Fermentation of biodiesel-derived crude glycerol to 1,3-propanediol with bio-wastes as support matrices: Polynomial prediction model.
Biodiesel production from used cooking oil is sustainable alternative, for bio-energy production. The process generates residual crude glycerol (RCG) as the major energy-rich waste which can be used to produce various bio-based chemicals like 1,3-propanediol (1,3-PDO) through biotechnological interventions. This RCG contains several impurities like methanol, soap, organic materials, salts non-transesterified fatty acids and metals in varied concentrations. These impurities significantly affect yield and productivity of the bio-process due to their marked microbial toxicity. In this work, previously isolated Clostridium butyricum L4 was immobilized on various abundantly available cheap bio-wastes (like rice straw, activated carbon and corn cob) to explore advantages offered and improve tolerance to various feed impurities. Amongst these, shredded rice straw was found most suitable candidate for immobilization and results in maximum improvement in 1,3-PDO production (18.4%) with highest porosity (89.28%), lowest bulk density (194.48Kg/m3), and highest cellular biofilm density (CFU/g-8.4 ×1010) amongst the three matrices. For practical purposes, recyclability was evaluated and it was concluded that even after reusing for five successive cycles the production retained to ∼82.4%. Subsequently, polynomial model was developed using 30 runs central composite factorial design experiments having coefficient of regression (R²) as 0.9520, in order to predict yields under different immobilization conditions for 1,3-PDO production. Plackett-Burman was employed (Accuracy= 99.17%) to screen significant toxic impurities. Based on statistical analysis six impurities were found to be significantly influential on PDO production in adverse manner. With negative coefficient of estimate (COE) varying in decreasing order: Linoleic acid >Oleic acid >Stearic acid >NaCl>K2SO4 >KCl. The study illustrates practical application for repurposing waste glycerol generated from biodiesel plants, thus developing improved agnostic process along with yield production models.


Stress-induced vascular damage and ulcer.
Factors controlling gastric mucosal blood flow are now better understood, and improved techniques have been established to study microcirculation in the gastrointestinal tract. In this paper, four areas are reviewed: gross and microscopic vessels that supply blood to the stomach; factors that control gastrointestinal blood flow; pathogenic role of disturbed mucosal blood flow circulation induced by stress; and findings in early vascular permeability and injury caused by cold restraint stress in the rat.


Patient-Reported Outcomes and the Patient-Reported Outcome Measurement Information System of Functional Medicine Care and Research.
The functional medicine model of care is focused on patient-centered rather than disease-centered care. Patient-centered care incorporates the patient's voice or experience of their condition alongside conventional biological factors to provide a "more complete" account of health. PROMIS Global, an NIH-validated patient-reported outcome (PRO) measure that evaluates the health-related quality of life, can be incorporated within the functional medicine model of care to evaluate self-reported physical, mental and social well-being across various conditions and guide personalized management strategies. Proper incorporation of PROMIS Global into clinical care and research is warranted to expand the available evidence base.


Prostacyclin (epoprostenol) induces headache in healthy subjects.
The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I(2), (PGI(2))) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI(2) might induce headache and vasodilatation of cranial vessels. A stable analog of PGI(2) epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V(mean MCA)) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI(2) day and no subjects reported headache on the placebo day (p=0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p=0.005). PGI(2) caused headache associated with the dilatation of STA (AUC, p<0.001), but no significant dilatation of the MCA (AUC, p=0.508). These data indicate that PGI(2) induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.


[Formation of sub-units of antihaemophilic globulin (factor VIII) by means of high centrifugal force (author's transl)].
The human coagulation factor VIII with a molecular weight greater than 1 X 10(6) Daltons forms active subunits under conditions of high centrifugal force, namely, 200.000 g at 20 degrees C for 32 minutes, as demonstrated by sedimentation analysis. This result was confirmed by Sepharose 4 B gel filtration analysis of the ultracentrifuged product, which revealed, in additon to mateial with a molecular weight of more than 1 X 10(6) Daltons, three F VIII-active fractions with smaller molecular weight values. These observations indicate that these sub-units so produced are not united in the starting matrial by covalent bonds.


[Antigens associated with herpes simplex viruses in human and animal tumors].
The paper deals with the mechanism of emergence of early virus-induced antigens in animal tumors and their association with carcinogenesis. Problems of the specificity of the antigens of tumors induced by herpes simplex virus in different animal species and their immunogenicity for the tumor carriers are discussed.


From the Cajal alumni Achúcarro and Río-Hortega to the rediscovery of never-resting microglia.
Under the guidance of Ramón y Cajal, a plethora of students flourished and began to apply his silver impregnation methods to study brain cells other than neurons: the neuroglia. In the first decades of the twentieth century, Nicolás Achúcarro was one of the first researchers to visualize the brain cells with phagocytic capacity that we know today as microglia. Later, his pupil Pío del Río-Hortega developed modifications of Achúcarro's methods and was able to specifically observe the fine morphological intricacies of microglia. These findings contradicted Cajal's own views on cells that he thought belonged to the same class as oligodendroglia (the so called "third element" of the nervous system), leading to a long-standing discussion. It was only in 1924 that Río-Hortega's observations prevailed worldwide, thus recognizing microglia as a unique cell type. This late landing in the Neuroscience arena still has repercussions in the twenty first century, as microglia remain one of the least understood cell populations of the healthy brain. For decades, microglia in normal, physiological conditions in the adult brain were considered to be merely "resting," and their contribution as "activated" cells to the neuroinflammatory response in pathological conditions mostly detrimental. It was not until microglia were imaged in real time in the intact brain using two-photon in vivo imaging that the extreme motility of their fine processes was revealed. These findings led to a conceptual revolution in the field: "resting" microglia are constantly surveying the brain parenchyma in normal physiological conditions. Today, following Cajal's school of thought, structural and functional investigations of microglial morphology, dynamics, and relationships with neurons and other glial cells are experiencing a renaissance and we stand at the brink of discovering new roles for these unique immune cells in the healthy brain, an essential step to understand their causal relationship to diseases.


Delta-6-desaturase gene polymorphism is associated with lipoprotein oxidation in vitro.
Oxidative modification of low-density lipoprotein (LDL) is a key event in the oxidation hypothesis of atherogenesis. We have previously shown that HDL does not protect LDL from oxidation in vitro, but is in fact oxidized fastest of all lipoproteins due to its rich polyunsaturated fatty acid (PUFA) composition, which is oxidation promoting. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA status. There is a deletion [T/-] in the promoter region of the Δ6 -desaturase gene (FADS2, rs 3834458), which has a direct inhibitory influence on production of PUFA from linoleic and alpha-linolenic acid. To investigate the possible role of rs 3834458 in lipoprotein modification, oxidation of LDL with HDL₂ or HDL₃ were analyzed from plasma of 58 free-living individuals. Total eicosapentaenoic acid and arachidonic acid were significantly decreased in plasma from the 10 subjects homozygous for the deletion in FADS2 rs 3834458. When the isolated LDL and HDL₂ were subjected to Cu²⁺-induced oxidation, these subjects showed decreased rate of appearance (p = 0.027) and the final concentration of conjugated dienes (p = 0.033) compared to the other genotypes. For oxidation of LDL with HDL₃, the final concentration of conjugated dienes was also significantly decreased in subjects with [-/-] compared with [T/T] and [T/-] (p = 0.034). We conclude that FADS2 genotype may play a role in peroxidation susceptibility of lipoproteins.


Classification of Heart Failure Events by Severity: Insights From the VICTORIA Trial.
Hospitalization due to heart failure (HFH) is a major source of morbidity, consumes significant economic resources and is a key endpoint in HF clinical trials. HFH events vary in severity and implications, but they are typically considered equivalent when analyzing clinical trial outcomes. We aimed to evaluate the frequency and severity of HF events, assess treatment effects and describe differences in outcomes by type of HF event in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). VICTORIA compared vericiguat with placebo in patients with HF with reduced ejection fraction (< 45%) and a recent worsening HF event. All HFHs were prospectively adjudicated by an independent clinical events committee (CEC) whose members were blinded to treatment assignment. We evaluated the frequency and clinical impact of HF events by severity, categorized by highest intensity of HF treatment (urgent outpatient visit or hospitalization treated with oral diuretics, intravenous diuretics, intravenous vasodilators, intravenous inotropes, or mechanical support) and treatment effect by event categories. In VICTORIA, 2948 HF events occurred in 5050 enrolled patients. Overall total CEC HF events for vericiguat vs placebo were 43.9 vs 49.1 events/100 patient-years (P = 0.01). Hospitalization for intravenous diuretics was the most common type of HFH event (54%). HF event types differed markedly in their clinical implications for both in-hospital and post-discharge events. We observed no difference in the distribution of HF events between randomized treatment groups (P = 0.78). HF events in large global trials vary significantly in severity and clinical implications, which may have implications for more nuanced trial design and interpretation. ClinicalTrials.gov (NCT02861534).


Influence of Patient-Centered Decision Making on Sustained Weight Loss and Risk Reduction Following Lifestyle Intervention Efforts in Rural Pennsylvania.
The purpose of this study was to determine whether weight loss and cardiovascular disease risk factor reduction was maintained following a lifestyle intervention. Five hundred fifty-five individuals without diabetes from 8 rural communities were screened for BMI ≥25 kg/m(2) and abdominal obesity (86.1% female, 95.1% white, 55.8% obese). Communities and eligible participants (n = 493; mean age, 51 years, 87.6% female, 94.1% Caucasian) were assigned to 4 study groups: face-to-face, DVD, Internet, and self-selection (SS) (n = 101). Self-selection participants chose the intervention modality (60% face-to-face, 40% Internet, 0% DVD). Outcomes included weight change and risk factor reduction at 18 months. All groups achieved maintenance of 5% weight loss in over half of participants. Self-selection participants had the largest proportion maintain (89.5%). Similarly, nearly 75% of participants sustained risk factor reduction. After multivariate adjustment, participants in SS were 2.3 times more likely to maintain 5% weight loss compared to the other groups, but not risk factor reduction. Despite the modality, lifestyle intervention was effective at maintaining weight loss and risk reduction. However, SS participants were twice as likely to sustain improvements compared to other groups. The importance of patient-centered decision making in health care is paramount.


Effects of triiodothyronine on the anemia of chronic renal failure.
The present study was done in order to determine whether treatment with triiodothyronine (T3) would improve the anemia of chronic renal insufficiency. Four patients with stable renal failure and anemia were treated with 75 microgram/day of T3 for a period of four weeks. The patients were not in chronic dialysis, had normochromic normocytic anemia and hypocellular bone marrow, and showed no evidence of external blood loss during the study. They had received no iron, folic acid, or androgenic steroids for at least six months prior to the study. The administered dose of T3 was adequate to depress the serum levels of thyroid-stimulating hormone (TSH); however, there was no detectable improvement in the levels of hemoglobin, hematocrit, bone marrow cellularity, serum and erythrocyte folate determinations, serum iron (Fe), 59Fe half-life, plasma iron turnover rate, percentage Fe incorporated into red blood cells, or in the ratio of surface radioactive counting over bone marrow/liver and spleen. It is concluded that the experimental observations concerning direct bone marrow stimulation by T3 in anephric rats are probably not clinically applicable for the treatment of the anemia associated with uremia.


Effect of larval crowding on mating competitiveness of Anopheles gambiae mosquitoes.
The success of sterile or transgenic Anopheles for malaria control depends on their mating competitiveness within wild populations. Current evidence suggests that transgenic mosquitoes have reduced fitness. One means of compensating for this fitness deficit would be to identify environmental conditions that increase their mating competitiveness, and incorporate them into laboratory rearing regimes. Anopheles gambiae larvae were allocated to three crowding treatments with the same food input per larva. Emerged males were competed against one another for access to females, and their corresponding longevity and energetic reserves measured. Males from the low-crowding treatment were much more likely to acquire the first mating. They won the first female approximately 11 times more often than those from the high-crowding treatment (Odds ratio = 11.17) and four times more often than those from the medium-crowding treatment (Odds ratio = 3.51). However, there was no overall difference in the total number of matings acquired by males from different treatments (p = 0.08). The survival of males from the low crowding treatment was lower than those from other treatments. The body size and teneral reserves of adult males did not differ between crowding treatments, but larger males were more likely to acquire mates than small individuals. Larval crowding and body size have strong, independent effects on the mating competitiveness of adult male An. gambiae. Thus manipulation of larval crowding during mass rearing could provide a simple technique for boosting the competitiveness of sterile or transgenic male mosquitoes prior to release.


Gold-catalyzed highly regioselective oxidation of C-C triple bonds without acid additives: propargyl moieties as masked α,β-unsaturated carbonyls.
Gold-catalyzed intermolecular oxidations of internal alkynes have been achieved with high regioselectivities using 8-alkylquinoline N-oxides as oxidants and in the absence of acid additives. Synthetically versatile α,β-unsaturated carbonyls are obtained in good to excellent yields and with excellent E-selectivities. A range of functional groups such as THP, MOMO, N(3), OTBS, and N-Boc are tolerated. This reaction allows α,β-unsaturated carbonyls to be masked as propargyl moieties, thus offering a practical solution to compatibility issues with these functional groups likely encountered in syntheses of complex structures.


Mebudipine and dibudipine protect PC12 cells against oxygen-glucose deprivation and glutamate-induced cell death.
The protective effect of two new L-type calcium-channel blockers, mebudipine and dibudipine on neurotoxic effects induced by glutamate and oxygen-glucose deprivation (OGD) in PC12 cells was investigated. PC12 cells were intoxicated with two different methods. First, the cells were incubated with glutamate (10muM/L), glutamate and mebudipine (10muM/L), dibudipine (10muM/L) or nimodipine (10muM/L), on three different treatment schedules (concurrently, pre-3h and pre-24h). In the second method PC12 cells were exposed to in vitro oxygen-glucose deprivation for 30min and 60min alone or with the drugs in the same time schedules described above. Cellular viability was assessed by MTT assay. Glutamate-induced cell death and OGD-induced cell injury were attenuated significantly by mebudipine, dibudipine in comparison with nimodipine in all three different treatment schedules. Application of MK801 (10muM/L), an antagonist of NMDA glutamate receptors inhibited PC12 cell death in both methods. Our study suggests that mebudipine and dibudipine, like nimodipine, may have protective effects against glutamate and oxygen-glucose deprivation-induced neurotoxicity.


Nuclear transport surveillance of p53 by nuclear pores in glioblastoma.
Nuclear pore complexes (NPCs) are the central apparatus of nucleocytoplasmic transport. Disease-specific alterations of NPCs contribute to the pathogenesis of many cancers; however, the roles of NPCs in glioblastoma (GBM) are unknown. In this study, we report genomic amplification of NUP107, a component of NPCs, in GBM and show that NUP107 is overexpressed simultaneously with MDM2, a critical E3 ligase that mediates p53 degradation. Depletion of NUP107 inhibits the growth of GBM cell lines through p53 protein stabilization. Mechanistically, NPCs establish a p53 degradation platform via an export pathway coupled with 26S proteasome tethering. NUP107 is the keystone for NPC assembly; the loss of NUP107 affects the integrity of the NPC structure, and thus the proportion of 26S proteasome in the vicinity of nuclear pores significantly decreases. Together, our findings establish roles of NPCs in transport surveillance and provide insights into p53 inactivation in GBM.


[Persistent subjective cognitive decline in middle age: diagnosis and treatment].
A 47-year-old highly educated man without psychiatric history was referred for psychiatric evaluation because of persistent subjective cognitive decline after repeated and extensive diagnostic evaluation in an outpatient memory clinic. The patient developed increasing preoccupation and anxiety with memory complaints and concerns, despite repetitive negative findings from clinical investigations. This clinical case is coined as 'neurocognitive hypochondria', a syndrome interfacing with cogniform and illness anxiety disorders, in which obsessions and concerns about progression of unexplained memory deficits are indicated for specialized treatment. This case study provides more insight into differential diagnosis, classification according to the current DSM-5 criteria and discussion on potential treatment approaches.


Deep learning-based identification of sinoatrial node-like pacemaker cells from SHOX2/HCN4 double-positive cells differentiated from human iPS cells.
Cardiomyocytes derived from human iPS cells (hiPSCs) include cells showing SAN- and non-SAN-type spontaneous APs. To examine whether the deep learning technology could identify hiPSC-derived SAN-like cells showing SAN-type-APs by their shape. We acquired phase-contrast images for hiPSC-derived SHOX2/HCN4 double-positive SAN-like and non-SAN-like cells and made a VGG16-based CNN model to classify an input image as SAN-like or non-SAN-like cell, compared to human discriminability. All parameter values such as accuracy, recall, specificity, and precision obtained from the trained CNN model were higher than those of human classification. Deep learning technology could identify hiPSC-derived SAN-like cells with considerable accuracy.


Membrane lipid composition, fluidity, and surface charge changes in response to growth of the fresh water cyanobacterium Synechococcus 6311 under high salinity.
The effect of adaptation to saline growth of a fresh water cyanobacterium Synechococcus 6311 on components of the cytoplasmic membranes and thylakoids was investigated. Significant changes in membrane surface charge, lipid, fatty acid, and carotenoid composition were observed upon transfer of the cells from a low salt (0.015 M NaCl) to a high salt (0.50 M NaCl) growth medium. Very similar changes in the polar lipid classes and fatty acid composition were observed in both membranes, but changes in fluidity and surface charge and a significant shift in the protein to lipid ratio were only apparent in the cytoplasmic membranes. The fluidity and surface charge data correlate well with functional studies and we can attribute the cytoplasmic membrane as the major site of interaction and adaptation to the saline environment.


Rosiglitazone-induced granulomatous hepatitis.
Granulomatous hepatitis has many causes. Drugs are an important etiologic factor. Several oral hypoglycemic agents are available for treatment of type II diabetes. Rosiglitazone, a thiazolidinedione, is a newer agent in this class. It has not been shown to be hepatotoxic in the premarketing trials. However, a few case reports have implicated it as a cause of acute hepatocellular injury. The authors report a case of granulomatous hepatitis associated with use of rosiglitazone. Liver function tests should be done regularly to monitor patients on this medication.


Two endoscopic submucosal dissection procedures for stripping huge segment of the gastric mucosa to treat early gastric signet ring cell carcinoma.
To introduce the method of stripping of early gastric signet ring cell carcinioma by two ESD procedures. A lesion of early gastric signet ring cell carcinoma in an elderly was removed by two consecutive ESD procedures. The pathology was analyzed and the patient was followed-up. The lesion removed by first ESD procedure, which was 10 cm in diameter, has tumor tissue on its edge, and the second lesion which was 5 cm in diameter had an edge without tumor. There was no metastasis or recurrence during 24-month follow-up. We first described the method using two consecutive ESD procedures in man with gastric signet ring cell carcinoma, and the procedure was proved to be safe and efficient.


Caprin-1 is a novel microRNA-223 target for regulating the proliferation and invasion of human breast cancer cells.
MicroRNAs (miRNAs) are 21-22 nucleotides regulatory small non-coding RNAs that inhibit gene expression by binding to complementary sequences especially the 3' untranslated region (3'UTR) of mRNA. One miRNA can target many messenger RNAs, leading to a complex metabolic network. Previous studies have shown that miRNA-223 regulates migration and invasion of tumor cells and targets cytoplasmic activation/proliferation-associated protein-1 (Caprin-1). In the present study, we detected the expression of miRNA-223 and Caprin-1 in MCF-7, T-47D and MDA-MB-231 cancer cell lines, and MCF-10A normal breast cell line, and analyzed the role of miRNA-223 in Caprin-1-induced proliferation and invasion of human breast cancer cells. We found that miRNA-223 expression levels are significantly lower in MCF-7, T-47D and MDA-MB-231 cancer cells than in MCF-10A normal breast cells, while Caprin-1 expression is higher in cancer cells than in normal breast cells. The most malignant cancer cell line MDA-MB-231 has the lowest expression of miR-223, but the highest expression of Caprin-1. Further, we found that miR-223 targets the 3'UTR of Caprin-1 miRNA and down-regulates the expression of Caprin-1. We also found that over-expression of Caprin-1 can promote the proliferation and the invasion of breast cancer cells, but miRNA-223 can inhibit the proliferation and the invasion. miRNA-223-induced inhibition can be reversed by ectopic over-expression of Caprin-1. These findings suggest that miR-223 may suppress the proliferation and invasion of cancer cells by directly targeting Caprin-1. Our study also indicates that expression levels of miR-223 and Caprin-1 can be used to predict the state of cancer in breast cancer patient.


Signet ring cell gastric schwannoma: report of a new distinctive morphological variant.
An 89-year-old woman was seen for indigestion, light chest pain, and melanotic stools. Endoscopic examination revealed 2 submucosal gastric masses. A subtotal gastrectomy showed 2 submucosal masses in the stomach: one infiltrating through the muscularis propria into the serosa, the second one, a well-circumscribed submucosal nodule. Histologic examination showed large tumor cells infiltrating diffusely through the muscularis propria into the subserosa. On higher magnification, numerous signet ring cells were present against a myxoid stroma, in addition to large vacuolated epithelioid cells. There was no evidence of invasion, necrosis, nuclear pleomorphism, or mitotic activity. Initial diagnostic considerations based on the histology included signet ring cell carcinoma, malignant melanoma, and a myxoid mesenchymal tumor, including gastrointestinal stromal tumor. A panel of immunohistochemical stains showed diffuse strong positivity for S-100 protein and negative reaction for CD117, bcl-2, cytokeratin AE1/AE3, Melan-A, HMB45, smooth muscle antigen, and other differentiation markers. Electron microscopic examination revealed elongated, complex, and interdigitating cell processes covered by a thin layer of continuous basement membrane material characteristic of peripheral nerve sheath differentiation. The presentation of this tumor was significant in that it was multifocal and infiltrative, mimicking a malignant neoplasm. The extensive myxoid/signet ring cell change represents a heretofore-unreported histologic variant of gastric schwannoma.


A new 9-methoxyyohimbine-type indole alkaloid from Mitragyna africanus.
A new yohimbine-type indole alkaloid (1). was isolated from the stem bark of Mitragyna africanus (WILLD.) collected in Nigeria, along with known seven Corynanthe-type oxindole alkaloids, two secoiridoids, three lignans, and a quinovic acid derivative. Their structures were elucidated by spectroscopic analyses.


Intraoperative assessment of myocardial revascularisation for the relief of ischaemia using monophasic action potential recordings.
We have been concerned with developing a method of assessing regional myocardial perfusion which is simple, quick and without hazard to the patient. Monophasic action potential (MAP) recordings provide a highly sensitive measure of localised myocardial ischaemia. We have developed a hand-held pressure contact silver/silver chloride electrode for recording MAP signals from the left ventricular epicardium. The design enables it to slide within the pericardium on the left ventricle/epicardium with minimal displacement of the heart. Three protocols were adopted providing different permutations of atrial pacing and graft occlusion. Protocol 1: after discontinuing bypass, atrial pacing was established. After 90 s, all grafts were occluded for a period of 90 s. Protocol 2: after discontinuing bypass, all grafts were occluded for 90 s in the absence of pacing. Protocol 3: atrial pacing was established for 60 s before grafting and bypass and repeated subsequent to grafting and discontinuing bypass. Our results show that the most promising method is protocol 3. The most important results were that when heart rate is taken into account, the ischaemic changes in the MAP were significantly less impressive (P less than 0.05) following grafting. With further refinement, this technique may be applicable to the assessment of individual grafts.


ESS equations sometimes do not specify an ESS.
The equations used to find an evolutionarily stable strategy in the basic game theory model (Maynard Smith, 1974, 1982; Maynard Smith & Price, 1973), and in sexual conflict models (Maynard Smith, 1977; Parker, 1979) do not, in fact, specify an ESS when the expected number of contests entered is not the same for each strategy. This means that the conclusions of many game theory models may be incorrect. This is particularly likely to be true when the mean durations of contests for different strategies are not the same, or when the probability that an individual enters a contest is not the same for all strategies. New ESS equations are developed which incorporate the expected number of contests entered.


Screening of senescence-associated genes with specific DNA array reveals the role of IGFBP-3 in premature senescence of human diploid fibroblasts.
Repeated exposures to sublethal concentrations of tert-butylhydroperoxide and ethanol trigger premature senescence of WI-38 human diploid fibroblasts. We found 16 replicative senescence-related genes with similar alterations in expression level in replicative senescence and two models of stress-induced premature senescence. Among these genes was IGFBP-3. Using a siRNA approach, we showed that IGFBP-3 regulates the appearance of several biomarkers of senescence after repeated exposures of WI-38 fibroblasts to tert-butylhydroperoxide and ethanol.


Discordance in Utility Measurement in Persons with Neurological Conditions: A Comparison of the SF-6D and the HUI3.
To examine the extent of disagreement in estimated utility between the six-dimensional health state short form (SF-6D) and the Health Utilities Index-Mark 3 (HUI3) in Canadians with neurological conditions and how discordance varied by participant and neurological condition attributes. The study analyzed cross-sectional survey data from the Living with and Managing the Impact of a Neurological Condition Study. Self-reported data were collected on the burden and impact of neurological conditions on participants' everyday lives. Disagreement was examined by comparing utility distributions, paired t tests of the means, Spearman ρ correlations, intraclass correlations, and Bland-Altman plots. Associations between participant and neurological condition attributes and utility differences were assessed using multiple regression models. Disagreement between the SF-6D and the HUI3 was substantial, with a mean utility difference of 0.15 (95% confidence interval 0.13-0.17). An intraclass correlation coefficient of 0.41 suggests only marginal agreement. The Bland-Altman plot and regression analysis showed systematic variation in utility difference associated with level of utility. Depending on the level of utility, utility differences between the SF-6D and the HUI3 shift in magnitude and direction. The pattern of disagreement did not vary substantially by participant or neurological condition characteristics. The SF-6D and the HUI3 provide inconsistent evaluations of utility in persons with neurological conditions. The magnitude and direction of differences in estimated utility are strongly associated with level of utility. Depending on the health status of the sample, the SF-6D and the HUI3 could provide widely contradictory utility estimates. A concern is that utility scores, and hence potential evaluations and health care decisions, may vary simply according to the choice of instrument.


Inhibitory effect of high oxygen pressure on potassium- induced activation of pyruvate dehydrogenase and glucose metabolism in rat brain slices.
The effects of high oxygen pressure on pyruvate dehydrogenase (pyruvate: lipoate oxidoreductase (decarboxylating and acceptor-acylating), EC 18.104.22.168) activity, tissue concentration of ATP, and CO2 production from glucose were studied in rat brain cortical slices. The increase in pyruvate dehydrogenase activity and the lowering of cellular ATP, occurring during potassium-induced depolarization at 1 atm of oxygen, were reversed by increasing the oxygen pressure to 5 atm. When brain slices were incubated at 1 atm oxygen with [U-14C]glucose, a high potassium medium approximately doubled the production of 14CO2. Oxygen at 5 atm abolished this potassium-dependent increase in 14CO2 production with no significant effect on glucose oxidation in normal Krebs-Ringer phosphate medium. Adding 4 atm helium to 1 atm oxygen did not interfere with the ability of potassium ions to activate pyruvate dehydrogenase, lower ATP, or increase glucose oxidation. The results show that toxic effects of hyperbaric oxygen, not manifest in "resting" tissue, may be revealed during stress such as potassium depolarization. The site of the toxic effects of oxygen is probably the cell membrane where excess oxygen appears to interfere with the action of the sodium pump, calcium transport or other processes stimulated by increased concentrations of extracellular potassium.


Crop Productivity Boosters: Native Mycorrhizal Fungi from an Old-Growth Grassland Benefits Tomato (Solanum lycopersicum) and Pepper (Capsicum annuum) Varieties in Organically Farmed Soils.
This paper investigates the response of five tomato and five pepper varieties to native arbuscular mycorrhizal (AM) fungal inoculation in an organic farming system. The field experiment was conducted across a growing season at a working organic farm in Lawrence, KS, USA. The researchers hypothesized that native AM fungi inoculation would improve crop biomass production for both crop species, but that the magnitude of response would depend on crop cultivar. The results showed that both crops were significantly positively affected by inoculation. AM fungal inoculation consistently improved total pepper biomass throughout the experiment (range of +2% to +8% depending on the harvest date), with a +3.7% improvement at the final harvest for inoculated plants. An interaction between pepper variety and inoculation treatment was sometimes observed, indicating that some pepper varieties were more responsive to AM fungi than others. Beginning at the first harvest, tomatoes showed a consistent positive response to AM fungal inoculation among varieties. Across the experiment, AM fungi-inoculated tomatoes had +10% greater fruit biomass, which was driven by a +20% increase in fruit number. The study highlights the potential benefits of using native AM fungi as a soil amendment in organic farmed soils to improve pepper and tomato productivity.


Deficiency of circ_0103809 Attenuates Non-small Cell Lung Cancer Malignant Progression by Controlling miR-153-3p/HDAC1 Network.
Circular RNAs are vital players in tumorigenesis. We held the purpose to investigate the role and mechanism of circ_0103809 in non-small cell lung cancer (NSCLC). The expressions of circ_0103809, miR-153-3p and HDAC1 mRNA were determined using quantitative real-time PCR assay, and HDAC1 protein was quantified using western blot analysis. MTT, EdU, flow cytometry, tube-formation, wound healing and tube-formation assays were conducted for functional analysis. The predicted relationship among circ_0103809, miR-153-3p and HDAC1 was ascertained using dual-luciferase analysis, RIP assay and pull-down analysis. Animal models were further constructed to realize circ_0103809's role in vivo. Circ_0103809 was upregulated NSCLC specimens, cells and serum-derived exosomes. Serum exosomal circ_0103809 had the potency to be a diagnostic biomarker for NSCLC. Circ_0103809 silencing inhibited NSCLC cell growth, metastasis and angiogenesis and triggered cell cycle arrest and apoptosis. Circ_0103809 deficiency also suppressed the growth of transplanted tumors. Circ_0103809 acted as the miR-153-3p sponge, and the biological effects of circ_0103809 knockdown were relieved by miR-153-3p inhibition. HDAC1 was directly targeted by miR-153-3p, and miR-153-3p enrichment inhibited NSCLC cell malignant phenotypes by sequestering HDAC1. Circ_0103809 knockdown repressed NSCLC malignant progression partly by regulating miR-153-3p/HDAC1 signaling.


Size matters. Understanding morbid obesity & its associated complications.
America is facing a health crisis that will test the limits of EMS resources and resourcefulness in coming years. In the United States, obesity is second only to cigarette smoking as the leading cause of preventable death--causing more than 300,000 deaths annually. It has also been implicated in the dramatic rise in diabetes and heart disease.


Metabolic rate and body composition in rats nutritionally deprived before or after weaning.
In order to manipulate cell size and cell number, rats were subjected to nutrient restriction either prenatally and until weaning at 3 weeks (group I), or from 3 until 10 weeks (group II). Body weights of group I rats were 30% of normal at the height of deprivation at 3 weeks. By 16 weeks of age maximum weights were reached, which remained subnormal in the majority; by 26 weeks only one of six had attained a normal weight. Body weights of group II were 27% of normal at the height of deprivation at 10 weeks; subsequently, only one of six did not recover. The weight, protein, and DNA content of liver, kidney, and heart were significantly decreased. The combined weight and protein content of the three organs was 30% of normal in group I and 25% of normal in group II; the DNA content of the three organs was 57% and 38% of normal in group I and group II, respectively. The greater deficit in weight than DNA content, and the mean protein/DNA ratios reflect a decrease in cell size (or increase in the cell density) of the three organs, which was greater in group I (60%) than group II (71%). Muscle cell density was increased in group I, but not in group II. At 16 weeks of age all parameters were similar in the two experimental groups (ranging from 68% to 82% or normal). Organ weight, protein, and DNA content remained deficient only in group I; these values were 74%, 70%, and 77% of normal, respectively, at 32 weeks. The deficit was proportionate to the deficit in body weight. The basal metabolic rate was measured 17-20 hr after food removal (BMR) on the day the animals were killed. In group I and II correlations between the BMR and four parameters of body composition were linear during a 4-period at the height of deprivation. Comparison of means from the regressions showed no difference between group I and II, or between these groups and normal controls with regard to the BMR per body weight, organ weight, and organ protein. The BMR per mg DNA was lower in group I and II than in normal control rats (P less than 0.05). The BMR of normal rats age 3-32 weeks showed a curvilinear correlation with body weight (BWt), BMR = 1.24 BWt0.583; organ weight (OWt), BMR = 4.30 OWt0.766; and organ protein (OPr), BMR = 4.30 OPr0.604. By contrast, the regression on DNA was linear (BMR = 7.97 + 0.449), although marked changes in body composition occurred between 3 and 32 weeks.


Odor impact of volatiles emitted from marijuana, cocaine, heroin and their surrogate scents.
Volatile compounds emitted into headspace from illicit street drugs have been identified, but until now odor impact of these compounds have not been reported. Data in support of identification of these compounds and their odor impact to human nose are presented. In addition, data is reported on odor detection thresholds for canines highlighting differences with human ODTs and needs to address gaps in knowledge. New data presented here include: (1) compound identification, (2) gas chromatography (GC) column retention times, (3) mass spectral data, (4) odor descriptors from 2 databases, (5) human odor detection thresholds from 2 databases, (6) calculated odor activity values, and (7) subsequent ranking of compounds by concentration and ranking of compounds by odor impact (reported as calculated odor activity values). For further interpretation and discussion, see Rice and Koziel [1] and Rice [2].


Murine neonatal dermal fibroblast acquires a lymphoid tissue organizer cell-like activity upon synergistic activation of TNF-α receptor and LTβ receptor.
Tertiary lymphoid organs (TLOs) are ectopic aggregates of immune cells. As accumulating studies demonstrate TLOs as a predictor of better prognosis in certain cancers, targeting TLO formation, which is tightly regulated by the lymphoid tissue organizer cells (LTOs), has become intriguing in cancer treatment. However, the clinical outcome of these attempts is limited, because the approaches for activating tumor adjacent LTO is lack and little is known about what type of self-cell can be used as LTO to initiate TLO formation. Here we demonstrate that co-stimulation with membrane-bound ligand LTα1β2 and soluble TNF-α could induced an LTO-like activity in murine neonatal dermal fibroblast, featured by high expression of cell migration-associated chemokines and adhesion molecules that resemble typical LTO gene signature. Furthermore, the LTO-phenotypic dermal fibroblast could enhance the attachment and survival of T and B cell and proliferation of T cell. These findings suggest dermal fibroblast as a promising target for TLO induction to improve cancer immunotherapy.


Regulation of the Pax6 : Pax6(5a) mRNA ratio in the developing mammalian brain.
Early in mammalian brain development cell proliferation generates a population of progenitor cells whose subsequent divisions produce increasing numbers of postmitotic neurons. Pax6 affects both processes and it has been suggested that this changing role is due at least in part to changes in the relative concentrations of its two main isoforms, (i) Pax6 and (ii) Pax6(5a), created by insertion of a 42 bp exon (exon 5a) into one of the two DNA-binding domains. Crucially, however, no previous study has determined whether the ratio between Pax6 and Pax6(5a) transcripts alters during mammalian neurogenesis in vivo. Using RNase protection assays, we show that Pax6 transcripts are 6-10 times more prevalent than Pax6(5a) transcripts early in neurogenesis in the murine telencephalon, diencephalon and hindbrain and that the ratio later falls significantly to about 3:1 in these regions. These changes in vivo are similar in magnitude to those shown previously to alter target gene activity in vitro and might, therefore, allow the single mammalian Pax6 gene to carry out different functions at different times in mammalian brain development.


Targeting ErbB-1 and ErbB-4 in irradiated head and neck cancer: results of in vitro and in vivo studies.
ErbB oncogenes have a major role in cancer. The role of ErbB-4 in cancer cell biology and the effect of anti-ErbB-1 and anti-ErbB-4 monoclonal antibodies were evaluated in this study. ErbB-4 expression and binding was evaluated by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescent microscopy, and flow cytometry. Cell survival was measured by XTT assay. Tumor progression was followed up in nude mice model. High ErbB-1 levels in head and neck cancer cell lines were determined, whereas ErbB-4 expression varied. Specific antibody binding to the cells was demonstrated. High ErbB-4 expressing squamous cell carcinoma 1 (SCC-1) cells proliferated faster and generated faster growing tumors in mice. Cetuximab and mAb-3 reduced cell survival proportional to ErbB-1 and ErbB-4 expression. Combination of antibodies with irradiation was most effective in reducing cell survival and tumor growth. ErbB-4 plays a role in head and neck cancer cell biology. Anti-ErbB-4 targeted therapy can serve as a new strategy against head and neck cancer when combined with established treatments.


Complementing the Latest APA Definition of Hypnosis: Sensory-Motor and Vascular Peculiarities Involved in Hypnotizability.
The aim of this article is to complement the recently revised American Psychological Association (APA) definition of hypnotizability. It (a) lists a few differences in sensorimotor integration between subjects with high (highs) and low (lows) hypnotizability scores in the ordinary state of consciousness and in the absence of suggestions, (b) proposes that hypnotizability-related cerebellar peculiarities may account for them,


Fabrication Characteristics of Silicon Nanowires via the Electrochemical Electroless Etching Method.
A silicon nanowire structure was fabricated using the electrochemical electroless etching method, involving electroless plating and the electrochemical etching process. The reflection of the absorption layer with the nanowires' structure was about 5%, which is better than a bulk-type solar cell (10%).


Phase mapping of radionuclide gated biventriculograms in patients with sustained ventricular tachycardia or Wolff-Parkinson-White syndrome.
Accuracy of Fourier phase mapping of radionuclide gated biventriculograms in detecting the origin of abnormal ventricular activation was studied during ventricular tachycardia or preexcitation. Group I included six patients suffering from clinical recurrent VT; 3 gated blood pool studies were acquired for each patient: during sinus rhythm, right ventricular pacing, and induced sustained VT-Group II included seven patients with Wolff-Parkinson-White syndrome and recurrent paroxysmal tachycardia; 3 gated blood pool studies were acquired for each patient: during sinus rhythm, right atrial pacing and orthodromic reciprocating tachycardia. Each acquisition lasted 5 min, in 30 degrees-40 degrees left anterior oblique projection. In Group I, the Fourier phase mapping was consistent with QRS morphology and axis during VT (5/6), except in one patient with LV aneurysm and LBBB electrical pattern during VT. Origin of VT on phase mapping was located in the right ventricle (n = 2) or in left ventricle (n = 4), at the border of wall motion abnormalities each time they existed (5/6). In Group II, the phase advance correlated with the location of the accessory pathway determined by ECG and endocardial mapping (n = 6) and per-operative epicardial mapping (n = 1). Discrimination between anterior and posterior localisation of paraseptal pathways and location of intermittent preexcitation was not possible. We conclude that Fourier phase mapping is an accurate method for locating the origin of VT and determining its etiology. It can help locate the site of ventricular preexcitation in patients with only one accessory pathway; its accuracy in locating multiple accessory pathways remains unknown.


Molecular cloning and sequence analysis of a gene encoding an extracellular serine protease from Streptomyces lividans 66.
A gene encoding a homolog of the chymotrypsin-like serine protease (SAM-P20), which was isolated as the target enzyme of a protease inhibitor (SSI), was cloned from Streptomyces lividans 66. This gene contained an open reading frame of 1065 nucleotides encoding 354 amino acid residues with a putative prepro portion of 157 amino acid residues. The deduced amino acid sequence of the cloned gene had significant homology to those of members of Streptomyces extracellular chymotrypsin-like protease family. By Southern blot analysis, it was suggested that protease genes of this type are found at a high frequency in Streptomyces. In this sense, we propose to categorize this protease as a member of the 'SAL' series (SAM-P20-like proteases).


Bone bruising of the knee.
Bone bruising demonstrated by MRI is discussed with histological findings and proposed classifications. The effects of the mechanism of injury on bone bruising at the knee and the natural history of the process are reviewed. The relationship of bone bruising to osteochondral sequelae and to osteoarthritis are considered.


High sensitivity C reactive protein levels and atrial fibrillation recurrence after catheter ablation for atrial fibrillation: A systematic review and meta-analysis.
Atrial fibrillation (AF) recurrence after AF ablation is not uncommon. High sensitivity C reactive protein (hs-CRP) is a widely used inflammatory marker with a potential property to predict AF recurrence. We conducted a systematic review and a meta-analysis to find an association between hs-CRP levels and AF recurrence after ablation. We searched PubMed, Embase, and Wiley-Cochrane Library from inception to January 2022 for studies that reported hs-CRP levels in patients who underwent AF ablation. Weighted mean difference (WMD) was used to evaluate the difference between hs-CRP levels in post-ablation AF recurrent and non-recurrent group. Also, the difference between hs-CRP levels in pre- and post-ablation was determined. We identified 10 studies, and a total of 789 patients were included (299 recurrent vs. 490 non-recurrent patients). The mean age was 57.7 years (76.4% male). There was no difference in baseline hs-CRP levels between AF recurrent and non-recurrent group (WMD = 0.05, 95% CI = -0.04 to 0.15, p = 0.045). However, higher hs-CRP levels post-ablation were found in AF recurrent group (WMD = 0.09, 95% CI = 0.03-0.15, p < 0.001). There is no significant difference in baseline hs-CRP levels between AF recurrent and non-recurrent patients after AF ablation. However, higher post-ablation hs-CRP level was found in AF recurrent group. High Sensitivity C reactive protein may play a role as a predictor of AF recurrence.


Screening, analysis and in vitro vasodilatation of effective components from Ligusticum Chuanxiong.
Effective components, ligustilide and butylidenephthalide, from Ligusticum Chuanxiong (Ligusticum wallichii Franchat, Umbelliferae) were screened and identified by using a cell membrane chromatography (CMC) and a gas chromatography/mass spectrometry (GC/MS). The components showed the effects of inhibiting vasoconstriction in vitro on rat abdominal aorta segments. The screening procedure was performed in a rat artery CMC column (50 mm x 2.0 mm I.D.) with a sodium phosphate buffer (pH 7.4) as mobile phase at 37 degrees C. The identification was accomplished by a DB-5MS 30 m capillary column (0.25 mm I.D., 0.25 microm film thickness) with helium as carrier gas operating under program control temperature and electron impact ionization mass spectrometer in a scan mode. Results demonstrated that ligustilide and butylidenephthalide can act on rat artery cell membrane similar to verapamil in CMC system. They significantly inhibited the vasoconstrictions induced by norepinephrine bitartrate (NE) and calcium chloride (CaCl2). The relaxing effect of ligustilide on the NE- and CaCl2-induced constrictions is more potent than that of butylidenephthalide. Ligustilide and butylidenephthalide seem to be the two main effective components of Ligusticum Chuanxiong as a traditional Chinese medicine for treating blood vessel diseases.


Protein kinase B (Akt) blockade inhibits LH/hCG-mediated 17,20-lyase, but not 17α-hydroxylase activity of Cyp17a1 in mouse Leydig cell steroidogenesis.
Androgens are produced by adrenal and gonadal cells thanks to the action of specific enzymes. We investigated the role of protein kinase B (Akt) in the modulation of Δ4 steroidogenic enzymes' activity, in the mouse Leydig tumor cell line mLTC1. Cells were treated for 0-24 h with the 3 × 50% effective concentration of human luteinizing hormone (LH) and choriogonadotropin (hCG), in the presence and in the absence of the specific Akt inhibitor 3CAI. Cell signaling analysis was performed by bioluminescence resonance energy transfer (BRET) and Western blotting, while the expression of key target genes was investigated by real-time PCR. The synthesis of progesterone, 17α-hydroxy (OH)-progesterone and testosterone was measured by immunoassay. Control experiments for cell viability and caspase 3 activation were performed as well. We found that both hormones activated cAMP and downstream effectors, such as extracellularly-regulated kinase 1/2 (Erk1/2) and cAMP response element-binding protein (Creb), as well as Akt, and the transcription of Stard1, Hsd3b1, Cyp17a1 and Hsd17b3 genes, boosting the Δ4 steroidogenic pathway. Interestingly, Akt blockade decreased selectively Cyp17a1 expression levels, inhibiting its 17,20-lyase, but not the 17-hydroxylase activity. This effect is consistent with lower Cyp17a1 affinity to 17α-OH-progesterone than progesterone. As a result, cell treatment with 3CAI resulted in 17α-OH-progesterone accumulation at 16-24 h and decreased testosterone levels after 24 h. In conclusion, in the mouse Leydig cell line mLTC1, we found substantial Akt dependence of the 17,20-lyase activity and testosterone synthesis. Our results indicate that different intracellular pathways modulate selectively the dual activity of Cyp17a1.


Elucidating the reinforcing effects of nicotine: a tribute to Nadia Chaudhri.
Nadia Chaudhri worked with us as a graduate student in the Center for Neuroscience at the University of Pittsburgh from 1999 until she earned her PhD in 2005, a time that coincided with the discovery in our lab of the dual reinforcing actions of nicotine, a concept that she played an important role in shaping. The research that was described in her doctoral thesis is among the foundational pillars of the now well-accepted notion that nicotine acts as both a primary reinforcer and an amplifier of other reinforcer stimuli. This reinforcement-enhancing action of nicotine is robust and likely to be a powerful driver of nicotine use. Below, we discuss the evidence that these two actions of nicotine - primary reinforcement and reinforcement enhancement - are distinct and dissociable, a finding that Nadia was closely associated with. We go on to address two other topics that greatly interested Nadia during that time, the generalizability of the reinforcement-enhancing action of nicotine to multiple classes of reinforcing stimuli and potential sex differences in the dual reinforcing actions of nicotine. The research has greatly expanded since Nadia's involvement, but the core ideas that she helped to develop remain central to the concept of the dual reinforcing actions of nicotine and its importance for understanding the drivers of nicotine use.


Modality-specificity of Selective Attention Networks.
To establish the modality specificity and generality of selective attention networks. Forty-eight young adults completed a battery of four auditory and visual selective attention tests based upon the Attention Network framework: the visual and auditory Attention Network Tests (vANT, aANT), the Test of Everyday Attention (TEA), and the Test of Attention in Listening (TAiL). These provided independent measures for auditory and visual alerting, orienting, and conflict resolution networks. The measures were subjected to an exploratory factor analysis to assess underlying attention constructs. The analysis yielded a four-component solution. The first component comprised of a range of measures from the TEA and was labeled "general attention." The third component was labeled "auditory attention," as it only contained measures from the TAiL using pitch as the attended stimulus feature. The second and fourth components were labeled as "spatial orienting" and "spatial conflict," respectively-they were comprised of orienting and conflict resolution measures from the vANT, aANT, and TAiL attend-location task-all tasks based upon spatial judgments (e.g., the direction of a target arrow or sound location). These results do not support our a-priori hypothesis that attention networks are either modality specific or supramodal. Auditory attention separated into selectively attending to spatial and non-spatial features, with the auditory spatial attention loading onto the same factor as visual spatial attention, suggesting spatial attention is supramodal. However, since our study did not include a non-spatial measure of visual attention, further research will be required to ascertain whether non-spatial attention is modality-specific.


The compatibility principle: on philosophies in the assessment of clinical competence.
The array of different philosophical positions underlying contemporary views on competence, assessment strategies and justification have led to advances in assessment science. Challenges may arise when these philosophical positions are not considered in assessment design. These can include (a) a logical incompatibility leading to varied or difficult interpretations of assessment results, (b) an "anything goes" approach, and (c) uncertainty regarding when and in what context various philosophical positions are appropriate. We propose a compatibility principle that recognizes that different philosophical positions commit assessors/assessment researchers to particular ideas, assumptions and commitments, and applies ta logic of philosophically-informed, assessment-based inquiry. Assessment is optimized when its underlying philosophical position produces congruent, aligned and coherent views on constructs, assessment strategies, justification and their interpretations. As a way forward we argue that (a) there can and should be variability in the philosophical positions used in assessment, and these should be clearly articulated to promote understanding of assumptions and make sense of justifications; (b) we focus on developing the merits, boundaries and relationships within and/or between philosophical positions in assessment; (c) we examine a core set of principles related to the role and relevance of philosophical positions; (d) we elaborate strategies and criteria to delineate compatible from incompatible; and (f) we articulate a need to broaden knowledge/competencies related to these issues. The broadened use of philosophical positions in assessment in the health professions affect the "state of play" and can undermine assessment programs. This may be overcome with attention to the alignment between underlying assumptions/commitments.


Optimal polar bodies angle for higher subsequent embryo viability: a pilot study.
To determine the optimal polar bodies (PB) angle for higher subsequent embryo implantation potential. Prospective study. Academic fertility center. From January to July 2015, 116 patients were recruited in their first IVF-ET cycles. At the pronuclear stage, PB angle was measured with the use of E-ruler 1.1. The primary outcome measure was good-quality embryo rate. Secondary measures were clinical pregnancy rate (CPR) and embryo implantation rate (IR). A total of 1,103 oocytes were retrieved. PB angle was measured in 454 zygotes, and 164 of their subsequent embryos were transferred into the uterus. All-or-none implantation took place in 129 embryos, and 89 patients accepted fresh embryo(s) transfer with known PB angle. By means of receiver operating characteristic analysis, the optimal PB angle for subsequent embryo implantation was 24.25°. Based on this cutoff value, 454 zygotes were divided into two groups: small-angle and large-angle. A higher percentage of small-angle zygotes developed into good-quality embryos (70.97% vs. 58.58%). CPR and IR both decreased progressively from purely small-angle embryos to mixed embryos to purely large-angle embryos (CPR: 72.41% vs. 38.46% vs. 26.47%, respectively; IR: 63.27% vs. 26.92% vs. 16.67%, respectively). Noninvasive assessment of PB angle is a viable technique for zygote selection and should be included in embryo selection parameters. ChiCTR-OOC-15005882.


The role of home care in palliative care services.
This article addresses the increasing interest in end of life care and the need for improving access to palliative care services in patients/families served by the home care industry. The author discusses factors leading to this growing demand as well as some of the recent research conducted in the field of palliative care. The benefits of and underutilization of hospice services are discussed. The author addresses a variety of options for home care providers to consider expanding access to palliative care services including recent changes in regulation that allow for collaboration with Medicare certified hospice programs. A discussion of key topics to include in staff development initiatives related to palliative care is included as are education and clinical practice resources.


Incidental gastrointestinal 18F-Fluorodeoxyglucose uptake associated with lung cancer.
F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used for the initial staging and restaging of lung cancer. Incidental gastrointestinal findings are often observed on (18)F-FDG PET/CT. The objective of this study was to assess incidental 18F-FDG uptake by the gastrointestinal tract (GIT) in patients with lung cancer. Two hundred thirty consecutive 18F-FDG PET/CT examinations performed for lung cancer over a 3-year period were retrospectively reviewed for the presence of incidental FDG uptake in the GIT. The charts of patients with positive FDG uptake were then reviewed and analysed to determine the GIT uptake sites, the standardized uptake value (SUV) max and the final clinical diagnosis. Fifty-two patients (52/230, 23%) demonstrated incidental FDG uptake in the GIT. Thirty-three patients (63.5%) had diffuse uptake (oesophagus, n = 2, colon, n = 31) and 19 patients (36.5%) had focal uptake (oesophagus, n = 1, small bowel, n = 1, ascending colon, n = 5, descending colon, n = 4, sigmoid, n = 4, rectum, n = 3, and anal margin, n = 1). Twelve of the 52 patients with GIT uptake were further investigated, revealing, a diagnosis of malignancy in 4 patients with focal FDG uptake. No significant differences in mean SUVmax were observed between patients with malignant and benign GIT diseases. This study demonstrates a high incidence of FDG uptake in the GIT associated with lung cancer. Focal GIT uptake was frequently associated with malignant disease. These results suggest that further GIT investigations should be performed in patients with focal GIT uptake.


Ballistic strength training in adults with cerebral palsy may increase rate of force development in plantar flexors, but transition to walking remains unclear: a case series.
Persons with cerebral palsy (CP) walk with reduced ankle plantar flexor power compared to typically developing. In this study, we investigated whether a ballistic strength-training programme targeting ankle plantar flexors could improve muscle strength, muscle architecture and walking function in adults with CP. Eight adults (mildly affected CP) underwent eight weeks of ballistic strength training, with two sessions per week. Before and after the intervention preferred walking speed, ankle plantar flexion rate of force development (RFD), maximal voluntary contraction (MVC), muscle thickness, pennation angle and fascicle length were measured. Data are presented for individuals, as well as for groups. Group changes were analysed using the Wilcoxon signed-rank test. Data were analysed for eight participants (five women, mean age 37.9 years; six GMFCS I and two GMFCS II). Two participants increased their walking speed, but there were no significant group changes. In terms of muscle strength, there were significant group changes for RFD at 100 ms and MVC. In the case of muscle architecture, there were no group changes. In this study, we found that eight weeks of ballistic strength training improved ankle plantar flexor muscle strength but walking function and muscle architecture were unchanged. Larger studies will be needed to obtain conclusive evidence of the efficacy of this training method.


The fate of plasmid DNA after intravenous injection in mice: involvement of scavenger receptors in its hepatic uptake.
We examined the stability and disposition characteristics of a naked plasmid DNA pCAT as a model gene after intravenous injection in mice to construct the strategy of in vivo gene delivery systems. After the injection of pCAT to the mice, stability, tissue distribution, hepatic cellular localization, and effect of some polyanions on the hepatic uptake were studied. The in vitro study demonstrated that the pCAT was rapidly degraded in mouse whole blood with a half-life of approximately 10 min at a concentration of 100 micrograms/ml. After intravenous injection, pCAT was degraded at a significantly faster rate than that observed in the whole blood, suggesting that pCAT in vivo was also degraded in other compartments. Following intravenous injection of [32P] pCAT, radioactivity was rapidly eliminated from the plasma due to extensive uptake by the liver. Hepatic accumulation occurred preferentially in the non-parenchymal cells. The hepatic uptake of radioactivity derived from [32P] pCAT was inhibited by preceding administration of polyanions such as polyinosinic acid, dextran sulfate, maleylated and succinylated bovine serum albumin but not by polycytidylic acid. These findings indicate that pCAT is taken up by the liver via scavenger receptors on the non-parenchymal cells. Pharmacokinetic analysis revealed that the apparent hepatic uptake clearance was fairly close to the liver plasma flow. These findings provide useful information for the development of delivery systems for in vivo gene therapy.


Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke.
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and synaptic alterations. Aspirin and docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, have beneficial effects on cerebrovascular diseases. DHA is the precursor of neuroprotectin D1 (NPD1), which downregulates apoptosis and, in turn, promotes cell survival. Here we have tested the effect of aspirin plus DHA administration and discovered the synthesis of aspirin-triggered NPD1 (AT-NPD1) in the brain. Then we performed the total chemical synthesis of this molecule and tested in the setting of 2h middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24h, 48 h, 72 h, and 7 days. At 3h post-stroke onset, an intravenous administration of 333 μg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or methyl-ester (AT-NPD1-ME) or vehicle (saline) as treatment was given. On day 7, ex vivo magnetic resonance imaging (MRI) of the brains was conducted on 11.7 T MRI. T2WI, 3D volumes, and apparent diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/macrophages) and SMI-71-positive vessels were counted in the cortex and striatum at the level of the central lesion. All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological scores compared to saline treatment at 24h, 48 h, 72 h and 7 days. Total lesion volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS and AT-NPD1-ME treatment in the cortex (by 44% and 81%), striatum (by 61% and 77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline group. In contrast, both AT-NPD1 decreased water content in the striatum on day 7. 3D volumes, computed from T2WI, were dramatically reduced with both AT-NPD1 and the lesion was mostly localized in the subcortical areas. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%), subcortical (by 61% and 70%) and total (69% and 84%, respectively) infarct volumes as defined by histopathology. In conclusion, a novel biosynthetic pathway that leads to the formation of AT-NPD1 mediator in the brain was discovered. In addition, administration of synthetic AT-NPD1, in either its sodium salt or as the methyl ester, was able to attenuate cerebral ischemic injury which leads to a novel approach for pharmaceutical intervention and clinical translation.


Cross-linked cytokeratin polypeptides in liver and hepatoma cells: possible association with the process of cell degeneration and death.
We investigated transglutaminase-induced cross-linking of cytokeratin polypeptides in liver and hepatoma cells. To overcome the difficulties in the biochemical analysis of highly cross-linked polymers and aggregates of cytokeratins, cross-linked cytokeratin dimers were analyzed by immunoblotting to evaluate the degree of cross-linking of cytokeratins. Covalently cross-linked cytokeratin dimers were not detectable in normal rat liver cells. However, cytokeratin dimers and high-molecular-weight cytokeratin polymers were detected in liver tissue with histological evidence of coagulative necrosis induced by ischemia or carbon tetrachloride. Treatment of cultured hepatoma cells with the Ca2+ ionophore A23187 showed a dose-dependent, time-dependent decrease of cell viability. The appearance of cytokeratin dimers was shown to be correlated with cell death. These results suggest that the transglutaminase-induced cross-linking of cytokeratin polypeptides in liver and hepatoma cells is closely associated with the process of cell degeneration and death.


Investigation and modeling of solar UV-induced chlorine decay in disinfection contact basins at full-scale wastewater treatment plants.
Residual chlorine loss due to UV sunlight in the chlorine disinfection contact basins (DCBs) was investigated at two full-scale wastewater treatment plants (WWTPs). Chlorine decay due to solar UV-induced photochemical reaction was found to be significant and had diurnal and seasonal variations. The total chlorine loss due to sunlight ranged from 19 to 26% of the total chlorine chemical use at the two plants studied. Covering chlorine contact basins led to more stable chlorine demand regardless of the diurnal and seasonal sunlight intensity. Therefore, covering chlorine contact basins offers more stable, or accurate, chlorine dosage and effluent residual control and requires less effort by plant operators. A mathematical model was developed to calculate the amount of UV-induced chlorine decay. The model developed can be used to estimate the UV-induced chlorine decay rate and total chlorine loss due to sunlight at WWTPs with various basin configurations, flowrates, chlorine dosages, and geographical locations. The model results allow the capital cost of covering needs to be assessed against the chlorine chemical cost savings.


Continuously Adjustable, Molecular-Sieving "Gate" on 5A Zeolite for Distinguishing Small Organic Molecules by Size.
Zeolites/molecular sieves with uniform, molecular-sized pores are important for many adsorption-based separation processes. Pore size gaps, however, exist in the current zeolite family. This leads to a great challenge of separating molecules with size differences at ~0.01 nm level. Here, we report a novel concept, pore misalignment, to form a continuously adjustable, molecular-sieving "gate" at the 5A zeolite pore entrance without sacrificing the internal capacity. Misalignment of the micropores of the alumina coating with the 5A zeolite pores was related with and facilely adjusted by the coating thickness. For the first time, organic molecules with sub-0.01 nm size differences were effectively distinguished via appropriate misalignment. This novel concept may have great potential to fill the pore size gaps of the zeolite family and realize size-selective adsorption separation.


Antimicrobial Pharmacology for the Neonatal Foal.
Neonatal foals are at high risk of developing sepsis, which can be life-threatening. Early antimicrobial use is a critical component of the treatment of sepsis. Because the neonatal foal has unique pharmacologic physiology, antimicrobial choice and dosing are often different than in adult horses. Broad-spectrum, bactericidal, and intravenous antimicrobials should be considered first-line therapy for septic foals. A combination of aminoglycoside and beta-lactam antimicrobial or third-generation cephalosporin is an excellent empirical first choice for treating septic foals, until culture and susceptibility results are available. Renal function should be monitored carefully in foals being treated with aminoglycosides.


Development of novel targeted agents in the treatment of metastatic colorectal cancer.
Colorectal cancer (CRC) remains the second most common cause of cancer death and third most common form of cancer in men and women. Although the incidence and mortality of CRC have been declining over the past 2 decades in the United States, nearly 140,000 new cases and 51,000 deaths were still estimated to occur in 2010.(1) These decreases have resulted primarily from earlier detection of premalignant colorectal polyps through CRC screening and to a lesser degree from adjuvant chemotherapy. Four cytotoxic chemotherapy drugs and 3 biologic agents have been approved by the US Food and Drug Administration (FDA) for CRC, but the contribution of each has been incremental and long-term survival of advanced disease remains poor. In addition, optimal populations for treatment with these agents remain to be fully characterized. Although the field of drug development in CRC was stagnant during a period of numerous large trials with approved agents, multiple new agents are currently in development. This review discusses molecular pathways and novel targeted agents in the treatment of CRC.


Surveillance of schistosomiasis in five provinces of China which have reached the national criteria for elimination of the disease.
Surveillance of schistosomiasis consists mainly of surveys carried out in formerly endemic areas to observe infection and re-infection of resident and mobile human populations, and domestic animals (e.g. bovines) plus snail monitoring. Here, we focus on the schistosomiasis situation in the five Chinese provinces which have reached the national criteria for elimination of the disease, i.e. Fujian, Guangdong, Guangxi, Shanghai and Zhejiang. With the exception of three newly infected persons in Guangdong province, detected in 1992, repeated surveys in these provinces have not detected any new locally infected case in either humans or bovines. When the newly infected persons were discovered in Guangdong, residual snail habitats including Schistosoma japonicum-infected snails were found in the neighbourhood. These were destroyed and the infected persons treated before further spread could take place. The surveillance system in place has thus been successful in consolidating the results of the control effort. We conclude that rigorous surveillance for and control of schistosomiasis is the way to prevent resurgence of infection and disease in areas which have reached the national criteria for elimination or transmission interruption.


Effects of blocking the renin-angiotensin system on expression and translocation of protein kinase C isoforms in the kidney of diabetic rats.
High glucose and angiotensin II (Ang II) can activate protein kinase C (PKC) in diabetes mellitus. However, it is not clear which isoform of PKC is activated by glucose or Ang II. Our study focused on the effects of angiotensin blockade, using the angiotensin-converting enzyme inhibitor fosinopril, the Ang II receptor blocker irbesartan and their combination, on the expression and translocation of PKC isoforms alpha and betaII in the renal cortex and medulla in diabetes. Hyperglycemia was induced with streptozotocin and diabetic rats were randomized to 4 groups: diabetic control, irbesartan group (40 mg/kg daily), fosinopril group (40 mg/kg daily) and combination group (irbesartan plus fosinopril, 20 mg/kg daily, respectively); age-matched normal rats served as normal control. After 4 weeks, expression and translocation of PKC-alpha and -betaII in the renal cortex and medulla were assessed by immunohistochemistry and Western immunoblotting. The expression of PKC-alpha in the membrane and cytosol fractions from the renal cortex was significantly higher in diabetic rats (276.83 +/- 32.44% in membrane, 149.04 +/- 23.42% in cytosol) than that in normal ones. The expression of PKC-betaII in the renal cortex of diabetic rats decreased significantly in the membrane (50.00 +/- 11.68%, p < 0.05) and remained unchanged in the cytosol (94.51 +/- 11.69%, p > 0.05) compared with normal controls. Treatment with irbesartan, fosinopril and their combination partially corrected the abnormalities mentioned above. For the expression of PKC-alpha and -betaII in the medulla, no difference was detected among the 5 groups. The renin-angiotensin system was implicated in the pathogenesis of diabetic nephropathy by regulating the activation of PKC isoforms.


Correlation between preoperative tomographic staging and definitive histopathologic results in gastric cancer at the Hospital Central Militar.
In relation to the number of new cases diagnosed, gastric cancer is the fourth most common cancer worldwide, and the second cause of cancer death. The development of multidetector tomography has improved the preoperative staging of gastric cancer. To correlate preoperative tomographic studies with the definitive pathologic results according to the TNM staging system. A retrospective, cross-sectional study within the time frame of January 2009 to December 2013 was conducted that included the case records of 67 patients. They all had upper endoscopy and preoperative multidetector tomography examinations, underwent surgical resection, and had the corresponding histopathology study. Statistical analysis was carried out with the SPSS version 15.0 software and the sensitivity and specificity calculations were made using the Excel 2011 program for Mac. The majority of the patients included in the case series had clinical stage iii and iv disease. When compared with the histopathologic result, the overall accuracy of multidetector CT was 83% (T0 96%, T1 94%, T2 93%, T3 67%, and T4 67%) for tumor size (T) and was 70% (N0 72%, N1 73%, N2 70%, and N3 66%) for lymph node involvement (N). Overall sensitivity was 48% (T0 100%, T1 0%, T2 33%, T3 44%, and T4 65%) for T and was 41% (N0 58%, N1 56%, N2 15%, and N3 35%) for N. A strong association between the multidetector CT results and the pathology results was demonstrated through the Spearman's correlation, especially in T4 and N3. Multidetector computed tomography showed greater congruency in detecting stages T4, N0, and N3 in gastric cancer, when compared with the definitive histopathologic results.


Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes.
Invasive aspergillosis (IA) is a fungal infection that particularly affects immunocompromised hosts. Recently, several studies have indicated a high incidence of IA in intensive care unit (ICU) patients. However, few data are available on the epidemiology and outcome of patients with IA in this setting. An observational study including all patients with a positive Aspergillus culture during ICU stay was performed in 30 ICUs in 8 countries. Cases were classified as proven IA, putative IA or Aspergillus colonization according to recently validated criteria. Demographic, microbiologic and diagnostic data were collected. Outcome was recorded 12 weeks after Aspergillus isolation. A total of 563 patients were included, of whom 266 were colonized (47%), 203 had putative IA (36%) and 94 had proven IA (17%). The lung was the most frequent site of infection (94%), and Aspergillus fumigatus the most commonly isolated species (92%). Patients with IA had higher incidences of cancer and organ transplantation than those with colonization. Compared with other patients, they were more frequently diagnosed with sepsis on ICU admission and more frequently received vasopressors and renal replacement therapy (RRT) during the ICU stay. Mortality was 38% among colonized patients, 67% in those with putative IA and 79% in those with proven IA (P < 0.001). Independent risk factors for death among patients with IA included older age, history of bone marrow transplantation, and mechanical ventilation, RRT and higher Sequential Organ Failure Assessment score at diagnosis. IA among critically ill patients is associated with high mortality. Patients diagnosed with proven or putative IA had greater severity of illness and more frequently needed organ support than those with Aspergillus spp colonization.


Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels.
Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.


Inhibitory effect of microwaved thinned nectarine extracts on polyphenol oxidase activity.
By-products from agricultural practices or from the fruit processing industry are a source of bioactive compounds that could be used in the food industry. Such by-products include thinned fruits, which are expected to contain high quantities of interesting compounds. One possible application of this fruits is the prevention of the enzymatic browning suffered by fruits and vegetables after minimal processing. The aim of this study is to determine the in vitro and in vivo activity of microwaved extracts obtained from thinned nectarines. It has been observed that in vitro the extracts obtained after the application of high microwave power levels (500, 1000 and 1500 W) are mixed type inhibitors of polyphenoloxidase enzyme, showing an irreversible inactivation. This inhibition could be attributed to the Maillard reaction products formed during the microwave treatment. In vivo, a solution of 2% of the extract obtained at 1500 W inhibited the enzymatic browning in minimally processed peaches for 8 days of storage.


Immunohistochemical localisation of macromolecules of the basement membrane and extracellular matrix of human gliomas and meningiomas.
The distribution of type I, III, IV and V collagen in 35 gliomas and 20 meningiomas was studied by indirect immunofluorescence staining. In addition, the presence of fibronectin (FN) and laminin (LN) is also reported. In gliomas expression of type IV collagen and LN was found in the vessel walls and associated with the endothelial glomerulus-like proliferations. FN and type V collagens were located in proliferating vessel walls in a pattern corresponding both to the basement membrane and the perivascular matrix around the vessels. In the extracellular matrix of grade III and IV gliomas occasional faint intercellular fluorescence was also observed with both FN and type V collagen. Type I and III collagens were localised in the vessel walls and in the perivascular connective sheet. Glioma cells did not express any of the antigens investigated. In meningiomas, type IV and V collagens, LN and FN were found in vessel walls, whorls formations and psammoma bodies. These stainings support the hypothesis of a vascular origin of these psammoma bodies which were only found in syncytial and transitional meningiomas. Both type I and III collagens were detected in the perivascular connective tissue. In general, meningioma cells and extracellular matrix did not express any of these molecules, except in transitional meningiomas where occasional fluorescence was observed in extracellular matrix with type V collagen and FN.


Colour vision in gyrate atrophy.
A follow-up study of colour vision in two patients with gyrate atrophy was performed. Gyrate atrophy was diagnosed in the first patient at the age of 17 years. Her colour vision was first tested at the age of 25 years; at the follow-up examination 7 years later, she correctly interpreted the Standard Pseudoisochromatic Plates part 2, however, with one mistake due to lens opacity. In the Farnsworth-Munsell 100 hue test and in the Color Vision Meter 712 (CVM) anomaloscope, the results were within normal ranges. In the second patient, gyrate atrophy was diagnosed at the age of 4 years. At the ages of 4 and 5 years, he correctly interpreted the Ishihara, AO H-R-R, and Lanthony Tritan Album plates as well as the City University test. At the ages of 6, 7, and 8 years, he correctly interpreted the plate tests, the Farnsworth Panel D 15, and Lanthony's Desaturated Panel. The CVM anomaloscope results were normal.


Calibration and Characterization of Autonomous Recorders Used in the Measurement of Underwater Noise.
The use of autonomous recorders is motivated by the need to monitor underwater noise, such as in response to the requirements of the European Union Marine Strategy Framework Directive. The performance of these systems is a crucial factor governing the quality of the measured data, providing traceability for future underwater noise-monitoring programs aimed at the protection of the marine environment from anthropogenic noise. In this paper, a discussion is presented of measurement methodologies for the key acoustic performance characteristics of the recorders, including self-noise, dynamic range, and the absolute sensitivity as a function of frequency of the hydrophone and recorder system.


The slow de-implementation of non-evidence-based treatments in low back pain hospital care-Trends in treatments using Dutch hospital register data from 1991 to 2018.
Low back pain (LBP) is the leading cause of disability worldwide and has an excessive societal burden. Accumulating evidence has shown that some medical approaches such as imaging in absence of clear indications, medication and some invasive treatments may contribute to the problem rather than alleviating it. To determine the extent of de-implementation of non-evidence-based hospital treatments for LBP care in the Netherlands in the last three decades. Using a register-based population-level observational study with Dutch hospital data, providing a nearly complete coverage of hospital admissions in the Netherlands in 1991-2018, we assessed five frequently applied non-evidence-based hospital treatments for LBP. Time trends in treatment use (absolute and per 100,000 inhabitants) were plotted and analysed using Poisson regression. The use of bed rest for non-specific LBP and hernia nuclei pulposi, and discectomy for spinal stenosis decreased 91%, 81% and 86% since the availability of evidence/guidelines, respectively. De-implementation, beyond 84%, was reached after 18 and 17 years for bed rest for non-specific LBP and discectomy respectively, while it was not reached after 28 years for bed rest for hernia nuclei pulposi. For spinal fusion and invasive pain treatment, there was an initial increase followed by a reduction. Overall, these treatments reduced by 85% and 75%, respectively. In the Netherlands, de-implementation of five non-recommended hospital LBP treatments, if at all, took several decades. Although de-implementation was substantial, slow de-implementation has likely resulted in considerable waste of resources and avoidable harm to many patients in Dutch hospitals. Medically intensive approaches to low-back pain care contribute to the high societal burden of this disease. There have been calls to avoid such care. Using Dutch hospital data, we showed that de-implementation of five non-recommended hospital low-back pain treatments, if at all, took several decades (i.e. ≥17 years) after availability of evidence and guidelines. Slow de-implementation has likely resulted in considerable waste of resources and avoidable harm to hospital patients; better ways for de-implementation of non-evidence-based care are needed.


Training on the Use of Technology to Collect Patient-Reported Outcome Data Electronically in Clinical Trials: Best Practice Recommendations from the ePRO Consortium.
Electronic capture of patient-reported outcome (PRO) data has many advantages over paper-based data collection. Regulatory agencies have consistently supported the use of electronic PRO (ePRO) data capture and recommended participant and site staff training on the correct use of electronic data capture systems. The objective of this paper is to outline best practice recommendations for training end users, including site staff and study participants, on the use of ePRO technology in clinical trials to enable consistent, accurate, and complete data collection. Site personnel should be trained on study-specific as well as technology-specific topics and be given instructions on whom to contact to obtain technical support. Optimal training takes place over time using multiple modalities, including hands-on, face-to-face training at an investigator meeting or directly in the clinical site; remote training via webinar or teleconference; interactive on-demand self-paced-training via e-learning modalities; and supplemented by proxy training performed by study clinical research associates. Like site personnel training, study participants should be provided with individual, hands-on training by site staff at the initiation of the trial and in conjunction with interactive electronic training modules that can be accessed on-demand throughout the duration of the trial. The recommendations put forth in this paper provide a structured framework for the training that site personnel and study participants need to optimize the advantages trials can gain from using ePRO data collection systems.


Clear cell sarcoma of soft tissue with plasmacytoid morphology: A rare case report.
Clear cell sarcoma of soft tissue (CCSST) is a rare malignant tumor that occurs in the extremities of young adults. CCSST has been documented to have atypical histopathological features, such as epidermotropism or myxoid differentiation, which may set pitfalls in the differential diagnosis. We report a case of CCSST with plasmacytoid morphology which has never been described. A 15-year-old male, presented with a 5-cm mass in his left inguinal area. Positron emission tomography-computed tomography examination showed nodules in the left groin and the lung, the latter was considered metastasis. A core needle biopsy with the diagnosis of CCSST with plasmacytoid morphology was made according to histology, immunostaining, and molecular analysis. The patient received chemotherapy of doxorubicin and ifosfamide. The patient failed to respond to the standard chemotherapy and deceased twelve months after diagnosis. This special case of CCSST with plasmacytoid features demonstrated a morphological variation never been documented and may easily lead to misdiagnosis. For such cases, molecular analysis is essential to provide solid evidence for accurate diagnosis.


Hot maté drinking and precancerous lesions of the oesophagus: an endoscopic survey in southern Brazil.
Thermal injury resulting from drinking very hot beverages has been incriminated as a risk factor for oesophageal cancer, although no information is available on the lesions caused by this injury in human or experimental animals. The drinking of hot maté tea is very common in areas of moderately high incidence of oesophageal cancer in south-eastern areas of South America. This study investigated the prevalence of precancerous lesions of the oesophagus in 60 unskilled male workers, of whom half were daily maté drinkers and the remainder were non-maté drinkers. These 2 groups were matched for age, smoking and alcohol intake. Maté drinkers were 2.2 times more likely (p = 0.046) to develop histologically confirmed oesophagitis than non-maté drinkers.


Pleural-based mesothelioma in immune competent rats: a model to study adenoviral gene transfer.
Despite multimodality approaches, pleural-based malignant mesothelioma remains a disease with a very poor prognosis. Novel therapeutic strategies such as gene therapy clearly are needed to improve the survival of patients with this neoplasm. To aid in the evaluation of new treatment strategies, animal models that closely mimic human disease are required. This article describes the establishment of a pleural-based model of malignant mesothelioma in immune-competent Fischer rats. Via a modified left anterior lateral thorocotomy, a syngeneic malignant mesothelioma cell line, called II-45, was placed into the pleural cavity of Fischer rats. Placement of II-45 cells into the pleural cavity of Fischer rats results in a model of pleural mesothelioma that closely resembles the disease seen in patients and is highly reproducible, with animals dying within 1 month. We also demonstrate the feasibility of adenoviral-mediated gene transfer to normal mesothelial cells lining the pleural cavity, as well as to malignant cells deep within the substance of pleural-based malignant mesothelioma. The model described here offers the opportunity to study a variety of new treatment modalities, especially somatic gene transfer, against pleural-based malignant mesothelioma in an immune competent setting.


Marine migrations.
There is great diversity in the animal species that migrate, the biomechanics that propel their locomotion and the ecosystems through which they transit. This diversity, however, is unified by a common condition: the relative suitability of places changes in predictable and cyclical ways. Owing to the periodicity of environmental change (e.g., seasons) and animal life-cycles (e.g., growth and maturation) locations become favorable, lose favorability and become favorable again at somewhat regular intervals. Migratory animals have adapted to these predictable fluctuations by moving among locations, sometimes over extraordinary distances (Figure 1).


The first gene of the Bacillus subtilis clpC operon, ctsR, encodes a negative regulator of its own operon and other class III heat shock genes.
The Bacillus subtilis clpC operon is regulated by two stress induction pathways relying on either sigmaB or a class III stress induction mechanism acting at a sigmaA-like promoter. When the clpC operon was placed under the control of the isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible Pspac promoter, dramatic repression of the natural clpC promoters fused to a lacZ reporter gene was noticed after IPTG induction. This result strongly indicated negative regulation of the clpC operon by one of its gene products. Indeed, the negative regulator could be identified which is encoded by the first gene of the clpC operon, ctsR, containing a predicted helix-turn-helix DNA-binding motif. Deletion of ctsR abolished the negative regulation and resulted in high expression of both the clpC operon and the clpP gene under nonstressed conditions. Nevertheless, a further increase in clpC and clpP mRNA levels was observed after heat shock, even in the absence of sigmaB, suggesting a second induction mechanism at the vegetative promoter. Two-dimensional gel analysis and mRNA studies showed that the expression of other class III stress genes was at least partially influenced by the ctsR deletion. Studies with different clpC promoter fragments either fused to the reporter gene bgaB or used in gel mobility shift experiments with the purified CtsR protein revealed a possible target region where the repressor seemed to bind in vivo and in vitro. Our data demonstrate that the CtsR protein acts as a global repressor of the clpC operon, as well as other class III heat shock genes, by preventing unstressed transcription from either the sigmaB- or sigmaA-dependent promoter and might be inactivated or dissociate under inducing stress conditions.