Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study.
Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown. Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC. Retrospective study of a uniformly treated cohort. Single institution retrospective cohort study. Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied. Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS). All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS. PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.


A Canadian cohort study of cognitive impairment and related dementias (ACCORD): study methods and baseline results.
The overall objective of the Canadian Collaborative Cohort of Related Dementias (ACCORD) study is to describe the diagnostic distribution, natural history and treatment outcomes of individuals referred from the community to dementia clinics in Canada. Between 1997 and 1999, an inception cohort of 1,136 subjects entered into this longitudinal study. At the baseline assessment, 10.9% of the subjects were classified as "not cognitively impaired" (NCI), 30.1% as "cognitively impaired not demented" (CIND), and 59% as demented. A subclassification of CIND included amnestic 25.1%, vascular cognitive impairment 18.1%, psychiatric 17.2%, neurologic 7.3%, medical/toxic metabolic 3.5%, mixed 7.6% and not specified 19.0%. The percentage of the cohort referred with dementia increased progressively each decade, while the proportions of CIND and NCI decreased. Within the dementia group, Alzheimer's disease accounted for 47.2% of the subjects, mixed dementias 33.7%, vascular dementia 8.7%, frontotemporal degenerations 5.4%, dementia with Lewy bodies 2.5%, and unclassifiable 1.8%. The ACCORD cohort will allow a detailed study of the longitudinal course of CIND, and the longer-term outcomes of both treated and untreated dementia subjects.


"Panic disorder" in schizophrenia.
A patient is described with operationally diagnosed chronic schizophrenia who simultaneously experienced repeated "attacks" during which times he had intense apprehension and autonomic hyperactivity entirely similar to that usually described under the rubric of "panic attacks" in nonschizophrenic patients. Delusional and hallucinatory symptoms were also transiently exacerbated during these episodes. Alprazolam, as an adjunct to fluphenazine decanoate, was effective in ameliorating these symptoms. Diagnostic and treatment implications are discussed.


Involvement of miR-451 in resistance to paclitaxel by regulating YWHAZ in breast cancer.
MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.


Intraocular and episcleral venous pressure increase during inverted posture.
We measured intraocular and episcleral venous pressure in 11 subjects in both the supine and the head-down vertical position. Gonioscopy was performed in eight subjects. The intraocular pressure changes were correlated with the alterations in episcleral venous pressure using linear regression analysis. We found that for each 0.83 +/- 0.21 mm Hg increase in episcleral venous pressure there was a rise of 1 mm Hg in intraocular pressure (r = .80, P = .003). Upon inversion, blood appeared in Schlemm's canal in half of the eyes studied with gonioscopy, suggesting that it refluxed into the canal from increased episcleral venous pressure. The mechanism of a sustained intraocular pressure rise during gravity inversion appears to be closely related to increased venous pressure in the orbit.


Membrane transformations in degenerating rodlet cells in fishes of two teleostean families (Salmonidae, Cyprinidae).
Rodlet cells (RCs) of teleosts are identified by their fibrillar capsule and peculiar inclusions, the rodlets, consisting of a club-like sac and a central dense core. Former ultrastructural studies showing signs of hypertrophy of endoplasmic reticulum (ER) were followed up in Salmonids (Oncorhynchus mykiss, Salmo trutta L.) and compared with Cyprinids (Cyprinus carpio L., Carassius auratus L., Alburnus alburnus). Focusing on membrane transformations, unusual undulations of the membranes of rodlet sacs and often apposed ER-membranes, which were observed in mature or discharging cells, increased continuously in degenerating stages and ejected cytoplasmic packages or rodlets. Tubular elements (ø 25-30 nm or 30-50 nm) or small vesicles appeared partly derived from them. Terminal stages of this development were represented by RCs retained in the epithelium, which were completely filled by stacks of tubules and cores. Convoluted membranes were also found persisting between mostly undissolved rodlets at the epithelial surfaces. In Cyprinid species, the membrane changes were less conspicuous but essentially similar, including stages with confluent ER reported only in trout up to now. The membrane transformations resemble structures known as "crystalloid ER" indicating a disturbance in the protein production. The positive immunocytochemical reaction for calreticulin in the rodlet sacs, a luminal ER chaperone mediating recycling of misfolded proteins and upregulated during stress, supports this interpretation. The ER stress-reaction is an evolutionary conservative cytoprotective mechanism during physiological, environmental, and genetic aberrations and fits the increase of RCs reported in quite different situations, although details of its triggering need further investigation.


Reconstruction of the posterior oblique ligament and the posterior cruciate ligament in knees with posteromedial instability.
Posterior cruciate ligament (PCL) injuries are often associated with injuries of the posteromedial structures of the knee. The motivation for this study was the attempt to test different reconstruction techniques for the structures of the posteromedial corner in a biomechanical experiment. Kinematic studies were carried out on 10 cadaveric knees exposed to a 134-N posterior tibial load, 10-Nm valgus torque, and 5-Nm internal torque at 0°, 30°, 60°, and 90° of flexion. The resulting posterior tibial translation (PTT) was determined using a robotic/universal force-moment sensor testing system for (1) intact knees, (2) PCL-deficient knees, (3) knees with deficiency of the PCL and the posteromedial structures, (4) knees with only the PCL reconstructed, (5) knees with the PCL and posterior oblique ligament (POL) reconstructed, and (6) knees with the PCL, medial collateral ligament (MCL), and POL reconstructed. Kinematic data were analyzed by a 2-factor repeated analysis of variance. When both the PCL and the posteromedial structures were cut, PTT increased significantly at all flexion grades under a posterior tibial load (P < .05). Reconstruction of only the PCL could not restore PTT at 0°, 30°, 60°, and 90° of flexion under loading conditions in a knee with combined injury of the PCL and the posteromedial structures (P > .05). Additional reconstruction of the POL improved PTT at all flexion angles in comparison with only the PCL-reconstructed knee. Reconstruction of the MCL had no significant effect on PTT. This study shows that reconstruction of the POL contributes significantly to the normalization of coupled PTT in knees with combined injury of the PCL and the posteromedial structures under valgus or internal rotational moment. The supplementary reconstruction of the MCL did not provide significant improvement in knee kinematics. The POL should be addressed in the patient with combined injuries of the PCL and the posteromedial structures.


Gestational Weight Gain Particularly Affects the Risk of Large for Gestational Age Infants in Non-obese Mothers.
Introduction The birth of a large for gestational age (LGA) infant is a significant risk factor for birth complications and maternal morbidity and an even higher risk factor for offspring obesity, metabolic syndrome and cardiovascular disease in later life. Relevant factors affecting the risk of delivering an LGA infant are maternal pre-gravid obesity, excessive gestational weight gain exceeding the recommendations of the Institute of Medicine (IOM) and diabetes in pregnancy. We aimed to determine what matters most in terms of the risk of fetal overgrowth. Materials and Methods We performed a database analysis of 12 701 singleton term deliveries documented in our university hospital birth registry from 2003 to 2014. Multivariate logistic regression analysis was used to determine the adjusted odds ratios. Results Excessive weight gain had the strongest impact on LGA (OR: 1.249 [95% CI: 1.018 - 1.533]) compared to maternal pre-gravid body mass index (BMI) (OR: 1.083 [95% CI: 1.066 - 1.099]) and diabetes (OR: 1.315 [95% CI: 0.997 - 1.734]). Keeping gestational weight gain within the recommendations of the IOM resulted in a risk reduction for LGA of 20% (OR: 0.801 [95% CI: 0.652 - 0.982]). The risk for LGA increases by 6.9% with each kg weight gain. Normal weight women (BMI 18.5 - 24.9 kg/m 2 ) and moderately overweight women (BMI 25 - 29.9 kg/m 2 ) showed the highest increase in LGA rates per kg weight gain during pregnancy (OR: 1.078 [95% CI: 1.052 - 1.104] and OR: 1.058 [95% CI: 1.026 - 1.09], resp.). Only in underweight (< 18.5 kg/m 2 ) and normal weight women the risk of LGA birth is strongly influenced by diabetes (OR 11.818 [95% CI: 1.156-120.782] and 1.564 [95% CI: 1.013-2.415]). Conclusion Excessive weight gain is particularly important for non-obese women. These women are therefore a target cohort for intervention, as each prevented additional kilogram weight gain reduces the risk of LGA by more than 5%.


Primary spinal extradural hydatid cyst.
We report a rare case of spinal cord compression caused by a primary extradural hydatid cyst.


Proximal contact loss between implant prostheses and adjacent natural teeth: A qualitative systematic review of prevalence, influencing factors and implications.
To evaluate the prevalence of proximal contact loss (PCL) between implant prostheses and natural teeth, and identify the risk factors and implications associated with PCL. PubMed (MEDLINE), Google Scholar, Cochrane Library Database, Scopus, EMBASE, Open Grey, ScienceDirect, and Web of Science were electronically searched to retrieve clinical studies on PCL around implant prostheses up to September 2021. A total of 19 studies were eligible. The short-term studies (less than 2 years) revealed a PCL prevalence of 11-30%, the medium-term studies (2-5 years) indicated a PCL prevalence of 13-65%, and the long-term studies (more than 5 years) showed a PCL prevalence of 29-83.3%. The likely influencing factors were the duration of service and the mesial location of proximal contacts. Other factors, such as occlusion, vitality of adjacent teeth, implant location, patient age and splinting had a less obvious relation to PCL. The reported implications of PCL were food impaction and patient dissatisfaction. Bone loss, peri-implant inflammation, bleeding on probing and pocket depth had a less clear association with PCL. PCL development between implant prostheses and natural teeth is frequent, inevitable and progressive. While the review identified several influencing factors and implications of PCL, future research is needed to outline the influence of prosthesis design on PCL and food impaction. Patients with implant prostheses should be informed about PCL likelihood and the risk of food impaction around implant prostheses. The proximal contact quality and its implications should be monitored during the review visits.


Spatiotemporal distribution of proliferation, proapoptotic and antiapoptotic factors in the early human limb development.
Involvement of proliferation and apoptosis in the human limb development was analyzed electronmicroscopically and immunohistochemically in histological sections of 8 human embryos, 4(th) -10(th) week old, using apoptotic (caspase-3, AIF, BAX), anti-apoptotic (Bcl-2) and proliferation (Ki-67) markers, and TUNEL method. The data were analyzed by Mann-Whitney test, Kruskal-Wallis and Dunn's post hoc test. Initially, developing human limbs consisted of mesenchymal core and surface ectoderm with apical ectodermal ridge (AER). During progression of development, strong proliferation activity gradually decreased in the mesenchyme (from 78% to 68%) and in the epithelium (from 62% to 42%), while in the differentiating finger cartilages proliferation was constantly low (26-7%). Apoptotic caspase-3 and AIF-positive cells characterized mesenchyme and AER at earliest stages, while during digit separation they appeared in interdigital mesenchyme as well. Strong Bcl-2 expression was observed in AER, subridge mesenchyme and phalanges, while BAX expression charaterized limb areas undergoing apoptosis. Ultrastructurally, proliferating cells showed mitotic figures, while apoptotic cells were characterized by nuclear fragmentation. Macrophages were observed around the apoptotic cells. We suggest that intense proliferation enables growth and elongation of human limb primordia, and differential growth of digits. Both caspase-3 and AIF-dependant pathways of cell death control the extent of AER and numer of cells in the subridge mesenchyme at earliest developmental stages, as well as process of digit separation at later stages of limb development. Spatio-temporal co-expresson of Bcl-2 and BAX indicates their role in suppression of apoptosis and selective stimulation of growth during human limb morphogenesis.


The role of NSAID in mediating the effect of genetically predicted major depressive disorder on osteomyelitis: A Mendelian randomization study.
Osteomyelitis and major depressive disorder (MDD) are significant health concerns with potential interconnections. However, the underlying mechanisms linking these conditions remain unknown. This study aimed to investigate the potential mediating role of non-steroidal anti-inflammatory drug (NSAID) medication in the association between MDD and the risk of osteomyelitis. We utilized summary data from large-scale genome-wide association studies (GWAS) to perform Mendelian randomization (MR) mediation analysis. Instrumental variables were selected based on genome-wide significance, and instrumental strength was assessed using F-statistics. Univariable and multivariable MR analyses were conducted to estimate causal effects and proportions mediated by NSAID medication. The univariable MR analysis revealed significant associations between MDD and osteomyelitis (odds ratio [OR] = 1.44, 95 % confidence interval [CI]: 1.18-1.874) and between MDD and NSAID medication (OR = 1.36, 95 % CI 1.24-1.49). In the multivariable MR analysis, the direct effect of MDD on osteomyelitis was OR 1.35 (95 % CI: 1.09, 1.67) after adjusting for NSAID medication. The proportion of mediation by NSAID medication was 23 % (95 % CI: 0.05 %, 38.6 %). This MR study provides evidence for a genetically predicted causal association between MDD, NSAID medication, and osteomyelitis. The findings emphasize the need for a comprehensive approach in managing individuals with comorbid depression and osteomyelitis, considering the potential risks and benefits of NSAID medication. Future research should address limitations and explore additional mediators and confounding factors to enhance understanding of this complex relationship.


Phenytoin effects on tissues of Mongolian gerbils (Meriones unguiculatus).
1. Phenytoin was intraperitoneally injected in six different experimental groups of adult Mongolian gerbils of both sexes at doses of 5, 100 and 150 mg/kg of body wt during 7 and 14 days. 2. Their brain, cerebellum, liver and kidney DNA, RNA and protein content were measured by conventional procedures. 3. The reference values of these rodents' cellular DNA were calculated through hepatocytes isolated following an intracardiac perfusion with collagenase in Hanks solution. 4. A concentration of 7.2 micrograms of DNA per 10(6) cells was found. 5. Phenytoin did not affect tissues of groups of animals receiving daily doses of 5 mg/kg of weight during 7 and 14 days of treatment; although a slight increase of protein concentration was observed in liver (P less than 0.01) and kidney (P less than 0.05). 6. RNA values were found to be significantly decreased in cerebellum (P less than 0.001), brain (P less than 0.05) and kidney (P less than 0.05) of those animals receiving the drug throughout 14 days. 7. DNA concentration was found to be decreased in all four tissues obtained from animals treated with daily doses of phenytoin of 100 (P less than 0.001) and 150 (P less than 0.001) mg/kg of body wt throughout 14 days. 8. These results indicate that phenytoin affected tissue cellularity only when administered at high doses and 14 days of interval of drug administration (P less than 0.001).


Serum Angptl2 levels are independently associated with albuminuria in type 2 diabetes.
Elevated serum Angptl2 levels are positively associated with the development of type 2 diabetes. We investigated whether serum Angptl2 levels are associated with diabetic nephropathy in patients with type 2 diabetes. Two hundred and thirty patients with type 2 diabetes and 63 healthy controls participated in this cross-sectional study. Subjects with type 2 diabetes were divided into three groups using urinary albumin-to-creatinine ratio (ACR): a normoalbuminuric group (n=57), a microalbuminuric group (n=130) and a macroalbuminuria group (n=43). Serum Angptl2 concentrations were measured by enzyme-linked immunosorbent assay. Median serum (interquartile range) Angptl2 levels in control subjects and patients with type 2 diabetes with normoalbuminuria, microalbuminuria and macroalbuminuria were 24.03 (16.3-33.45), 36.14 (27.91-43.07), 44.6 (37.47-49.92), 50.19 (45.95-60.13)ng/ml (p<0.01) respectively. Angptl2 levels correlated with urinary ACR in participants with type 2 diabetes (r=0.38, p<0.01). Significant intercorrelations of Angptl2 were found with age, duration of diabetes, and fasting plasma glucose. After adjustment for significant covariates, albuminuria was still significantly associated with Angptl2 levels in type 2 diabetes (r=0.31, p<0.01). Angptl2 levels are elevated in patients with type 2 diabetes with an independent association between increasing Angptl2 levels and increasing levels of albuminuria. This suggests a possible role of Angptl2 in progressive nephropathy in patients with type 2 diabetes.


Comparing the results of coagulation tests on blood drawn by venipuncture and through heparinized tunneled venous access devices in pediatric patients with cancer.
To compare the accuracy of three coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen [FBG]) performed on blood samples collected through heparinized tunneled venous access devices (TVADs) with those from venipuncture. Descriptive comparative with patients serving as their own controls. Pediatric comprehensive care setting for children and adolescents experiencing catastrophic diseases. 53 patients who had TVADs, had not received asparaginase during the previous 14 days, and had coagulation studies ordered. Patients ranged in age from 2-20 years (mean = 9.2 years, SD = 5). The most common diagnoses were neuroblastoma and acute myelocytic leukemia. Blood was collected through TVADs within seconds of collection of the venipuncture sample. The first 3 ml of blood from a TVAD was discarded; the research nurse then drew three sequential samples of 3 ml each. Laboratory personnel were blinded to the source of all four samples until all analyses had been completed. PT, aPTT, and FBG. For all patients, results of PT, aPTT, and FBG tests on each of the three blood samples obtained through the TVAD differed significantly from results of the same tests on blood obtained by venipuncture. These findings indicate that neither a 6 ml, 9 ml, nor 12 ml discard from a heparinized TVAD is sufficient to yield clinically trustworthy PT, aPTT, or FBG values. Nurses who have been persuaded by patients or parents to withdraw blood samples for coagulation indicators from a TVAD rather than from a venipuncture should have access to this research-based information that the three indicators, particularly aPTT, differ significantly from each other as to make it unreliable and potentially unsafe to sample blood from a TVAD to assess coagulation.


Splenectomy as a therapeutic approach in refractory hemophagocytic lymphohistiocytosis.
Zhang et al. have reported a case of an adult man with hemophagocytic lymphohistiocytosis (HLH) with an unknown etiology who has achieved a remission of HLH following comprehensive treatment based on splenectomy. In the present communication, the author critically discusses diagnostic and therapeutic issues related to the reported case, and questions utility of splenectomy in the treatment of active HLH.


Effect of nitrogen amendment on respiration and respiratory quotient (RQ) in three hydrocarbon contaminated soils of different type.
Three soil types (sandy gravel, silty clay and sandy loam) from sites historically contaminated with total petroleum hydrocarbon (TPH) were amended with NH(4)NO(3) at concentrations ranging from 16 to 2133 mg/kg soil(dry weight). Microbial activity was measured as O(2) consumption and CO(2) production in order to assess nitrogen limitation. Although activity was stimulated in all three soils under NH(4)NO(3) amendment (after 72 h), the level of nitrogen required was soil specific. For the sandy gravel and silty clay soils, O(2) consumption and CO(2) production both showed enhanced microbial activity when amended with 16 mg/kg soil(dry weight) NH(4)NO(3), whereas, these two parameters gave differing results for the sandy loam soil. Specifically, CO(2) production and O(2) consumption were stimulated with 66 mg/kg and 133 mg/kg soil(dry weight) of NH(4)NO(3) respectively. In addition, respiratory quotient kinetic analysis suggested different decomposition processes occurring in this soil under different NH(4)NO(3) amendment concentrations.


National Institutes of Health Update: Translating Basic Behavioral Science into New Pediatric Obesity Interventions.
Pediatric obesity increases the risk of later-life obesity and chronic diseases. Basic research to better understand factors associated with excessive weight gain in early life and studies translating research findings into preventive and therapeutic strategies are essential to our ability to better prevent and treat childhood obesity. This overview describes several National Institutes of Health efforts designed to stimulate basic and translational research in childhood obesity prevention and treatment. These examples demonstrate the value of research in early phase translational pediatric obesity research and highlight some promising directions for this important area of research.


A Systematic Review and Meta-Analysis of Long-Term Outcomes After Septal Reduction Therapy in Patients With Hypertrophic Cardiomyopathy.
The aim of this meta-analysis was to compare long-term outcomes after myectomy and alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM). Surgical myectomy and ASA are both accepted treatment options for medical therapy-resistant obstructive HCM. Previous meta-analyses only evaluated short-term outcomes. A systematic review was conducted for eligible studies with a follow-up of at least 3 years. Primary outcomes were all-cause mortality and (aborted) sudden cardiac death (SCD). Secondary outcomes were periprocedural complications, left ventricular outflow tract gradient, and New York Heart Association functional class after ≥3 months, and reintervention. Pooled estimates were calculated using a random-effects meta-analysis. Sixteen myectomy cohorts (n = 2,791; mean follow-up, 7.4 years) and 11 ASA cohorts (n = 2,013; mean follow-up, 6.2 years) were included. Long-term mortality was found to be similarly low after ASA (1.5% per year) compared with myectomy (1.4% per year, p = 0.78). The rate of (aborted) SCD, including appropriate implantable cardioverter defibrillator shocks, was 0.4% per year after ASA and 0.5% per year after myectomy (p = 0.47). Permanent pacemaker implantation was performed after ASA in 10% of the patients compared with 4.4% after myectomy (p < 0.001). Reintervention was performed in 7.7% of the patients who underwent ASA compared with 1.6% after myectomy (p = 0.001). Long-term mortality and (aborted) SCD rates after ASA and myectomy are similarly low. Patients who undergo ASA have more than twice the risk of permanent pacemaker implantation and a 5 times higher risk of the need for additional septal reduction therapy compared with those who undergo myectomy.


Does the polymorphism 677C-T of the 5,10-methylenetetrahydrofolate reductase gene contribute to homocysteine-related vascular disease?
Whether the 677C-T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene acts as a risk factor for homocysteine-related vascular disease remains a matter of debate. Testing for the 677C-T nucleotide substitution and assay of plasma homocysteine were carried out simultaneously in 69 controls and 113 vascular disease patients from the Paris area. The variant gene frequency as well as the variant homozygous genotype frequency were very similar in controls and patients. Conversely, plasma homocysteine levels were substantially higher in patients than in controls. A slight interaction between the 677C-T MTHFR polymorphism and homocysteinaemia was observed in the patient group only, while a negative correlation between fasting homocysteine and plasma folate levels was found in all individuals homozygous for the 677C-T MTHFR genotype, irrespective of vascular disease. These data suggest that the 677C-T MTHFR polymorphism is not a major determinant of the vascular disease but contributes to increased plasma homocysteine concentration in conjunction with low plasma folate levels.


"Watch out for the gerbils, my child!" the role of maternal information on children's fear in an experimental setting using real animals.
Using an experimental approach, we examined the effects of verbal information as provided by the mothers on children's fear of real novel animals. Mothers of children aged 8 to 12 years (N=47) were shown a cage containing a pair of exotic rodents (i.e., Mongolian gerbils) and then received either positive or negative information about these animals. Mothers were told that their child would have to approach the animals and had the opportunity to prepare their children for this confrontation. Results showed that mothers spontaneously passed over the information they had received to their children. Most importantly, this information to some extent determined children's fear reactions towards the animals. That is, whereas no clear effects of information were found on subjective fear ratings, the data did indicate that children of mothers in the negative information condition were more reluctant to approach the animals as compared to children of mothers who had received positive information. The findings provide further support for the idea that verbal information as provided by parents may induce fear in their offspring.


A movement criterion for running.
The adjustment of the leg during running was addressed using a spring-mass model with a fixed landing angle of attack. The objective was to obtain periodic movement patterns. Spring-like running was monitored by a one-dimensional stride-to-stride mapping of the apex height to identify mechanically stable fixed points. We found that for certain angles of attack, the system becomes self-stabilized if the leg stiffness was properly adjusted and a minimum running speed was exceeded. At a given speed, running techniques fulfilling a stable movement pattern are characterized by an almost constant maximum leg force. With increasing speed, the leg adjustment becomes less critical. The techniques predicted for stable running are in agreement with experimental studies. Mechanically self-stabilized running requires a spring-like leg operation, a minimum running speed and a proper adjustment of leg stiffness and angle of attack. These conditions can be considered as a movement criterion for running.


Therapeutic doses of acetaminophen stimulate the turnover of cysteine and glutathione in man.
In spite of the importance of glutathione (GSH) in the detoxification of toxic metabolites of drugs, virtually nothing is known about the regulation of hepatic GSH homeostasis in man. In order to estimate the turnover of hepatic GSH and to assess the effect of different doses of acetaminophen (paracetamol) on the synthesis of GSH in man, [3H]cystine and varying doses of acetaminophen were administered to healthy volunteers, and the time course of the specific activity of the cysteine moiety of N-acetylcysteinyl-acetaminophen excreted in urine was followed. The fractional rate of turnover of the tracer in N-acetylcysteinyl-acetaminophen increased significantly from 0.031 +/- 0.007 h-1 after doses of acetaminophen ranging from 50 to 300 mg to 0.045 +/- 0.011 and 0.121 +/- 0.027 h-1 following 600 and 1200 mg of acetaminophen, respectively. The data indicate that therapeutic doses of acetaminophen markedly stimulate the rate of turnover of the pool of cysteine available for the synthesis of GSH, most likely due to an increased rate of synthesis of GSH which is required to detoxify the toxic metabolite of acetaminophen. Patients who are not able to respond to a similar demand on their stores of GSH by increasing the synthesis of GSH may be at higher risk of developing hepatic injury from drugs that require GSH for their detoxification.


Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.
Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women's health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in "normal" vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast cancer patients should avoid red clover and isoflavone based BDSs when making choices for menopausal symptom relief.


3D fractures analysis and conservation assessment of wrought iron javelin through advanced non-invasive techniques.
3D imaging is a powerful tool of high resolution and non-destructive imaging technology for the study of ancient weapons and military technology, which reveals the original microstructures and corrosion patterns that threaten these artefacts. Here we report quantitative analysis of the 3D distribution and the orientation of fractures, and uncorroded metal particles within a wrought iron javelin unearthed at the Phoenician-Punic site of Motya, Italy. The study aimed to gain a better understanding of the relationship between corrosion and local stresses within the artifact and to evaluate its manufacturing technology, as well as the effects of post-treatment with Paraloid B72 on concretion and mineralized layers. The cracks were quantified in terms of content, size, and orientation. The condition of artefact storage was evaluated by a multi-analytical approach, including X-ray microscopy, field emission electron microscopy and micro-Raman spectroscopy. The results indicated that a specific technique was used to create a sturdy, lightweight javelin with a central shaft for piercing or thrusting. The fractures appear elongated in the direction of the longitudinal axis of the blade, showing the forging direction of the original metallic block. The study concluded that the artifact had not yet been stabilized due to the presence of lepidocrocite.


Organismal Fructose Metabolism in Health and Non-Alcoholic Fatty Liver Disease.
NAFLD has alarmingly increased, yet FDA-approved drugs are still lacking. An excessive intake of fructose, especially in liquid form, is a dietary risk factor of NAFLD. While fructose metabolism has been studied for decades, it is still controversial how fructose intake can cause NAFLD. It has long been believed that fructose metabolism solely happens in the liver and accordingly, numerous studies have investigated liver fructose metabolism using primary hepatocytes or liver cell lines in culture. While cultured cells are useful for studying detailed signaling pathways and metabolism in a cell-autonomous manner, it is equally important to understand fructose metabolism at the whole-body level in live organisms. In this regard, recent in vivo studies using genetically modified mice and stable isotope tracing have tremendously expanded our understanding of the complex interaction between fructose-catabolizing organs and gut microbiota. Here, we discuss how the aberrant distribution of fructose metabolism between organs and gut microbiota can contribute to NAFLD. We also address potential therapeutic interventions of fructose-elicited NAFLD.


The natural history of chronic limb-threatening ischemia after technical failure of endovascular intervention.
The treatment for chronic limb-threatening ischemia (CLTI) has changed dramatically in the last few decades with a shift toward an endovascular-first approach and aggressive revascularization to achieve limb salvage. As the size of the CLTI population and intervention rates increase, patients will continue to experience technical failure (TF). Here, we describe the natural history of patients after TF of endovascular intervention for CLTI. We conducted a retrospective cohort study of patients with CLTI who attempted endovascular intervention or bypass at our multidisciplinary limb salvage center from 2013 to 2019. Patient characteristics were collected according to the Society for Vascular Surgery's reporting standards. Primary outcomes included survival, limb salvage, wound healing, and revascularization patency. Product-limit Kaplan-Meier estimated survival functions for these outcomes, and between-group comparisons were made using Mantel-Cox log-rank nonparametric tests. We identified 242 limbs from 220 unique patients who underwent primary bypass (n = 30) or attempted endovascular intervention (n = 212) at our limb salvage center. Endovascular intervention was a TF in 31 (14.6%) limbs. After TF, 13 limbs underwent secondary bypass and 18 limbs were managed medically. Patients who experienced TF tended to be older (P < .001), male (P = .003), current tobacco users (P = .014), have longer lesions (P = .001), and have chronic total occlusions of target arteries (P < .001) as compared with those who experienced technical success. Furthermore, the TF group had worse limb salvage (P = .047) and slower wound healing (P = .028), but their survival was not different. Survival, limb salvage, and wound healing were not different in patients who received secondary bypass or medical management after TF. The secondary bypass group was older (P = .012) and had a lower prevalence of tibial disease (P = .049) than the primary bypass group and trended toward decreased survival, limb salvage, and wound healing (P = .059, P = .083, and P = .051, respectively). Increased age, male sex, current tobacco use, longer arterial lesions, and occluded target arteries are associated with TF of endovascular intervention. Limb salvage and wound healing are relatively poor after TF of endovascular intervention, but survival appears comparable with patients who experience technical success. Secondary bypass may not always rescue patients after TF, though our sample size limits statistical power. Interestingly, patients who received a secondary bypass after TF trended toward decreased survival, limb salvage, and wound healing compared with primary bypass.


Association between First-Generation Antihistamine Use in Children and Cardiac Arrhythmia and Ischemic Heart Disease: A Case-Crossover Study.
Cardiotoxicity from first-generation H1-antihistamines has been debated since the 1990s. However, large-scale studies on this topic in a general pediatric population are lacking. This study aimed to assess the association between first-generation H1-antihistamine use and cardiovascular events in a nationwide pediatric population. In this case-crossover study, the main cohort included children with cardiovascular events from the National Health Insurance Service database (2008-2012 births in Korea) until 2018. The second cohort excluded children with specific birth histories or underlying cardiovascular diseases from the main cohort. Cardiovascular events of interest included cardiac arrhythmia and ischemic heart disease. Odds ratios (ORs) of cardiovascular events were estimated using conditional logistic regression models, comparing first-generation H1-antihistamine use during 0-15 days before cardiovascular events (hazard period) with use during 45-60 and 75-90 days before events (control periods). Among the participants, 1194 (59.9%) were aged 24 months to 6 years, and 1010 (50.7%) were male. Cardiovascular event risk was increased among users of first-generation H1-antihistamines (adjusted OR [aOR], 1.201; 95% confidence interval, 1.13-1.27). Significant odds of cardiovascular events persisted within 10 and 5 days (aOR, 1.25 and 1.25). In the second cohort, the association was comparable with that in the main cohort. Our findings indicate that cardiovascular event risk is increased in children who are administered first-generation H1-antihistamines.


Accuracy of four types of rubber impression materials compared with time of pour and a repeat pour of models.
The accuracy of four types of elastomeric impression materials was studied as a function of model location, time of pouring, and repetition of pouring. There was little change in dimension among abutment preparations for all materials, for all times of pour, and with a repeat pouring. It appears that measurements between posts are not sensitive to detecting differences between materials and that other dimensions should be examined to discern where differences might lie. The diameter of the stone post was larger than the standard for the AS and PS materials and was unchanged or smaller than the standard for the CS and the PE. The vertical dimensions of stone posts were, in general, shorter than the standard for all materials, with the AS demonstrating the smallest change. The AS and CS products demonstrated the best recovery from undercuts and the least change in dimensions between an initial and second pour of an impression. The AS and PE were the least affected with delays of 1, 4, and 24 hours in pouring the impression.


Assessing most practical and effective protocols to sanitize hands of poultry catching crew members.
Catching crew members can heavily contaminate their hands with organic material. They can act as mechanical vector and spread diseases between farms. Hand hygiene is an important issue for the industry as a whole and for human health by reducing contamination risks. Many studies, in human medicine, tend to make hand rub a standard for hand hygiene. However, few studies have tested the effectiveness of hand hygiene products on visibly contaminated hands. The objective of this study was to evaluate the effectiveness of practical hand sanitization protocols: water and soap, degreasing cream and hand wipes, all combined with alcohol-based hand gel. The use of alcohol-based gel alone was also evaluated. For the reduction of coliforms after washing, there was no statistically significant difference between protocols when the initial level of bacterial contamination was low to moderate. When hands were highly contaminated, the alcohol-based gel alone was less effective than the degreasing cream combined with the alcohol-based gel (p=0.002). As for the reduction in total aerobic bacteria counts, there was no difference between protocols when the initial level of bacterial contamination was low. The water, soap and alcohol-based gel protocol was more effective than the scrubbing wipes and alcohol-based gel protocol when hands were moderately (p=0.002) and highly contaminated (p=0.001). All protocols were effective in neutralizing Salmonella on hands. Reducing the level of bacterial contamination on hands before using an alcohol-based gel seems important to ensure effective hand sanitation for highly and moderately contaminated hands. This can be done by using a degreasing cream or water and soap. Based on the survey, catching crew members preferred using warm water and soap compared to a degreasing cream.


Functional promoter -308G>A variant in tumor necrosis factor α gene is associated with risk and progression of gastric cancer in a Chinese population.
Tumor necrosis factor-α (TNF-α) plays a crucial role in the development and progression of gastric cancer. A functional polymorphism, -308 G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. In the present study, we sought to investigate whether this polymorphism has effects on the risk and progression of gastric cancer in a Chinese population. We genotyped the TNFA -308 G>A polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with occurrence and progression of gastric cancer. We found a significant association between the variant genotypes and increased risk of gastric cancer [P = 0.034, odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.01-1.67, GA/AA vs. GG]. Similar results were observed in the follow-up replication study. When combined the data from the two studies, we found a more significant association (P = 0.001, OR = 1.34, 95%CI = 1.13-1.59), especially for older subjects (>65 years). Furthermore, the patients carrying the variant genotypes had a significantly greater prevalence of T4 stage of disease (P = 0.001, OR = 2.19, 95%CI = 1.39-3.47) and distant metastasis (P = 0.013, OR = 1.61, 95%CI = 1.10-2.35). Our results suggest that the functional promoter -308 G>A polymorphism in TNFA influence the susceptibility and progression of gastric cancer in the Chinese population.


Digiscan activity: automated measurement of thigmotactic and stereotypic behavior in rats.
Visual measures of stereotypy, margin time (thigmotaxis or wall-hugging), and center time were correlated with automated measures using a revised 16 beam version of the Digiscan Animal Activity Monitor System. Rats were injected with d-amphetamine (1.25, 2.5, 5.0 and 10.0 mg/kg), scopolamine (1.25 and 2.5 mg/kg) or saline and drugs were found to increase center time and decrease margin time in a dose-dependent manner, with the maximum effect occurring with 1.25 and 2.5 mg/kg, respectively. At higher doses, an opposite effect was observed. Extremely high correlations between visual and automated recordings of both margin time and center time were found. Since thigmotaxic or wall-hugging behavior has been used as an indicator of emotionality in rats, the results of the present study suggest that these two locomotor variables may be useful additions to the Digiscan multivariate analysis of locomotor behavior. It was also found that a redefinition of stereotypic behavior improved its correlation with visual measurements compared to earlier studies.


Prey availability and eclosion-help of callow workers in the formicine ant Camponotus mus.
In the ant Camponotus mus the eclosion of imagines from the cocoons was shown to be controlled by nurse workers, which broke the cocoons and assisted the callows to energe. Short-term colony prey deprivation modified the eclosion-help behavior resulting in a delay in cocoon opening times. During long-term prey deprivation, no new cocoons were spun; the starved larvae grew and pupated when prey was again available. These findings as a colony strategy adapted to the changing condition of prey availabitity in a temperate habitat are discussed.


Resonance light scattering sensor of the metal complex nanoparticles using diethyl dithiocarbamate doped graphene quantum dots for highly Pb(II)-sensitive detection in water sample.
This study was aimed to detect Pb2+ using diethyl dithiocarbamate-doped graphene quantum dots (DDTC-GQDs) based pyrolysis of citric acid. The excitation maximum wavelength (λmax, ex = 337 nm) of the DDTC-GQDs solution was blue shift from bare GQDs (λmax, ex = 365 nm), with the same emission maximum wavelength (λmax, em = 459 nm) indicating differences in the desired N, S matrices decorating in the nanoparticles. Their resonance light scattering intensities were peaked at the same λmax, ex/em = 551/553 nm without any background effect of both ionic strength and masking agent. Under optimal conditions, the linear range was 1.0-10.0 μg L-1 (R2 = 0.9899), limit of detection was 0.8 μg L-1 and limit of quantification was 1.5 μg L-1. The precision, expressed as the relative standard deviations, for intra-day and inter-day analyses was 0.87% and 4.47%, respectively. The recovery study of Pb2+ for real water samples was ranged between 80.8% and 109.5%. The proposed method was also proved with certified water sample containing 60 μg L-1 Pb2+ giving an excellent accuracy and was then implied satisfactorily for ultra-trace determination of Pb2+ in drinking water and tap water samples.


The role of noncoding RNAs in metabolic reprogramming of cancer cells.
Metabolic reprogramming is a well-known feature of cancer that allows malignant cells to alter metabolic reactions and nutrient uptake, thereby promoting tumor growth and spread. It has been discovered that noncoding RNAs (ncRNAs), including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), have a role in a variety of biological functions, control physiologic and developmental processes, and even influence disease. They have been recognized in numerous cancer types as tumor suppressors and oncogenic agents. The role of ncRNAs in the metabolic reprogramming of cancer cells has recently been noticed. We examine this subject, with an emphasis on the metabolism of glucose, lipids, and amino acids, and highlight the therapeutic use of targeting ncRNAs in cancer treatment.


Drug interactions in primary health care. A retrospective database study and its implications for the design of a computerized decision support system.
To investigate the occurrence of potential drug interactions in primary health care from the perspective of the prescribing general practitioner. Retrospective database study of computer-based patient records with a query language. All drug prescriptions during a four year period were compared with concurrent or overlapping prescriptions for the same patient and these drug pairs were compared with a database of drug interactions from the Swedish drug catalogue. One health centre in Sweden with six general practitioners and two doctors on vocational training. All patients who had visited a doctor at the health centre between 1 November 1986 and 31 October 1990. The rate of potential interactions in relation to all drug prescriptions and the incidence rate of potential interactions for patients at risk (those receiving two or more drugs). Approximately 55,000 drug prescriptions were analysed for potential drug interactions. A total of 1,074 cases of potential drug interactions were found, which corresponds to a rate of 1.9% of all drug prescriptions. The incidence rate of potential interactions was 12% for all patients at risk (those receiving two or more drugs) and 22% for elderly (> = 65 years of age) patients at risk. Major interactions were investigated concerning the extent to which the prescribing doctors were aware of the potential interactions. Potential drug interactions occur at a high rate in general practice, in particular for elderly patients. Properly designed computer-based decision-support might increase the prescribing doctor's awareness of clinically significant interactions and improve the quality of drug treatment.


Nuclear accumulation of p53 in colorectal adenocarcinoma: prognostic importance differs with race and location of the tumor.
Although several studies have been conducted to examine the role of p53 genetic abnormalities and their prognostic value in colorectal carcinoma, the incidence of nuclear accumulation of p53 and the prognostic importance of nuclear accumulation of p53 in African-American and white patients have not been investigated separately. Therefore, the authors evaluated the prognostic significance of p53 nuclear accumulation in these two racial groups. Nuclear accumulation of p53 was evaluated immunohistochemically in archival tissue specimens from 204 African-American and 300 white patients with primary colorectal adenocarcinomas who had undergone surgery. Survival times from colorectal adenocarcinoma were analyzed using Kaplan-Meier survival estimates and the Cox proportional hazards model for nuclear accumulation of p53 with adjustments for other confounding demographic and clinical variables. Approximately equivalent proportions of distal (54%) and proximal adenocarcinomas (47%) were positive for nuclear accumulation of p53 in African-American patients. In contrast, distal colorectal adenocarcinomas from white patients more frequently were positive for nuclear accumulation of p53 than adenocarcinomas of the proximal colon (63% vs. 38%, respectively). Nuclear accumulation of p53 was found to be a strong predictor of poor survival in white patients (hazard ratio = 6.77; P = 0.0001) but not in African-American patients with primary adenocarcinomas of the proximal colon. Nuclear accumulation of p53 was not of prognostic value in patients of either race with primary adenocarcinomas of the distal colorectum. Nuclear accumulation of p53 is a valuable indicator of poor prognosis only for white patients with adenocarcinomas of the proximal colon. The current study also suggests that the role of p53 dysregulation in colorectal adenocarcinomas may vary with the anatomic location of the tumor and the race of the patient. These findings suggest that the demographic characteristics of patients should be considered in the evaluation of prognostic markers of colorectal neoplasia.


Activity of Tissue Factor in Microparticles Produced in vitro by Endothelial Cells, Monocytes, Granulocytes, and Platelets.
Activity of tissue factor (TF) in membrane microparticles (MPs) produced in vitro by endothelial cells (ECs), monocytes, THP-1 monocytic cells, granulocytes, and platelets was investigated. ECs were isolated from human umbilical vein, and monocytes, granulocytes, and platelets - from the blood of healthy donors. ECs, monocytes, and THP-1 cells were activated by bacterial lipopolysaccharide, granulocytes - by lipopolysaccharide or phorbol myristate acetate, and platelets - by SFLLRN, thrombin receptor-activating peptide. MPs were sedimented from the culture medium or supernatant of activated cells at 20,000g for 30 min. Coagulation activity of MPs was analyzed in a modified recalcification assay by assessing their effects on coagulation of donor plasma depleted of endogenous MPs (by centrifuging at 20,000g for 90 min). MPs from all cell types accelerated plasma coagulation. Antibodies blocking TF activity prolonged coagulation lag-phase in the presence of MPs from ECs, monocytes, and THP-1 cells (by 2.7-, 2.0-, and 1.8-fold, respectively), but did not influence coagulation in the presence of MPs from granulocytes and platelets. In accordance with these data, TF activity measured by its ability to activate factor X was found in MPs from ECs, monocytes, and THP-1 cells, but not in MPs from granulocytes and platelets. The data obtained indicate that active TF is present in MPs produced in vitro by ECs, monocytes, and THP-1 cells, but not in MPs derived from granulocytes and platelets.


Towards the development of phytoextract based healthy ageing cognitive booster formulation, explored through Caenorhabditis elegans model.
The positive effect of herbal supplements on aging and age-related disorders has led to the evolution of natural curatives for remedial neurodegenerative diseases in humans. The advancement in aging is exceedingly linked to oxidative stress. Enhanced oxidative stress interrupts health of humans in various ways, necessitating to find stress alleviating herbal resources. Currently, minimal scientifically validated health and cognitive booster resources are available. Therefore, we explored the impact of plant extracts in different combinations on oxidative stress, life span and cognition using the multicellular transgenic humanized C. elegans, and further validated the same in Mus musculus, besides testing their safety and toxicity. In our investigations, the final product-the HACBF (healthy ageing cognitive booster formulation) thus developed was found to reduce major aging biomarkers like lipofuscin, protein carbonyl, lipid levels and enhanced activity of antioxidant enzymes. Further confirmation was done using transgenic worms and RT-PCR. The cognitive boosting activities analyzed in C. elegans and M. musculus model system were found to be at par with donepezil and L-dopa, the two drugs which are commonly used to treat Parkinson's and Alzheimer's diseases. In the transgenic C. elegans model system, the HACBF exhibited reduced aggregation of misfolded disease proteins α-synuclein and increased the health of nicotinic acetylcholine receptor, levels of Acetylcholine and Dopamine contents respectively, the major neurotransmitters responsible for memory, language, learning behavior and movement. Molecular studies clearly indicate that HACBF upregulated major genes responsible for healthy aging and cognitive booster activities in C. elegans and as well as in M. musculus. As such, the present herbal product thus developed may be quite useful for healthy aging and cognitive boosting activities, and more so during this covid-19 pandemic. The online version contains supplementary material available at 10.1007/s13237-022-00407-1.


Renal function in sheep during infusion of alkali metal ions into the renal artery.
1. The effect on renal function of 1 M solutions of LiCl, NaCl, KCl, RbCl and CsCl and 3 M-NaCl infused close-arterially to the kidney for 10 min at 0-7ml./min has been studied in nine experiments on four unilaterally nephrectomized sheep. The levels of flow, electrolyte concentration and electrolyte excretion in the urine were measured before, during and for 50 min after the infusions. 2. The infusion of 1-M-NaCl produced little change in urine flow and composition whereas 3 M-NaCl resulted in relatively small increases in urine flow and sodium excretion. 3. The infusion of lithium, potassium, rubidium and caesium resulted in marked increases in urine flow, urinary sodium concentration and excretion, urinary potassium excretion and osmolal clearance while the urinary potassium concentration decreased. 4. Changes in urine flow and urinary pH during the infusions of all the alkali ions except sodium were consistent with increased urinary bicarbonate excretion. 5. The osmolal clearance was increased by the infusion of lithium, potassium, rubidium and caesium, but equivalent increases in the rate of solutefree water reabsorption did not occur. 6. The infusion of caesium resulted in a depression of the glomerular filtration rate (G.F.R.) which was not observed when the other alkali ions were infused. 7. The effects of lithium, potassium and rubidium on urine flow and composition were rapid in onset and the residual effects on these ions, on cessation of infusion, were relatively short. The effects on caesium were slow in onset and prolonged in duration. 8. It was concluded that lithium, potassium, rubidium, and caesium altered urine flow and electrolyte excretion by acting upon common mechanisms which were predominantly intra-renal and located in the proximal segment of the nephron.


A draft genome, resequencing, and metabolomes reveal the genetic background and molecular basis of the nutritional and medicinal properties of loquat (Eriobotrya japonica (Thunb.) Lindl).
Loquat (Eriobotrya japonica) is a popular fruit and medicinal plant. Here, a high-quality draft genome of the E. japonica 'Big Five-pointed Star' cultivar that covers ~98% (733.32 Mb) of the estimated genome size (749.25 Mb) and contains a total of 45,492 protein-coding genes is reported. Comparative genomic analysis suggests that the loquat genome has evolved a unique genetic mechanism of chromosome repair. Resequencing data from 52 loquat cultivars, including 16 white-fleshed and 36 yellow-fleshed variants, were analyzed, and the flower, leaf, and root metabolomes of 'Big Five-pointed Star' were determined using a UPLC-ESI-MS/M system. A genome-wide association study identified several candidate genes associated with flesh color in E. japonica, linking these phenotypes to sugar metabolism. A total of 577 metabolites, including 98 phenolic acids, 95 flavonoids, and 28 terpenoids, were found, and 191 metabolites, including 46 phenolic acids, 33 flavonoids, and 7 terpenoids, showed no differences in concentration among the leaves, roots, and flowers. Candidate genes related to the biosynthesis of various medicinal ingredients, such as phenolics, flavonoids, terpenoids, and polysaccharides, were identified. Some of these genes were confirmed to be members of expanding gene families, suggesting that the high concentrations of beneficial metabolites in loquat may be associated with the number of biosynthetic genes in this plant. In summary, this study provides fundamental molecular insights into the nutritional and medical properties of E. japonica.


Is There a Role of Using a Rapid Finger Prick Antibody Test in Screening for Celiac Disease in Children?
Celiac disease (CD) is an autoimmune disease triggered by gluten in genetically predisposed individuals. Despite the increasing prevalence of CD, many patients remain undiagnosed. Standard serology tests are expensive and invasive, so several point-of-care tests (POC) for CD have been developed. We aimed to determine the prevalence of CD in first-grade pupils in Primorje-Gorski Kotar County, Croatia, using a POC test. A Biocard celiac test that detects IgA antibodies to tissue transglutaminase in whole blood was used to screen for celiac disease in healthy first-grade children born in 2011 and 2012 who consumed gluten without restrictions. 1478 children were tested, and none of them were tested positive with a rapid test. In 10 children (0,6%), IgA deficiency has been suspected; only 4 of them agreed to be tested further for total IgA, anti-tTG, and anti-DGP antibodies. IgA deficiency was confirmed in 3 patients, and in all 4 children, CD has been excluded. Our results have not confirmed the usefulness of the POC test in screening the general population of first-grade schoolchildren. Further research is needed to establish the true epidemiology of CD in Primorje-Gorski Kotar County and to confirm the value of the rapid test in comparison with standard antibody CD testing.


Elucidation of Neu-P11 metabolism in urine of volunteers by liquid chromatography-tandem mass spectrometry.
The novel melatonin agonist Neu-P11 is used in treatment of physiological insomnia. In animal studies Neu-P11 showed sleep-promoting effects. In a phase 1 study Neu-P11 was administered to cohorts of healthy young male volunteers in an ascending single dose study. Up to now the metabolism of this new drug in humans has not been investigated. The first aim of this study was to identify possible metabolites in pooled urine samples of the first collecting period (0-8 h) of volunteers with the highest Neu-P11 oral dosage (200 mg). The objective of the second part of the study was to estimate the concentrations of the main metabolites of Neu-P11 - in this urine sample. The analyte Neu-P11 and metabolites were separated from human urine using dilution and precipitation with acetonitrile. Samples were analyzed for formation of both phase I and phase II metabolites using LC-MS/MS in precursor ion mode, product ion mode, neutral loss mode and the multi-reaction monitoring mode (MRM). Urine samples were analyzed before and after addition of beta-glucuronidase and sulfatase. In the pooled urine sample eight metabolites could be proved. The parent drug, the sulfated demethylated Neu-P11, the sulfated 6OH-Neu-P11 and the di-oxygenated product gave the highest signals in these urine samples and probably had the highest concentration. But quantification without reference substances is not possible. So in the second part of the study the urine samples were additionally analyzed with UV-detection for a better estimation of the metabolite concentrations. The concentration of the sulfated metabolites was more than ten times higher than the concentration of the unchanged drug in urine. Other metabolites were not measurable with UV-detection. The di-oxygenated Neu-P11 and an additional mono-oxygenated Neu-P11 showed relatively high signals in MS/MS. Probably the other metabolites, namely glucuronides, unconjugated demethylated Neu-P11 and unconjugated 6OH-Neu-P11, were formed at a lesser extent.


Solubility, partitioning, oxidation and photodegradation of dichloroacetamide herbicide safeners, benoxacor and furilazole.
Approximately 242 million kg of herbicides are applied in the United States (US) annually. While herbicides prevent the growth of weeds, they can damage crops resulting in so called "herbicide injury." To increase herbicidal tolerance of crops, herbicide safeners are commonly added to formulations. Herbicidal safeners are labeled as inert ingredients in herbicide formulations and typically minimal fate and transport information is available. The objective of this study is to experimentally derive the aqueous solubility, octanol-water partition coefficient, and photo-degradation and permanganate oxidation of two dichloroacetamide safeners, benoxacor and furilazole. These results can be used to understand the environmental chemodynamics of these compounds and their degradation via common drinking water treatment systems containing permanganate. The aqueous solubility of benoxacor and furilazole was 22 and 235 mg L-1 respectively while the estimated solubility from EPI Suite was 102.7 and 255 mg L-1 respectively. The log octanol-water partition coefficient of benoxacor and furilazole was 2.23 and 1.96 respectively. The selected safeners were not photodegradable to any great extent. Both benoxacor and furilazole oxidation were found to be second order with respect to initial KMnO4 concentrations. The results of this study can be used to predict distribution of safeners after application in agricultural fields and aid in the design of treatment systems.


Comparison of the effects of amlodipine and losartan on 24-hour ambulatory blood pressure in hypertensive patients.
Effects of amlodipine (AML), a long-acting calcium antagonist, and losartan (LOS), an angiotensin II receptor antagonist, on 24-hr blood pressure profile were compared in 15 patients with essential hypertension. After 4 weeks of placebo period, the patients were treated with AML or LOS in a random crossover design for 12-16 weeks each. Either drug was given once daily at 0800 and the doses were titrated so that the office blood pressure was reduced lower than 140/90mmHg. At the end of each period, 24-hr blood pressure was monitored. Average office blood pressure was lowered from 158 +/- 2/ 98 +/- 2 mmHg to 134 +/- 1/87 +/- 1 mmHg by AML and 134 +/- 2/88 +/- 1 mmHg by LOS. Average 24-hr blood pressure was also reduced from 144 +/- 3/ 92 +/- 2 mmHg to 131 +/- 2/84 +/- 2 mmHg by AML and 135 +/- 3/85 +/- 2 mmHg by LOS. The averaged 24-hr systolic blood pressure was significantly lower in AML than in LOS (p < 0.05). Then, the 24-hr blood pressure was analyzed for four segments; morning (0530-0900 h), daytime (0930-1800 h), evening (1830-2300 h) and night (2330-0500 h). Although the daytime blood pressure was comparable between AML and LOS, systolic blood pressure in the evening and morning hours were lower in AML than in LOS (133 +/- 2 vs. 138 +/- 3mmHg,p<0.01; 129 +/- 3 vs. 134 +/- 4,p<0.05). Troughtopeakratio of antihypertensive effect on systolic blood pressure was significantly greater in AML than in LOS (62 +/- 5% vs. 55 +/- 4%, p < 0.05). Either drug did not cause reflective increase in pulse rate over 24 hours. These results suggest that both AML and LOS are equally effective in lowering daytime blood pressure without eliciting reflex tachycardia, however, the antihypertensive effect of AML lasts longer than that of LOS. Such information seems important to achieve 24-hr blood pressure control using these drugs.


Predictors of Ectopic Fat in Humans.
In the last decade there has been increasing focus on body fat distribution, rather than on the degree of obesity. More recently, great interest has also been dedicated to ectopic fat deposition in overnourished individuals that reflects a failure of the system of intracellular lipid homeostasis, which, in normal conditions, prevents lipotoxicity in the organs, by confining lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Consequently, excess body weight leads to fat infiltration of multiple organs including liver, pancreas, skeletal muscle, and heart thus forming "ectopic fat". Although overfeeding is considered the main predictor of ectopic fat deposition, other factors may be also involved. The purpose of this review is to evaluate the current available data on the predictors of ectopic fat deposition in humans.


American Diabetes Association "Standards of Medical Care-2020 for Gestational Diabetes Mellitus": A Critical Appraisal.
Gestational diabetes mellitus (GDM) is a major public health problem, affecting about one in every six pregnancies globally. The guidelines provided by the American Diabetes Association (ADA) on diagnosis and management of hyperglycemia in pregnancy are widely followed. We aim to provide a critical appraisal of the recently published ADA guidance document, highlighting its strength and limitations with regard to the diagnosis of GDM. We reviewed the recent ADA recommendations for the diagnosis and management of hyperglycemia in pregnancy. A periodic update in keeping with the emerging evidence, an inclusive diagnostic approach which increases generalizability, and a clear proposed approach for prenatal testing and postpartum follow-up are strengths of the ADA guidance document. On the other hand, its limitations are a lack of clarity on the applicability of diagnosis of GDM during early pregnancy, use of scientifically inaccurate terms such as "prediabetes" in the context of pregnancy and "overt diabetes prior to gestation" in the definition of GDM, and inconsistent use of terminology between successive publications. Certain issues which merit attention in future publications include a need for uniform global definition of GDM, demarcation of overt diabetes in pregnancy as a distinct entity, clarity on the diagnosis of GDM during early pregnancy, and clear delineation of timelines and appropriate testing strategy for the first prenatal visit. This article provides a critical appraisal of the recently published ADA guidance document with regard to the diagnosis of GDM. We also share our perspective on issues warranting attention in the future publications. Experts from various professional organizations should aim for a consensus document which can resolve existing controversies in this field, and help clinicians and researchers achieve better health for women in their care.


Initial impact of a clinical laboratory computer system. Themes common to expectations and actualities.
A longitudinal study is being conducted of a clinical laboratory computer information system's impact. This paper reports on effects that laboratory directors anticipated prior to installation, and effects reported by laboratory technologists 7 months postimplementation. Primary changes caused by the computer system were increases in the amount of paper work performed by technologists, and improvements in laboratory results reporting. The system generally was well accepted, but laboratory technologists differed in their responses to it. Technologists in some laboratories focused on work increases, whereas in other laboratories they emphasized improved information flow. The paper considers how changes in processes and outcomes of work might affect responses to a computer system. It also considers the implementation process, and suggests some areas where management could benefit from an improved understanding of responses to a computer information system.


[Cannabis--Position Paper of the German Respiratory Society (DGP)].
In this position paper, the adverse health effects of cannabis are reviewed based on the existing scientific literature; in addition possible symptom-relieving effects on some diseases are depicted. In Germany, cannabis is the most widely used illicit drug. Approximately 600,000 adult persons show abusive or addictive cannabis consumption. In 12 to 17 year old adolescents, cannabis use increased from 2011 to 2014 from 2.8 to 6.4%, and the frequency of regular use from 0.2 to 1.5%. Currently, handling of cannabinoids is much debated in politics as well as in general public. Health aspects have to be incorporated into this debate. Besides analysing mental and neurological side effects, this position paper will mainly focus on the influences on the bronchopulmonary and cardiovascular system. There is strong evidence for the induction of chronic bronchitis. Allergic reactions including asthma are known, too. Associations with other diseases like pulmonary emphysema, lung cancer and pneumonia are not sufficiently proven, however cannot be excluded either. In connection with the use of cannabis cardiovascular events such as coronary syndromes, peripheral vascular diseases and cerebral complications have been noted. Often, the evidence is insufficient due to various reasons; most notably, the overlapping effects of tobacco and cannabis use can frequently not be separated adequately. Empirically, early beginning, high-dosed, long-lasting and regular cannabis consumption increase the risk of various psychological and physical impairments and negatively affect age-based development. Concerns therefore relate especially to children and adolescents. There is only little scientific evidence for medical benefits through cannabis as a remedy; systematic research of good quality, in particular prospective, randomised, placebo-controlled double-blinded studies are rare. The medical societies signing this position paper conclude that cannabis consumption is linked to adverse health effects which have to be taken into consideration in the debate about the social attitude towards cannabinoids. The societies agree that many aspects regarding health effects of cannabis are still uncertain and need clarification, preferably through research provided by controlled studies.


High frequency of chromosome 14 deletion in early-onset colon cancer.
Several genes have been recognized, when mutated in the germline, to highly predispose to colorectal cancer, impairing the DNA mismatch repair system in hereditary nonpolyposis colon cancer syndrome, or APC/MYH in adenomatous polyposis. However, 10 percent of microsatellite stable colorectal cancer is reported to develop in an unexplained context of genetic predisposition. This study was designed to depict the genetic mechanisms underlying early-onset microsatellite stable colon cancers. Patients younger than aged 50 years undergoing primary surgical resection for colon carcinoma were collected prospectively between 1993 and 2003. A first series of 8 samples has been allelotyped using 361 poly-CA polymorphisms distributed on the 39 autosomal arms within a larger set of 166 sporadic tumors. Genotyping of 24 poly-CA polymorphisms distributed on the 8 chromosomes exhibiting allelic losses in more than 30 percent of the previous cases was then applied to an independent series of 40 tumors. A third series of 70 tumors has been genotyped on chromosome 14 only. Comparison of genomic profile from patients younger and older than aged 50 years at the 8 most frequently lost chromosomes allowed, identify chromosome 14 as showing a significant difference between the two groups. Dense chromosome 14 genotyping detected two partial deletions in a general background of 57 percent allelic loss, pointing at a region located between D14S63 and D14S292. These observations suggest that a tumor-suppressor gene located on chromosome 14 might have an important role in microsatellite stable colon carcinogenesis. Because it seems to be more frequently involved in early-onset cases, it could be a good candidate in inherited conditions.


A Bibliometric mapping of peer-to-peer lending research based on economic and business perspective.
This study aims to conduct a bibliometric analysis on peer-to-peer lending literature published in Scopus indexed journals from an economic and business perspective. The data were processed and analyzed using VOSviewer software. To the best of authors' knowledge, this is the first paper that conducts a bibliometric analysis of the peer-to-peer lending literature using VOSviewer. The results of study showed the most popular authors, countries, organizations and keywords. Moreover, this study also discovered trending topics from recent publications. A direct benefit of this study is to provide input for stakeholders, businessmen and investors to identify important issues regarding peer-to-peer lending and directions for further researchers.


Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research.
For last 2 years since PACAP was first discovered, many important findings on PACAP have been reported. cDNAs encoding the precursor proteins of PACAP in sheep, human and rat were cloned, and the precursor proteins characterized. PACAP was found in a high concentration in the central nervous system, adrenal medulla and testis. Immunohistochemical study indicated that PACAP containing neural fibers are present throughout the brain, including both internal and external zones of the median eminence. In the hypothalamus many PACAP positive cell bodies were demonstrated in the supraoptic nucleus and the paraventricular nucleus in various species. Four types of high affinity PACAP receptor were demonstrated. PACAP receptors in the central nervous system, pituitary, adrenal medulla and germ cells of the testis are highly specific for PACAP, and not shared with VIP. The PACAP receptor was solubilized and cross-linking of 125I-PACAP27 with the binding protein suggest that the molecular weight of the receptor is around 57,000. Various biological actions of PACAP were reported, but the physiological cellular events linked with PACAP-induced activation of adenylate cyclase remain to be investigated.


Efficacy and safety of endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy in obese subjects with Non-Alcoholic SteatoHepatitis (NASH): study protocol for a randomized controlled trial (TESLA-NASH study).
Non-alcoholic steatohepatitis (NASH) is frequently associated with obesity, and its standard treatment is weight loss with diet and exercise; a dy% weight reduction has been associated with improvement in liver histological and analytical abnormalities. However, less than 25% of subjects achieve this goal. Laparoscopic sleeve gastrectomy (LSG) represents the most common procedure of bariatric surgery, providing effective weight loss and improvement in comorbidities such as NASH, but it is associated with several postoperative complications. Endoscopic bariatric techniques are currently on the rise as a new tool in the fight against obesity, offering patients an alternative to more invasive surgery. However, their efficacy and safety compared with LSG is unclear. The TESLA-NASH study is a randomized, controlled, open-label, unicentric clinical trial with a medical device. The aim of this study is to evaluate and compare the efficacy and safety of endoscopic sleeve gastroplasty (ESG) versus laparoscopic sleeve gastrectomy (LSG) in liver histology improvement of patients with obesity +/- metabolic syndrome and NASH. A total of 30 patients will be randomized 1:1 to the experimental or control group. LSG is an effective treatment for weight reduction and for the remission of hepatic alterations. However, LSG is associated with acute and chronic postoperative complications. Bariatric endoscopic techniques promise less invasive and more cost-effective approaches to the treatment of obesity and metabolic comorbidities. ESG represents one of the most promising novel endoscopic interventions and it is mainly proposed for patients with mild-to-moderate obesity, but there are still no guidelines that specify its applicability criteria. This clinical trial will help us apply different tactics to the treatment of obesity and NASH. ClinicalTrials.gov NCT04060368. Registered on Nov 15, 2019.


Exon organisation of the mouse gene encoding the Adrenoleukodystrophy related protein (ALDRP).
ALDR is one of the four genes encoding an ATP Binding Cassette (ABC) hemi-transporter of the peroxisomal membrane so far identified in mammalian cells. The best known of these is X-ALD, whose dysfunction has been causally associated with X-linked adrenoleukodystrophy. ALDR and X-ALD protein product are closely related and we show here that this striking conservation is maintained at the genomic level. Although extending to a larger genomic region, the organisation of the mouse ALDR gene mirrors exactly that of X-ALD. This supports further the hypothesis that among the four known peroxisomal ABC hemi-transporters ALDRP is the most likely candidate as a modifier contributing to the phenotypic variability of X-linked adrenoleukodystrophy.


Hybrid brain/neural interface and autonomous vision-guided whole-arm exoskeleton control to perform activities of daily living (ADLs).
The aging of the population and the progressive increase of life expectancy in developed countries is leading to a high incidence of age-related cerebrovascular diseases, which affect people's motor and cognitive capabilities and might result in the loss of arm and hand functions. Such conditions have a detrimental impact on people's quality of life. Assistive robots have been developed to help people with motor or cognitive disabilities to perform activities of daily living (ADLs) independently. Most of the robotic systems for assisting on ADLs proposed in the state of the art are mainly external manipulators and exoskeletal devices. The main objective of this study is to compare the performance of an hybrid EEG/EOG interface to perform ADLs when the user is controlling an exoskeleton rather than using an external manipulator. Ten impaired participants (5 males and 5 females, mean age 52 ± 16 years) were instructed to use both systems to perform a drinking task and a pouring task comprising multiple subtasks. For each device, two modes of operation were studied: synchronous mode (the user received a visual cue indicating the sub-tasks to be performed at each time) and asynchronous mode (the user started and finished each of the sub-tasks independently). Fluent control was assumed when the time for successful initializations ranged below 3 s and a reliable control in case it remained below 5 s. NASA-TLX questionnaire was used to evaluate the task workload. For the trials involving the use of the exoskeleton, a custom Likert-Scale questionnaire was used to evaluate the user's experience in terms of perceived comfort, safety, and reliability. All participants were able to control both systems fluently and reliably. However, results suggest better performances of the exoskeleton over the external manipulator (75% successful initializations remain below 3 s in case of the exoskeleton and bellow 5s in case of the external manipulator). Although the results of our study in terms of fluency and reliability of EEG control suggest better performances of the exoskeleton over the external manipulator, such results cannot be considered conclusive, due to the heterogeneity of the population under test and the relatively limited number of participants.


Selective recognition of pyrophosphate in water using a backbone modified cyclic peptide receptor.
A cyclic peptide based receptor, bearing two dipicolylamino arms complexed to zinc(II) ions, binds pyrophosphate ions with high affinity and selectivity in aqueous solution as determined using an indicator displacement assay.


Benchmarking pediatric cranial CT protocols using a dose tracking software system: a multicenter study.
To benchmark regional standard practice for paediatric cranial CT-procedures in terms of radiation dose and acquisition parameters. Paediatric cranial CT-data were retrospectively collected during a 1-year period, in 3 different hospitals of the same country. A dose tracking system was used to automatically gather information. Dose (CTDI and DLP), scan length, amount of retakes and demographic data were stratified by age and clinical indication; appropriate use of child-specific protocols was assessed. In total, 296 paediatric cranial CT-procedures were collected. Although the median dose of each hospital was below national and international diagnostic reference level (DRL) for all age categories, statistically significant (p-value < 0.001) dose differences among hospitals were observed. The hospital with lowest dose levels showed smallest dose variability and used age-stratified protocols for standardizing paediatric head exams. Erroneous selection of adult protocols for children still occurred, mostly in the oldest age-group. Even though all hospitals complied with national and international DRLs, dose tracking and benchmarking showed that further dose optimization and standardization is possible by using age-stratified protocols for paediatric cranial CT. Moreover, having a dose tracking system revealed that adult protocols are still applied for paediatric CT, a practice that must be avoided. • Significant differences were observed in the delivered dose between age-groups and hospitals. • Using age-adapted scanning protocols gives a nearly linear dose increase. • Sharing dose-data can be a trigger for hospitals to reduce dose levels.


Contextual factors influencing the delegation of tasks to Multi-skilled Community Health Workers in Haiti
In Haiti, the delegation of tasks to Multi-skilled Community Health Workers (locally called ASCP) is a strategy implemented by the Ministry of Public Health and Population to improve universal health coverage. To contribute to the successful implementation of this strategy, this article reports on a case study of its implementation in the northern health department of Haiti. More specifically, this article provides information on the contextual factors that facilitate or hinder the implementation of task delegation to ASCP. The results obtained show notable progress in the implementation of task delegation to ASCP in the northern health department of Haiti. These mainly concern the following activities: selection, training, and deployment of ASCPs, endowment of work materials, supervision, collection and analysis of data on the results obtained. In September 2019, 215 ASCPs were active in the department. This corresponds to 44.3% of the 485 ASCPs planned to cover the department's needs. Several contextual factors hindering or facilitating the implementation of this intervention were also identified with 35 resource persons during semi-structured interviews. These relate to the planning and monitoring of the implementation of the intervention (cited by 12 out of 35 people), the institutional context (10/35), and political (17/35), structural (30/35) and environmental factors (7/35). This study highlights several contextual factors that need to be considered to ensure the successful implementation of the delegation of tasks to ASCP in Haiti and possibly in other contexts.


Protein and lipid composition analysis of oil bodies from two Brassica napus cultivars.
Oil bodies were purified from mature seed of two Brassica napus crop cultivars, Reston and Westar. Purified oil body proteins were subjected to both 2-DE followed by LC-MS/MS and multidimensional protein identification technology. Besides previously known oil body proteins oleosin, putative embryo specific protein ATS1, (similar to caleosin), and 11-beta-hydroxysteroid dehydrogenase-like protein (steroleosin), several new proteins were identified in this study. One of the identified proteins, a short chain dehydrogenase/reductase, is similar to a triacylglycerol-associated factor from narrow-leafed lupin while the other, a protein annotated as a myrosinase associated protein, shows high similarity to the lipase/hydrolase family of enzymes with GDSL-motifs. These similarities suggest these two proteins could be involved in oil body degradation. Detailed analysis of the two other oil body components, polar lipids (lipid monolayer) and neutral lipids (triacylglycerol matrix) was also performed. Major differences were observed in the fatty acid composition of polar lipid fractions between the two B. napus cultivars. Neutral lipid composition confirmed erucic acid and oleic acid accumulation in Reston and Westar seed oil, respectively.


Spontaneous perforation of cervical oesophagus associated with oesophageal web.
A case is described, of a patient who sustained a spontaneous perforation of the cervical oesophagus in association with a congenital oesophageal web.


Safety and efficacy of dimethyl fumarate in multiple sclerosis: a multi-center observational study.
Dimethyl fumarate (DMF) was recently approved for treating patients with relapsing-remitting multiple sclerosis (RRMS) based on two phase III clinical trials demonstrating its efficacy. This prompts the need for demonstrating the clinical efficacy and safety of DMF in the real world. By retrospective analysis of medical records at two German MS centers, 644 MS patients treated with DMF were identified. All were included in a safety analysis, and a subgroup of patients with available efficacy data during previous MS therapies (n = 352) was further analyzed for annualized relapse rate and disability progression assessed by the EDSS. In the overall DMF population studied, the annualized relapse rate decreased from 0.52 at baseline to 0.35, and the annualized disability progression from 0.15 to 0.10. Patients who were switched from interferons or glatiramer acetate to DMF revealed a greater benefit, whereas patients pretreated with more potent immunotherapies did not respond that well. Interestingly, patients with a lymphocyte count ≥2000/µl after 0.52 years (mean, SD 0.2) of DMF treatment did not benefit compared to those with lower lymphocyte counts. In total, 22.2 % of the patients withdrew from DMF due to side effects, with gastrointestinal discomfort (12.7 %) and lymphopenia (5.3 %) as most frequently reported reasons. Our study corroborates that DMF is an overall safe and effective drug that reduces relapse rate as well as disability progression in MS patients. Further prospective studies are warranted to establish the additional parameters predicting DMF response, especially in patients switching from other first-line immunotherapies.


Vaginal vault prolapse after nonsurgical and surgical treatment of MAAdullerian agenesis.
Women with Mayer-Rokitansky-Küster-Hauser syndrome fail to develop müllerian ducts, present with primary amenorrhea, and an absent or rudimentary uterus and vagina. After creation of a neovagina, vaginal vault prolapse may occur because of lack of support to the artificially created vagina. The first patient presented with vaginal vault prolapse 10 years after her vagina was mechanically dilated. The second patient presented with vaginal vault prolapse 27 years after a McIndoe procedure. Women with Mayer-Rokitansky-Küster-Hauser syndrome with an artificially created neovagina by dilatation or surgical procedure with a graft are at risk for vaginal vault prolapse. They can be successfully treated with abdominal sacrocolpopexy and paravaginal repair.


Fine definition of the epitopes on the human gp91phox/NOX2 for the monoclonal antibodies CL-5 and 48.
Superoxide-producing NADPH oxidase, gp91phox/NOX2, in phagocytes plays a critical role in the host defenses against pathogens. Moreover, gp91phox/NOX2 contributes to the oxidative stress in endothelial cells. Therefore, investigating the level of gp91phox/NOX2 with immunoblotting is important for estimating the amount of superoxide produced. Here, we showed that the epitopes in human gp91phox/NOX2 recognized by monoclonal antibodies (mAbs) CL-5 and 48 were in amino acids 132-147 and 136-144, respectively. Although the epitopes were close to the N-glycosylation sites, N-glycan maturation did not affect mAbs recognition. When Pro-136 was substituted with Arg, the corresponding mouse residue, human gp91phox/NOX2 was not recognized by mAbs CL-5 and 48; however, the substitution did not affect gp91phox/NOX2-based oxidase activity. This finding explains why these mAbs specifically recognize the human but not mouse gp91phox/NOX2. Hence, these mAbs are useful for investigating the level of gp91phox/NOX2 without amino acid substitutions in the epitopes.


Safe cycling: how do risk perceptions compare with observed risk?
Safety concerns deter cycling. The Bicyclists' Injuries and the Cycling Environment (BICE) study quantified the injury risk associated with 14 route types, from off-road paths to major streets. However, when it comes to injury risk, there may be discordance between empirical evidence and perceptions. If so, even if protective infrastructure is built people may not feel safe enough to cycle. This paper reports on the relationship between perceived and observed injury risk. The BICE study is a case-crossover study that recruited 690 injured adult cyclists who visited emergency departments in Toronto and Vancouver. Observed risk was calculated by comparing route types at the injury sites with those at randomly selected control sites along the same route. The perceived risk was the mean response of study participants to the question "How safe do you think this site was for cyclists on that trip?", with responses scored from +1 (very safe) to -1 (very dangerous). Perceived risk scores were only calculated for non-injury control sites, to reduce bias by the injury event. The route type with the greatest perceived risk was major streets with shared lanes and no parked cars (mean score = -0.21, 95% confidence interval [CI]: -0.54-0.11), followed by major streets without bicycle infrastructure (-0.07, CI -0.14-0.00). The safest perceived routes were paved multi-use paths (0.66, CI 0.43-0.89), residential streets (0.44, CI 0.37-0.51), bike paths (0.42, CI 0.25-0.60) and residential streets marked as bike routes with traffic calming (0.41, CI 0.32-0.51). Most route types that were perceived as higher risk were found to be so in our injury study; similarly, most route types perceived as safer were also found to be so. Discrepancies were observed for cycle tracks (perceived as less safe than observed) and for multiuse paths (perceived as safer than observed). Route choices and decisions to cycle are affected by perceptions of safety, and we found that perceptions usually corresponded with observed safety. However, perceptions about certain separated route types did not align well. Education programs and social media may be ways to ensure that public perceptions of route safety reflect the evidence.


Now You See Me Now You Don't: Subaortic Membrane Causing a Diagnostic Dilemma.
Subaortic stenosis secondary to subaortic membrane is the second most common form of left ventricular outflow tract obstruction. We present the case of a 70-year-old male patient who presented with a 6-week history of progressive signs of heart failure. Multimodality imaging was required to confirm the presence of a subaortic membrane. (Level of Difficulty: Beginner.).


An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes.
β-lactamases inactivate β-lactam antibiotics leading to drug resistance. Consequently, inhibitors of β-lactamases can combat this resistance, and the β-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor. The widespread CTX-M-14 and CTX-M-15 β-lactamases have an 83% sequence identity. In this study, we show that BLIP weakly inhibits CTX-M-14 but potently inhibits CTX-M-15. The structure of the BLIP/CTX-M-15 complex reveals that binding is associated with a conformational change of an active site loop of β-lactamase. Surprisingly, the loop structure in the complex is similar to that in a drug-resistant variant (N106S) of CTX-M-14. We hypothesized that the pre-established favorable loop conformation of the N106S mutant would facilitate binding. The N106S substitution results in a ~100- and 10-fold increase in BLIP inhibition potency for CTX-M-14 and CTX-M-15, respectively. Thus, this indicates that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility. These findings highlight the role of accessible active site conformations in controlling enzyme activity and inhibitor susceptibility as well as the influence of mutations in selectively stabilizing discrete conformations.


Laparoscopic cholecystectomy in patients with ventriculoperitoneal (VP) shunts.
Increased intracranial pressure is often relieved by a ventriculoperitoneal shunt. The shunt has a one-way valve which can withstand pressures of 300 mmHg and prevent reflux of intraabdominal fluid. We have utilized laparoscopy for cholecystectomy in four patients with VP shunts. In all patients the peritoneal cavity was free of adhesions. When CO2 insufflation pressure was as high as 10-15 mmHg cerebrospinal fluid was still noted to flow from the end of the shunts. In three patients the entire procedure was performed laparoscopically. In the fourth patient the procedure was converted to an open cholecystectomy because of extensive inflammation surrounding a gangrenous gallbladder. Postoperatively the shunts remained intact and functional. There were no central nervous system sequelae. None of the shunts became infected. Elective laparoscopic cholecystectomy in patients with VP shunts can be done safely without a need for clamping or other manipulation of the shunt.