Linoleic acid reduces vascular reactivity and improves the vascular dysfunction of the small mesentery in hypertension.
We aimed to investigate the effect of linoleic acid (LA) treatment on the blood pressure and function of mesenteric resistance arteries (MRA) in spontaneous hypertensive rats (SHR). Male SHR were treated daily with LA (15 mg/kg) or vehicle (control) for 15 days. Compared with controls, LA treatment decreased blood pressure and showed the following in MRA: (1) increased lumen and external diameter, (2) decreased wall:lumen ratio and wall thickness, (3) decreased stiffness and (4) less collagen deposition. LA treatment reduced the contractile response to phenylephrine, although there were no changes observed in MRA in regard to the acetylcholine or sodium nitroprusside responses. Incubation with L-NAME left-shifted the reactivity to phenylephrine only in the MRA treated group, suggesting that LA treatment can improve NO bioavailability. This result was accompanied by an increase "in situ" NO production. Incubation with tiron decreased vascular reactivity to phenylephrine in MRA in LA rats, which was accompanied by decreased superoxide anion production. Moreover, incubation with indomethacin (non-selective COX inhibitor, 10 μM), NS 398 (COX-2 specific inhibitor, 1 μM), furegrelate (TXA2 synthase inhibitor, 1 μM), SQ 29.548 (TP receptor antagonist, 1 μM) and SC 19220 (EP1 receptor antagonist, 10 μM) reduced the vasoconstrictor responses to phenylephrine in MRA in the treated group. These results were accompanied by a reduction in COX-2 protein expression. In conclusion, these findings show that LA treatment decreases blood pressure. In addition, the improvement of endothelial dysfunction and structural changes in this hypertension model may be responsible for the reduction in blood pressure.


Hemostasis Evaluation of Antibacterial and Highly Absorbent Composite Wound Dressings in Animal Hemostasis Models.
To reduce the bleeding time and to shorten the surgery time are vital to patients' prog-nosis, therefore, in this study, high moisture absorption nonwoven composites are proposed to attain hemostasis in time. Polyacrylate fiber and Tencel® fibers at different blending ratios (10:90, 20:80, 30:70, 40:60, and 50:50) are used to form PT composite nonwoven. Next, composed of a 50:50 ratio, PT composite nonwoven exhibits the maximal vertical wicking height of 4.4 cm along the cross direction. Additionally, the UV-Vis absorption spectra analysis shows that at absorption waves of 413-415 nm, the occurring of distinct peaks suggests the presence of nanoparticles. The XRD patterns indicate the presence of silver nanoparticles with corresponding crystal planes of characteristic peaks at (111), (200), and (220). Polyacrylate/Tencel® nonwoven composites exhibit comparable adsorption capacity of blood and water molecules. In particular, 30PT composite nonwoven outperforms the control group, exhibiting 3.8 times and 4.7 times greater the water absorption and blood absorption, respectively. Moreover, a great number of red blood cells with a size of 4-6 μm agglomerate among fibers as observed in SEM images, while 6hr-PT composite dressing demonstrates the optimal antibacterial efficacy against Escherichia coli and Staphylococcus aureus, proven by the zone of inhibition being 1.9 mm and 0.8 mm separately. When in contact with plasma, hemostasis composites have plasma hemostasis prothrombin time of 97.9%, and activated partial thromboplastin time of 96.7%. As for animal hemostasis model, the arteria over the rats' thigh bones is cut open perpendicularly, generating mass arteria hemorrhage. To attain hemostasis, it takes 46.5% shorter time when using composite dressings (experimental group) than the control group.


Comparative Screening of DalPhos/Ni Catalysts in C-N Cross-couplings of (Hetero)aryl Chlorides Enables Development of Aminopyrazole Cross-couplings with Amine Base.
A systematic competitive evaluation of the DalPhos ligand family in nickel-catalyzed N-arylation chemistry is reported, involving primary (linear and branched) and secondary alkylamines, as well as a primary five-membered heteroarylamine (aminopyrazole), in combination with a diverse set of test electrophiles and bases (NaOtBu, K2 CO3 , DBU/NaTFA). In addition to providing optimal ligand/catalyst identification, and bringing to light methodology limitations (e. g., unwanted C-O cross-coupling with NaOtBu), our survey enabled the development of the first efficient catalyst system for heteroatom-dense C-N cross-coupling of aminopyrazoles and related nucleophiles with (hetero)aryl chlorides by use of an amine 'dual-base' system.


Hexose metabolism in pancreatic islets: regulation of mitochondrial hexokinase binding.
A major fraction of hexokinase was found to be bound, presumably to mitochondria, in both normal and tumoral rat pancreatic islet cells examined after either mechanical disruption or digitonin treatment. Spermidine enhanced the binding and glucose 6-phosphate caused the release of hexokinase to and from islet mitochondria, in a manner comparable to that seen in parotid or brain homogenates. In hepatocytes, some hexokinase, but no glucokinase, was found in the bound form. In islet cells, however, the pattern of glucokinase binding was similar to that of hexokinase. It is speculated that the preferential location of both hexokinase and glucokinase on mitochondria may favor the maintenance of a high cytosolic ATP content in islet cells.


The Severe Cognitive Impairment Rating Scale--an instrument for the assessment of cognition in moderate to severe dementia patients.
This study aimed to develop a brief, reliable and valid test for cognitive function of severely demented patients. We constructed the Severe Cognitive Impairment Rating Scale, which consisted of 11 items covering memory, language, visuospatial function, frontal function and orientation, and investigated its reliability and validity on 267 subjects [normal: 65, very mild Alzheimer's disease (AD): 42, mild AD: 58, moderate AD: 36, severe AD: 44, profound AD: 22]. The internal consistency obtained by Cronbach's coefficient alpha was 0.93. The interrater reliability and test-retest reliability in the moderately to severely impaired subjects with an MMSE score of <or=14 was 0.99 (p < 0.001) and 0.90 (p < 0.001), respectively. It showed significant correlation with Severe MMSE (r = 0.96, p < 0.01), MMSE (r = 0.86, p < 0.01) and Clinical Dementia Rating (r = -0.83, p < 0.01). It was robust to both the floor effect in the severe/profound stage of AD and the ceiling effect in the mild/moderate stage of AD. Exploratory factor analysis yielded 2 factors (automatic informational processing and controlled informational processing) accounting for 73.5% of the total variance. The Severe Cognitive Impairment Rating Scale is a valid and reliable test for evaluating the cognitive function of advanced AD patients.


Congenital atresia of the external auditory canal.
Children with congenital atresia of the external auditory canal require an early assessment of hearing and a determination of the degree of atresia and associated pathology by polytomography and/or high-resolution CT scanning. We analyzed the otologic findings in 302 ears (239 patients) with severe atresia of the external auditory canal. Eighty-seven primary or revision surgeries were performed. Fifty-three percent obtained a residual conductive deficit of 20 dB or less. Lateralization of the tympanic membrane graft was the primary cause of failure in obtaining good hearing results. The use of split-thickness skin graft instead of a full-thickness skin graft to cover the reconstructed external canal has decreased the incidence of restenosis and revision surgery.


Scholarly literature review: Efficacy of psychological interventions for pediatric chronic illnesses.
To review empirical studies of the efficacy of psychological interventions as adjuvant therapies for children with pediatric diabetes, cancer, cystic fibrosis, and sickle cell disease. A search was conducted for qualifying studies published since 1980. Only studies meeting basic criteria for external and internal validity were included. Nineteen studies were identified, providing data on 62 outcome variables. Effect sizes (ESs) were analyzed by illness type, intervention type, and strength of internal and external validity of the research design. Overall, interventions were associated with large ESs, which were not significantly moderated by illness type or intervention type. However, larger ESs were associated with lower scores on validity of research design. Adjuvant psychological interventions for pediatric chronic illnesses appear in general to be efficacious, associated with a large mean ES across a range of outcome variables. However, until more studies have been completed using stronger research designs, only tentative conclusions can be drawn.


EU-wide survey of polar organic persistent pollutants in European river waters.
This study provides the first EU-wide reconnaissance of the occurrence of polar organic persistent pollutants in European river waters. More than 100 individual water samples from over 100 European rivers from 27 European Countries were analysed for 35 selected compounds, comprising pharmaceuticals, pesticides, PFOS, PFOA, benzotriazoles, hormones, and endocrine disrupters. Around 40 laboratories participated in this sampling exercise. The most frequently and at the highest concentration levels detected compounds were benzotriazole, caffeine, carbamazepine, tolyltriazole, and nonylphenoxy acetic acid (NPE(1)C). Only about 10% of the river water samples analysed could be classified as "very clean" in terms of chemical pollution. The rivers responsible for the major aqueous emissions of PFOS and PFOA from the European Continent could be identified. For the target compounds chosen, we are proposing "indicative warning levels" in surface waters, which are (for most compounds) close to the 90th percentile of all water samples analysed.


Ambulance Crash in a Rural Area of Thailand.
Ambulance crashes delay patient transfer and endanger patients, ambulance crews, and other road users. In low- and middle-income countries, where motor vehicle crash rates are typically high, ambulances have a high risk of being involved in a crash. This case report describes an ambulance crash in Thailand to elucidate modifiable problems in current protocols and practices of emergency medical services. In November 2016, a 28-year-old male driver of an ambulance died in a crash while transferring a female patient with dizziness to a rural hospital. The driver and another ambulance crew member were sitting in the front seats unrestrained. The other occupants were in the patient compartment unrestrained. The driver was driving the ambulance within the speed limit. He made a sharp turn trying to evade a dog, and the ambulance crashed head-on into a roadside tree. The cabin sustained severe damage, and the occupants in the patient compartment were struck against the compartment wall and were struck by unsecured equipment and the stretcher. The driver sustained a severe brain injury. The other occupants, including the female patient, sustained minor injuries. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case raises safety issues concerning the following aspects of ambulance operations in low- and middle-income countries: speed limit, safety device use, seatbelt use, securing equipment, and vehicle safety standards. Systematic measures to change protocols or even legislation, as well as data collection, are required to address these issues.


Suicide prevention--a medical breakthrough?
The author hypothesized, based on research until 1991, that a five-fold increase in the use of antidepressants might reduce Swedish suicide rates by 25%. A subsequent 3.5-fold increase in the use of antidepressants provided a 'natural experimental situation' for prospectively testing this hypothesis. Swedish statistics on suicide, use of antidepressants, unemployment and alcohol consumption were obtained for 1978-96. Time-series of the latter variables were compared with suicide rates. Demographic subgroups regarding age, gender and county were analysed. Suicide rates were also compared with the use of antidepressants in Denmark, Norway and Finland. Suicide rates decreased in accordance with the a priori hypothesis. Alcohol consumption and unemployment rates did not correlate well with suicide rates. This naturalistic study is not conclusive. The increased use of antidepressants appears, however, to be one of the contributing factors to the decrease in the suicide rate. It is of great scientific and clinical importance that this be evaluated by further studies.


Isolation and phylogenomic analysis of two Senecavirus A isolates in Sichuan Province, 2018.
In our study, we isolated and characterised two new Senecavirus A (SVA) isolates in Sichuan Province, China. Phylogenetic analysis of both the SVA full-length genomes and the VP1 genes revealed that the two new SVA isolates are more closely related to previous Chinese strains and US strains. The most variable isolate, SVV-SC-01, showed a significant difference from previous SVA strains, and it was identified as a recombinant using several algorithms. Study findings indicate that the SVA virus in China is constantly evolving and new SVA variants may have emerged. Hence, we must take effective measures to prevent further spread of SVA. This report provides evidence that SVA infection of pigs has occurred in Sichuan Province, and the results will contribute to our understanding of the genetic characteristics and recombinant events of SVA in China.


Type 2 Diabetes Mellitus and Impact of Heart Failure on Prognosis Compared to Other Cardiovascular Diseases: A Nationwide Study.
Heart failure (HF) in patients with type 2 diabetes mellitus (T2D) has received growing attention. We examined the effect of HF development on prognosis compared with other cardiovascular or renal diagnoses in patients with T2D. Patients with new T2D diagnosis patients were identified between 1998 and 2015 through Danish nationwide registers. At yearly landmark timepoints after T2D diagnosis, we estimated the 5-year risks of death, 5-year risk ratios, and decrease in lifespan within 5 years associated with the development of HF, ischemic heart disease, stroke, peripheral artery disease, and chronic kidney disease. A total of 153 403 patients with newly diagnosed T2D were followed for a median of 9.7 years (interquartile range, 5.8-13.9) during which 48 087 patients died. The 5-year risk ratio of death associated with HF development 5 years after T2D diagnosis was 3 times higher (CI, 2.9-3.1) than patients free of diagnoses (CI, 2.9-3.1). Five-year risk ratios were lower for ischemic heart disease (1.3 [1.3-1.4]), stroke (2.2 [2.1-2.2]), chronic kidney disease (1.7 [1.7-1.8]), and peripheral artery disease (2.3 [2.3-2.4]). The corresponding decrease in lifespan within 5 years when compared with patients free of diagnoses (in months) was HF 11.7 (11.6-11.8), ischemic heart disease 1.6 (1.5-1.7), stroke 6.4 (6.3-6.5), chronic kidney disease 4.4 (4.3-4.6), and peripheral artery disease 6.9 (6.8-7.0). HF in combination with any other diagnosis imposed the greatest risk of death and decrease in life span compared with other combinations. Supplemental analysis led to similar results when stratified according to age, sex, and comorbidity status, and inclusion period. HF development, at any year since T2D diagnosis, was associated with the highest 5-year absolute and relative risk of death, and decrease in lifespan within 5 years, when compared with development of other cardiovascular or renal diagnoses.


Haemorrhagic diathesis as a possible early sign of hereditary fructose intolerance.
An infant girl three weeks of age with the leading symptom of skin haemorrhages is presented. On further investigation, the signs of severe hepatic damage with hypofibrinogenaemia and prothrombin complex impairment, and renal tubular dysfunction were disclosed. All these pathological symptoms, which were reversed on fructose free diet, were caused by hereditary fructose intolerance.


Is a previous unplanned pregnancy a risk factor for a subsequent unplanned pregnancy?
The objective of the study was to determine whether a history of unplanned pregnancy was a risk factor for a subsequent unplanned pregnancy. We analyzed 542 women aged 14-35 years, enrolled in Project PROTECT, a randomized clinical trial to promote dual-method contraception use to prevent sexually transmitted diseases and unplanned pregnancy. Predictors of unplanned pregnancy were assessed by comparing women with and without a history of unplanned pregnancy. More than 1 in 5 women (22.5%) experienced an unintended pregnancy. History of an unintended pregnancy was a predictor of unintended pregnancy (adjusted odds ratio, 1.91; 95% confidence interval, 1.09-3.34). Other factors that were significantly associated with unplanned pregnancy included young age and low educational status. Future efforts should focus on bridging the gap between identifying risk factors for unplanned pregnancy and interventions aimed at reducing the incidence in high-risk groups.


Fixed-Dose Combination Therapy for the Prevention of Cardiovascular Diseases in CKD: An Individual Participant Data Meta-Analysis.
Fixed-dose combination treatments reduce cardiovascular disease in primary prevention. We aim to explore whether those benefits differ in the presence of CKD. We conducted an individual participant data meta-analysis in 18,162 participants on the efficacy and safety of treatment for the primary prevention of cardiovascular disease. Combination therapies consisted of at least two BP-lowering drugs and a statin, with or without aspirin versus placebo or minimal care. Here, we examine the differential effect of fixed-dose combination treatment on the risk of developing cardiovascular disease in participants with a low eGFR (<60 ml/min per 1.73 m 2 ; Chronic Kidney Disease Epidemiology Collaboration formula) compared with a normal eGFR (≥60 ml/min per 1.73 m 2 ). The primary composite outcome was time to first occurrence of a combination of cardiovascular death, myocardial infarction, stroke, or arterial revascularization. At baseline, the mean level of eGFR was 76 ml/min per 1.73 m 2 (SD 17). In total, 3315 (18%) participants had low eGFR at baseline. During a median follow-up of 5 years, among participants with normal eGFR, the primary outcome occurred in 232 (3%) participants in the treatment group compared with 339 (5%) in the control group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P < 0.001). In participants with low eGFR, the primary outcome occurred in 64 (4%) participants in the treatment group compared with 130 (8%) in the control group (hazard ratio, 0.49; 95% confidence interval, 0.36 to 0.66; P < 0.001; P for interaction 0.047). The relative risk reduction among participants with low eGFR was larger for combination strategies, including aspirin compared with treatments without aspirin. Apart from dizziness, other side effects did not differ between treatment and control groups, regardless of the stage of their kidney function. A fixed-dose combination treatment strategy is effective and safe at preventing cardiovascular disease, irrespective of eGFR, but relative and absolute risk reductions are larger in individuals with low eGFR. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_08_CJN0000000000000251.mp3.


[Health literacy and commitment to a general practitioner in low-acuity patients of emergency departments: results of the PiNo observational study in Northern Germany].
High utilization of emergency departments by low-acuity patients remains a major challenge for the health care system. Surveys of treatment urgency show that a considerable part of the emergency department population could also be cared for in the outpatient sector. Little is known about the contributing circumstances of non-utilization of outpatient care (despite indication). The expression of health literacy is often called to explain non-urgent use of emergency departments. The extent to which a distinguished commitment to primary care might have a moderating effect is currently not known. The data for this secondary evaluation of a non-urgent emergency department population were taken from the cross-sectional observational study PiNo Nord ("Patients in the emergency departments of hospitals in Northern Germany") (Scherer et al. 2017). In five hospitals in Hamburg and the federal state of Schleswig-Holstein, health literacy and 'intensity of the commitment to a general practitioner' were measured by self-assessment questionnaires (HLS-EU-Q16, F-HaBi). In addition to descriptive data analysis, linear regression was used to estimate the 'intensity of the commitment to a general practitioner' and other somatic, psychological, and sociodemographic characteristics of the population on health literacy. 548 non-urgent adult patients (mean age 41.5 years, 54.4% men) were included in the evaluation: 55.5% had sufficient, 31.4% problematic and 13.1% inadequate health literacy. 88.3% of the population had a general practitioner. A higher 'intensity of the commitment to a general practitioner', female gender, a higher subjective urgency for treatment, better self-efficacy and better social support were associated with higher health literacy. No associations were found with regard to age, household income, education and migration background, current pain or the degree of physical complaints. The extent of health literacy of a non-urgent sample of the PiNo North study population, responding to the HLS-EU-Q16, was comparable to the health literacy of the general population. Health literacy and intensity of commitment to a general practitioner were positively associated. However, the intensity of GP commitment was rather low. The fact that younger respondents were more likely to provide information about their health literacy and the availability of specialists in urban areas could explain these findings. Improving commitment to primary care physicians could include providing individualized information on how to navigate the health care system. This could make it easier for patients to choose an adequate level of care - and thus have a steering effect on emergency department utilization.


Maternal alcohol ingestion and the incidence of respiratory distress syndrome.
The risk of respiratory distress syndrome in infants born to mothers with varying quantities of alcohol intake during pregnancy was assessed. In infants less than 37 weeks' gestation, there was a decreasing incidence of respiratory distress syndrome with increasing maternal alcohol consumption (p less than 0.02). In addition, in infants less than 37 weeks' gestation, maternal alcohol ingestion was associated with a decreased risk of respiratory distress syndrome even when adjusted for other factors such as smoking, gestational age, birth weight, Apgar score, and sex of the infant. It is suggested that maternal alcohol ingestion enhances the maturation of the fetal lung.


Cesium uptake studies on human erythrocytes.
The uptake of Cs+ ions into the erythrocytes of abstemious volunteers and of alcoholic patients was followed using 133Cs NMR. The uptake rates are approximately linear with a rate of 0.33 mM.h-1 at an extracellular Cs+ concentration of 10 mM. There is no discernible difference in the uptake rate between the two classes of subject despite earlier reports that Cs+ distribution is different and consequently that Cs+ transport might be anomalous in alcoholics. There is no evidence of saturation of the input rate and Cs(+)-loaded cells retain their Cs+ when incubated in a Cs(+)-free buffer, strongly suggesting that there is no transport mechanism for the removal of Cs+ from the erythrocyte. Experiments designed to ascertain which intracellular ion is being replaced by Cs+ indicate that it predominantly displaces K+.


The NAD(P)H:flavin oxidoreductase from Escherichia coli as a source of superoxide radicals.
The NAD(P)H:flavin oxidoreductase (encoded by the fre gene) of Escherichia coli is a soluble enzyme which, under aerobic conditions and together with NAD(P)H and flavins, generates superoxide radicals selectively. This was demonstrated from spin trapping experiments and from the ability of the flavin reductase to achieve a superoxide dismutase (SOD)-sensitive reduction of cytochrome c. The participation of the flavin reductase to O2-. generation in E. coli cells has been studied. Superoxide production in dialyzed cytosolic fraction of SOD-deficient E. coli was stimulated by the addition of flavins. There was no stimulation in soluble extracts of flavin reductase-deficient strains. Moreover, using fusions of sodA promoter to lacZ, we showed that sodA transcription was diminished in flavin reductase-deficient E. coli and that the induction of MnSOD by flavin reductase was SoxRS-independent. These results suggest that the flavin reductase might: (i) in vivo, be an important cytosolic site of O2-. generation; (ii) in vitro, serve as a simple, efficient, and selective O2-. generator.


Purification of a peptidylglycine alpha-amidating enzyme from transplantable rat medullary thyroid carcinomas.
A peptidyl glycine alpha-amidating activity has been isolated from total tissue extracts of rat medullary thyroid carcinoma (MTC). Purification of the activity by ammonium sulfate fractionation, Sephacryl S-300 chromatography, and strong anion-exchange chromatography at pH 6.0 has resolved at least four peaks of activity. The activity associated with peak III has been further purified to apparent homogeneity by strong anion-exchange chromatography at pH 8.0. The purified peak III enzyme has an apparent molecular mass of 75,000 Da as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The identity of the 75,000-Da band as the alpha-amidating enzyme has been confirmed by recovery of activity from a nondenaturing polyacrylamide gel. The enzyme is catalytically active as a monomer, exhibits a pH optimum between 5.0 and 5.5, and has a turnover number of 300 min-1 for N-dansyl-Tyr-Val-Gly amidation at pH 5.5. The larger size, more acidic pH optimum, and higher specific activity distinguish the purified peak III rat MTC enzyme from the enzymes isolated from bovine and porcine pituitary or from frog skin.


[Hyponatremia-induced life-threatening cerebral edema after ecstasy use].
Ecstasy, a psychoactive amphetamine derivative, is a popular party drug. We report the cases of 2 young adults who developed cerebral edema due to hyponatremia. One patient was released from the hospital without any sequelae, whereas the second patient died due to cerebral edema. Severe cases of symptomatic hyponatremia after ecstasy consumption are described in the literature with partially fatal clinical outcomes. Thus, physicians should be aware of early and consequent control of the sodium and choose an interdisciplinary treatment decision.


Norplant use by adolescents: viewpoints of three stakeholder groups.
In the months following FDA approval of Norplant, discussions of the controversies surrounding its introduction took place largely in newspaper and magazine articles detailing interviews with legal and health professionals and scientists who developed the device. This qualitative study brings the viewpoints of selected groups of consumers, reproductive health care workers, and local policy makers to the public discussions of Norplant. This article explores one of several themes raised by study participants--Norplant use by adolescents. Eighteen different focused group interviews were conducted in California between November 1991 and November 1992. A total of 146 individuals attended--63 consumers, 44 health care providers, and 39 policy makers. Participants included consumers identified as so-called "targets" of Norplant use, individuals providing reproductive health services, and individuals in policy and decision-making roles. Participants in all the focus groups agreed that Norplant should not be used to accomplish social goals or viewed as the answer to society's pressing social and economic problems. There was no agreement, however, on the issue of Norplant use by adolescents. Study participants argued persuasively on both sides of the question, expressing ambivalence concerning the incidence of teenage pregnancies, the longterm health effects of Norplant use on adolescents, and the threat of increased risk of STDs and HIV/AIDS among adolescents using Norplant. Study findings highlight a critical need for ongoing dialogue among key stakeholder groups to develop an understanding of the diverse values informing the debate. Participants' responses reinforced that decision-making in public health need not only be the jurisdiction of policy makers, elected officials, and others. Ordinary citizens can be part of the task as well by offering insights for practical and ethical solutions to some of our most pressing social issues.


Calcitriol supplementation effects on Ki67 expression and transcriptional profile of breast cancer specimens from post-menopausal patients.
High concentration of 1,25(OH)2D3 (50-100 nM), which cause hypercalcemia in vivo, induce the hormone transcriptional targets and exert antiproliferative effects in cultured breast cancer lineages, however, no studies investigated whether these effects might be reproduced in tumor specimens in vivo. Our aim was to evaluate the effects of calcitriol supplementation on the proliferative index (Ki67 expression) and gene expression profile of post-menopausal breast cancer samples. Tumor samples were collected from 33 patients, most of whom (87.5%) presenting 25(OH)D3 insufficiency, before and after a short term calcitriol supplementation (0.50 μg/day PO, for 30 days). Tumor dimension remained stable in ultrasound evaluations. A slight reduction in Ki67 immunoexpression was detected, however in only 10/32 post-calcitriol samples an expressively low proliferative index [Ln (%Ki67+) < 1] was achieved. Gene expression from 15 matched pre/post-supplementation samples was analyzed by microarray (U133 Plus 2.0 GeneChip, Affymetrix) and 15 genes were over-expressed in post-supplementation tumors, including FOS and EGR1, which were previously shown to be regulated by vitamin D. However, these results were not confirmed in another four breast cancer samples. Calcitriol supplementation is neither sufficient to expressively elicit an antiproliferative response nor to induce the hormone transcriptional signaling pathway in breast cancer specimens.


FGF signals from the nasal pit are necessary for normal facial morphogenesis.
Fibroblast growth factors (FGFs) are required for brain, pharyngeal arch, suture and neural crest cell development and mutations in the FGF receptors have been linked to human craniofacial malformations. To study the functions of FGF during facial morphogenesis we locally perturb FGF signalling in the avian facial prominences with FGFR antagonists, foil barriers and FGF2 protein. We tested 4 positions with antagonist-soaked beads but only one of these induced a facial defect. Embryos treated in the lateral frontonasal mass, adjacent to the nasal slit developed cleft beaks. The main mechanisms were a block in proliferation and an increase in apoptosis in those areas that were most dependent on FGF signaling. We inserted foil barriers with the goal of blocking diffusion of FGF ligands out of the lateral edge of the frontonasal mass. The barriers induced an upregulation of the FGF target gene, SPRY2 compared to the control side. Moreover, these changes in expression were associated with deletions of the lateral edge of the premaxillary bone. To determine whether we could replicate the effects of the foil by increasing FGF levels, beads soaked in FGF2 were placed into the lateral edge of the frontonasal mass. There was a significant increase in proliferation and an expansion of the frontonasal mass but the skeletal defects were minor and not the same as those produced by the foil. Instead it is more likely that the foil repressed FGF signaling perhaps mediated by the increase in SPRY2 expression. In summary, we have found that the nasal slit is a source of FGF signals and the function of FGF is to stimulate proliferation in the cranial frontonasal mass. The FGF independent regions correlate with those previously determined to be dependent on BMP signaling. We propose a new model whereby, FGF-dependent microenvironments exist in the cranial frontonasal mass and caudal maxillary prominence and these flank BMP-dependent regions. Coordination of the proliferation in these regions leads ultimately to normal facial morphogenesis.


Mechanism of inactivation of a Fasciola proteolytic enzyme by peptide aldehydes and alkylating agents.
A proteolytic enzyme of the liver fluke Fasciola sp. was purified as described previously by ammonium sulfate fractionation, gel filtration on Sephadex G-200 column and L-phenylalanine-agarose chromatography. Leupeptin, a peptide aldehyde of microbial origin, competitively inhibited the enzyme activity with respect to the substrate alpha-N-benzoyl-L-argininamide; the apparent Ki value for leupeptin is 45 000-fold less than the apparent Km for the substrate. Incubation of the enzyme with leupeptin resulted in time-dependent inactivation of the globinolytic activity, with an inactivation constant (Kinact) of 0.4 microM giving the half-maximum inactivation velocity, and with a minimum inactivation half-time (T) of 2.7 min at infinite concentration of this compound. The inactivated enzyme was not reactivated by extensive dialysis. These results imply that leupeptin yields an affinity labelling of an active site of the enzyme. The activity of the Fasciola proteolytic enzyme was also inactivated by other peptide aldehydes and alkylating agents and inactivation constants observed were 0.5 microM for chymostatin, 13 microM for antipain, 2 microM for p-toluenesulfonyl-L-lysine chloromethyl ketone, 140 microM for p-toluenesulfonyl-L-phenylalanine chloromethyl ketone and 40 microM for iodoacetate under the conditions used.


Association between MMP16 rs60298754 and clinical phenotypes of Parkinson's disease in southern Chinese.
The aim was to investigate the association between MMP16 rs60298754 and symptoms of Parkinson's disease (PD) in southern Chinese. Seven hundred forty-five PD patients were recruited in this study. All patients were evaluated by Brief Pain Inventory (BPI), Hamilton anxiety rating scale and Hamilton depression rating scale, 39-item Parkinson's disease Questionnaire (PDQ-39), and MDS-Unified PD Rating Scale (MDS-UPDRS). Symptoms were also recorded. The difference of BPI and Parkinson's disease sleep scale (PDSS) between two groups was showed (BPI: MMP16 wildtypes: 14.73 ± 14.45; MMP16 carriers: 10.95 ± 10.67, p 0.002; PDSS: MMP16 wildtypes: 117.80 ± 21.45; MMP16 carriers: 108.40 ± 23.95, p < 0.001). The association of apathy, nocturia, and sensitive to light were found (apathy: p 0.001, OR: 0.49, 0.32-0.76; nocturia: p < 0.001, OR: 3.57, 1.90-7.26; sensitive to light: p < 0.001, OR: 3.99, 2.01-7.74). MMP16 rs60298754 was associated with the presence of apathy, pain, nocturia, and sensitive to light.


Penetration of temafloxacin into body tissues and fluids.
The new fluoroquinolone antimicrobial temafloxacin shows good penetration into a range of body tissues and fluids, after single or repeated oral administration to healthy volunteers and patients undergoing various procedures. Temafloxacin concentrations in respiratory tissues and fluids, nasal secretions, tonsils, prostate, semen, bone and blister fluid were similar to, or greater than, concurrent serum concentrations. Penetration into sinus secretions and cerebrospinal fluid is less marked; nevertheless, temafloxacin concentrations of approximately 2.4 and 1 mg/L, respectively, were achieved. Concentrations of temafloxacin observed in these tissues and fluids exceed the minimum concentrations required to eradicate the majority of bacterial pathogens associated with respiratory infections, tonsillitis, sinusitis, prostatitis, bone infections and meningitis. Since elimination of temafloxacin occurs by the renal route, high concentrations of the drug are also found in the urine. Biliary excretion of temafloxacin accounts for about 3% and leads to high biliary concentrations of the drug.


Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore.
Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity.


The feeding ecology of a carnivorous plant (Pinguicula nevadense): prey analysis and capture constraints.
The taxonomic composition and size of arthropods captured by Pinguicula nevadense, an endemic carnivorous plant of the high-mountain zone of the Sierra Nevada (southern Spain), are analysed. The actual prey of P. nevadense and the available arthropods trapped by "mimic-traps" are compared, in order to identify the capture constraints of the plant. The results show that P. nevadense captures various arthropod taxa. Winged insects, especially Nematocera, make up the main component of the diet. The range of prey sizes in all P. nevadense populations studied is similar. The taxonomic composition of arthropods trapped by the mimic-traps is similar to that of the actual prey of P. nevadense. However, the plant captures prey only below a specific size threshold. These size constraints appear to be the principal factor determining the actual prey of this carnivorous plant.


Electrospray ionization mass spectrometric peptide mapping: a rapid, sensitive technique for protein structure analysis.
Electrospray ionization mass spectrometric peptide mapping is demonstrated to be a useful new technique for protein structure analysis. The procedure involves the digestion of the protein with trypsin and subsequent analysis of the total unfractionated digest by electrospray ionization mass spectrometry. The utility of the technique for investigating protein structure is illustrated by a peptide mapping analysis of human apolipoprotein AI (Mr = 28 kDa). The technique is rapid, sensitive, and requires no prior separation of the peptides. The discrimination effects observed in other mass spectrometric methods are less important in the present procedure.


New treatments for COPD.
Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. It is characterised by chronic inflammation in the lungs that leads to progressive chronic airflow obstruction. The main strategy for treating COPD is control of the chronic inflammation. However, current anti-inflammatory treatments fail to prevent disease progression. New long-acting bronchodilators and their combinations are currently under development. Research has been focused on identifying the key inflammatory regulators. CXCR2 antagonists inhibit neutrophilic inflammation; inhibitors of phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (p38), Janus kinases and IL-6 have also shown some promising effects. There is an emerging need for identification of key modulators of the oxidative stress-regulated corticosteroid function aiming the development of monotherapies which will resolve any side effects issues currently faced.


Tropane-based amino acids for peptide structure-function studies: inhibitors of platelet aggregation.
Novel tropane (azabicycloheptane) and azabicyclohexane containing amino acids have been prepared and incorporated into analogues of reported inhibitors of platelet aggregation. The influence of these central constraints upon biological activity suggest their utility in peptide structure function studies.


Evaluating protective effects of botanicals under inflammation and oxidative stress in chicken apical-out enteroids.
Botanicals (BOTs) are well known for their anti-inflammatory and antioxidant activities. They have been widely used as feed additives to reduce inflammation and improve intestinal functions in agricultural animals. However, the effects of BOTs on chicken intestinal epithelial functions are not fully understood. The 3D apical-out chicken enteroids recapitulate the intestinal tissue, and allow convenient access to the luminal surface, thus serving as a suitable model for investigating gut functions. The aim of this study was to identify the roles of BOTs in protecting the intestinal epithelium in chicken enteroids under challenging conditions. Apical-out enteroids were isolated from the small intestines of 18 days-old chicken embryos. Lipopolysaccharide (LPS, 10 µg/mL) and menadione (400 µM) challenges were performed in the media with or without BOTs. Paracellular Fluorescein isothiocyanate-dextran 4kD (FD4) permeability, inflammatory cytokine gene expression, and reactive oxygen species (ROS) generation were analyzed post-BOTs and challenges treatments. Statistical analysis was performed using one-way ANOVA and post hoc multiple comparisons among treatments. The results showed that the LPS challenge for 24 h induced a 50% increase in FD4 permeability compared with nontreated control; thymol, thyme essential oil, and phenol-rich extract significantly (P < 0.02) reduced FD4 permeability by 25%, 41%, and 48% respectively, in comparison with LPS treatment. Moreover, the gene expression of inflammatory cytokines was upregulated, tight junction proteins and defensins were downregulated (P < 0.05) after 6 h of LPS treatment, while these BOTs treatments significantly restored the LPS-induced gene expression alterations (P < 0.05). Menadione oxidative challenge for 1 h significantly increased the ROS level compared with unchallenged control. Enteroids treated with thymol and thyme essential oils showed 30% reduced ROS levels, while the phenol-rich extract reduced them by 60%, in comparison with the challenged group (P < 0.0001). These data confirmed the role of BOTs in supporting the barrier function and reducing the disruptive effects of inflammation and oxidation in the chicken intestine.


Angiographic and angioscopic observations of the arterial luminal changes induced by vasospasm.
Angiography and angioscopy were used to examine arterial luminal changes induced by experimental vasospasm. The right common carotid artery of the dog was perfused with Krebs-Henseleit solution at a constant pressure, 3,4-diaminopyridine (DAP), a selective potassium channel blocker was applied on the adventitia, and the luminal changes were observed with angiography and angioscopy. Angiographically vasospasm (defined as a reduction in the internal diameter to less than 50% of the control value) was always induced by the topical application of 5 X 10(-1) mol/L DAP. The internal diameter decreased to 25% +/- 7% (mean +/- standard error, n = 6) 15 minutes after the application. The vasospasms propagated 2.7 +/- 0.6 and 1.1 +/- 0.3 cm downstream and upstream, respectively. Angioscopy showed that the lumen narrowed gradually and concentrically. Perfusion of the artery during vasospasm for 15 minutes with a backflow of blood from the contralateral artery resulted in thrombosis at the spastic segment. The results indicate that carotid vasospasm can be constantly induced by DAP, thrombosis occurs in the spastic artery, and angioscopy is useful for serial observation of the luminal changes induced by vasospasm.


Development of electrochemiluminescent inhibition method for determination of gentian violet in aquatic water.
Gentian violet (GV) was found to quench the electrochemiluminescence (ECL) of the tris(2,2'-bipyridyl)ruthenium(II)/tris-n-propylamine (Ru(bpy)3(2+)-TPA) system at a glass carbon electrode (GCE). Based on the ECL signal changes, a simple and ultrasensitive detection method for GV in aquatic water was established. Under the optimized conditions, the quenched ECL intensity versus the logarithm of the concentration of GV was linear over a concentration range from 1.0×10(-10) to 5.0×10(-7) mol L(-1), and the limit of detection (LOD) was found to be 4.5×10(-12) mol L(-1) (S/N=3). The results obtained by the ECL system were better than other reported methods in literatures in terms of sensitivity or linear response range. The method was successfully applied to determine GV in aquatic water, and the relative standard deviations (RSDs) were found less than 6.3%, and the recoveries were obtained from 98.7 to 111.0%. Moreover, a possible mechanism of the quenching effect was primarily discussed based on UV-visible absorption spectra, cyclic voltammograms and IECL-E curves.


Recombinant antimicrobial peptide hPAB-β expressed in Pichia pastoris, a potential agent active against methicillin-resistant Staphylococcus aureus.
As a potential therapeutic agent, antimicrobial peptide has received increased attention in recent years. However, high-level expression of a small peptide with antimicrobial activity is still a challenging task. In this study, the coding sequence of antimicrobial peptide hPAB-β, a variant derived from human beta-defensin 2, was cloned into pPIC9K vector and transformed into Pichia pastoris. P. pastoris transformants harbored with multi-copy plasmids were screened by G418 selection. When the transformed cells were induced by methanol, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot, and matrix-assisted laser desorption ionization-time of flight mass spectrometry revealed recombinant hPAB-β products consisting of three protein species of 4,680.4, 4,485.3, and 4,881.9 Da at proportions of 58%, 36%, and 6%, respectively, which may be due to the incomplete processing of the fusion signal peptide of α-factor by the STE13 protease. Expressed hPAB-β was secreted into the culture medium at a level of 241.2 ± 29.5 mg/L. Purified hPAB-β with 95% homogeneity was obtained by 10 kDa membrane filtration followed by cation ion-exchange chromatography with a SP-Sepharose XL column. The two major protein species separated through a SOURCE 30RPC reverse phase chromatography column showed definite antimicrobial activities against Staphylococcus aureus. All 22 methicillin-resistant S. aureus (MRSA) isolates with multidrug resistance phenotype were sensitive to the recombinant hPAB-β with minimal inhibitory concentrations of 8-64 μg/ml. Our results show that the methylotrophic yeast-inducible system is suitable for high-level expression of active hPAB-β, and that expressed hPAB-β in P. pastoris may be a potential antimicrobial agent against MRSA infection.


[Raised glucagon levels of the blood induced by arginine: relation to blood sugar, blood insulin and STH in aged non-diabetics and diabetics].
In a group of aged nondiabetic and diabetic subjects and in a group of young subjects the glycemic, insulin, growth hormone and glucagon response to intravenous arginine was studied. A prompt increase in blood glucose, serum insulin and glucagon levels was observed, but glucose and glucagon peaks were significantly higher in older non diabetic and diabetic subjects. Growth hormone secretion did not show any difference between aged nondiabetic and young subjects, on the contrary it is lower in diabetics. These findings might suggest the hypothesis of the glucose intolerance during old age due to increased release of glucagon.


Association of cytomegalovirus (CMV) infection with cervical cancer: isolation of CMV from cell cultures derived from cervical biopsy.
Cytomegalovirus (CMV) was isolated from cell cultures derived from 2 of 10 cervical cancer biopsies from patients in an advanced stage of the disease. Five serial passages were necessary before extensive cytopathic changes characteristic of CMV infection appeared. All patients tested had complement-fixing antibodies to both isolates in higher titers than to the prototype AD169 strain. 6 of 8 patients tested also had herpesvirus type 2 antibodies.


Predictive value of lncRNA ZFAS1 in patients with lumbar disc degeneration.
Increasing evidences have indicated the association of non-coding RNAs with the progression of lumbar disc degeneration (LDD), but the role of lncRNA ZFAS1 in LDD remains undefined. Therefore, this study was designed to determine the predictive value of lncRNA ZFAS1 in patients with LDD. A total of 80 patients with LDD confirmed and treated in the Gansu Provincial Hospital from May 2018 to May 2020 were enrolled into the patient group, and 50 healthy controls who concurrently underwent physical examination in our hospital were enrolled into the control group. The expression and diagnostic value of serum lncRNA ZFAS1 in the two groups were determined. The expression of lncRNA ZFAS1 was compared between the two groups before and one month after therapy, and the associations of lncRNA ZFAS1 with inflammatory factors were analyzed. In addition, logistic regression was carried out to analyze risk factors for the prognosis of patients, and corresponding curves about prediction were drawn. The patient group showed a notably higher lncRNA ZFAS1 level than the control group (P<0.001), and the area under the receiver operating characteristic (ROC) of lncRNA ZFAS1 in diagnosing LDD was 0.807. In addition, after therapy, the patient group showed a remarkable decrease in serum lncRNA ZFAS1 (P<0.01). Serum lncRNA ZFAS1 was positively correlated with serum TNF-α, IL-6 and IL-1β in patients (all P<0.05). Moreover, serum lncRNA ZFAS1 in the good efficacy group was notably lower than that in the general efficacy group (P<0.01). Age and lncRNA ZFAS1 expression before therapy were independent risk factors for patients' prognosis (both P<0.05). LncRNA ZFAS1 is highly expressed in patients with LDD and is a potential prognostic indicator for LDD.


Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells.
Previous studies have demonstrated that a small subset of cancer cells is capable of tumor initiation. The existence of tumor initiating cancer stem cells (CSCs) has several implications in terms of future cancer treatment and therapies. However, recently, several researchers proposed that differentiated cancer cells (non-CSCs) can convert to stem-like cells to maintain equilibrium. These results imply that removing CSCs may prompt non-CSCs in the tumor to convert into stem cells to maintain the equilibrium. Interleukin-6 (IL-6) has been found to play an important role in the inducible formation of CSCs and their dynamic equilibrium with non-stem cells. In this study, we used CSC-like human breast cancer cells and their alternate subset non-CSCs to investigate how IL-6 regulates the conversion of non-CSCs to CSCs. MDA-MB-231 and MDA-MB-453 CSC-like cells formed mammospheres well, whereas most of non-stem cells died by anoikis and only part of the remaining non-stem cells produced viable mammospheres. Similar results were observed in xenograft tumor formation. Data from cytokine array assay show that IL-6 was secreted from non-CSCs when cells were cultured in ultra-low attachment plates. IL-6 regulates CSC-associated OCT-4 gene expression through the IL-6-JAK1-STAT3 signal transduction pathway in non-CSCs. Inhibiting this pathway by treatment with anti-IL-6 antibody (1 μg/ml) or niclosamide (0.5-2 μM)/LLL12 (5-10 μM) effectively prevented OCT-4 gene expression. These results suggest that the IL-6-JAK1-STAT3 signal transduction pathway plays an important role in the conversion of non-CSCs into CSCs through regulation of OCT-4 gene expression.


Urothelial carcinoma in situ: diagnostic update.
Based on the current WHO 2016 classification, the spectrum of flat urothelial lesions with atypia includes reactive urothelial atypia, urothelial atypia of unknown significance, urothelial dysplasia, and urothelial carcinoma in situ (CIS). Classification along this continuous spectrum of atypia can be one of the most challenging areas in all genitourinary pathology. This review will focus on the diagnosis of urothelial CIS in routine clinical practice, emphasising histological criteria, histological spectrum (i.e., 'variant' types), adjunctive immunohistochemistry, intraoperative evaluation, and distinction from its morphological mimics.


Changes in attitudes, practices and barriers among oncology health care professionals regarding sexual health care: Outcomes from a 2-year educational intervention at a University Hospital.
To examine the attitudes, practices and perceived barriers in relation to a sexual health care educational intervention among oncology health care professionals at the Landspítali-National University Hospital of Iceland. The design was quasi experimental, pre - post test time series. A comprehensive educational intervention project, including two workshops, was implemented over a two year time period. A questionnaire was mailed electronically to all nurses and physicians within oncology at baseline (T1, N = 206), after 10 months (T2, N = 216) and 16 months (T3, N = 210). The response rate was 66% at T1, 45% at T2 and 38% at T3. At all time points, the majority of participants (90%) regarded communication about sexuality part of their responsibilities. Mean scores on having enough knowledge and training, and in six of eight practice issues increased significantly over time. Overall, 10-16% reported discussing sexuality-related issues with more than 50% of patients and the frequency was significantly higher among workshop attendants (31%) than non-attendants (11%). Overall, the most common barriers for discussing sexuality were "lack of training" (38%) and "difficult issue to discuss" (27%), but the former barrier decreased significantly by 22% over time. The intervention was successful in improving perception of having enough knowledge and training in providing sexual health care. Still, the issue remains sensitive and difficult to address for the majority of oncology health care professionals. Specific training in sexual health care, including workshops, should be available to health care professionals within oncology.


Effects of mercury chloride (HgCl2) on Betta splendens aggressive display.
Mercury chloride (HgCl2) is a toxic mercury salt and a major pollutant, that can be found in soil, water and air, with influences on behavior, physiology and adaptation to the environment. In this study two experiments were designed to examine interactions and effects of HgCl2 on some behavioral patterns of Siamese fighting fish (Betta splendens). In the first experiment we tested the effect of a progressive dose (five 0.04 mg) on aggressive display with exposure to a mirror, whereas in the second experiment we tested the effect of an acute dose (0.2 mg) on the aggressive display with exposure to a mirror. The experiments were performed on 5 consecutive sessions at intervals of 18 hours between sessions. Differences of performance were shown by subjects in the acute and progressive treatments when compared with a control treatment in the majority of behaviors evaluated, namely Floating, Slow Swimming, Wavy Swimming, Emerging, Bend, Square Move and Motor Display Components. Acute treatment was different from control only on Show Body, while the progressive group differed on Resting, Horizontal Display and Appropriate Display Components. Differences between Correlate Display Components and Total were also shown. Both the acute and progressive contamination with HgCl2 decrease the motor activity in the aggressive display, mirror-image test of Betta splendens, mainly on the progressive dose. This implies an impairment on feeding behavior, predator avoidance, reproductive behavior, mate choice and territoriality. These results suggest that in this fish species, the progressive dose has a greater effect on behavior in general and that both the acute and progressive contamination with mercury chloride affect many other aspects of behavior.


An Integrated In Silico, In Vitro and Tumor Tissues Study Identified Selenoprotein S (SELENOS) and Valosin-Containing Protein (VCP/p97) as Novel Potential Associated Prognostic Biomarkers in Triple Negative Breast Cancer.
Triple negative breast cancer (TNBC) is a heterogeneous group of tumors with early relapse, poor overall survival, and lack of effective treatments. Hence, new prognostic biomarkers and therapeutic targets are needed. The expression profile of all twenty-five human selenoproteins was analyzed in TNBC by a systematic approach.In silicoanalysis was performed on publicly available mRNA expression datasets (Cancer Cell Line Encyclopedia, CCLE and Library of Integrated Network-based Cellular Signatures, LINCS). Reverse transcription quantitative PCR analysis evaluated selenoprotein mRNA expression in TNBC versus non-TNBC and normal breast cells, and in TNBC tissues versus normal counterparts. Immunohistochemistry was employed to study selenoproteins in TNBC tissues. STRING and Cytoscape tools were used for functional and network analysis. GPX1, GPX4, SELENOS, TXNRD1 and TXNRD3 were specifically overexpressed in TNBC cells, tissues and CCLE/LINCS datasets. Network analysis demonstrated that SELENOS-binding valosin-containing protein (VCP/p97) played a critical hub role in the TNBCselenoproteins sub-network, being directly associated with SELENOS expression. The combined overexpression of SELENOS and VCP/p97 correlated with advanced stages and poor prognosis in TNBC tissues and the TCGA dataset. Combined evaluation of SELENOS and VCP/p97 might represent a novel potential prognostic signature and a therapeutic target to be exploited in TNBC.


TANGLED1 mediates microtubule interactions that may promote division plane positioning in maize.
The microtubule cytoskeleton serves as a dynamic structural framework for mitosis in eukaryotic cells. TANGLED1 (TAN1) is a microtubule-binding protein that localizes to the division site and mitotic microtubules and plays a critical role in division plane orientation in plants. Here, in vitro experiments demonstrate that TAN1 directly binds microtubules, mediating microtubule zippering or end-on microtubule interactions, depending on their contact angle. Maize tan1 mutant cells improperly position the preprophase band (PPB), which predicts the future division site. However, cell shape-based modeling indicates that PPB positioning defects are likely a consequence of abnormal cell shapes and not due to TAN1 absence. In telophase, colocalization of growing microtubules ends from the phragmoplast with TAN1 at the division site suggests that TAN1 interacts with microtubule tips end-on. Together, our results suggest that TAN1 contributes to microtubule organization to ensure proper division plane orientation.


Oxysterol (7 beta-hydroxycholesteryl-3-oleate) promotes serotonergic reinnervation in the lesioned rat spinal cord by reducing glial reaction.
In the present study, following previous experience with electrolytic lesion of the rat brain, and subsequent reduction of reactive gliosis with 7 beta-hydroxycholesterol derivatives (Bochelen et al.: Neuroscience 51:827-834, 1992), we have performed a hemisection of the spinal cord in adult rats and investigated the influence of 7 beta-hydroxycholesteryl-3-oleate (oxysterol) on the intensity of the astrocytic reaction and the axonal regeneration. We have shown here that local administration of liposomes containing this oxysterol reduced the intensity of the astroglial reaction on the sectioned side, as seen with immunocytochemical detection of glial fibrillary acidic protein (GFAP) and by in situ hybridization with a specific RNA probe. Moreover, radioautographic evaluation of astrocyte proliferation with tritiated thymidine evidenced a reduction of the astrocyte labelling index. In addition, double immunocytochemical detection of GFAP and polysialylated neural cell adhesion molecule (E-NCAM) revealed a decrease of the expression of this molecule in reactive astrocytes of the treated animals. Finally, immunocytochemical detection of serotonin (5HT) was determined in the raphespinal projections, which constitute a major descending system. In treated animals, serotonergic axons originating from the intact side reinnervated the dorsal horn of the sectioned side, below the hemisection. These results demonstrate that 7 beta-hydroxycholesteryl-3-oleate can reduce the astrocytic reaction following spinal cord injury, promoting the serotonergic reinnervation of a denervated territory.


High intratumoral plasma cells content in primary prostate cancer defines a subset of tumors with potential susceptibility to immune-based treatments.
Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials. We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival. We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy. Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment.


Contribution of new cryomethods to a better knowledge of bacterial anatomy.
Electron microscopy has largely contributed to the study of bacterial anatomy. However, as varied alterations can occur during cell preparation, at the level of cell structure and at the molecular level, it is difficult to know to what extent electron micrographs correspond to the true appearance of the living state. The recent development of cryomethods which avoid some of the alterations which may occur during conventional fixation and embedding procedures, has shed new light on bacterial anatomy. These have definitively proved that mesosomes do not exist, but are artefactual structures induced by the fixative. New features of the bacterial "nucleus" relating to its shape and fine structure appeared in thin sections of Gram-positive and Gram-negative bacteria prepared by cryosubstitution. New information has also been obtained on the cell wall structure of different bacterial species.


Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA).
Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited. To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment. Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation. We calculated the relative risks of SAE and ESI for ETA and ADA compared with methotrexate (MTX). Among the 1414 patients treated with ETA (n=1414; 4461 exposure years (EY)) and ADA (n=320; 493 EY), significantly more SAE, infections and medically important infections were observed (ETA: 4.5, 5.7, 0.9; ADA: 4.7, 11.4, 0.4 per 100 EY) compared with those treated with MTX alone (n=1455; 2.907 EY; 2.6, 5.5, 0.5 per 100 EY). The risk for malignancies was not significantly increased for ETA and ADA compared with MTX (0.09, 0.27 and 0.07/100 person-years). Patients under ETA monotherapy developed more frequently incident inflammatory bowel disease (IBD) and incident uveitis (0.5 and 0.8/100 EY) than patients treated by ETA in combination with MTX (0.1 and 0.2/100 EY) or MTX alone (0.03 and 0.1/100 EY). Our data confirm the acceptable long-term tolerability of ETA and ADA in pJIA. However, whether the onset of IBD and uveitis during ETA monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort.


The relevance of compartmentation for cysteine synthesis in phototrophic organisms.
In the vascular plant Arabidopsis thaliana, synthesis of cysteine and its precursors O-acetylserine and sulfide is distributed between the cytosol, chloroplasts, and mitochondria. This compartmentation contributes to regulation of cysteine synthesis. In contrast to Arabidopsis, cysteine synthesis is exclusively restricted to chloroplasts in the unicellular green alga Chlamydomonas reinhardtii. Thus, the question arises, whether specification of compartmentation was driven by multicellularity and specified organs and tissues. The moss Physcomitrella patens colonizes land but is still characterized by a simple morphology compared to vascular plants. It was therefore used as model organism to study evolution of compartmented cysteine synthesis. The presence of O-acetylserine(thiol)lyase (OAS-TL) proteins, which catalyze the final step of cysteine synthesis, in different compartments was applied as criterion. Purification and characterization of native OAS-TL proteins demonstrated the presence of five OAS-TL protein species encoded by two genes in Physcomitrella. At least one of the gene products is dual targeted to plastids and cytosol, as shown by combination of GFP fusion localization studies, purification of chloroplasts, and identification of N termini from native proteins. The bulk of OAS-TL protein is targeted to plastids, whereas there is no evidence for a mitochondrial OAS-TL isoform and only a minor part of OAS-TL protein is localized in the cytosol. This demonstrates that subcellular diversification of cysteine synthesis is already initialized in Physcomitrella but appears to gain relevance later during evolution of vascular plants.


Using nanoliter plugs in microfluidics to facilitate and understand protein crystallization.
Protein crystallization is important for determining protein structures by X-ray diffraction. Nanoliter-sized plugs--aqueous droplets surrounded by a fluorinated carrier fluid--have been applied to the screening of protein crystallization conditions. Preformed arrays of plugs in capillary cartridges enable sparse matrix screening. Crystals grown in plugs inside a microcapillary may be analyzed by in situ X-ray diffraction. Screening using plugs, which are easily formed in PDMS microfluidic channels, is simple and economical, and minimizes consumption of the protein. This approach also has the potential to improve our understanding of the fundamentals of protein crystallization, such as the effect of mixing on the nucleation of crystals.


Sympathetic-leptin relationship in obesity: effect of weight loss.
Obese patients have high plasma leptin concentrations that do not induce the expected responses on weight regulation, suggesting a leptin resistance in obesity. Elevated leptin levels are also thought to be related to a high sympathetic nervous system (SNS) activity. This effect could be preserved, lowered, or even abolished in obesity. We planned to investigate the possible association in a longitudinal study. Ninety-five normotensive healthy women, aged 40.4 +/- 11.4 years and body mass index of 33.2 +/- 2.3 kg/m(2), were studied. Baseline leptin, fat mass, and heart rate variability were measured and included in a 6-month longitudinal study. Body composition was measured by dual-energy x-ray absorption. Time domain heart rate variability, QT dynamicity, and spectral components on ambulatory electrocardiographs were analyzed. Dietary advice was given by a dietitian to the patient (maximum caloric reduction of 30%), and subjects were randomized in 3 treatment groups: sibutramine 10 mg, sibutramine 20 mg, or placebo. At baseline, low frequencies (LF) and the LF-high frequencies (HF) ratio, mainly related to the SNS, were negatively correlated to leptin concentration (r = -0.30, P = .002 and r = -0.36, P < .001) and to the leptin-fat mass ratio (r = -0.28, P = .004 and r = - 0.33, P = .0007), thus explaining 38% of the LF variance and 33% of the LF/HF variance. Diastolic blood pressure was also negatively correlated to leptin concentrations (-0.20, P = .04) and to the leptin-fat mass ratio (-0.22, P = .022). In contrast, no consistent correlations between leptin and the time domain components related to vagal activity were observed. At 6 months, after completion of the weight loss program, LF significantly decreased (-7.7% +/- 7.9%, P < .001), whereas HF was higher than the initial value (+20% +/- 5.2%). The leptin-fat mass ratio remained negatively correlated to the LF (r = -0.34, P = .030) and to LF/HF (r = -0.35, P = .021) values, explaining 21% of the LF variation. None of the pairwise comparisons between the 2 sibutramine groups and the placebo group were statistically significant for heart rate variability. High leptin concentration is associated with low indexes of cardiac SNS activity and with a lower diastolic blood pressure in normotensive obese women. Our results imply therefore that the relationship between leptin and the autonomic nervous system is disturbed in normotensive obese subjects.


Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.
CD8+ T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+ T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+ T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+ T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+ T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+ T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+ T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+ T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+ CD8+ T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+ T cells in MS, indicates these cells may be attractive targets in MS therapy.


Compensatory functional connectome changes in a rat model of traumatic brain injury.
Penetrating cortical impact injuries alter neuronal communication beyond the injury epicentre, across regions involved in affective, sensorimotor and cognitive processing. Understanding how traumatic brain injury reorganizes local and brain wide nodal interactions may provide valuable quantitative parameters for monitoring pathological progression and recovery. To this end, we investigated spontaneous fluctuations in the functional MRI signal obtained at 11.1 T in rats sustaining controlled cortical impact and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12 879 pairwise correlations between functional MRI signals from 162 regions. Our data indicate that on Days 2 and 30 post-controlled cortical impact there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic and basal forebrain areas. Rats imaged on Day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By Day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality and participation coefficient track early and late traumatic brain injury effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to controlled cortical impact may be unfavourable to brain wide communication in the early post-injury period.


A case of polyarteritis nodosa with lesions of the superior mesenteric artery illustrating the diagnostic usefulness of three-dimensional computed tomographic angiography.
A 40-year-old Japanese man who developed upper abdominal pain, weight loss, and hypertension was diagnosed as suffering with polyarteritis nodosa (PAN) with lesions of the superior mesenteric artery (SMA). Three-dimensional computed tomographic angiography (3D-CTA) and conventional angiography revealed smooth segmental luminal narrowing of the branches of the SMA. In addition, an enhanced abdominal CT scan demonstrated diffuse thickening of the wall of the affected SMA. Treatment with high-dose corticosteroids resulted in immediate improvement of the abdominal manifestations and normalized the serum C-reactive protein levels. Furthermore, the subsequent enhanced CT and 3D-CTA revealed improvement of the wall thickening and luminal narrowing of the SMA and its branches during the treatment period. In addition to possessing the diagnostic usefulness of conventional angiography, 3D-CTA is also less invasive and facilitates the prompt and accurate diagnosis of PAN. Furthermore, thickening of the wall of medium-sized arteries evidenced by enhanced CT scan may also support a diagnosis of PAN.


Structure of the mouse activin receptor type II gene.
Knowledge of the structures of the activin receptor genes is crucial to our understanding of the role of the activins, inhibins, and their receptors in developmental and physiological processes. The type II activin receptor (ActRc) has been shown to be a transmembrane protein with putative serine/threonine kinase activity. Using a human ActRc type II cDNA as a probe, 18 overlapping lambda clones containing portions of the mouse ActRc type II gene were isolated from a mouse 129SvE genomic library. Sequence analysis of the exons, exon-intron boundaries, and 5' and 3' non-translated regions as well as Southern blot analysis of mouse genomic DNA were used to establish the structure of the mouse ActRc type II gene. The mouse ActRc type II gene is encoded by 11 exons and spans greater than 66 kilobases. Two large introns (introns 1 and 4) contribute the majority of the gene size and are found to delineate exons which encode important domains of the activin receptor. Analysis of the 5' region of the gene reveals several putative transcription factor binding sites which may be important for the complex transcriptional regulation of this gene.


Body dissatisfaction mediates the association between body mass index and risky weight control behaviors among White and Native American adolescent girls.
The developmental path leading to eating disorders among adolescent girls often proceeds from increasing body size, to increasing body dissatisfaction, to increasing eating disorder (ED) risk. To determine whether body dissatisfaction (BD) mediates the association between body size and risky weight control behaviors, we examined data from White (n=709) and Native American (n=253) girls, who differ substantially in terms of average body mass and reported weight control behaviors. Measures of BD included weight, shape, and appearance concerns. Measures of ED risk included dieting, exercising to control weight, binge eating, and vomiting. Results showed body dissatisfaction was a highly significant mediator of the relationship between body mass index (BMI) and ED risk for both ethnic groups; although, BD did not mediate the association between BMI and binge eating for either group. BD is apparently an important mediator of the association between body size and some, but not all, risky weight control behaviors.


Nationwide Survey of Patients' Perspectives Regarding Their Radiation and Multidisciplinary Cancer Treatment Experiences.
The perspectives of patients with cancer about their treatment can inform interventions to improve the approaches of treating oncologists and experiences of future patients. We sought to identify areas where current toxicity management, informed consent processes, and physician-patient communication merit improvement. In a Web-based survey administered from March to May 2018 using quota-based sampling to draw a nationwide sample of US patients with cancer treated with radiotherapy within the past 5 years, we evaluated patient perceptions of adequacy of information about adverse effects, severity of actual adverse effects experienced, and experiences divergent from expectations. Among 403 respondents, 18% felt inadequately informed about what adverse effects to expect from radiotherapy, and 37% experienced radiation adverse effects that they wished they had known more about. Similar proportions of patients treated with chemotherapy (36%) and surgery (34%) experienced toxicities related to those treatments that they wished they had known more about. Patients who noted their adverse effects to be minimal versus severe were significantly more likely to feel informed about radiotherapy adverse effects (odds ratio, 13.05; 95% CI, 5.6 to 30.38; P < .001). Across all evaluated measures, a majority of patients indicated that they did not experience the potentially anticipated radiotherapy adverse effect or that it was the same as or better than expected. This study suggests that experiences with radiation adverse effects generally are congruent with expectations. Nevertheless, improvement of pretreatment counseling across all cancer therapy modalities seems warranted to improve informed decision making and treatment experiences.


Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.
KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.


Effect of PNPLA3 polymorphism on diagnostic performance of various noninvasive markers for diagnosing and staging nonalcoholic fatty liver disease.
Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) genotype influences clinical/biochemical characteristics in patients with nonalcoholic fatty liver disease (NAFLD), but whether PNPLA3-I148M (rs738409) genotype also influences the diagnostic performance of noninvasive diagnostic tests for NAFLD is uncertain. Our aim was to investigate the differences in diagnostic performance of noninvasive diagnostic tests for NAFLD according to PNPLA3-I148M (rs738409) genotype. Fifty-eight healthy controls and 349 patients with biopsy-proven NAFLD were included. Areas under the receiver operating characteristic curve (AUROCs) were calculated to predict hepatic steatosis (fatty liver index and hepatic steatosis index), nonalcoholic steatohepatitis (cytokeratin-18 M30 and M65), and significant fibrosis (≥F2 fibrosis) (fibrosis-4 and BARD), stratifying by rs738409 genotypes (CC and CG + GG groups). Fatty liver index and hepatic steatosis index showed good diagnostic performance for diagnosing steatosis only in the CG + GG group with AUROCs ranging from 0.819 to 0.832. Cytokeratin-18 M30 (AUROC = 0.688) and M65 (AUROC = 0.678) had suboptimal performance for diagnosing nonalcoholic steatohepatitis in the CG + GG group, whereas both had good performance (AUROC = 0.814 and 0.813, respectively) in the CC group. BARD score showed good performance in the CG + GG group compared with the CC group (AUROC = 0.805 and 0.532, respectively). Fibrosis-4 had suboptimal performance in the CG + GG group and good performance in the CC group (AUROC = 0.662 and 0.801, respectively). Diagnostic performance of noninvasive tests for NAFLD varied markedly according to PNPLA3 genotypes. Clinicians should be aware that PNPLA3 genotype limits the clinical utility of noninvasive diagnostic tests for diagnosing NAFLD.


European Liver Transplant Registry: Donor and transplant surgery aspects of 16,641 liver transplantations in children.
The European Liver Transplant Registry (ELTR) has collected data on liver transplant procedures performed in Europe since 1968. Over a 50-year period (1968-2017), clinical and laboratory data were collected from 133 transplant centers and analyzed retrospectively (16,641 liver transplants in 14,515 children). Data were analyzed according to three successive periods (A, before 2000; B, 2000-2009; and C, since 2010), studying donor and graft characteristics and graft outcome. The use of living donors steadily increased from A to C (A, n = 296 [7%]; B, n = 1131 [23%]; and C, n = 1985 [39%]; p = 0.0001). Overall, the 5-year graft survival rate has improved from 65% in group A to 75% in group B (p < 0.0001) and to 79% in group C (B versus C, p < 0.0001). Graft half-life was 31 years, overall; it was 41 years for children who survived the first year after transplant. The late annual graft loss rate in teenagers is higher than that in children aged <12 years and similar to that of young adults. No evidence for accelerated graft loss after age 18 years was found. Pediatric liver transplantation has reached a high efficacy as a cure or treatment for severe liver disease in infants and children. Grafts that survived the first year had a half-life similar to standard human half-life. Transplantation before or after puberty may be the pivot-point for lower long-term outcome in children. Further studies are necessary to revisit some old concepts regarding transplant benefit (survival time) for small children, the role of recipient pathophysiology versus graft aging, and risk at transition to adult age.


Intravenous contrast enhanced computed tomography colonoscopy in children with suspected colonic polyps.
The purpose of this study was to evaluate the diagnostic performance of intravenous contrast enhanced computed tomographic colonoscopy (IVCTC) in the diagnosis of clinically suspected colorectal polyps in children, using conventional colonoscopy (CC) as the gold standard. This was a prospective study conducted between July 2008 and June 2010. 30 pediatric patients with history of rectal bleeding and clinically suspected to have colorectal polyps were enrolled. All of the patients underwent IVCTC followed by CC. 30 IVCTC and 31 CC were performed in 30 patients. The findings of IVCTC were compared with those of CC. Statistical analysis was performed to obtain diagnostic performance values of IVCTC on per polyp (sensitivity and positive predictive value) and per patient (sensitivity, specificity, positive predictive value and negative predictive value) basis. By IVCTC, 63 polyps were detected in 28 patients of which 53 polyps were eligible for inclusion in the statistical analysis. 60 polyps were detected by CC in 28 patients of which 50 polyps were eligible for inclusion in the statistical analysis. The per polyp sensitivity and positive predictive values were 94% and 88.6% respectively. The per patient sensitivity, specificity, positive predictive value, and negative predictive values were 96.4, 50, 96.4, and 50% respectively. Twenty polyps, in 10 patients, were visualized only after intravenous contrast administration of which 5 polyps, in 5 patients, were likely to have been missed in the absence of the intravenous contrast injection as these polyps were submerged in fluid. Four patients would have had a false negative CTC examination if the intravenous contrast had not been injected; while in another patient, the number of polyps would have been underestimated. CTC is capable of serving as a safe and efficient non-invasive tool for evaluating children with clinically suspected colorectal polyps. Administration of intravenous contrast improves the sensitivity of polyp detection on CTC.


Kinetics of cellular and humoral immunogenicity and effectiveness of SARS-CoV-2 booster vaccination in hematologic neoplasms.
Data on the effect of booster SARS-CoV-2 vaccination are mainly focused on humoral immunogenicity, while the kinetics of vaccine-induced cellular response and its correlation with effectiveness in hematologic patients are less explored. Our aim was to evaluate the longitudinal cellular and humoral immunogenicity induced by two and three doses of the mRNA-1273 SARS-CoV-2 vaccine in 270 patients with hematologic malignancies, and its relationship with the severity of breakthrough SARS-CoV-2 infection. Results indicate that at 23 weeks after the second dose, the seroconversion rate declined from 68.5% to 59.3%, with a reduction in median anti-S titers from 1577 to 456 BAU/mL, mainly in patients over 65 years of age or chronic lymphocytic leukemia (CLL) patients undergoing active therapy. Cellular immunogenicity, however, remained positive in 84.4% of cases. A third vaccine dose seroconverted 42.7% (41/96) and triggered cellular response in 36.7% (11/30) of previously negative patients. Notably, only 7.2% (15/209) of patients failed to develop both humoral and cellular response. Active therapy, anti-CD20 antibodies, lymphopenia, hypogammaglobulinemia, and low CD19+ cell count were associated with poor humoral response, while active disease, GvHD immunosuppressive therapy, lymphopenia, and low CD3+ , CD4+ , CD56+ cell count determined an impaired cellular response. After 13.8 months of follow-up, the incidence of SARS-CoV-2 infection was 24.8% (67/270), including 6 (9%) severe/critical cases associated with a weaker cellular (median interferon gamma (IFN-γ) 0.19 vs. 0.35 IU/mL) and humoral response (median anti-S titer <4.81 vs. 788 BAU/mL) than asymptomatic/mild cases. In conclusion, SARS-CoV-2 booster vaccination improves humoral response and COVID-19 severity is associated with impaired vaccine-induced immunogenicity.


Do the guidelines do what they are supposed to?
The unwritten purpose of the guidelines appears to be to reduce risk to patients of cervical manipulation and to provide legal indemnity to physiotherapists. Do the guidelines achieve this purpose?


A novel collision warning system based on the visual road environment schema: An examination from vehicle and driver characteristics.
Drivers pay unequal attention to different road environmental elements and visual fields, which greatly influences their driving behavior. However, existing collision warning systems ignore these visual characteristics of drivers, which limits the performance of collision warning systems. Therefore, this study proposes a novel collision warning system based on the visual road environment schema, in order to enhance the support for avoiding potential dangers in objects and areas that are easily overlooked by the drivers' vision. To capture the above visual characteristics of drivers, the visual road environment schema that consists of the semantic layer, the scene depth layer, the sensitive layer, and the visual field layer is established by using several different deep neural networks, which realizes the recognition, quantization, and analysis of the road environment from the drivers' visual perspective. The effectiveness of the novel collision warning system is verified by the driving simulation experiment from six indicators, including warning distance, maximum lateral acceleration, maximum longitudinal deceleration, minimum collision time, reaction time, and heart rate. Additionally, a grey target decision-making model is built to comprehensively evaluate the system. The results show that compared with the traditional collision warning system, the novel collision warning system proposed in this study performs significantly better and can discover potential dangers earlier, give timely warnings, enhance the vehicles' lateral stability and driving comfort, shorten reaction time, and relieve the drivers' nervousness. By integrating the drivers' visual characteristics into the collision warning system, this study could help to optimize the existing collision warning system and promote the mutual understanding between intelligent vehicles and human drivers.


Will the Early Use of Biomarkers Prevent the Development of Heart Failure?
Alterations in biomarkers are associated with the development and progression of heart failure. As indicated by the study of Ergatoudes and colleagues in the current issue of this journal, biomarkers may also be the first sign of increased risk of developing heart failure. Prior studies also suggest that elevations in certain biomarkers can lead to more frequent clinical surveillance and initiation of therapeutic strategies that may prevent or delay the development of heart failure.


Microarray-based identification of a novel Streptococcus pneumoniae regulon controlled by an autoinduced peptide.
We have identified in the Streptococcus pneumoniae genome sequence a two-component system (TCS13, Blp [bacteriocin-like peptide]) which is closely related to quorum-sensing systems regulating cell density-dependent phenotypes such as the development of genetic competence or the production of antimicrobial peptides in lactic acid bacteria. In this study we present evidence that TCS13 is a peptide-sensing system that controls a regulon including genes encoding Blps. Downstream of the Blp TCS (BlpH R) we identified open reading frames (blpAB) that have the potential to encode an ABC transporter that is homologous to the ComA/B export system for the competence-stimulating peptide ComC. The putative translation product of blpC, a small gene located downstream of blpAB, has a leader peptide with a Gly-Gly motif. This leader peptide is typical of precursors processed by this family of transporters. Microarray-based expression profiling showed that a synthetic oligopeptide corresponding to the processed form of BlpC (BlpC*) induces a distinct set of 16 genes. The changes in the expression profile elicited by synthetic BlpC* depend on BlpH since insertional inactivation of its corresponding gene abolishes differential gene induction. Comparison of the promoter regions of the blp genes disclosed a conserved sequence element formed by two imperfect direct repeats upstream of extended -10 promoter elements. We propose that BlpH is the sensor for BlpC* and the conserved sequence element is a recognition sequence for the BlpR response regulator.


Psychological distress as a determinant of changes in body mass index over a period of 10years.
To examine the longitudinal relationship between psychological distress and body mass index (BMI) changes over a period of five and ten years. Data were used from the Dutch, prospective, population based Doetinchem Cohort study over the period 1995/1999 until 2005/2009 (N=5504). Psychological distress was assessed using the Mental Health Inventory (MHI-5). BMI (kg/m(2)) was calculated from measured body height and body weight. GEE analyses were used to examine the relationship between psychological distress at baseline and BMI change, and the development of overweight over five years. Linear and logistic regression analyses were used to examine these relations over ten years. Psychological distress predicted an extra overall increase in BMI of 0.14kg/m(2) (95% CI 0.03-0.25) over five years and an increase of 0.18kg/m(2) (95% CI 0.01-0.35) over ten years, when comparing psychologically distressed participants to psychologically healthy participants. This was especially the case among persons with normal weight (five years; B=0.26kg/m(2), 95% CI=0.12-0.40/ten years; B=0.32kg/m(2) 95% CI=0.11-0.53) and moderate overweight (five years: B=0.18kg/m(2), 95% CI=0.02-0.35) at baseline. Psychological distress did not predict the development of overweight five and ten years later. The results in this study indicated that psychological distress predicted an increased risk in gaining weight, but did not result in an increased risk for developing overweight.


Highly responsive and sensitive non-enzymatic electrochemical sensor for the detection of β-NADH in food, environmental and biological samples using AuNP on polydopamine/titanium carbide composite.
In this study, a polydopamine/titanium carbide adorned with gold nanoparticles (Au@PDA/TiC) composite was prepared by a simple stirring technique and it was used for the dual-technique detection of β-Nicotinamide adenine dinucleotide (NADH). The Au@PDA/TiC-modified glassy carbon electrode (GCE) oxidized NADH at a very low oxidation potential of approximately 0.60 V vs Ag/AgCl in pH = 7.0 (0.1 M PBS) via the transfer of two electrons and one proton (from NADH to NAD+). Based on the (i-t) amperometry mode, NADH can be quantified with a linear range of 0.018-674 μM and LOD of 0.0062 µM. In addition to the DPV mode, the electrochemical sensor had a linearity of 5-450 µM with a LOD of 3.17 µM. The developed sensor exhibited remarkable analytical performances concerning high sensitivity, electrocatalytic activity, low detection limit, wide linearity, appreciable specificity, repeatability, stability, reproducibility, and adequate recovery results in food, environmental and biological samples.


Left ventricular twist mechanics and its relation with aortic stiffness in chronic kidney disease patients without overt cardiovascular disease.
Recent studies hypothesized left ventricular (LV) twist as a potential biomarker for evaluation of sub clinical myocardial disease, however its relationship with aortic stiffness has yet to be investigated. Chronic kidney disease (CKD) has been identified as a risk factor for both myocardial and arterial disease. As such we sought to explore the relationship between aortic stiffness and LV twist in CKD patients without known cardiovascular disease (CVD). In this prospective, observational study we enrolled 106 CKD patients (Stages 1 to 5) with normal LVEF as assessed by conventional echocardiography. Aortic stiffness was measured using aortic pulse wave velocity (aPWV). We defined increased aPWV as ≥10 m/s. LV Twist was measured using two-dimensional speckle tracking echocardiography. Patients with increased aPWV had higher LV twist (p = 0.002) but similar LVEF (p = 0.486). Aortic PWV correlated crudely with age (p < 0.001), the presence of diabetes (p < 0.001), hypertension (p < 0.001), eGFR (p < 0.001), LVMI (p = 0.01), e/e' (p < 0.001) and LV twist (p = 0.003). In multivariable analyses after adjusting for age, gender, cardiovascular risk factors and hypertensive medication, aPWV was independently associated with LV twist (β = 0.163, p = 0.025). Aortic stiffness independently associates with LV Twist in asymptomatic CKD patients. These findings suggest a close interaction between LV twist mechanics and arterial remodeling even before CVD becomes clinically relevant.