Polymorphonuclear (PMN) elastase in patients after severe traumatic brain injury.
Data on PNM elastase levels in cerebrospinal fluid following traumatic brain injury (TBI) in humans are not available in the literature. Therefore, the aim of this prospective study was to evaluate the dynamics of PMN elastase in the cerebrospinal fluid (CSF) of patients after TBI. Patients suffering from isolated, closed TBI, presenting with an initial Glasgow coma score ≤ 8 and with intracerebral hemorrhage on the initial cranial computed tomography scan (performed within 90 min after TBI) were enrolled. CSF and blood samples were obtained immediately, 12 h, 24 h, 48 h, and 72 h after admission. ELISA testing was used to quantify the PMN elastase levels in CSF. In addition, the ratio of CSF albumin to serum albumin was calculated to evaluate the role of the blood-cerebrospinal fluid barrier (BCSFB). As controls, CSF samples were taken from patients receiving spinal anesthesia for elective orthopedic surgery of the lower extremity. Twenty-three patients meeting the inclusion criteria and ten control patients were enrolled. The PMN elastase showed a significant elevation at 48 and 72 h after TBI. When comparing the PMN elastase levels of patients with intact BCSFB to patients with defective BCSFB, there was no significant difference for the respective observation points. This is the first study to demonstrate that the PMN elastase levels in CSF significantly increased in the early posttraumatic phase (48 h and 72 h after TBI) in patients. The function of the BCSFB showed no significant influence on the PMN levels.


TF--a novel cell-permeable and selective inhibitor of human protein kinase CK2 induces apoptosis in the prostate cancer cell line LNCaP.
Abnormally high activity of protein kinase CK2 is linked to various diseases including cancer. Therefore, the inhibition of CK2 is a promising therapeutic strategy to fight this disease. We screened a library of synthetic molecules concerning their capacity to inhibit CK2. The activity of CK2 and their IC50 and Ki values were determined by a capillary electrophoresis assay. The effects of the inhibitor in a cell culture model were analyzed by cell counting, a viability assay, cytofluorimetry and Western blot. The best CK2 inhibitor found in this screen was 6,7-dichloro-1,4-dihydro-8-hydroxy-4-[(4-methylphenylamino)methylen]dibenzo [b,d]furan-3(2H)-one, which we refer to as "TF". TF showed tight binding to CK2 with low IC50 (29 nM) and Ki (15 nM) values. TF inhibited only seven out of 61 human kinases tested (>70% inhibition). Incubation of LNCaP cells with 50 μM TF for 48 h decreased the intracellular CK2 activity by 50%, confirming that the inhibitor is membrane permeable. The decrease in activity was correlated with a severe reduction in cell viability. The reduction in cell viability is at least partly due to the induction of apoptosis. In many cancers the protein kinase CK2 is significantly up-regulated and supports the neoplastic phenotype. New therapeutic strategies should be based on diverse reliable inhibitors to reverse the abnormal high levels to normal settings.


Drug development in anaesthesia: industrial perspective.
In this review, we summarize the new drugs in development in the anaesthesia field. There are some interesting approaches, including pro-drugs of propofol such as Aquavan (MGI Pharma, Bloomington, Minnesota, USA) and novel 'soft-drug' sedatives and hypnotics (e.g. CNS-7259X and TD-4756) as well as a novel approach to terminate the action of steroidal neuromuscular blockers (sugammadex). There is also significant activity in the field of novel analgesics. Particularly addressing the fields of sedatives, hypnotics and neuromuscular blockers, however, there is relatively little drug discovery activity currently. Part of the reason for this may be that the mechanisms of action of anaesthetics are not fully understood. This cannot be the whole story, however, since attractive new targets have recently been identified. For example, an agent with selective actions at the beta3-containing subunit of the gamma-amino butyric acid-A receptor is likely to have the hypnotic effects of propofol without the cardiac depressant side-effects. We consider the main reason for low activity is the perception in industry that there is little need for new drugs in anaesthesia because the needs are well addressed by existing agents. If this is not the case then anaesthesiologists need to be more effective in communicating their requirements.


Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.
We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30-45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2-93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan-Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18-58%) and 35% at 5 years (95% CI: 15-55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19-73%) and 34% at 5 years (95% CI: 17-51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P < 0.001). The bcr-abl fusion transcript (p210 vs p190 vs p210/190) did not affect disease-free or overall survival. In our experience, an intensified conditioning regimen seems to improve the results of bone marrow transplantation in patients with Ph+ acute lymphoblastic leukemia. However, the high relapse rate warrants novel approaches to enhance anti-leukemic efficacy.


Teenage pregnancy in Sweden and Finland. Implications for the United States.
Fertility and the rates of pregnancy, live births, and abortion in teenagers in the United States are considerably higher than in most other developed countries of northern and western Europe. Fertility rates in teenagers in Sweden have declined significantly. The teaching of family life education is universal in Sweden and almost universal in Finland. Sex is openly discussed within society in both countries. Family planning and abortion services are geographically very available in both countries and both services and supplies are free. The educational level of both males and females is high in both countries. The United States has the opportunity to reduce teenage pregnancy by applying the experience of Sweden and Finland in the fields of family life education and family planning services.


Dissecting the heterogeneous subcortical brain volume of autism spectrum disorder using community detection.
Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15-22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.


The effect of endometriosis on placental histopathology and perinatal outcome in singleton live births resulting from IVF.
Does endometriosis have an effect on the placental histopathology pattern and perinatal outcome in singleton live births resulting from IVF treatment? Retrospective cohort study evaluating the data on all live births following IVF treatment between 2009 and 2017 at one university-affiliated tertiary hospital. All patients had placentas sent for full gross and histopathology assessment, irrespective of complication status or delivery mode. The primary outcomes of the study included anatomical, inflammation, vascular malperfusion and villous maturation placental disorders. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate logistic model was used to adjust the results for confounding factors potentially associated with significant placental characteristics. A total of 1057 live births were included in the final analysis and were allocated to the group of women with endometriosis (n = 75) and those without (n = 982). After adjustment for confounding factors, endometriosis was found to be significantly associated with acute chorioamnionitis with moderate to severe maternal (odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.1-4.6) and fetal (OR 4.9, 95% CI 1.8-13.1) inflammatory response, placenta previa (OR 3.1, 95% CI 1.2-7.8), subchorionic fibrin deposition (OR 3.4, 95% CI 1.2-9.1), intervillous thrombosis (OR 3.4, 95% CI 1.5-8.1), and fetal vascular malperfusion (OR 5.1, 95% CI 1.4-18.1), as well as with preterm birth (OR 2.5, 95% CI 1.4-4.7). Endometriosis has a significant impact on the placental histopathology and is associated with a higher incidence of preterm birth.


Bilateral acoustic neurofibromatosis camouflaged by corticosteroid treatment of sudden sensorineural hearing loss.
We report a case of bilateral acoustic neurofibromatosis which presented with the atypical symptom of sudden sensorineural deafness. Following corticosteroid therapy the hearing loss returned to near normal levels. The pathogenesis of reversible sudden sensorineural hearing loss in the presence of an acoustic neuroma is discussed. The importance of Gadolinium-enhanced magnetic resonance imaging in the detection of bilateral acoustic neurofibromatosis is highlighted by the case report.


Building momentum for malaria vaccine research and development: key considerations.
To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.


The emerging role of microRNA in regulation of endotoxin tolerance.
Endotoxin tolerance is a phenomenon where cells show reduced responsiveness toward repeated endotoxin stimulation. Regulation of tolerance occurs at multiple levels of the cell signaling cascade, and many of these levels are potentially regulated by miRNA, which are a class of small RNA that bind to mRNA to down-regulate gene expression at the post-transcriptional level. Roles have been identified for miR-146a, miR-221, miR-579, miR-125b, miR-155, let-7e, and miR-98 in regulating the TLR4 signaling pathway during the development of endotoxin tolerance at receptor, signaling pathway, and gene transcription and translational levels. miRNA represent exciting, new potential targets in attempts to exogenously modulate development of endotoxin tolerance.


Mining TCGA database for genes of prognostic value in gastric cancer microenvironment.
Gastric cancer (GC) is the sixth most common malignancy and the third leading cause of cancer-related death worldwide. Emerging evidence suggests that tumour microenvironment cells play a vital role in the development and prognosis of GC. To investigate the possible effect of stromal scores and immune scores on the overall survival (OS) on the GC patients, we divided GC patients into 'high' and 'low' groups based on their stromal and immune scores, and found differentially expressed genes related to prognosis of GC patients. Functional enrichment analysis and GSVA further revealed that focal adhesion and ECM-receptor interaction are associated with GC patients' survival. Finally, we analysed the effects of genes commonly involved in focal adhesion and ECM-receptor interaction on GC patients' survival and validated our results in another GC cohort from GEO data sets. In conclusion, we obtained a list of tumour microenvironment-related genes that predict poor prognosis in GC patients.


Leishmania major thialysine Nepsilon-acetyltransferase: identification of amino acid residues crucial for substrate binding.
Thialysine N(epsilon)-acetyltransferases and spermidine/spermine N-acetyltransferases (SSAT) are closely related members of the GCN5-related N-acetyltransferase superfamily. Accordingly, a putative orthologue from the human protozoan parasite Leishmania major exhibits an almost equal similarity to human SSAT and thialysine N(epsilon)-acetyltransferase. Characterisation of the recombinantly expressed L. major protein indicated that it represents a thialysine N(epsilon)-acetyltransferase, preferring thialysine (S-aminoethyl-l-cysteine) and structurally related amino acids as acceptor molecules. The known thialysine N(epsilon)-acetyltransferases contain five conserved amino acid residues that are replaced in SSAT sequences. Kinetic analyses of the respective recombinant mutant proteins suggest that Ser(82) and Thr(83) of L. major thialysine N(epsilon)-acetyltransferase are key residues for acceptor binding. In addition, the conserved Leu(130) is tentatively involved in specific interaction with the sulphur-containing side chain of thialysine. The presence of these three amino acid residues is suggested to be a means by which thialysine N(epsilon)-acetyltransferases can be distinguished from SSAT sequences.


Prevalence of habitual snoring and its correlates in young children across the Asia Pacific.
To evaluate: (i) the prevalence of habitual snoring (HS) in a large sample of children aged from birth to 36 months in 14 countries across Asia Pacific; and (ii) the different correlates associated with HS in Caucasians, Chinese and non-Chinese, non-Caucasian Asians. This was a multi-centre, cross-sectional survey conducted across Asia Pacific. Parents/caregivers of 23,481 infants and toddlers completed an expanded version of the Brief Infant Sleep Questionnaire. We defined HS as snoring more than three nights per week. Chinese and non-Caucasian non-Chinese (NCNC) children had a lower prevalence of HS across the age range from birth to 3 years than their Caucasian counterparts (6.2% and 5.1% vs. 11%, P < 0.01). Boys had a higher prevalence of HS compared to girls (χ(2) = 98.5, P < 0.0001). History of prematurity (OR = 1.37-1.56, CI (1.1-2.17), P < 0.01) and gender (OR = 1.53-1.54, CI (1.26-1.85), P < 0.0001) were found to be significant predictors for HS. Current breastfeeding (OR = 0.69, CI (0.54-0.88), P < 0.005) and greater parental age (OR = 0.86, CI (0.78-0.96), P < 0.01) were protective against HS among NCNC children. HS was less prevalent in younger Chinese subjects (OR = 0.88, CI (0.84-0.93), P < 0.0001). In Caucasians, parents' education (OR = 0.78, CI (0.67-0.91), P < 0.005) and their not sleeping in the same room as their child (OR = 0.62, CI (0.45-0.86), P < 0.005) were negatively associated with parental report of HS. Prevalence of HS shows racial differences among countries across Asia Pacific. Future studies should assess craniofacial structure and body fat distribution as contributory factors for this differential prevalence.


Bone healing by sterilizable calcium phosphate tetrapods eluting osteogenic molecules.
Although bone grafts and prosthetic implants have shown some clinical success in the treatment of bone defects, the graft availability, biocompatibility, function, and longevity still remain to be improved. One possible solution to these problems is to develop bone implants acting on host cells to induce rapid bone regeneration. Here, we demonstrate bone healing by means of a sterilizable and osteogenic molecule-eluting implant system in which two small molecules, a smoothened agonist (SAG) and a helioxanthin derivative (TH), are loaded onto tetrapod-shaped calcium phosphate granules (Tetrabone). We succeeded in directing progenitor cells toward mature osteoblasts with the combined application of the two small molecules acting on different stages of osteogenesis. Tetrabone released SAG and TH for prolonged periods when loaded with these molecules. EOG sterilization did not affect the osteogenic activity of the SAG- and TH-loaded Tetrabones. The combinatorial use of SAG- and TH-loaded Tetrabones achieved bone healing without cell transplantation in a rat femur bone defect model within two weeks. This system will allow us to vary the combination rate of implants loaded with different osteogenic factors depending on the types and sizes of defects, potentially allowing full temporal and spatial control of the bone regeneration.


Cellular prion protein is expressed on endothelial cells and is released during apoptosis on membrane microparticles found in human plasma.
Blood and plasma of animals experimentally infected with transmissible spongiform encephalopathies (TSEs) can transmit TSE infection by transfusion. A conformational isoform of prion protein (PrPsc) is believed to be the TSE-infectious agent that propagates by converting the cellular prion protein (PrPc) to additional molecules of PrPsc. In orally infected animals, PrPsc accumulates in intestinal endothelial cells. In blood, two thirds of PrPc resides in plasma, but its source is not known. The expression of PrPc in cultured human umbilical vein endothelial cells (HUVECs) was studied using flow cytometry, immunoblotting, and RT-PCR. Flow cytometry was used to characterize endothelial membrane microparticles (MPs) in cell culture supernatants and in normal human plasma. HUVECs and bovine aorta endothelial cells express PrPc. The number of surface PrPc molecules per cell in HUVECs was 58,000 +/- 2,800. The induction of apoptosis in HUVECs led to a marked release of membrane MPs (60,000-80,000 MPs/10(3) cells) that expressed PrPc and other endothelial antigens. The presence of endothelial cell-derived MPs expressing PrPc was demonstrated in platelet-free human plasma. Endothelial cell apoptosis is associated with the release of PrPc-positive MPs. These MPs contribute to the PrPc pool in plasma and may have a role in disseminating TSE infectivity in blood.


Reduced kappa-opioid activity in a rat model of cholestasis.
Increased endogenous opioid activity has been implicated in cholestatic pruritus. In the present study, we have further defined the involvement of opioids in cholestasis. Rats underwent either bile duct ligation or a sham operation. Five days after surgery, brains were removed and agonist-stimulated [35S]GTPgammaS binding was measured in ten brain regions. Serum endomorphin-2, leu-enkephalin and dynorphin A levels were measured using ELISA on day five. Microdialysis to the dorsal hypothalamic area was conducted in the same animal before and after cholestasis. Dialysate endomorphin-1, leu-enkephalin and dynorphin A levels also were measured. Delta- and kappa-stimulated binding was significantly decreased in cholestasic animals compared to controls in the dorsal hypothalamic area. The serum dynorphin A level was lower in the cholestasic group than in controls (2.56+/-0.09 and 3.29+/-0.22 ng/ml, respectively, P<0.01). We propose that pruritus in cholestasis may result from an impaired balance between mu- and kappa-opioid systems.


Primary and secondary pesticide drift profiles from a peach orchard.
Atmospheric drift is considered a major loss path of pesticide from target areas, but there is still a large gap of knowledge regarding this complex phenomenon. Pesticide drift may occur during application (Primary drift) and after it (Secondary drift). The present study focuses on primary and secondary drift from ground applications in peach orchard (tree height of 3 m), under Mediterranean climate. Detailed and prolonged vertical drift profiles at close proximity to orchard are presented, together with detailed measurements of key meteorological parameters. The effect of volatility on drift was also studied by simultaneously applying two pesticides that differ in their volatility. Drifting airborne pesticides were detected both during and after applications at sampling distances of 7 and 20 m away from orchard edge. Concentrations ranged between hundreds ng m-3 to a few μg m-3 and showed clear decrease with time and with upwind conditions. Almost no decline in concentrations with height was observed up to thrice canopy height (i.e., 10 m). These homogeneous profiles indicate strong mixing near orchard and are in line with the unstable atmospheric conditions that prevailed during measurements. While air concentrations during pesticide application were higher than after it, overall pesticide load drifted from the orchard during primary and secondary drift are comparable. To the best of our knowledge this is the first work to show such large vertical dispersion and long duration of secondary drift following ground application in orchards. The obtained information indicates that secondary drift should not be neglected in exposure and environmental impact estimations.


Retrograde (transseptal) activation of right bundle branch during sinus rhythm.
A 40-year-old man undergoing electrophysiologic study for recurrent palpitations was found to have a right bundle branch block during sinus rhythm and right bundle potentials occurring after ventricular activation. The sequence of activation of the proximal and distal right bundle potentials was suggestive of a retrograde invasion of the right bundle during sinus rhythm. This transseptal activation of the right bundle via the left bundle exhibited decremental conduction characteristics during atrial as well as ventricular stimulation. Observations made in this case may provide some important information concerning the electrophysiologic behavior of transseptal impulses.


Do emotional labour strategies influence emotional exhaustion and professional identity or vice versa? Evidence from new nurses.
The aim was to examine the reciprocal relationships of emotional labour strategies with emotional exhaustion and professional identity. This study adopted a four-wave cross-lagged panel design. Survey data were collected in 2018 from a sample of 171 newly hired nurses from 58 hospitals in 11 provinces of China. Nurses' emotional labour (i.e., deep acting and surface acting), emotional exhaustion and professional identity were repeatedly measured. Cross-lagged panel analyses were conducted to examine the reciprocal relationships we hypothesized. We found that emotional exhaustion was positively related to surface acting (but not vice versa); deep acting was negatively related to emotional exhaustion (but not vice versa); professional identity was positively related to deep acting (but not vice versa). Our findings suggest that deep acting and professional identity may decrease the level of emotional exhaustion, whereas emotionally exhausted nurses are more likely to employ surface acting strategies. This research finding will have an impact on the nursing management. Healthcare managers may consider workshops or training and development programs that promote nurses' professional identify to promote nurses' use of deep acting and consequently reduce their level of emotional exhaustion, which has been associated with a variety of negative consequences, such as low quality of patient service, high medical accidents, and turnover rate.


Smooth muscle dysfunction in patients older than 54 years of age with objective evidence of arteriosclerosis.
This investigation was designed to assess the relationship between flow-mediated vasodilatation (FMD) and nitroglycerin (NTG)-mediated vasodilatation (NMD) with atherosclerotic risk factors. FMD and NMD were measured in 75 subjects including 57 patients with atherosclerotic disease (AAA/PAOD=30/27, age 72+/-7 years) and 18 controls. Brachial response to hyperemia and NTG were measured every minute after cuff deflation and NTG administration. In the 75 subjects, responses to NTG showed a sigmoid curve. Only 2 cases reached maximal diameter within 4 minutes after NTG, and 90% of the cases reached maximal diameter at 6 minutes or later (7.5+/-2.0 minutes). In patients with atherosclerotic disease, a multiple regression analysis showed higher FMD was associated with higher NMD, and higher NMD was associated with smaller vessel size, lower systolic blood pressure, higher FMD, lower carotid maximal IMT, lower serum levels of insulin, and lower HOMA-IR. In subjects older than 54, NMD measured at 3 or 4 minutes after NTG administration would underestimate the NTG-dependent vasodilatation. NMD measured with the maximal responded diameter was associated with atherosclerotic risk factors, and it is therefore considered to be an important parameter in patients with atherosclerotic disease.


Immunodeficiency, malabsorption and secretory diarrhea. A new syndrome.
Described here is a patient with severe watery diarrhea associated with common variable immunodeficiency. Malabsorption for fat, bile acids, vitamin B12 and xylose was demonstrated, but the patient failed to respond to all the usual therapeutic maneuvers. The diarrhea responded only to high dose steroid therapy. Intestinal perfusion studies showed a hitherto undescribed, presumably acquired, glucose-stimulated water, sodium and chloride secretion in the jejunum and ileum, whereas normal fluid and electrolyte transport occurred from bicarbonate and mannitol solutions. Glucose absorption itself was normal and no hormonal, morphologic or biochemical defect was demonstrated to account for the phenomenon. The patient was also interesting when compared with other patients with common variable immunodeficiency in having normal plasma cells in the intestinal mucosa and an extensive family involvement.


Single-vehicle crashes along rural mountainous highways in Malaysia: An application of random parameters negative binomial model.
Mountainous highways generally associate with complex driving environment because of constrained road geometries, limited cross-section elements, inappropriate roadside features, and adverse weather conditions. As a result, single-vehicle (SV) crashes are overrepresented along mountainous roads, particularly in developing countries, but little attention is known about the roadway geometric, traffic and weather factors contributing to these SV crashes. As such, the main objective of the present study is to investigate SV crashes using detailed data obtained from a rigorous site survey and existing databases. The final dataset included a total of 56 variables representing road geometries including horizontal and vertical alignment, traffic characteristics, real-time weather condition, cross-sectional elements, roadside features, and spatial characteristics. To account for structured heterogeneities resulting from multiple observations within a site and other unobserved heterogeneities, the study applied a random parameters negative binomial model. Results suggest that rainfall during the crash is positively associated with SV crashes, but real-time visibility is negatively associated. The presence of a road shoulder, particularly a bitumen shoulder or wider shoulders, along mountainous highways is associated with less SV crashes. While speeding along downgrade slopes increases the likelihood of SV crashes, proper delineation decreases the likelihood. Findings of this study have significant implications for designing safer highways in mountainous areas, particularly in the context of a developing country.


Chimarrão consumption and prognostic factors in breast cancer: Correlation with antioxidants and blood caffeine levels.
Breast cancer is the second most common malignancy among women. Ilex paraguariensis A. St. Hil, known as yerba mate, is widely consumed in southern Brazil as a hot infusion drink known as chimarrão. This herb has a complex chemical composition and is rich in antioxidants, which may interfere in the course of chronic inflammatory diseases as breast cancer. This study investigated the impact of chimarrão consumption on the clinicopathological profile of women with breast cancer attended at Francisco Beltrão Cancer Hospital, Paraná, Brazil. Blood antioxidants and caffeine profiles were assessed. Decreases in reduced glutathione and metallothionein levels, and increase in catalase activity were observed among breast cancer patients that were chimarrão consumers. The levels of circulating caffeine in breast cancer patients with luminal A tumors were higher than those in patients with luminal B and HER-2 subtypes. Furthermore, overweight patients presented higher caffeine levels than the eutrophic ones. It was found positive associations between chimarrão intake and high body mass index, and chimarrão intake and menopause at diagnosis. Altogether, these findings suggest that chimarrão consumption affects the blood antioxidants of breast cancer patients, and that the caffeine present in this mixture may favor the development of tumor of good prognosis. HIGHLIGHTS: Chimarrão consumption may affect the course of chronic inflammatory diseases, as breast cancer. Chimarrão intake changed blood antioxidants in breast cancer patients who were current consumers when compared to the non-consumers ones. High levels of caffeine were detected in patients bearing luminal A tumors, suggesting a protective role.


H pylori eradication therapy reduces gastric cancer in patients with or without gastric neoplasia.
Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020. [Epub ahead of print]. 32205420.


p38γ activity is required for maintenance of slow skeletal muscle size.
p38γ kinase is highly enriched in skeletal muscle and is implicated in myotube formation. However, the activation status of p38γ in muscle is unclear. p38γ activity in slow and fast adult mouse skeletal muscle tissue was examined, as was the impact of p38γ deficiency on muscle development and gene expression. p38γ is preferentially activated in slow muscle, but it is inactive in fast muscle types. Furthermore, the loss of p38γ in mice led to decreased muscle mass associated with a smaller myofiber diameter in slow muscle, but there was no impact on fast muscle in either mass or myofiber diameter. Finally, p38γ-deficient muscle showed selective changes in genes related to muscle growth in slow muscle fibers. This study provides evidence that p38γ is selectively activated in slow skeletal muscle and is involved in the normal growth and development of a subset of skeletal muscle.


Differential susceptibility of species of slugs to metaldehyde/bran and to methiocarb baits.
Laboratory experiments were designed to study differential susceptibility of nine species of slugs to metaldehyde/bran and to methiocarb baits. Differential susceptibility was found between some of the species for each type of bait, both immediately after baiting and also after a 48 h recovery period. Thus neither type of bait is suitable for use in ecological investigations. This conclusion was supported by evidence that interspecific behavioural interactions occurred when metaldehyde, but not methiocarb, baits were used.At the same time the relative efficiency of the two types of baits as molluscicides was estimated. Methiocarb was shown to be a better molluscicide because, not only did it initially poison more slugs than did metaldehyde, but also a number of the slugs initially poisoned by metaldehyde recovered during the following 48 h period, whereas this did not happen with methiocarb. The similarity between these results and those obtained from field experiments by other workers is discussed.


Foam rolling improvements in passive hip flexion last up to 60-minutes in ice hockey players.
Ice hockey players often lack hip mobility which may be attributed to excessive time spent in a flexed position during competition and the intensive use of hip external rotators and extensors. Previous investigations demonstrate that foam rolling increases range-of-motion in healthy populations. It is unclear whether such benefits occur in athletes with chronic hip tightness. Further, athletes often perform pre-competition warm-up up to 60-min prior to a game, therefore we investigated the retention of the effects of foam rolling. The purpose of this study was to analyze the effects of foam rolling the anterior and posterior aspects of the thigh on passive hip flexion in ice hockey players, up to 60-min post-rolling. Sixteen amateur ice hockey players (8 ♀, 22 ± 2 years, 25.1 ± 3.5 kg m-2) warmed up for 5-min then performed 2, 1-min bouts of foam rolling using a high density multi-rigid roller on the quadriceps and hamstrings, with 1-min break between sets. Passive hip flexion was measured before and immediately after rolling, 10-min, 30 and 60-min post-rolling using the Coach's Eye application during a passive straight leg raise. Compared to baseline, passive hip flexion was greater immediately after foam rolling (p < 0.01), 10 min (p = 0.05), 30 (p < 0.01) and 60-min post-rolling (p < 0.01). Regardless of measurement time point, significant increases in passive hip flexion occurred up to 60-min compared to baseline. Incorporation of foam rolling into pre-competition warm-ups may be beneficial when increases in hip mobility are warranted, up to 1-h before competition.


Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo.
Abundant data indicate that overexpression of apolipoprotein A-I (apoA-I) in mice inhibits atherosclerosis. One mechanism is believed to be promotion of reverse cholesterol transport, but no direct proof of this concept exists. We developed a novel approach to trace reverse transport of labeled cholesterol specifically from macrophages to the liver and feces in vivo and have applied this approach to investigate the ability of apoA-I overexpression to promote macrophage-specific reverse cholesterol transport. J774 macrophages were loaded with cholesterol by incubation with acetylated LDL, labeled with 3H-cholesterol, and then injected intraperitoneally into mice. Plasma and feces were collected at 24 hours and 48 hours, when mice were exsanguinated, tissues were harvested, and all were analyzed for tracer counts. 3H-cholesterol was found in the plasma, liver, and feces. For apoA-I overexpression, mice were injected intravenously with apoA-I adenovirus (1011 particles per animal) 3 days before labeled macrophages were injected. ApoA-I overexpression led to significantly higher 3H-cholesterol in plasma, liver, and feces. The amount of 3H-tracer in the liver was 35% higher (P<0.05) and the 3H-tracer excreted into feces over 48 hours was 63% higher (P<0.05) in apoA-I-expressing mice than in control mice. Injection of 3H-cholesterol-labeled macrophage foam cells is a method of measuring reverse cholesterol transport specifically from macrophages to feces in vivo, and apoA-I overexpression promotes macrophage-specific reverse cholesterol transport.


Morbid obesity: issues and challenges in home health.
People coping with morbid obesity face many complex issues and challenges, as do the home healthcare providers who care for them. Morbid obesity among adults in the United States has reached epidemic proportions. It is estimated that 1 in 20 Americans has class 3 morbid obesity, also known as extreme obesity (Arterburn, Maciejewski, & Tsevat, 2005). Morbid obesity is on the rise. Understanding the emotional and physical needs of this population allows the home health clinician to optimize the chances for successful outcomes.


Biogenesis of Type V pili.
Pili or fimbriae, which are filamentous structures present on the surface of bacteria, were purified from a periodontal pathogen, Porphyromonas gingivalis, in 1980s. The protein component of pili (stalk pilin), which is its major component, was named FimA; it has a molecular weight of approximately 41 kDa. Because the molecular weight of the pilin from P. gingivalis is twice that of pilins from other bacterial pili, the P. gingivalis Fim pili were suggested to be formed via a novel mechanism. In earlier studies, we reported that the FimA pilin is secreted on the cell surface as a lipoprotein precursor, and the subsequent N-terminal processing of the FimA precursor by arginine-specific proteases is necessary for Fim pili formation. The crystal structures of FimA and its related proteins were determined recently, which show that Fim pili are formed by a protease-mediated strand-exchange mechanism. The most recent study conducted by us, wherein we performed cryoelectron microscopy of the pilus structure, provided evidence in support of this mechanism. As the P. gingivalis Fim pili are formed through novel transport and assembly mechanisms, such pili are now designated as Type V pili. Surface lipoproteins, including the anchor pilin FimB of Fim pili that are present on the outer membrane, have been detected in certain Gram-negative bacteria. Here, we describe the assembly mechanisms of pili, including those of Type V and other pili, as well as the lipoprotein transport mechanisms.


Phase I study of the cisplatin analogue 1,1-diamminomethylcyclohexane sulfatoplatinum (TNO-6) (NSC 311056).
The cisplatin derivative TNO-6 was evaluated for clinical toxicity in a phase I trial. TNO-6 was given daily for 5 days every 3 weeks as a 30-min IV infusion without hydration. In all, 39 patients with advanced cancer were treated at doses of 2.5-9.0 mg/m2. No dose-limiting nephrotoxicity occurred, but evidence of mild, reversible tubular damage was found. Dose-limiting toxicity was hematologic with both thrombopenia and leukocytopenia, which with high dose levels reached WHO grade 4. Hematologic toxicity was most pronounced for pretreated patients. No antitumor activity was seen. The recommended dose for phase II trials will be 9.0 mg/m2 for previously untreated and 8.0 mg/m2 for pretreated patients.


Antagonistic modulatory influences of negative affect on cognitive control: Reduced and enhanced interference resolution capability after the induction of fear and sadness.
The present behavioral study investigated the influence of negative affect on the neural mechanisms of cognitive control. We expected to find evidence for an antagonistic modulation of cognition by threat-relevant and threat-irrelevant negative affect (i.e. fear and sadness) that should promote bottom-up monitoring and top-down selection, respectively. Subjects performed one of three conflict tasks (Stroop, Flanker, or Simon) that tap distinct control mechanisms of conflict resolution, comprising specific attentional and motor control processes. On each task trial, target stimuli were preceded by a face stimulus exhibiting a fearful, sad, or neutral expression, providing three affect conditions. Our data provides strong evidence for substantially increased selection (attentional and motor selection) after priming of threat-irrelevant negative affect (sadness). Deviating from the results of previous studies, our analysis did not consistently yield increased monitoring after fear priming. We discuss these findings with respect to the effectiveness of different experimental affect priming procedures (i.e. stimuli) and the role of the task context, among others.


[Comparative compositional mapping of chicken and quail chromosomes].
The distribution of various isochore families on mitotic chromosomes of domestic chicken and Japanese quail was studied by the method of fluorescence in situ DNA--DNA hybridization (FISH). DNA of various isochore families was shown to be distributed irregularly and similarly on chromosomes of domestic chicken and Japanese quail. The GC-rich isochore families (H2, H3, and H4) hybridized mainly to microchromosomes and a majority of macrochromosome telomeric regions. In chicken, an intense fluorescence was also in a structural heterochromatin region of the Z chromosome long arm. In some regions of the quail macrochromosome arms, hybridization was also with isochore families H3 and H4. On macrochromosomes of both species, the pattern of hybridization with isochores of the H2 and H3 families resembled R-banding. The light isochores (L1 and L2 families) are mostly detected within macrochromosome internal regions corresponding to G bands, whereas microchromosomes lack light isochores. Although mammalian and avian karyotypes differ significantly in organization, the isochore distribution in genomes of these two lineages of the warm-blooded animals is similar in principle. On macrochromosomes of the two avian species studied, a pattern of isochore distribution resembled that of mammalian chromosomes. The main specific feature of the avian genome, a great number of microchromosomes (about 30% of the genome), determines a compositional specialization of the latter. This suggests the existence of not only structural but also functional compartmentalization of the avian genome.


Buffering characteristics of eel blood at the extreme conditions in the swimbladder.
CO2 binding in whole blood and true plasma of the eel was estimated by measuring CO2 content and pH in blood aliquots equilibrated with various PCO2 values over a wide range expected to occur in the swimbladder. Bicarbonate concentration, [HCO3-], was calculated using the CO2 solubility coefficient, which was measured to average 50 mumols.L-1.Torr-1 (20 degrees C). Buffer lines of non-bicarbonate buffers were obtained in plots of [HCO3-] against pH, and non-bicarbonate buffer values, beta NB, were obtained by curve fitting. In the pH range 6.6-8.2, the buffer line for oxygenated whole blood was sigmoid, while that for deoxygenated blood increased its slope monotonously with increasing pH. The beta NB for oxygenated blood displayed a maximum of about 8.6 mmol.L-1.pH-1 at pH = 7.4 and dropped down to below 1 mmol.L-1.pH-1 at higher and lower pH. Similar shapes of the buffer lines were obtained in true plasma; the [HCO3-] levels and beta NB values were, however, somewhat higher than in whole blood. These data are useful to assess the back-diffusion of CO2 and HCO3- in the rete mirabile of the fish swimbladder and to estimate the effects CO2 back-diffusion exerts on the counter-current enhancement of O2 in the rete.


Induction of chicken interferon by avian infectious bronchitis virus.
The ability of nine strains of avian infectious bronchitis virus (IBV) to induce chicken interferon has been investigated using Semliki Forest virus for the tests. The Beaudette, H120 and Connecticut 46 strains induced interferon in the allantoic fluids of embryonated hens' eggs, the highest titre (1 : 30) being associated with Beaudette; but these as well as the Massachusetts M-41 and H52 strains failed to yield interferon in primary monolayer cultures of chick kidney cells as did all nine strains in organ cultures of chick embryo trachea. None of six strains of IBV investigated was susceptible to the inhibitory effects of chicken interferon.


Ultrasound-guided core-needle biopsy and magnetic resonance imaging in the accurate diagnosis of intramuscular haemangiomas of the head and neck.
Intramuscular haemangiomas of the digastric muscle are often misdiagnosed due to their low incidence and non-specific manifestation. Only two out of six previously reported cases were diagnosed correctly before excision. Ultrasound may not reveal their vascularity, and fine-needle aspiration biopsy is unhelpful as it reveals only blood. A case of intramuscular haemangioma of the posterior belly of the digastric muscle is described. Previously reported cases are reviewed. Investigations used to diagnose the lesions and reasons for their common failure are discussed. Core-needle biopsy led to the correct histological diagnosis, and magnetic resonance imaging precisely located the lesion within the digastric muscle. Core-needle biopsy was safely used in the diagnosis of an intramuscular haemangioma. The combination of core-needle biopsy and meticulous review of magnetic resonance imaging enables accurate diagnosis pre-operatively.


[Radiological study of the chest involvement during angioimmunoblastic lymphadenitis (A.I.L.) Twenty observations (author's transl)].
From 20 observations, the authors worked out the frequency and the radiological picture of chest localizations of angio-immunoblastic lymphadenitis (A.I.L.). There are 2 kinds of pulmonary involvement: --a specific one by interstitial immunoblastic infiltration (20 to 45% of cases) and showing on X ray a reticulomicronodular interstitial syndrome; --a secondary infection (33% of cases) often the cause of death. Pleural involvement is unfrequent (11% to 25% of cases) and its onset late. Mediastinal lymph-node involvement is found in 37 to 50% of cases. It is usually discovered straight away.


Framing effects on financial and health problems in gambling disorder.
Gambling disorder (GD) patients show excessively risky decision-making in the financial domain. We aimed to clarify whether GD patients show risky decision-making in domain-general or in domain-specific. Furthermore, we also investigated the effect of the well-known cognitive bias, the framing effect on GD's decision-making under risk. Sixty-two male GD patients and 74 age-matched healthy male controls (HC) conducted a risky choice task in which they should choose solutions for difficult situations between a sure and a risky option that had the same expectations. Six situations were prepared for each financial and health domain. For each domain, three situations were presented with options using positive frames, and the other three situations were presented with options using negative frames. The results showed that GD chose more risky options in the financial domain with positive frames than HC, but chose comparably in the financial domain with negative frames, whereas GD and HC chose comparably in the health domain regardless of the frames. Thus, GD showed risky decision-making in domain-specific. In addition, the results indicate the importance of considering the influence of the framing effect for assessment of risky decision-making by GD. Domains and the influence of the framing effect should be considered when decision-making patterns of neuropsychiatric disorders are studied.


PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors.
Clonal loss of PTEN expression occurs frequently in endometrial carcinoma and endometrial hyperplasia. Limited data from immunohistochemical studies suggest that PTEN-null appearing endometrial glands are detectable in women without pathologic abnormalities, but the relationship of PTEN expression to endometrial cancer risk factors has not been extensively explored. We evaluated relationships between endometrial cancer risk factors and loss of PTEN expression in a set of benign endometrial samples prospectively collected from women undergoing hysterectomy and in endometrial cancer tissues from a population-based case-control study. We used a validated PTEN immunohistochemical assay to assess expression in epidemiological studies designed to assess benign endometrium [Benign Reproductive Tissue Evaluation Study (n = 73); Einstein Endometrium Study (n = 19)], and endometrial cancer [Polish Endometrial Cancer Study (n = 148)] tissues. Associations between endometrial cancer risk factors (collected via study-specific risk factor questionnaires) and PTEN expression in endometrial tissues were determined using Fisher's exact tests. PTEN loss was detected in 19% of benign endometrial tissues versus 55% in endometrial cancers. NSAID use was statistically significantly associated with PTEN loss in the benign endometrium (p = 0.02). Our data demonstrate that PTEN loss is detectable in endometrial tissues that are benign and malignant, with substantially more frequent loss in endometrial cancer compared with benign endometrium. However, alterations in expression were unrelated to most risk factors in this analysis, except for the association with NSAID use, which may represent a chance finding or reverse causality among patients with endometriosis who may have PTEN pathway abnormalities in eutopic endometrium. Further evaluation of factors associated with PTEN loss and long-term follow-up of women with PTEN-null endometrial glands may be useful in understanding early events in endometrial carcinogenesis.


Residual monomer leaching from chemically cured and visible light-cured orthodontic adhesives.
The objective of this study was to quantify the amount of residual monomer leached from chemically cured and visible light-cured orthodontic adhesives based on Bis-GMA/TEGDMA monomers, when bonded to ceramic and stainless steel brackets. The residual TEGDMA and Bis-GMA monomer concentrations were determined by high performance liquid chromatographic (HPLC) analysis of the extracts after specimen immersion in ethanol/water solution for 15 days at 37 +/- 1 degree C. According to the results the highest monomer concentrations eluted were obtained from the chemically cured adhesive. Direct (through the bracket) irradiation of stainless steel brackets bonded to the visible light-cured adhesive showed high monomer elution as well. A polycarbonate base ceramic bracket manifested significantly greater amount of monomer release compared with ceramic brackets when combined with the visible light-cured adhesive. Indirect (from the incisal and cervical edges of the bracket) irradiation of the visible light-cured adhesive bonded to the stainless steel brackets resulted in lower residual monomer elution compared to that of directly (through the bracket) irradiated metallic brackets. No statistical difference was found between direct or indirect irradiation of the ceramic brackets tested, with respect to monomer elution from the light-cured adhesive.


Numerical simulation of a stochastic model for cancerous cells submitted to chemotherapy.
A stochastic model is proposed to study the problem of inherent resistance by cell populations when chemotherapeutic agents are used to control tumor growth. Stochastic differential equations are introduced and numerically integrated to simulate expected response to the chemotherapeutic strategies as a function of different parameters. Satisfactory demonstration runs of the model indicate that it could represent a useful tool in verifying the results of experimental and clinical chemotherapy courses and planning treatment strategies. Some types of behaviour are illustrated graphically.


Dynamic control of the larynx and future perspectives in the management of deglutitive aspiration.
The approach to deglutitive aspiration presented in this article is original. It permitted restoring the dynamic nature of the swallowing process in immobile largynges, a situation found when function has been abolished through central neurological deficit. The necessity, in the author's view, for a miniaturized electronic system bypassing the diseased centers able to produce tight glottic closure in a canine model during pharyngeal stimulation is emphasized. There is hope that we may ultimately move towards human implantation if the proposed electronics will be well tolerated over time.


Web-based experiment control software for research and teaching on human learning.
In this article we describe some of the experimental software we have developed for the study of associative human learning and memory. All these programs have the appearance of very simple video games. Some of them use the participants' behavioral responses to certain stimuli during the game as a dependent variable for measuring their learning of the target cue-outcome associations. Some others explicitly ask participants to rate the degree of relationship they perceive between the cues and the outcomes. These programs are implemented in Web pages using JavaScript, which allows their use both in traditional laboratory experiments as well as in Internet-based experiments.


Immunoglobulin G antibodies against environmental moulds in a Norwegian healthy population shows a bimodal distribution for Aspergillus versicolor.
Immunoglobulin G (IgG) antibodies against moulds related to indoor dampness problems are used as biomarkers to indicate exposure. In the present study, we evaluated the frequency of mould exposure in an adult healthy population by examining levels of mould-specific IgG antibodies in Norwegian blood donors. Using enzyme-linked immunosorbent assay, 106 blood donor sera were analyzed for IgG antibodies to Aspergillus versicolor, Penicillium chrysogenum, Cladosporium herbarum, Stachybotrys chartarum and Fusarium oxysporum. The levels of specific IgG antibodies to P. chrysogenum, C. herbarum and S. chartarum correlated (r = 0.46-0.62). Responses to A. versicolor were considerably stronger than to the other moulds, and another 996 blood donor sera were analyzed for IgG antibodies to this mould. Women had significantly higher levels of specific IgG antibodies to A. versicolor than men. The concentration of A. versicolor-specific IgG antibodies showed a non-Gaussian, bimodal distribution profile, in which 12.5% were defined as positive to exposure. This suggests that significant mould exposure in a healthy population can be calculated from mean + 1SD. Western blotting analyses showed that antibody responses to A. versicolor were largely directed against carbohydrate antigens of unknown saccharides.


Triptolide activates the Nrf2 signaling pathway and inhibits the NF-κB signaling pathway to improve Alzheimer disease.
Alzheimer disease (AD) is a common neurodegenerative disease with pathological features of accumulated amyloid plaques, neurofibrillary tangles, and the significant inflammatory environment. These features modify the living microenvironment for nerve cells, causing the damage, dysfunction, and death. Progressive neuronal loss directly leads to cognitive decline in AD patients and is closely related to brain inflammation. Therefore, impairing inflammation via signaling pathways may facilitate either the prevention or delay of the degenerative process. Triptolide has been evidenced to possess potent anti-inflammatory effect. In this review, we elaborate on two signaling pathways (the NF-κB and Nrf2 signaling pathways) that are involved in the anti-inflammatory effect of triptolide.


A comparison of the cornell scale for depression in dementia and the Montgomery-Aasberg depression rating scale in a memory clinic population.
The aim of this study was to explore the correlation between the Cornell Scale for Depression in Dementia (CSDD) and the Montgomery-Aasberg Depression Rating Scale (MADRS) among memory clinic patients. The CSDD (based on an interview with the caregiver) and the MADRS (based on the patient's opinion) were filled in independently of each other among 520 patients. Principal component and correlation analyses were performed. The mean score of the CSDD was 7.6 (SD: 6.0), and the mean MADRS score was 9.7 (SD: 6.7). The correlation between the two scales was 0.36 for the whole group, 0.22 in the group with dementia and 0.48 for those without dementia, respectively. Principal component analyses revealed four factors for the CSDD and two factors for the MADRS. Using two different sources of information, we found a poor correlation between the two scales. We suggest that evaluation of depression among memory clinic patients should be done by interviewing both the patient and the caregiver.


Succession of soil bacterial community along a 46-year choronsequence artificial revegetation in an arid oasis-desert ecotone.
How the bacterial community structure and potential metabolic functions will change after revegetation in arid desert ecosystems is still unknown. We used high-throughput pyrosequencing to explore changes in soil bacterial diversity, structure and metabolic pathways, and the key driving factors along a chronosequence of 46-year Haloxylon ammodendron revegetation in an oasis-desert ecotone in the northwestern China. Our results indicated that establishment of H. ammodendron on shifting sand dunes significantly changed the structure of bacterial communities and increased their diversity and richness. The main dominant phyla were Actinobacteria (32.1-41.3%) and Proteobacteria (19.2-27.0%); in that, α-Proteobacteria (16.4-20.7%) were the most abundant Proteobacteria. Kocuria coexisted at different succession stage after year 0, and their relative abundance ranged from 3.8-9.0%. Principal coordinates analysis (PCoA) showed that bacterial community from the same revegetation site grouped together and generally separated from each other, indicating that significant shifts in bacterial community structure occurred after revegetation. LEfSe analysis identified unique biomarkers in the soil samples from seven sites. Moreover, PICRUSt analysis indicated similar overall patterns of metabolic pathways in different succession stage. Redundancy analysis (RDA) showed that total carbon, pH and total phosphorus were major abiotic factors driving the structure of bacterial communities, which explained 57.5% of the variation in bacterial communities. Our findings advance the current understanding of plant-soil interactions in the processes of ecological restoration and desertification reversal.


The Rise of Shop Floor Ergonomics: A Personal Perspective.
OCCUPATIONAL APPLICATIONS Based on a 45-year career as a practitioner in industrial ergonomics, I offer in this paper a personal memoir on how ergonomics came to the shop floor in North America, involving ordinary workers in an early effort to prevent what was at the time an unknown problem - work-related Musculoskeletal Disorders. The actions included the beginning of a low-tech, practical improvement process that is still effective today. In total, the experience can provide encouragement to everybody to be confident in their ability when trying new endeavors and to remember that small initial steps can eventually lead to major change.


Frequency of headache in emergency department patients with anaphylaxis: A cross-sectional study.
Multiple anaphylaxis mediators have been demonstrated to provoke migraine-like attacks following intravascular infusion, suggesting that anaphylaxis could cause headache; however, headache is rarely noted in anaphylaxis and is not included among diagnostic criteria. Our study objectives were to estimate the frequency of headache among prospectively enrolled emergency department (ED) patients with anaphylaxis and assess the association of headache with patient and anaphylaxis characteristics. A cross-sectional study of ED patients aged ≥5 years who met anaphylaxis diagnostic criteria from January 8, 2020 to September 9, 2022 was conducted. The primary outcome of interest was headache frequency among patients who met at least one anaphylaxis criterion. We explored the association of headache with patient characteristics and anaphylaxis characteristics. We included 63 patients with anaphylaxis. In all, 17 (27%, 95% confidence interval [CI] 17%-40%) patients reported the presence of a headache. Female patients had more than a nine times increased odds of having headache (odds ratio [OR] 9.3, 95% CI 1.14-77.1, p = 0.016). Presentation with headache was associated with the presence of dyspnea (OR 5.5, 95% CI 1.56-19.7, p = 0.006). Headache in anaphylaxis may be more common than previously recognized, especially in females. Larger prospective studies are needed to characterize headache as a marker of neurological involvement in anaphylaxis.


Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening.
The dried unripe fruit of Rubus coreanus, which is well-known in Korea and referred to as 'Bok-bun-ja', has been employed as a traditional medicine for centuries. This crude drug is utilized in Korea for the management of impotence, spermatorrhea, enuresis, asthma and allergic diseases. The principal objective of the present study was to conduct a comparison of the antiinflammatory effects of ethanol extracts of the unripe (URCE), half-ripened (HRCE) and ripe fruits (RCE) of Rubus coreanus. URCE and HRCE were found to reduce the production of nitric oxide (NO) and prostaglandin E2 (PGE2) as well as pro-inflammatory cytokines, in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. However, RCE exerted no inhibitory effects against the production of NO and IL-6. The results of the study show that the degree of fruit ripening of Rubus coreanus affects the production of inflammatory mediators such as NO, PGE2 and inflammatory cytokines.


Interdisciplinary Management of Acute Leukemia Across the Continuum of Care.
To describe the interdisciplinary management of acute leukemias across the continuum of care. Literature review and experiential knowledge. Acute leukemia, including acute myelogenous leukemia, acute promyelocytic leukemia, and acute lymphoblastic leukemia, represent a heterogeneous group of hematologic malignancies with complex diagnostic requirements that drive risk-adapted treatment selection. Involvement of clinicians from a variety of specialties and disciplines is required to ensure safe and effective treatment, mitigate adverse events, and maintain or improve quality of life. Patient-centered communication, shared decision-making, and interdisciplinary communication are integral to patient outcomes. Oncology clinicians play a primary role in coordinating the interdisciplinary team and navigating the patient and caregiver experience across the acute leukemia continuum.


Mesulergine (CU32-085) in the treatment of Parkinson's disease.
Twenty patients with Parkinson's disease were treated with the 8-alpha-ergoline derivative mesulergine. Participants were divided into two groups, and over a nine-week period, mesulergine dosage was increased to a maximum of either 10 or 20 mg daily. During this time levodopa-carbidopa (LD-CD) dosage was reduced and treatment was discontinued if possible. The dosage of LD-CD was reduced 75% in the 10 mg group and 74% in the 20 mg group. Patients in the low-dose group maintained their functional status and showed improvement in postural stability. Patients in the high-dose group showed improvement in each of the cardinal signs of parkinsonism. Adverse effects were generally mild and infrequent. Many adverse effects induced by LD-CD diminished or resolved. Our results suggest that mesulergine can be valuable in the management of Parkinson's disease, particularly in those individuals experiencing dose-limiting adverse effects from LD-CD.


Block by phencyclidine of acetylcholine and barium induced adrenal catecholamine secretion.
Activation of the sympathetic system by phencyclidine (PCP) should result in catecholamine release from the adrenals. However, adrenalectomy does not reduce PCP-induced hypertension. In an attempt to rectify this inconsistency, the direct effects of PCP on the bovine adrenal medulla were examined. At (3 X 10(-6) M), PCP reduced the acetylcholine-(ACh)-induced catecholamine release by 50%. Surprisingly, barium-induced secretion of catecholamines was also reduced by PCP. ACh-induced catecholamine release was not altered by 10(-3)M 4-aminopyridine (4 AP), the potassium channel blocker. Thus, calcium antagonist actions of PCP and consequent block of catecholamine secretion from adrenal medulla may explain the lack of effect of adrenalectomy on PCP-induced hypertension. Possible contributions of calcium and/or potassium channel blockade to other manifestations of PCP overdosage are discussed.


Comparing patients who leave the ED prematurely, before vs after medical evaluation: a National Hospital Ambulatory Medical Care Survey analysis.
Many patients leave the Emergency Department (ED) before beginning or completing medical evaluation. Some of these patients may be at higher medical risk depending on their timing of leaving the ED. To compare patient, hospital, and visit characteristics of patients who leave before completing medical care to patients who leave before ED evaluation. Retrospective cross-sectional analysis of ED visits using the 2009-2011 National Hospital Ambulatory Medical Care Survey. A total of 100962 ED visits were documented in the 2009-2011 National Hospital Ambulatory Medical Care Survey, representing a weighted count of 402211907 total ED visits. 2646 (2.62%) resulted in a disposition of left without completing medical care. Of these visits, 1792 (67.7%) left before being seen by a medical provider versus 854 (32.3%) who left after medical provider evaluation but before a final disposition. Patients who left after being assessed by a medical provider were older, had higher acuity visits, were more likely to have visited an ED without nursing triage, arrived more often by ambulance, and were more likely to have private insurance than to be self-paying or to have other payment arrangements (e.g. worker's compensation or charity/no charge). When comparing all patients who left the ED before completion of care, those who left after versus before medical provider evaluation differed in their patient, hospital, and visit characteristics and may represent a high risk patient group.


Can Machine Learning Help Identify Patients at Risk for Recurrent Sexually Transmitted Infections?
A substantial fraction of sexually transmitted infections (STIs) occur in patients who have previously been treated for an STI. We assessed whether routine electronic health record (EHR) data can predict which patients presenting with an incident STI are at greatest risk for additional STIs in the next 1 to 2 years. We used structured EHR data on patients 15 years or older who acquired an incident STI diagnosis in 2008 to 2015 in eastern Massachusetts. We applied machine learning algorithms to model risk of acquiring ≥1 or ≥2 additional STIs diagnoses within 365 or 730 days after the initial diagnosis using more than 180 different EHR variables. We performed sensitivity analysis incorporating state health department surveillance data to assess whether improving the accuracy of identifying STI cases improved algorithm performance. We identified 8723 incident episodes of laboratory-confirmed gonorrhea, chlamydia, or syphilis. Bayesian Additive Regression Trees, the best-performing algorithm of any single method, had a cross-validated area under the receiver operating curve of 0.75. Receiver operating curves for this algorithm showed a poor balance between sensitivity and positive predictive value (PPV). A predictive probability threshold with a sensitivity of 91.5% had a corresponding PPV of 3.9%. A higher threshold with a PPV of 29.5% had a sensitivity of 11.7%. Attempting to improve the classification of patients with and without repeat STIs diagnoses by incorporating health department surveillance data had minimal impact on cross-validated area under the receiver operating curve. Machine algorithms using structured EHR data did not differentiate well between patients with and without repeat STIs diagnosis. Alternative strategies, able to account for sociobehavioral characteristics, could be explored.


Degradation of hemin IX and synthetic hemins to alpha-bilirubins and their conjugates in the isolated perfused rat liver.
Hemin IX was perfused through rat liver of a normal, untreated animal. Its degradation products, collected in the bile fluid over a period of 90 min, were found to consist of the bilirubin IX-alpha diglucuronide (56%), the mixture of bilirubin IX-alpha monoglucuronides (42%), and free bilirubin IX-alpha (2%). When the synthetic hemin XIII 2 was perfused with the same technique, it was found to be degraded in the same way. The bile fluid contained the diglucuronide of bilirubin XIII-alpha 10 (55%), the monoglucuronide of bilirubin XIII-alpha 9 (43%) and the free bilirubin XIII-alpha 8 (2%). Similar results were obtained when the iron 1,4-di(beta-hydroxyethyl)-2,3,5,8-tetramethyl-6,7-di(beta-carboxyethyl) porphyrin 3 was perfused; the diglucuronide of the alpha-bilirubin 11 comprised 65% of the excreted bile bilirubins, the monoglucuronide was 25% of the total and the free alpha-bilirubin 11 10% of the total. Perfusion of hematohemin gave 58% of the diglucuronide of alpha-hematobilirubin, as well as 40% of the monoglucuronides, and 2% of the free alpha-hematobilirubin. The simultaneous perfusion of hematohemin and of hemin IX produced an inhibition of the degradation of the hemin IX, while hematohemin was degraded as described above. It was concluded that the normal rat liver is prepared to dispose of exogenously added hemins by their oxidation to alpha-biliverdins, reduction of the latter to the corresponding alpha-bilirubin and excretion of their conjugated derivatives through the bile duct.


Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.
Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.


An Evaluation of the Factors Related to Internet Gaming Disorder in Young Adults.
Game addiction is a growing problem all over the world. The present study aimed to evaluate the prevalence and psychological, social, and behavioral effects of internet gaming disorder (IGD) on young adults. A preliminary study was conducted and the game types most commonly played on the internet were determined. Then, approximately 60 gaming site managers were contacted. After obtaining consent, the questionnaires were sent to gaming site members and they were asked to complete the questionnaires. Data were collected through a sociodemographic form, Internet Gaming Disorder Scale-Short Form (IGDS9-SF), Strengths and Difficulties Questionnaire (SDQ), and State-Trait Anxiety Inventory (STAI). The study was conducted with 613 participants. The age of the participants ranged from 15 to 30 years, with a mean age of 20.80±4.63 years. The prevalence of IGD was 10% (n=67). Those with low-income families and low academic performance were identified as more likely to develop IGD. Moreover, IGD was revealed to be more likely in individuals with fewer close friends, playing games from an early age, and those with a habit of devoting extensive time to watching online game videos on Twitch or YouTube. In addition, the risk of gaming disorder was approximately two times higher in individuals who preferred First Person Shooter (FPS) games and Massively Multiplayer Online Role-Playing Games (MMORPG). The results of this study could be useful for estimating the level of IGD and carrying out more comprehensive studies to possibly be able to control IGD.


Exploring Social Support for Women Coping with a Cardiac Rehabilitation Programme after Acute Coronary Syndrome: A Systematic Review of Qualitative Studies.
Female sex is a major barrier to completing a programme of cardiac rehabilitation (CR) after acute coronary syndrome (ACS). Women require significant social support to promote compliance and the ability to cope with CR programme attendance. The aim of this systematic review of qualitative studies was to explore social support among women coping with CR programme attendance at phase II CRP is 3 months after their cardiac event. Articles were searched through CINAHL (Cumulative Index and Allied Health Literature), Science Direct and PubMed databases using the following terms: "women", "acute coronary syndrome", "coping", "social support" and "cardiac rehabilitation". A total of 6 articles were selected based on eligibility criteria. Thematic analysis was used to analyse the data using line to line coding into descriptive themes, interpreting further to generate new insights. The 3 most common themes regarding social support for women attending the CR programme were: family support, female as the primary caregiver in the family, and peer support. For most women who perceived themselves as the primary caregiver in the family there was a negative impact on their ability to cope fully with CR programme attendance. On the other hand, encouraging support from family and peers positively improved their coping mechanism for attending the CR programme, leading to improved compliance. Women with ACS consider that support from their family plays a vital role as a coping mechanism in their attendance at a CR programme. Healthcare providers should teach the importance of social support among women after discharge to help them cope with CR programme attendance.


IgM antibodies in sera from patients with chronic active hepatitis reacting with the measles virus matrix protein and nucleoprotein.
The antigenic specificity of measles virus IgM antibodies in sera from patients with chronic active hepatitis not caused by hepatitis B virus has been examined. An immunosorbent column containing antihuman IgM covalently bound to Sepharose was used to pick up IgM from the sera. Radiolabelled measles virus antigens were then allowed to react with the IgM antibodies. The immune complexes were eluted and analysed by sodium dodecyl sulfate [SDS]-polyacrylamide gel electrophoresis. Four sera from patients with hepatitis B surface antigen [HBsAg]-negative chronic active hepatitis with high measles virus haemagglutination inhibition [HI] and complement fixation [CF] antibody titres and positive enzyme-linked immunosorbent assay [ELISA] for measles-virus-specific IgM were examined. The results were compared with those obtained using sera from patients with an acute measles virus infection and from healthy controls. In both patient groups, IgM antibodies with specificity against the matrix protein represented the major portion of the measles virus IgM. IgM antibodies against the measles virus nucleoprotein and probably against host-cell-derived actin were also present. The patient sera contained only traces of IgM antibodies with specificity against the measles virus haemagglutinin or fusion protein. No specific IgM antibodies were found in sera from healthy controls.


Impaired vasodilator function in hypertension: the role of alterations in receptor-G protein coupling.
Defects in vascular relaxation mechanisms may have an important role in the pathogenesis and maintenance of the elevation in peripheral vascular resistance characteristic of the hypertensive state. Receptor systems that mediate vasorelaxation via elevation of vascular smooth muscle intracellular cAMP concentrations appear to be globally impaired. Recent studies have indicated that this defect may be due to alterations in the transmembrane signaling processes that link receptor activation with the stimulation of adenylyl cyclase. Reduced G-protein function has been reported. However, increased activity of a member of a family of enzymes, the G protein-receptor kinases (GRK), which reduces the efficiency of coupling between the receptor and G protein, may be the key factor accounting for impaired receptor-mediated adenylyl cyclase activation and impaired vasodilator function in the hypertensive state.


Epidemiology of alcohol-associated cancers.
Alcohol, especially in combination with smoking, is a well-established risk factor for cancers of the oral cavity and pharynx, esophagus, and larynx, with 25% to 80% of these cancers being attributable to alcohol. Rates of these cancers in the United States have been decreasing in recent years, possibly because of reductions in cigarette smoking and alcohol use. Chronic alcohol consumption has been linked with increased risk of liver cancer in epidemiologic studies. However, the rising rates of this cancer in the United States are most likely due to the increasing prevalence of chronic hepatitis B and C infections. Epidemiologic evidence has linked light to moderate intake of alcohol to cancers of the colorectum and female breast. These cancers are common in developed countries, so even small increases in risk can have important public health implications. Although results of most epidemiologic studies have provided little or no support for a causal relation between light and moderate alcohol use and risk of pancreatic cancer, a possible role of heavy alcohol consumption cannot be ruled out. Further studies of these cancers are needed to clarify the role of type of alcoholic beverage, the role of alcohol concentration, and the dose-response curve at low concentrations of alcohol. Future research also should be designed to promote the use of uniform ways to report alcohol intake and uniform measures for analysis, to include the investigation of alcohol-associated cancer risks in U.S. minority populations, to enhance experimental work to better understand the underlying mechanisms through which alcohol promotes carcinogenesis, and to develop preventive strategies.


Potentials of curcumin against polycystic ovary syndrome: Pharmacological insights and therapeutic promises.
Polycystic ovary syndrome (PCOS) is a common hormonal disorder among women (4%-20%) when the ovaries create abnormally high levels of androgens, the male sex hormones that are typically present in women in trace amounts. The primary characteristics of PCOS include oxidative stress, inflammation, hyperglycemia, hyperlipidemia, hyperandrogenism, and insulin resistance. Generally, metformin, spironolactone, eflornithine and oral contraceptives are used to treat PCOS, despite their several side effects. Therefore, finding a potential candidate for treating PCOS is necessary. Curcumin is a major active natural polyphenolic compound derived from turmeric (Curcuma longa). A substantial number of studies have shown that curcumin has anti-inflammatory, anti-oxidative stress, antibacterial, and anti-apoptotic activities. In addition, curcumin reduces hyperglycemia, hyperlipidemia, hyperandrogenism, and insulin resistance in various conditions, including PCOS. The review highlighted the therapeutic aspects of curcumin against the pathophysiology of PCOS. We also offer a hypothesis to improve the development of medicines based on curcumin against PCOS.


The information system of REIN
On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of its information system, the following key messages were retained. The REIN information system accompanies the register throughout the life cycle of the data. Two collection tools, one for dialysis, the other for transplantation are accessible via a secure WEB site. Several data quality control tools have been added. Finally, several reporting tools, including a geographic information system completes REIN's information system.


Role of spinal NO in antiallodynic effect of intrathecal clonidine in neuropathic rats.
The role of spinal nitric oxide (NO) in neuropathic pain remains uncertain. Although intrathecal clonidine causes NO release in the spinal cord, the functional role of spinal NO in clonidine-produced analgesia has not been examined. The objectives of this study were to assess the role of spinal NO in maintenance of allodynia and to determine the role of spinal NO in the antiallodynic effect of intrathecal clonidine. Allodynia was produced in rats by tight ligation of the left L5-L6 spinal nerves. Intrathecal catheters were inserted with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the left hindpaw. In the first series of experiments, allodynia was assessed before and after intrathecal injection of saline, L-arginine, an NO donor (SNAP), two NO synthase inhibitors (TRIM and NMMA), or an NO scavenger (PTIO). In the second series of experiments, 20 microg of clonidine was injected intrathecally 15 min after intrathecal injection of saline, TRIM, NMMA, or PTIO. Allodynia was not affected significantly by intrathecal injection of L-arginine, SNAP, TRIM, NMMA, or PTIO. The antiallodynic effect produced by intrathecal injection of clonidine was attenuated significantly by pretreatment with TRIM, NMMA, or PTIO. These results demonstrate that spinal NO neither contributes significantly to maintenance of allodynia nor produces detectable antiallodynic effect in this neuropathic pain model. Furthermore, this study provides functional evidence that spinal NO plays an important role in the antiallodynic effect of intrathecal clonidine in neuropathic pain.


A case report of comminuted trapezium fracture with surgical treatment.
Comminuted trapezium fracture is very rare. As the trapezium is necessary for thumb movements, delayed diagnosis and treatment can result in thumb carpometacarpal (CM) joint osteoarthritis and restricted mobility. The K-wire or screw fixation is recommended for repairing displaced fractures. However, there is currently no established treatment protocol for this rare fracture. In trapezium fracture, a technique with K-wire fixation in addition to open reduction and internal fixation (ORIF) has been reported with favorable clinical outcomes. In this report, we present a case of comminuted trapezium fracture successfully treated with surgery. The present case involved a 26-year-old woman who was injured while driving her car, which led to a comminuted trapezium fracture. ORIF was conducted with headless screws and a locking plate, and the first and second metacarpals were temporarily fixed by K-wire with the thumb in traction. Six months after surgery, bony union and favorable clinical outcomes were achieved. This technique could be beneficial to prevent articular surface collapse in the comminuted trapezium fracture and to achieve favorable clinical outcomes.


Evolution of the p53-MDM2 pathway.
The p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published. Here, we have examined the evolution of the p53/p63/p73 protein family with particular focus on the p53/p63/p73 transactivation domain (TAD) and its co-evolution with the p53/p63/p73-binding domain (p53/p63/p73BD) of MDM2. We found that the TAD and p53/p63/p73BD share a strong evolutionary connection. If one of the domains of the protein is lost in a phylum, then it seems very likely to be followed by loss of function by the other domain as well, and due to the loss of function it is likely to eventually disappear. By focusing our phylogenetic analysis to p53/p63/p73 and MDM proteins from phyla that retain the interaction domains TAD and p53/p63/p73BD, we built phylogenetic trees of p53/p63/p73 and MDM based on both vertebrate and invertebrate species. The trees follow species evolution and contain a total number of 183 and 98 species for p53/p63/p73 and MDM, respectively. We also demonstrate that the p53/p63/p73 and MDM families result from whole genome duplications. The signaling pathway of the TAD and p53/p63/p73BD in p53/p63/p73 and MDM, respectively, dates back to early metazoan time and has since then tightly co-evolved, or disappeared in distinct lineages.


Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup.
Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor is not easily identified using conventional imaging techniques because of small primary tumor sizes. In this setting (which is referred to as a "NEN of unknown primary"; NEN-UP), a tissue biopsy is often procured to allow the surgical pathologist to diagnose the metastatic lesion. If indeed a metastatic NEN-UP is found, several clues can be obtained from morphological assessment and immunohistochemical staining patterns that individually or in concert may help identify the primary tumor site. Herein, histological and auxiliary analyses of value in this context are discussed in order to aid the pathologist when encountering these lesions in clinical practice.


Photochemical synthesis and properties of 1,6- and 1,8-naphthalenophanes.
Various 1,6- and 1,8-naphthalenophanes were synthesized by using the Photo-Dehydro-Diels-Alder (PDDA) reaction of bis-ynones. These compounds are easily accessible from ω-(3-iodophenyl)carboxylic acids in three steps. The obtained naphthalenophanes are axially chiral and the activation barrier for the atropisomerization could be determined in some cases by means of dynamic NMR (DNMR) and/or dynamic HPLC (DHPLC) experiments.


Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells.
Glucocorticoid-induced apoptosis is exploited clinically for the treatment of hematologic malignancies. Determining the required molecular events for glucocorticoid-induced apoptosis will identify resistance mechanisms and suggest strategies for overcoming resistance. In this study, we found that glucocorticoid treatment of WEHI7.2 murine thymic lymphoma cells increased the steady-state [H(2)O(2)] and oxidized the intracellular redox environment before cytochrome c release. Removal of glucocorticoids after the H(2)O(2) increase resulted in a 30% clonogenicity; treatment with PEG-CAT increased clonogenicity to 65%. Human leukemia cell lines also showed increased H(2)O(2) in response to glucocorticoids and attenuated apoptosis after PEG-CAT treatment. WEHI7.2 cells that overexpress catalase (CAT2, CAT38) or were selected for resistance to H(2)O(2) (200R) removed enough of the H(2)O(2) generated by glucocorticoids to prevent oxidation of the intracellular redox environment. CAT2, CAT38, and 200R cells showed a 90-100% clonogenicity. The resistant cells maintained pERK survival signaling in response to glucocorticoids, whereas the sensitive cells did not. Treating the resistant cells with a MEK inhibitor sensitized them to glucocorticoids. These data indicate that: (1) an increase in H(2)O(2) is necessary for glucocorticoid-induced apoptosis in lymphoid cells, (2) increased H(2)O(2) removal causes glucocorticoid resistance, and (3) MEK inhibition can sensitize oxidative stress-resistant cells to glucocorticoids.


Molecular characterization of breast cancer CTCs associated with brain metastasis.
The enumeration of EpCAM-positive circulating tumor cells (CTCs) has allowed estimation of overall metastatic burden in breast cancer patients. However, a thorough understanding of CTCs associated with breast cancer brain metastasis (BCBM) is necessary for early identification and evaluation of treatment response to BCBM. Here we report that BCBM CTCs is enriched in a distinct sub-population of cells identifiable by their biomarker expression and mutational content. Deriving from a comprehensive analysis of CTC transcriptomes, we discovered a unique "circulating tumor cell gene signature" that is distinct from primary breast cancer tissues. Further dissection of the circulating tumor cell gene signature identified signaling pathways associated with BCBM CTCs that may have roles in potentiating BCBM. This study proposes CTC biomarkers and signaling pathways implicated in BCBM that may be used either as a screening tool for brain micro-metastasis detection or for making rational treatment decisions and monitoring therapeutic response in patients with BCBM.Characterization of CTCs derived from breast cancer patients with brain metastasis (BCBM) may allow for early diagnosis of brain metastasis and/or help for treatment choice and its efficacy. In this study, the authors identify a unique signature, based on patient-derived CTCs transcriptomes, for BCBM- CTCs that is different from primary tumors.


Flexor Tendon Repair: Healing, Biomechanics, and Suture Configurations.
Successful outcome after flexor tendon repair requires a delicate balance between tendon healing and limiting scar tissue formation. Recent studies have highlighted the importance of the number of core sutures crossing the repair and the benefits of specific suture configurations in determining the strength of tendon repair. Researchers have attempted to augment the biological environment to improve the speed and strength of tendon repair.


A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ1-40 fibrils with cholesterol-mixed DPPC bilayers.
Alzheimer's disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Although multiple experimental studies have suggested that Aβ oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 μs-long simulations to investigate the interaction between trimeric or hexameric Aβ1-40 fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50% cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous Aβ1-40 fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the Aβ1-40 fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help Aβ1-40 fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against Aβ oligomer/fibril-membrane interaction.


Rapid on-site evaluation of EBUS-TBNA specimens of lymph nodes: Comparative analysis and recommendations for standardization.
There is no widely accepted rapid on-site evaluation (ROSE) reporting system for endobronchial ultrasound-guided transbronchial needle aspiration. At the University of Arkansas for Medical Sciences, ROSE reporting was unstructured. The goal was to evaluate, compare, and improve upon 2 structured approaches proposed in the literature. One hundred eighteen consecutive nodal aspirates were retrospectively reviewed by a pathology resident and a staff cytopathologist, both of whom were blinded to the original unstructured readings. Each reviewer interpreted every specimen with 2 different structured criteria proposed in the literature: criteria from the University of Minnesota (the Minnesota [MN] criteria) and criteria from the North Shore Long Island Jewish Health System (the New York [NY] criteria). The data allowed a comparison of the original unstructured ROSE system with the MN and NY scoring schemes and the final diagnosis. Original on-site adequacy (OSA) had been assessed at 96%. Three cases were false-adequate according to the original unstructured approach; these had been called adequate on site, but a subsequent slide review including cell blocks did not show definite nodal tissue. OSA dropped to 86% with the MN criteria and to 85% with the NY criteria. No false-adequate on-site diagnoses would have been rendered with the application of either structured criteria. There were no significant differences between the MN and NY criteria with respect to the determination of OSA. An assessment of ease of application favored the NY criteria. With respect to diagnostic categories, each of the systems (MN and NY) was felt to have a category of value not used by the other system. A standardized intra- and inter-institutional system for ROSE reporting is needed. On the basis of comparative analyses and consensus, modifications to prior criteria have been proposed in the hope of approaching this goal.


Screening women and elderly adults for family and intimate partner violence: a review of the evidence for the U. S. Preventive Services Task Force.
Family and intimate partner violence is common in the United States and is often associated with acute and chronic health problems. Although the clinician's role in identification and intervention is considered a professional, ethical, and sometimes legal responsibility, the effectiveness of screening is uncertain. To examine evidence on the benefits and harms of screening women and elderly adults in health care settings for family and intimate partner violence. MEDLINE, PsycINFO, CINAHL, Health & Psychosocial Instruments, AARP Ageline, Cochrane Controlled Trials Register, reference lists, and experts. The authors selected English-language studies that included original data focusing on the performance of screening instruments (14 studies for women, 3 for elderly persons) and the effectiveness of interventions based in health care settings (2 studies for women, none for elderly persons). Study design, patient samples and settings, methods of assessment or intervention, and outcome measures were extracted, and a set of criteria was applied to evaluate study quality. No trials of the effectiveness of screening in a health care setting for reducing harm have been published. Several screening instruments have been developed; some have demonstrated fair to good internal consistency and some have been validated with longer instruments, but none have been evaluated against measurable violence or health outcomes. Few intervention studies have been conducted. Existing intervention studies focused on pregnant women, and study limitations restrict their interpretation. Although the literature on family and intimate partner violence is extensive, few studies provide data on detection and management to guide clinicians.


Simplification to monotherapy with lopinavir/ritonavir in adolescents with vertically acquired HIV-1 infection.
In recent years, the use of boosted protease inhibitors monotherapy has become increasingly important, especially considering the advantages in terms of costs, tolerability, and simplification. Despite that, knowledge about the efficacy and safety of this approach in HIV-1-infected adolescents who have acquired HIV-1 infection through perinatal transmission is still limited. We report here our experience with two adolescents who have been successfully treated with lopinavir/ritonavir monotherapy.