 mM EGTA to MEM (reducing the estimated Ca(++) below 0.3 microM) results in the structural preservation of both microtubules and neurofilaments within transected axons. A transient focal swelling of amputated axons occurs, however, in cultures with normal and reduced calcium. These observations suggest that an alteration in the permeability of the axolemma is a crucial initiating event leading to axonal degenerative changes distal to nerve transection. The loss of microtubules and neurofilaments and the associated granular alterations of the axoplasm in transected fibers appears to result from the influx of calcium into the axoplasm.


Multidisciplinary management of malignant pleural effusion.
Approximately 50% of patients with metastatic disease develop a malignant pleural effusion (MPE). Prompt clinical evaluation and treatment to achieve successful palliation are the main goals of management of MPE. Optimal treatment is still controversial and there is no universal standard approach. Management options include observation, thoracentesis, indwelling pleural catheter (IPC) or chest tube placement, pleurodesis, and surgical pleurectomy. The treatment for each patient should be based on symptoms, general condition, and life expectancy.


Interobserver Variability in Assessment of Depth of Submucosal Invasion for Colonic Endoscopic Resections Among Subspecialized Gastrointestinal Pathologists.
Recent data support that low-risk submucosally invasive (pT1) colonic adenocarcinomas (ie, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion) are considered cured via endoscopic resection, provided that the submucosal invasion is less than 1000 μm. Hence, the pathologists' assessment of depth of submucosal invasion may guide further management (ie, surveillance versus colectomy). To assess interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. Six gastrointestinal pathologists from 5 academic centers independently measured the greatest depth of submucosal invasion in micrometers on 52 hematoxylin-eosin-stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round 1 scoring). Two separate measurements (round 2 scoring) were subsequently performed by each pathologist following a consensus meeting, (1) from the surface of the lesion and (2) from the muscularis mucosae, and pathologists were asked to choose their (3) "real-life (best)" assessment between the first 2 measurements. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen κ statistics. Round 1 had poor ICC (0.43; 95% CI, 0.31-0.56). Round 2 agreement was good when measuring from the surface (ICC = 0.83; 95% CI, 0.76-0.88) but moderate (ICC = 0.59; 95% CI, 0.47-0.70) when measuring from the muscularis mucosae and became poor (ICC = 0.49; 95% CI, 0.36-0.61) for the best-assessment measurement. Our findings indicate that clearer and reproducible guidelines are needed if clinical colleagues are to base important management decisions on pathologists' estimate of the depth of submucosal invasion in colonic endoscopic resections.


Imiquimod for actinic keratosis: systematic review and meta-analysis.
Benefit and harm associated with treating actinic keratosis (AK) with the immune response modifier imiquimod was assessed using published randomized-controlled trials. Five randomized double-blind trials lasted 12-16 weeks and treated 1,293 patients. Complete clearance occurred in 50% of patients treated with imiquimod, compared to 5% treated with vehicle, and the number needed to treat (NNT) for one patient to have their keratosis completely cleared after 12-16 weeks was 2.2 (95% confidence interval 2.0-2.5). For partial (>/=75%) clearance the NNT was 1.8 (1.7-2.0). The proportion of patients with any adverse event, any local adverse event, or any treatment-related adverse event was substantially higher with imiquimod than with vehicle, and numbers needed to harm for one additional adverse event with imiquimod over 12-16 weeks ranged from 3.2 to 5.9. Particular local adverse events with imiquimod included erythema (27%), scabbing or crusting (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%). Imiquimod 5% cream was effective in the treatment of AK, preventing potential development of squamous cell carcinoma. Future investigation might be aimed at elucidating optimal dosing to minimize adverse events without detriment to efficacy, and evaluating long-term recurrence.


Knowledge and skills of primary health care workers trained on integrated management of neonatal and childhood illness: follow-up assessment 3 years after the training.
The primary health care workers of a district in northern India were trained in the year 2006 for Integrated Management of Neonatal and Childhood Illness (IMNCI) using two different training methods: conventional 8-day training and new interrupted 5-day training. Knowledge and skills may decline over a period of time. Rate of decline may be associated with the type of training. A study was thus conducted to see the retention of knowledge and skills in the two training groups, 3 years after the initial training. This study was done in the Panchkula district of Haryana state in northern India. In the year 2006, 50 primary health care workers were given new interrupted 5-day training and another 35 workers were given conventional 8-day training on IMNCI. Knowledge and skills of the same workers were evaluated in the year 2009, using the same methodology and tools as were used in the year 2006. Data analysis was done to see the extent of decline in knowledge and skills in these 3 years and whether decline was more in any particular training group. Compared to post-training score in the year 2006, composite knowledge and skill scores for Auxilliary Nurse Midwives (ANMs) and Anganwari workers (AWWs) together declined significantly in the year 2009 from 74.6 to 58.0 in 8-day training group and from 73.2 to 57.0 in 5-day training group (P < 0.001). Follow-up composite scores in the two training groups were similar. Whereas the decline was more for knowledge scores in 8-day training group and for skill score in 5-day training group, the pattern of decline was inconsistent for different health conditions and among ANMs and AWWs. Long-term retention of knowledge and skills in 5-day group was equivalent to that in 8-day training group. Refresher trainings may boost up the decline in the knowledge and skills.


Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder?
Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3' end of the CACNA1A gene, coding for the alpha(1A) subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.


The role of the pedicle omental flap in ruptured abdominal aortic aneurysm: a case report and literature review.
A ruptured infrarenal abdominal aortic aneurysm (rAAA) is associated with an in-hospital mortality rate of 40% and an overall mortality rate of 60-80%. Open surgical repair for rAAA remains the principal method of treatment when endovascular repair is not available. Graft infection occurs in 1-4% of patients at 5 years, with a high incidence following emergency treatment. Other graft-related complications include pseudoaneurysm, graft occlusion and aorto-enteric fistula. This case report describes a 66-year-old male patient that was admitted to hospital complaining of intense abdominal pain, low blood pressure and tachycardia. He was diagnosed with a rAAA and treated using segmental resection of the abdominal aorta followed by reconstruction with a synthetic Dacron prosthesis. A pedicle omental flap was wrapped around the prosthetic graft and it was also used to fill the retroperitoneal cavity in order to reduce the risk of graft-related complications. Computed tomography angiography after 6 months showed good integration of the aortic prosthetic graft and the viability of the omental flap. In our opinion, vascular surgeons should consider the pedicle omental flap when they perform open surgical repair for rAAA in order to reduce the incidence of graft-related complications.


Preparation of monodisperse polylactide microspheres by dispersion polymerization using a polymeric stabilizer with hydroxy groups.
Monodisperse poly(D,L-lactide) (PDLLA) microspheres have been prepared by dispersion polymerization of D,L-lactide with a synthetic polymeric stabilizer. The polymerization is carried out in xylene/heptane (1:2, v/v) at 368 K for 3 h with poly[(dodecyl methacrylate)-co-(2-hydroxyethyl methacrylate)] (P(DMA-co-HEMA)). P(DMA-co-HEMA) has hydroxy groups as an initiation group for pseudoanionic dispersion polymerization. The particle diameter and the coefficient of variation concerning the diameter distribution of the obtained PDLLA microspheres are 3.9 µm and 4.3%, respectively. In addition, from the results of dynamic light scattering measurements, it is found that P(DMA-co-HEMA) and the PDLLA-grafted copolymer form a micellar structure in solution.


Pericardial exploration by pericardioscopy during a surgical sub xyphoid approach.
This clinical feasibility study was planned to evaluate pericardioscopy as a means of control of the pericardial cavity during drainage for pericardial effusion by a surgical sub xyphoid approach. Seventeen patients who underwent an operation for surgical drainage of the pericardium (11 medical and 6 postoperative pericardial effusions) benefited from a pericardial exploration with a mediastinoscope or rigid thoracoscope (Karl Storz, Germany). In 7 of the 11 medical cases, a severe inflammation of the pericardium associated with false membranes was visualized; in 3 cases, the pericardium was considered as normal; and in 1 case, pericardial metastases were visualized. In the 6 postoperative cases, clots were visualized with a venous bypass graft and the pulmonary cannula of a right ventricular assist device (Thoratec, USA) was also perfectly controlled. The cause of bleeding was reported in one case and suspected in another, but required total sternotomy for repair in both cases. No mortality or morbidity was reported to be directly due to the technique. The peroperative assessment of pericardial cavity is possible by use of pericardioscopy with a satisfactory resolution, but visualization of the left lateral part of the heart remains difficult. The possibility exists to partially remove clots and false membranes, obtain various samples, and control the position of the drains. Improvement in the optic device with the possibility of a flexible device that has a tip protector for optimal visualization, may improve both the technique and results.


New approaches to disease mapping in admixed populations.
Admixed populations such as African Americans and Hispanic Americans are often medically underserved and bear a disproportionately high burden of disease. Owing to the diversity of their genomes, these populations have both advantages and disadvantages for genetic studies of complex phenotypes. Advances in statistical methodologies that can infer genetic contributions from ancestral populations may yield new insights into the aetiology of disease and may contribute to the applicability of genomic medicine to these admixed population groups.


Safety and effectiveness of ipragliflozin in elderly versus non-elderly Japanese type 2 diabetes mellitus patients: 12 month interim results of the STELLA-LONG TERM study.
Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of ipragliflozin in real-world clinical practice in Japan. This interim report of STELLA-LONG TERM examined the safety and effectiveness of ipragliflozin in non-elderly and elderly Japanese patients with type 2 diabetes mellitus (T2DM) using data up to 12 months. Methods: Data from T2DM patients who were first prescribed ipragliflozin between July 2014 and October 2015 and whose 12 month data were locked by January 2018 were analyzed and compared between non-elderly (<65 years) and elderly patients (≥65 years). Results: The safety and efficacy analysis sets included 11,051 and 8788 patients, respectively. Elderly patients accounted for 28.6% (n = 3157) of the study population. The mean body mass index was 29.9 kg/m2 and 26.8 kg/m2, the percentage of patients with glycated hemoglobin (HbA1c) <8.0% was 50.1% and 59.5%, and the percentage of patients with complications was 83.2% and 87.3% in the non-elderly and elderly groups, respectively. Mean HbA1c and body weight decreased significantly from baseline to 12 months in both age groups, regardless of baseline HbA1c and body weight (all p < .05). The incidence of adverse drug reactions (ADRs) was 14.8% and 14.2% and that of serious ADRs was 0.8% and 1.4% in non-elderly and elderly patients, respectively (p = .002 for serious ADRs). Conclusion: The incidence of serious ADRs was higher in elderly patients than non-elderly patients. Ipragliflozin was effective in both non-elderly and elderly patients with T2DM in the real-world clinical setting.


Factors that influence standard automated perimetry test results in glaucoma: test reliability, technician experience, time of day, and season.
To determine the influence of several factors on standard automated perimetry test results in glaucoma. Longitudinal Humphrey field analyzer 30-2 Swedish interactive threshold algorithm data from 160 eyes of 160 glaucoma patients were used. The influence of technician experience, time of day, and season on the mean deviation (MD) was determined by performing linear regression analysis of MD against time on a series of visual fields and subsequently performing a multiple linear regression analysis with the MD residuals as dependent variable and the factors mentioned above as independent variables. Analyses were performed with and without adjustment for the test reliability (fixation losses and false-positive and false-negative answers) and with and without stratification according to disease stage (baseline MD). Mean follow-up was 9.4 years, with on average 10.8 tests per patient. Technician experience, time of day, and season were associated with the MD. Approximately 0.2 dB lower MD values were found for inexperienced technicians (P < 0.001), tests performed after lunch (P < 0.001), and tests performed in the summer or autumn (P < 0.001). The effects of time of day and season appeared to depend on disease stage. Independent of these effects, the percentage of false-positive answers strongly influenced the MD with a 1 dB increase in MD per 10% increase in false-positive answers. Technician experience, time of day, season, and the percentage of false-positive answers have a significant influence on the MD of standard automated perimetry.


[Circulation support in left thoracotomy for descending thoracic aorta diseases in pediatric patients].
Complications of surgery of the descending thoracic aorta could include neurological problems such as paraparesis and paraplegia. Intestinal ischemia and acute renal failure could occur, too. During the cross-clamping time, the perfusion of the distal aorta by means of extracorporeal circulatory assistance can be useful to protect the spinal cord and the splanchnic organs and to reduce the incidence of these untoward events. The aim of this study was to verify the efficacy and suitability of this type of circulatory assistance in a pediatric age group. From January 1996 to March 2000, in the Pediatric Cardiac Surgery Department of the Gaslini Institute (Genoa, Italy), 6 patients (mean age 39 months, mean weight 14.4 kg) were treated using extracorporeal circulatory assistance through the left thoracotomy. Indications for surgery included the removal of a migrated device previously inserted in order to close a patent ductus arteriosus in 1 patient, recurrent coarctation in 2 patients, and native coarctation with a poor collateral circulation in 3 patients. The early and late mortality rates as well as the morbidity rates (both neurological and splanchnic) were nil. Extracorporeal circulatory assistance can be helpful in pediatric patients and it can prevent neurological and renal injuries in cases of a) coarctation of the aorta with a poor collateral circulation and low distal pressure (< 40 mmHg during aortic occlusion); b) recoarctation with complex anatomy; c) other pathologies requiring prolonged descending thoracic aorta cross-clamping.


Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation.
There is no reliable laboratory indicator of the onset of chronic graft-versus-host disease (cGVHD). This study looks at whether the expression of OX40, a member of the tumor necrosis factor receptor family, is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplantation. Peripheral blood mononuclear cells from 22 patients after day 100 were subjected to multicolor flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+ T cells were significantly higher in patients with cGVHD than those without (P <.0001 and P =.001, respectively). Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and closely correlated with the therapeutic response. The expression of CD25, CD69, and HLA-DR was partially detectable on OX40+ T cells. These results indicate that serial measurement of OX40+ T cells is useful for predicting the onset as well as the therapeutic response of cGVHD and raise a possibility that the OX40/gp34 system is involved in the pathogenesis of cGVHD.


Spectroscopic IR, EPR, and operando DRIFT insights into surface reaction pathways of selective reduction of NO by propene over the Co-BEA zeolite.
Interaction of a Co-BEA catalyst with individual components (NO, C(3)H(6), CO, O(2)) and mixtures simulating the real feed of the selective catalytic reduction (SCR) of nitric oxide in static and pulse experiments at variable temperatures was investigated by means of IR, EPR, and operando DRIFT spectroscopy coupled with QMS/GC analysis of the products. Speciation of cobalt active sites into Co(II), mono- and polynuclear oxo-cobalt species as well as CoO clusters was quantified by IR using CO and NO as probe molecules. The key intermediates, by-products, and final products of the SCR reaction were identified and their spectroscopic signatures ascertained. Based on the spectroscopic operando results, a concise mechanistic scheme of the selective catalytic reduction of nitric oxide by propene, triggered by a two-electron Co(II)/Co(0) redox couple, was developed. It consists of a complex network of the sequential/parallel selective reduction steps that are interlocked by the rival nonselective oxidation of the intermediates and their thermal decomposition. It has been shown that the SCR process is initiated by the chemoselective capture of NO from the reaction mixture by the cobalt active sites leading to the cobalt(II) dinitrosyls, which in the excess of oxygen are partially oxidized to surface nitrates and nitrites. N(2)O is produced by semi-decomposition of the dinitrosyl intermediates on the mononuclear centers, whereas NO(2)via NO oxidation on the polynuclear oxo-cobalt sites. Cyanide and isocyanate species, formed together with propene oxygenates in the course of the C=C bond scission, are the mechanistically pivotal reaction intermediates of C(3)H(6) interaction with the dinitrosyles and NO(3)(-)/NO(2)(-) surface species. Dinitrogen is produced by three main reaction routes involving oxidation of cyanides by NO/NO(2), reduction of dinitrosyls, nitrates, and nitrites by propene oxygenates (medium temperature range) or their reduction by carbon monoxide (high temperature range).


Biosynthetic gene cluster of the non-ribosomally synthesized cyclodepsipeptide skyllamycin: deciphering unprecedented ways of unusual hydroxylation reactions.
The cyclic depsipeptide skyllamycin A is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway by inhibiting binding of homodimeric PDGF BB to the PDGF β-receptor. Its structure contains a cinnamoyl side chain and shows a high amount of β-hydroxylated amino acids as well as an unusual α-hydroxyglycine moiety as a rare structural modification. The skyllamycin biosynthetic gene cluster was cloned and sequenced from Streptomyces sp. Acta 2897. Its analysis revealed the presence of open reading frames encoding proteins for fatty acid precursor biosynthesis, non-ribosomal peptide synthetases, regulators, and transporters along with other modifying enzymes. Specific in-frame mutagenesis of these tailoring enzymes resulted in the production of novel skyllamycin derivatives revealing that β-hydroxy groups in skyllamycin A are introduced by a promiscuous cytochrome P450 monooxygenase, whereas a two-component flavin-dependent monooxygenase is involved in α-hydroxylation.


Transient spectroscopy of bacterial rhodopsins with an optical multichannel analyzer. 1. Comparison of the photocycles of bacteriorhodopsin and halorhodopsin.
We used a gated optical multichannel analyzer to measure transient flash-induced absorption changes in bacteriorhodopsin (BR) and halorhodopsin (HR) and developed criteria for calculating the absorption spectra of the photocycle intermediates and the kinetics of their rise and decay. The results for BR agree with data reported by a large number of other authors. The results for HR in the presence of chloride are consistent with earlier data and reveal an additional intermediate, not previously seen, in the submicrosecond time scale. Although an M412-like intermediate is not in the HR photocycle, a one-by-one comparison of the rest of the intermediates observed for BR and HR indicates a striking similarity between the photocycles of the two bacterial rhodopsins. This was previously not apparent, perhaps because the experimental approaches to the spectroscopy of the two pigments were different and the data were thus more fragmented.


Poor glycemic control of diabetes mellitus is associated with higher risk of prostate cancer detection in a biopsy population.
To evaluate the impact of glycemic control of diabetes mellitus (DM) on prostate cancer detection in a biopsy population. We retrospectively reviewed the records of 1,368 men who underwent prostate biopsy at our institution. We divided our biopsy population into three groups according to their history of DM, and their Hemoglobin A1c (HbA1c) level: a no-DM (DM-) group; a good glycemic control (DM+GC) group (HbA1c <6.5%); and a poor glycemic control (DM+PC) group (HbA1c ≥6.5%). For sub-analyses, the DM+PC group was divided into a moderately poor glycemic control (DM+mPC) group (6.5≤ HbA1c <7.5%) and a severely poor glycemic control (DM+sPC) group (HbA1c ≥7.5%). Among 1,368 men, 338 (24.7%) had a history of DM, and 393 (28.7%) had a positive biopsy. There was a significant difference in prostatic specific antigen density (PSAD) (P = 0.037) and the frequency of abnormal DRE findings (P = 0.031) among three groups. The occurrence rate of overall prostate cancer (P<0.001) and high-grade prostate cancer (P = 0.016) also presented with a significantly difference. In the multivariate analysis, the DM+PC group was significantly associated with a higher rate of overall prostate cancer detection in biopsy subjects compared to the DM- group (OR = 2.313, P = 0.001) but the DM+PC group was not associated with a higher rate of high-grade (Gleason score ≥7) diseases detected during the biopsy (OR = 1.297, P = 0.376). However, in subgroup analysis, DM+sPC group was significantly related to a higher risk of high-grade diseases compared to the DM- group (OR = 2.446, P = 0.048). Poor glycemic control of DM was associated with a higher risk of prostate cancer detection, including high-grade disease, in the biopsy population.


Distortion-matched T1 maps and unbiased T1-weighted images as anatomical reference for high-resolution fMRI.
The increasing availability of ultra-high field scanners has led to a growing number of submillimetre fMRI studies in humans, typically targeting the gray matter at different cortical depths. In most analyses, the definition of surfaces at different cortical depths is based on an anatomical image with different contrast and distortions than the functional images. Here, we introduce a novel sequence providing bias-field corrected T1-weighted images and T1-maps with distortions that match those of the fMRI data, with an image acquisition time significantly shorter than standard T1-weighted anatomical imaging. For 'T1-imaging with 2 3D-EPIs', or T123DEPI, 3D-EPI volumes are acquired centred at two inversion times. These 3D-EPIs are segmented into half, quarter or smaller blocks of k-space to allow for optimisation of the inversion times. T1-weighted images and T1-maps are then generated as for MP2RAGE acquisitions. A range of T123DEPI data acquired at 7 T is shown with resolutions ranging from 0.7 mm to 1.3 mm isotropic voxels. Co-registration quality to the mean EPI of matching fMRI timecourses shows markedly less local deviations compared to co-registration of a standard MP2RAGE to the same echo planar volume. Thus, the T123DEPI T1-weighted images and T1-maps can be used to provide cortical surfaces with matched distortions to the functional data or else to facilitate co-registration between functional and undistorted anatomical data.


Involvement of erythrocyte calpain in glycine- and carnitine-treated isovaleric acidemia.
When a 12-y-old girl suffering from isovaleric acidemia was treated with L-carnitine, there was a considerable increase in her blood and urine concentration of isovalerylcarnitine. When later the patient received an infusion of glycine in place of carnitine, isovalerylcarnitine reverted toward the low levels found in a normal subject. At the end of either treatment, erythrocyte calpain was measured and found to be decreased after carnitine therapy (140 versus 96 U/mg Hb with glycine or carnitine, respectively). Because we have previously shown that the activity of calpain isolated from erythrocytes was markedly modified by isovalerylcarnitine, the present results might be seen as the consequence of the chronic exposure of the patient's red blood cells to high levels of isovalerylcarnitine. The lowered calpain activity was also proved by an increase in erythrocyte band 3 phosphorylation together with an increased erythrocyte fragility after calcium loading in the presence of the ionophore A-23187. Calpastatin, the natural inhibitor of calpain, was only slightly modified.


Catabolism of Ap3A and Ap4A in human plasma. Purification and characterization of a glycoprotein complex with 5'-nucleotide phosphodiesterase activity.
A hydrolase splitting adenosine(5')triphospho(5')adenosine (Ap3A) to AMP and ADP has recently been detected in human plasma [Lüthje, J. and Ogilvie, A. (1984) Biochem. Biophys. Res. Commun. 118, 704-709]. The enzyme has been purified to apparent homogeneity, as stained in a native polyacrylamide gel. From gel filtration data a Stokes radius of 5.9 nm was calculated, suggesting a molecular mass of about 230 kDa. The presence of the non-ionic detergent Triton X-100 did not change the molecular mass. The hydrolase dissociated to three major protein components (66 kDa; 45 kDa; 16 kDa) during polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and mercaptoethanol. Binding of the native enzyme to concanavalin-A--Sepharose and specific inhibition of binding by methyl mannoside indicated that the hydrolase is a glycoprotein. Two of the subunits (66 kDa; 45 kDa) could be affinity-labeled with radioiodinated concanavalin A. Active hydrolase could be prepared in buffers without added metal ions. Treatment with EDTA, however, completely abolished the hydrolytic activity. The enzyme could be reactivated by incubation with Ca2+, Co2+ and, at best, with Zn2+, whereas Mg2+ was ineffective. The affinity of the enzyme for Ap3A was high (Km = 1 microM), with normal Michaelis-Menten kinetics. The homolog dinucleotide Ap4A was also substrate (Km = 0.6 microM) yielding AMP and ATP as products after the asymmetric split. Other dinucleotides, such as NAD, and also mononucleotides (ATP,UTP) were degraded to nucleoside monophosphates indicating a broad specificity of the enzyme. The synthetic compound thymidine 5'-monophosphate p-nitrophenyl ester was substrate with low affinity whereas its 3'-homolog was not hydrolyzed. Optimal activity of the hydrolase was found at pH 8.5.


[Prognostic analysis of splenectomy in patients with advanced proximal gastric cancer.].
To evaluated the prognostic impact of splenectomy on patients with advanced proximal gastric cancer. The clinical records of 237 patients with advanced proximal gastric cancer who underwent D2 curative resection combined with splenectomy from January 1980 to June 2003 were analyzed retrospectively. Seventy-five patients presented with No.10 lymph nodes metastasis, while 162 patients did not. Potential patient prognostic factors were evaluated by univariate and multivariate analysis. The independent prognostic factors of patients were performed subgroup analysis. The 5-year survival rate was 27.7% for patients with No.10 lymph nodes metastasis and 35.4% for patients without, the difference was statistically significant between the two groups (P < 0.05). On univariate analysis, lymph node metastasis, macroscopic appearance, depth of invasion, type of gastrectomy and No.10 lymph nodes metastasis were predictive factors of survival. The depth of invasion, type of gastrectomy and No.10 lymph nodes metastasis were independent prognostic factors. In the subgroup analysis, the survival rates of T3 patients with and without No.10 lymph nodes metastasis was 34.5% and 39.7%, respectively (P > 0.05). For patients undergoing total gastrectomy, survival rates were 31.2% and 36.7%, respectively (P > 0.05). To improve patient prognosis, total gastrectomy with splenectomy should be recommended for patients with T3 proximal gastric cancer with No.10 lymph node metastasis.


Does the Muscle Action Duration Induce Different Regional Muscle Hypertrophy in Matched Resistance Training Protocols?
Diniz, RCR, Tourino, FD, Lacerda, LT, Martins-Costa, HC, Lanza, MB, Lima, FV, and Chagas, MH. Does the muscle action duration induce different regional muscle hypertrophy in matched resistance training protocols? J Strength Cond Res 36(9): 2371-2380, 2022-The manipulation of the muscle action duration (MAD) can influence the instantaneous torque along the range of motion, which can lead to adaptations of regional muscle hypertrophy. The aim of this study was to compare the effects of matched resistance training (RT) on the knee extension machine with different MAD in the cross-sectional area (CSA) responses within the quadriceps femoris (QF) and its muscles. Forty-four subjects were allocated into a control and 3 experimental groups. For a period of 10 weeks, subjects in the experimental groups performed the training protocols that were different only by the MAD: group 5c1e (5s concentric action [CON] and 1s eccentric action [ECC]; group 3c3e (3s CON and 3s ECC) and group 1c5e (1s CON and 5s ECC). Magnetic resonance imaging was performed (before and after the intervention) to determine the relative change (%) in CSA of the QF muscles along proximal (30%), middle (50%), and distal regions (70% distal of the femur). The change in CSA of the rectus femoris at the middle region are greater in 5c1e (6.8 ± 6.5%) and 1c5e (7.4 ± 6.0%) groups than 3c3e (3.4 ± 6.6%) and control groups (0.2 ± 1.8%). In addition, vastus lateralis at the distal region (5c1e = 15.9 ± 11.8%; 1c5e = 14.4 ± 10.0%) presenting greater increases in change of CSA than the others vastus only 5c1e (vastus lateralis [VI] = 5.0 ± 4.7%; vastus medialis [VM] = 4.2 ± 3.2%) and 1c5e groups (VI = 4.7 ± 3.6%; VM = 3.4 ± 3.1%). In conclusion, this study showed that matched RT protocols with different MAD resulted in different region-specific muscle hypertrophic across the individual muscles of QF.


Contribution of Neuromuscular Factors to Quadriceps Asymmetry After Anterior Cruciate Ligament Reconstruction.
To quantify quadriceps weakness after anterior cruciate ligament reconstruction (ACLR), researchers have often analyzed only peak torque. However, analyzing other characteristics of the waveform, such as the rate of torque development (RTD), time to peak torque (TTP), and central activation ratio (CAR), can lend insight into the underlying neuromuscular factors that regulate torque development. To determine if interlimb neuromuscular asymmetry was present in patients with ACLR at the time of clearance to return to activity. Cross-sectional study. Laboratory. A total of 10 individuals serving as controls (6 men, 4 women; age = 23.50 ± 3.44 years, height = 1.73 ± 0.09 m, mass = 71.79 ± 9.91 kg) and 67 patients with ACLR (43 men, 24 women; age = 21.34 ± 5.73 years, height = 1.74 ± 0.11 m, mass = 77.85 ± 16.03 kg, time postsurgery = 7.52 ± 1.36 months) participated. Isokinetic (60°/s) and isometric quadriceps strength were measured. Peak torque, TTP, and RTD were calculated across isometric and isokinetic trials, and CAR was calculated from the isometric trials via the superimposed burst. Repeated-measures analyses of variance were used to compare limbs in the ACLR and control groups. No between-limbs differences were detected in the control group ( P > .05). In the ACLR group, the involved limb demonstrated a longer TTP for isokinetic strength ( P = .04; Cohen d effect size [ES] = 0.18; 95% confidence interval [CI] = -0.16, 0.52), lower RTD for isometric ( P < .001; Cohen d ES = 0.73; 95% CI = 0.38, 1.08) and isokinetic ( P < .001; Cohen d ES = 0.84; 95% CI = 0.49, 1.19) strength, lower CAR ( P < .001; Cohen d ES = 0.37; 95% CI = 0.03, 0.71), and lower peak torque for isometric ( P < .001; Cohen d ES = 1.28; 95% CI = 0.91, 1.65) and isokinetic ( P < .001; Cohen d ES = 1.15; 95% CI = 0.78, 1.52) strength. Interlimb asymmetries at return to activity after ACLR appeared to be regulated by several underlying neuromuscular factors. We theorize that interlimb asymmetries in isometric and isokinetic quadriceps strength were associated with changes in muscle architecture. Reduced CAR, TTP, and RTD were also present, indicating a loss of motor-unit recruitment or decrease in firing rate.


ERCC1 protein as a guide for individualized therapy of late-stage advanced non-small cell lung cancer.
Excision repair cross-complementation group 1 (ERCC1) protein has been associated with cisplatin resistance. The objective of this study was to investigate the correlation between ERCC1 protein levels and the therapeutic effect of individualized therapy in advanced non-small cell lung cancer (NSCLC). A total of 190 advanced NSCLC patients were included in this study. Patients were randomized into either the individualized therapy group or the standard therapy group at a ratio of 2:1. Patients in the standard therapy group were treated with either gemcitabine plus cisplatin or vinorelbine plus cisplatin. The expression of ERCC1 protein in lung cancer tissues of patients from the individualized therapy group was detected with immunohistochemistry. Patients with low ERCC1 levels received either gemcitabine plus cisplatin or vinorelbine plus cisplatin, and patients with high levels received gemcitabine plus vinorelbine. The main outcome assessments were response rate (RR), overall survival (OS) and time to progression (TTP). Follow-up data were recorded until September 30, 2010. RR, 1-year survival rate and TTP were not statistically significant. The median survival time was 10.10 months in the standard therapy group (95% CI 8.48-11.92) and 13.59 months in the individualized therapy group (95% CI 11.86-14.74). The difference in median survival time was significantly different between these groups (P=0.036). The median survival time was longer in the individualized group compared to the standard therapy group. ERCC1 protein expression in advanced NSCLC patients, however, was not significantly correlated with RR, OS and TTP in the individualized therapy group. Therefore, this study suggests that ERCC1 protein levels should be assessed in combination with additional biomarkers to determine an optimal index for individualized therapy in advanced NSCLC patients.


4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation.
eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit translation initiation. Some 4E-BPs contain non-canonical 4E-BMs (NC 4E-BMs), but the contribution of these motifs to the repressive mechanism--and whether these motifs are present in all 4E-BPs--remains unknown. Here, we show that the three annotated Drosophila melanogaster 4E-BPs contain NC 4E-BMs. These motifs bind to a lateral surface on eIF4E that is not used by eIF4G. This distinct molecular recognition mode is exploited by 4E-BPs to dock onto eIF4E-eIF4G complexes and effectively displace eIF4G from the dorsal surface of eIF4E. Our data reveal a hitherto unrecognized role for the NC4E-BMs and the lateral surface of eIF4E in 4E-BP-mediated translational repression, and suggest that bipartite 4E-BP mimics might represent efficient therapeutic tools to dampen translation during oncogenic transformation.


[HPLC analysis of 2-(P-dimethylaminostyryl) pyridine methiodide concentration in plasma].
A reversed phase high performance liquid chromatography (RP-HPLC) method for determination of 2-(p-dimethylaminostyryl) pyridine methiodide (DSPM) concentration in rabbit plasma is reported. The stationary phase was YWG-C18H37. The mobile phase consisted of 80% CH3OH, 20% CH3COOH-CH3COONa buffer (pH 4.0, 0.20 mol/L) and (C2H5)2NH 25 mmol/L. Its flow rate was 1.0 ml/min. The column temperature and pressure was 28 degrees C and 10.13 MPa, respectively. The detect wavelength was 460 nm. The detection limit of DSPM was 2 ng or 0.08 mumol/L in plasma. The RSD (%) of within-day and between-days were less than 7%. A good linear relationship between peak area and DSPM concentration in plasma (0.68-13.65 mumol/L) was found (r = 0.9996).


Do occupational justice concepts inform occupational therapists' practice? A scoping review.
Occupational justice and related concepts can inform practices directed at injustice and the lack of rights in daily life. Brazilian ideas about social occupational therapy seem to be similar to these concepts about inequality. This study aimed to answer the questions, "Do occupational justice concepts inform occupational therapists' professional actions?" and "How are occupational justice concepts connected to Brazilian ideas about social occupational therapy?" A secondary analysis was undertaken of a scoping review using occupational justice and related concepts as keywords. Descriptive and categorical analyses were used to classify the extract data. We selected 42 articles that specify occupational therapy practices, classified as individual approaches (n = 13), individual-integrated-with-social approaches (n = 22), and social approaches (n = 7). It was found that occupational justice concepts have informed individual approaches and that the second and third approaches can be connected with social occupational therapy. Dialogue for sharing knowledge, concepts, and practices of occupational therapy worldwide can be inspired by this review.


A responsive evaluation of mental health treatment in Cambodia: Intentionally addressing poverty to increase cultural responsiveness in therapy.
Mental health issues are significant contributors to the global burden of disease with the highest incidence in resource poor countries; 90% of those in need of mental health treatment reside in low resource countries but receive only 10% of the world's resources. Cambodia, the eighth least developed country in the world, serves as one example of the need to address mental health concerns in low-income, resource poor countries. The current study utilises responsive evaluation methodology to explore how poverty-stricken Cambodian clients, therapists and supervisors experience Western models of therapy as culturally responsive to their unique needs. Quantitative and qualitative data were triangulated across multiple stakeholders using numerous methods including a focus group, interviews, surveys, case illustrations and live supervision observation and analysed using constant comparative analysis. Emerging findings suggest that poverty, material needs, therapy location and financial situations greatly impact the daily lives and mental health conditions of Cambodians and hinder clients' therapeutic progress. The local community needs and context of poverty greatly hinder clients' therapeutic progress in therapy treatment and when therapy does not directly address the culture of poverty, clients did not experience therapy as valuable despite some temporary decreases in mental health symptoms.


Early identification of autism: a comparison of the Checklist for Autism in Toddlers and the Modified Checklist for Autism in Toddlers.
There is still debate as to what is the most effective strategy for identifying the early signs of autism in very young children. Two levels of screening having been advocated: broad-based developmental surveillance and targeted screening. Two popular tools for use in developmental surveillance are the Checklist for Autism in Toddlers (CHAT) and the Modified Checklist for Autism in Toddlers (M-CHAT). The purpose of this article is to summarise the current evidence for screening for autistic symptoms in very young children using CHAT and M-CHAT. A systematic search was carried out of electronic database and other sources for original studies which evaluated the use of CHAT and M-CHAT in screening for autism in children younger than 5 years of age. Studies were included for review if they evaluated the sensitivity and/or specificity of CHAT or M-CHAT, or described the best age to administer these instruments. The available evidence suggests that characteristic behaviours in autism should be evident in simple forms before the age of 18 months, while screening at 24 months should be conducted to identify those who regress. Administering a screening tool during 18- to 24-month well-child visits improves early identification of autism, while the stability of diagnosis at the ages of 18 months and 24 months is confirmed. M-CHAT has slightly better sensitivity and specificity compared to CHAT, and is preferable to use as a developmental surveillance screening instrument.


miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14.
Upregulation of matrix metalloproteinase MMP-14 (MT1-MMP) is associated with poor prognosis in cancer patients, but it is unclear how MMP-14 becomes elevated in tumors. Here, we show that miR-181a-5p is downregulated in aggressive human breast and colon cancers where its levels correlate inversely with MMP-14 expression. In clinical specimens, enhanced expression of MMP-14 was observed in cancer cells located at the invasive front of tumors where miR-181a-5p was downregulated relative to adjacent normal cells. Bioinformatics analyses defined a potential miR-181a-5p response element within the 3'-untranslated region of MMP-14 that was validated in reporter gene experiments. Ectopic miR-181a-5p reduced MMP-14 expression, whereas miR-181a-5p attenuation elevated MMP-14 expression. In support of a critical relationship between these two genes, miR-181a-5p-mediated reduction of MMP-14 levels was sufficient to decrease cancer cell migration, invasion, and activation of pro-MMP-2. Furthermore, this reduction in MMP-14 levels was sufficient to reduce in vivo invasion and angiogenesis in chick chorioallantoic membrane assays. Taken together, our results establish the regulation of MMP-14 in cancers by miR-181a-5p through a posttranscriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis.


Performance of point-of-care Xpert HIV-1 plasma viral load assay at a tertiary HIV care centre in Southern India.
Sustainable suppression of HIV replication forms the basis of anti-retroviral therapy (ART) medication. Thus, reliable quantification of HIV viral load has become an essential factor to monitor the effectiveness of the ART. Longer turnaround-time (TAT), batch testing and technical skills are major drawbacks of standard real-time PCR assays. The performance of the point-of-care Xpert HIV-1 viral load assay was evaluated against the Abbott RealTime PCR m2000rt system. A total of 96 plasma specimens ranging from 2.5 log10 copies ml-1 to 4.99 log10 copies ml-1 and proficiency testing panel specimens were used. Precision and accuracy were checked using the Pearson correlation co-efficient test and Bland-Altman analysis. Compared to the Abbott RealTime PCR, the Xpert HIV-1 viral load assay showed a good correlation (Pearson r=0.81; P<0.0001) with a mean difference of 0.27 log10 copies ml-1 (95 % CI, -0.41 to 0.96 log10 copies ml-1; sd, 0.35 log10 copies ml-1). Reliable and ease of testing individual specimens could make the Xpert HIV-1 viral load assay an efficient alternative method for ART monitoring in clinical management of HIV disease in resource-limited settings. The rapid test results (less than 2 h) could help in making an immediate clinical decision, which further strengthens patient care.


[Results of functional endoscopic sinus surgery].
Chronic rhinosinusitis (CRS) and polyposis cavi nasi (PCN) are two frequently occurring, disabling diseases. Many international studies have obtained very good results with the functional endoscopic sinus surgery (FESS) technique in cases of resistance to conservative treatment. This is the first study in Denmark that attempts to compare Danish results with international results. The study included 31 patients operated on in the period 1 January-31 December 2002 in the ENT Department, Aarhus University Hospital. After a retrospective journal study, all patients were followed up on by means of a postoperative cross-sectional examination, with a questionnaire and endoscopic inspection of the nasal cavity. We found significant improvement as regarded sense of smell, degree of nasal obstruction, rhinorrhoea and facial pain. The endoscopic inspections showed a significant reduction in nasal polyps. Eighty-six percent of the patients said they would recommend the same kind of surgery to a similar patient. The study showed good results using functional endoscopic sinus surgery on Danish patients with CRS and PCN. The Danish population of those suffering from CRS and PCN undergoing surgery was not comparable to those in international studies. The study raised questions concerning the lack of national references and database programme.


Peer loss: Posttraumatic stress, depression, and grief symptoms in a traumatized adolescent community.
In our prospective study, 168 adolescents exposed directly or indirectly to the same traumatic event-a fatal school bus accident-in which seven students were killed instantly, were assessed for post-traumatic stress, depression and grief symptoms at 2- and 18-months post-accident. Prevalence rates of likely PTSD and depression were noted across all types of physical proximity exposure: 77.6% and 48.1% respectively in the indirectly exposed group, 79.4% and 47.1% respectively in the directly in-the-area exposed group, and 77.8% and 42.1% respectively in the directly in-bus exposed group. One-fifth experienced high and unremitting levels of grief symptoms over time ("persistent grief"); 17% with initially high levels of grief symptoms showed a decrease at 18 months but were still within the low medium range ("towards recovery"); 39% with initially medium/high grief symptoms reported low levels of grief at the follow-up ("recovery"); and 23% of the participants experienced grief symptoms that remained persistently low ("resilient"). The absence of both PTSD and depression at 18 months predicted adjustment to loss, whereas the absence of depression at 18 months predicted a recovering course of grief. The findings highlight the impact of high levels of post-traumatic stress and depression symptoms on the long-term persistent grief outcome.


"Bystander" amplification of PBMC cytokine responses to seasonal allergen in polysensitized atopic children.
Atopic children show increased expression and production of the Th2-associated cytokines IL-4, IL-5, IL-13, and IL-9 from PBMCs after stimulation with allergen, but it has previously not been clearly determined whether the Th2-cytokine production is restricted to the inhalant allergen the child is sensitized to, and whether perennial or seasonal allergens induce different cytokine responses. Our purpose was to determine whether in vitro Th2 cytokine production is specific to the sensitizing allergen, and to compare the cytokine responses to a perennial and a seasonal allergen in monosensitized and polysensitized children. Using semiquantitative RT-PCR, we analyzed the expression of the cytokines IL-4, IL-5, IL-13, IL-9, IL-10, and IFN-gamma after stimulation of PBMCs with house-dust-mite (HDM) or ryegrass allergen. The cells were sampled from groups of 6-year-old children sensitized to either HDM (n=20) or ryegrass (n=24), or to both allergens (n=20), as well as from a nonatopic group (n=20). After stimulation with HDM allergen, PBMCs from children sensitized only to HDM expressed increased mRNA levels of the Th2 cytokines, but not of IL-10 and IFN-gamma, whereas ryegrass stimulation did not result in increased cytokine expression. PBMCs from children sensitized to HDM and ryegrass expressed increased Th2 cytokines after stimulation with either of the two allergens. In contrast, PBMCs from children sensitized only to ryegrass did not express increased levels after stimulation with either of the allergens. The expression of Th2 cytokines after in vitro stimulation of PBMCs from atopic children is specific to the sensitizing allergen, indicating that atopic status per se does not affect the type of T-cell response. In addition, T cells specific to seasonal allergens circulate in the blood out of season only if the child is concomitantly sensitized to a perennial allergen.


A case of malonyl coenzyme A decarboxylase deficiency with novel mutations and literature review.
Malonyl coenzyme A decarboxylase deficiency is caused by an abnormality in the MLYCD gene. The clinical manifestations of the disease involve multisystem and multiorgan. We collected and analyzed a patient's clinical characteristics, genetic chain of evidence and RNA-seq. We use the search term "Malonyl-CoA Decarboxylase Deficiency" on Pubmed to collect cases reported. We report a 3-year-old girl who is presented with developmental retardation, myocardial damage and elevated C3DC. High-throughput sequencing identified heterozygous mutation (c.798G>A, p.Q266?) in the patient inherited from her father. The other heterozygous mutation (c.641+5G>C) was found in the patient inherited from her mother. RNA-seq showed that there were 254 differential genes in this child, among which 153 genes were up-regulated and 101 genes were down-regulated. Exon jumping events occurred in exons encoding PRMT2 on the positive chain of chromosome 21, which led to abnormal splicing of PRMT2. (P<0.05, FDR<0.05). The result of SNP showed that there were multiple mutation sites on chromosome 1, which may affect the downstream gene variation at the DNA level. The literature review identified 54 cases described since 1984. It is the first report about the locus, adding a new item to the MLYCD mutation library. Developmental retardation and cardiomyopathy are the most common clinical manifestations, with commonly elevated malonate and malonyl carnitine levels in children.


Optimizing antiviral therapy for influenza: understanding the evidence.
Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations.


Urinary biomarkers in prostate cancer detection and monitoring progression.
Prostate cancer (CaP) is the most common cancer in men and the second leading cause of cancer deaths in males in Australia. Although serum prostate-specific antigen (PSA) has been the most widely used biomarker in CaP detection for decades, PSA screening has limitations such as low specificity and potential association with over-diagnosis. Current biomarkers used in the clinic are not useful for the early detection of CaP, or monitoring its progression, and have limited value in predicting response to treatment. Urine is an ideal body fluid for the detection of protein markers of CaP and is emerging as a potential source for biomarker discovery. Gene-based biomarkers in urine such as prostate cancer antigen-3 (PCA3), and genes for transmembrane protease serine-2 (TMPRSS2), and glutathione S-transferase P (GSTP1) have been developed and evaluated in the past decades. Among these biomarkers, urinary PCA3 is the only one approved by the FDA in the USA for clinical use. The study of urine microRNAs (miRNAs) is another burgeoning area for investigating biomarkers to achieve a pre-biopsy prediction of CaP to contribute to early detection. The development of mass spectrometry (MS)-based proteomic techniques has sparked new searches for novel protein markers for many diseases including CaP. Urinary biomarkers for CaP represent a promising alternative or an addition to traditional biomarkers. Future success in biomarker discovery will rely on collaboration between clinics and laboratories. In addition, research efforts need to be moved from biomarker discovery to validation in a large cohort or separate population of patients and translation of these findings to clinical practice. In this review, we discuss urine as a potential source for CaP biomarker discovery, summarise important genetic urine biomarkers in CaP and focus on MS-based proteomic approaches as well as other recent developments in quantitative techniques for CaP urine biomarker discovery.


Temporal discrimination in schizophrenic and affective disorders: evidence for a dopamine-dependent internal clock.
Performance in temporal discrimination of time intervals in the range of milliseconds was compared in 80 healthy subjects, 27 patients with schizophrenic disorders, 33 patients with major depression, 21 patients with dysthymic disorders. For schizophrenic patients as well as for patients with major depression, pronounced deficits in duration discrimination could be demonstrated as compared to the healthy control group (p less than .01). Patients with dysthymic disorders and schizophrenic patients differed significantly from the melancholic group (p less than .01 and p less than .05, respectively). The results are discussed on the basis of the assumption of an internal clock, implying that the clock rate is highest and therefore temporal resolution is best with healthy subjects. With psychiatric patients performance in temporal discrimination was impaired to a slowing down in clock rate and thus decreased temporal resolution. There is strong evidence that changes in clock rate depend on the effective level of dopamine. This leads to the conclusion that temporal discrimination thresholds may be seen as an indicator for deviations from the optimal level of dopaminergic activity in psychiatric patients. In addition, possible effects due to age and medication are discussed.


News from around the RNA world: new avenues in RNA biology, biotechnology and therapeutics from the 2022 SIBBM meeting.
Since the formalization of the Central Dogma of molecular biology, the relevance of RNA in modulating the flow of information from DNA to proteins has been clear. More recently, the discovery of a vast set of non-coding transcripts involved in crucial aspects of cellular biology has renewed the enthusiasm of the RNA community. Moreover, the remarkable impact of RNA therapies in facing the COVID19 pandemics has bolstered interest in the translational opportunities provided by this incredible molecule. For all these reasons, the Italian Society of Biophysics and Molecular Biology (SIBBM) decided to dedicate its 17th yearly meeting, held in June 2022 in Rome, to the many fascinating aspects of RNA biology. More than thirty national and international speakers covered the properties, modes of action and applications of RNA, from its role in the control of development and cell differentiation to its involvement in disease. Here, we summarize the scientific content of the conference, highlighting the take-home message of each presentation, and we stress the directions the community is currently exploring to push forward our comprehension of the RNA World 3.0.


Prevalence of CCR5-tropic HIV-1 among treatment-experienced individuals in Spain.
To determine the prevalence of CCR5-tropic HIV-1 among treatment-experienced patients in Spain. Epidemiologic, cross-sectional, and non-interventional study between January and June 2008 in HIV-1-infected patients in Spain. A total of 485 treatment-experienced patients from across Spainand with a plasma viral load of not greater-than1000 copies/mL were studied. Viral tropism, CD4+ cell count, plasma viral load, stage of disease, and current treatment strategies were determined. Univariate and multivariate logistic regression analyses were used to determine association of coreceptor use with patients' characteristics. Coreceptor usage was determined by viral tropism assays: 290 (68.9%) patients had CCR5-tropic HIV-1 virus, and 131 (31.1%) had dual-tropic/mixed or CXCR4 virus variants. Mean CD4+ cell counts in the R5 group (319.4 cells/mm3) were higher than in the non-R5 group (237.9 cells/mm3) (p = .0005). There was an inverse relationship between CD4+ cell counts and plasma viral load, but regression analyses on covariates associated with CCR5 tropism showed that only a higher CD4+ cell number was significantly associated with CCR5 coreceptor usage. The prevalence of CCR5-tropic HIV-1 among treatment-experienced patients in Spain is higher than previously found in other geographical settings. We did not find independent markers predictive of coreceptor usage other than a relationship with CD4+ levels.