Effect of photobiomodulation adjunct to periodontal therapy on individuals with type 2 diabetes mellitus regarding periodontal clinical parameters: a systematic review and meta-analysis.
The purpose of this study is to evaluate the scientific evidence on the impact of photobiomodulation adjunct to non-surgical periodontal treatment on individuals with type 2 diabetes mellitus (T2DM). The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement was followed. A protocol was registered in the International Prospective Registry of Systematic Reviews (PROSPERO #CRD42022310756). The research was carried out in seven databases, with no restrictions regarding the year of publication. Our work included studies that compared periodontal clinical parameters among individuals undergoing non-surgical periodontal therapy associated with photobiomodulation and a control group of individuals undergoing non-surgical periodontal treatment. Study selection, data extraction, and risk of bias assessment (RoB 2.0) were performed by two review authors. Meta-analysis was performed. Mean difference (MD) and a 95% confidence interval (CI) were provided. Three hundred forty-one studies were identified, of which eight studies were included. The meta-analysis demonstrated that photobiomodulation adjunctive to periodontal therapy in individuals with diabetes resulted in a greater reduction in probing depth and greater attachment gain in comparison to periodontal treatment alone (p < 0.05). The included studies exhibited a low risk of bias. Photobiomodulation adjunct to periodontal therapy contributes to the improvement of periodontal clinical parameters in individuals with T2DM.


An audit of Grade III or more skin reactions in consecutively assessed patients at a modern radiation oncology center.
Radiation dermatitis is most common and debilitating side effects of radiotherapy leading to treatment interruption, thereby compromising the local control, and effecting quality of life. With the invent of modern imaging and recent advances in megavoltage radiotherapy, radiation-related side effects have reduced. In this audit, we report the risk factors associated with Grade III dermatitis in modern centers. We analyzed 172 patients treated with volume modulated arc therapy (VMAT) and static field intensity-modulated radiotherapy (SFIMRT) at our center. All head and neck, breast, gynecological, GU malignancies, and sarcoma patients treated with a dose of >45 Gy from April 2018 to December 2019 were included in the study. On couch, treatment verification was done with cone-beam computer tomography (CBCT). Slice-by-slice verification of planning target volume (PTV) with CBCT was done in the first three fractions and weekly thereafter. Skin evaluation was done using CTCAE v. 5. Statistical analysis was done using SPSS v. 22. Of the 172 patients treated with VMAT and SFIMRT, 15 patients (8.7%) had Grade III dermatitis. Grade III dermatitis was mostly seen in breast cancer followed by head-and-neck patients. More reactions were observed in patients with advanced stage disease. Treatment verification is important at the later course of treatment, especially in head-and-neck cases where the treatment volume is large and PTV may extend outside skin. Contributing factors of radiation dermatitis at modern radiotherapy center are gene mutation, use of concurrent chemoradiotherapy, and bolus. We hereby conclude that PTV mismatch in weekly treatment verification, genetic mutations, concurrent chemo-radiotherapy, use of thermoplastic mask, and bolus are the contributing factors for Grade III dermatitis in modern radiotherapy centers.


Enhanced activation of peroxymonosulfate by a floating FeMo3Ox/C3N4 photocatalyst under visible-light assistance for oxytetracycline degradation: Performance, mechanisms and comparison with H2O2 activation.
In this study, a floating FeMo3Ox/C3N4-EP (FM-C-P) composite with highly stability and reusability was synthesized by an impregnation/calcination process and used to activate peroxymonosulfate (PMS) for oxytetracycline (OTC) degradation under visible light irradiation. The results demonstrated that 98.1% of OTC (50 mg/L) removal can be achieved by the activation of PMS (5 mM) using FM-C-P (1 g/L) in 30 min under visible light irradiation. The pseudo-first-order rate constant was calculated to be 0.181 min-1. The degradation process with PMS was hardly affected by pH (3-11) and co-existing substance. ·SO4-, ·OH, ·O2- and 1O2 were produced in the Vis/PMS/FM-C-P system and 1O2 was determined to be the main reactive oxygen species (ROSs). The high efficiency of ROSs production mainly contributed to two mechanisms. Firstly, via the combination of ≡Fe (II)-·SO5- and free state ·SO5-, 1O2 could be generated on the Fe-Nx site. Secondly, photo-induced electrons in the FeMo3Ox/g-C3N4 heterojunction could react with Fe (III) and Mo (VI) to form catalytically active species Fe (II) and Mo (IV). Moreover, the proposed degradation pathway and the toxicity of intermediated products was analyzed. Overall, this study was expected to deepen the understanding of the photo-assisted PMS activation and the generation of 1O2 with the presence of metal-oxide/C3N4 heterojunction.


Factorial experimental design applied to the immunological study of two foot-and-mouth disease virus subtypes. 1. A Greece 1969 -- A Allier example.
A double immunological cross-test, carried out with the index K method, is subjected to a statistical analysis by a factorial experiment. The A Greece and A Allier viruses, which have been taken as an example of the calculations procedure, seem to be in 2 immunologically different subtypes.


Genetically determined oxidation polymorphism and drug hepatotoxicity. Study of 51 patients.
The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl, is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.


Chelation of cytoplasmic Ca2+ increases plasma membrane permeability in murine macrophages.
Cytoplasmic free Ca2+ (Ca2+i) was chelated to 10-20 nM in the macrophage cell line J774 either by incubation with quin2 acetoxymethyl ester in the absence of external Ca2+ (Di Virgilio, F., Lew, P.D., and Pozzan, T. (1984) Nature 310, 691-693) or by loading [ethyl-enebis(oxyethylenenitrilo)]tetraacetic acid (EGTA) into the cytoplasm via reversible permeabilization of the plasma membrane with extracellular ATP (Steinberg, T.H., Newman, A.S., Swanson, J.A., and Silverstein, SS.C. (1987) J. Biol. Chem. 262, 8884-8888; Di Virgilio, F., Meyer, B.C., Greenberg, S., and Silverstein, S.C. (1988) J. Cell Biol. 106, 657-666). After removal of ATP from the incubation medium, ATP-permeabilized Ca2+i-depleted macrophages recovered a near-normal plasma membrane potential which slowly depolarized over a 2-4 h incubation at low [Ca2+]i. In both ATP-treated and quin2-loaded cells, depolarization of plasma membrane potential was paralleled by an increase in plasma membrane permeability to low molecular weight aqueous solutes such as eosin yellowish (Mr 692), ethidium bromide (Mr 394), and lucifer yellow (Mr 463). This increased plasma membrane permeability was not accompanied by release of the cytoplasmic marker lactic dehydrogenase for incubations up to 4 h and was likely a specific effect of Ca2+i depletion since it was not caused by: (i) the mere incubation of macrophages with extracellular EGTA, i.e. at near-normal [Ca2+]i; and (ii) loading into the cytoplasm of diethylenetriaminepentaacetic acid, a specific chelator of heavy metals with low affinity for Ca2+. Treatment of Ca2+i-depleted cells with direct (phorbol 12-myristate 13-acetate) or indirect (platelet-activating factor) activators of protein kinase C prevented the increase in plasma membrane permeability. Down-regulation of protein kinase C rendered Ca2+i-depleted macrophages refractory to the protective effect of phorbol 12-myristate 13-acetate. This report suggests a role for Ca2+i and possibly protein kinase C in the regulation of plasma membrane permeability to low molecular weight aqueous solutes.


Role of the PKC/CPI-17 pathway in enhanced contractile responses of mesenteric arteries from diabetic rats to alpha-adrenoceptor stimulation.
Protein kinase C (PKC) may contribute to enhanced contractile responses of arteries from streptozotocin-diabetic rats to stimulation of G-protein coupled receptors. This was investigated by comparing the effects of PKC inhibitors on contractile responses of mesenteric arteries from diabetic and age-matched control rats to noradrenaline (NA) and endothelin-1 (ET-1). The effects of NA and ET-1 on the distribution of three isoforms of PKC implicated in contraction were also determined. In addition, the effect of NA on phosphorylation of CPI-17, a substrate for PKC, was investigated. Contractile responses of endothelium-denuded arteries from diabetic rats to NA were enhanced, but were normalized by PKC inhibition. In contrast, contractile responses to ET-1 were not significantly different, and were blocked to a similar extent by PKC inhibition, in arteries from control and diabetic rats.NA produced only a small increase in particulate levels of PKCepsilon in control arteries (to 125+/-8% of levels in untreated arteries), but a significant increase in particulate PKCalpha (to 190+/-22%) and a much greater increase in particulate PKCepsilon (to 230+/-19%) in arteries from diabetic rats. ET-1 increased particulate PKCalpha and epsilon to a similar extent in arteries from control and diabetic rats.NA significantly enhanced CPI-17 phosphorylation from a basal level of 22+/-10 to 71+/-7% of total in arteries from diabetic rats, and this was prevented by PKC inhibition. NA had no detectable effect on CPI-17 phosphorylation in arteries from control rats. These data suggest that NA-induced activation of PKC and CPI-17, its downstream target, is selectively enhanced in arteries from diabetic rats, and mediates the enhanced contractile responses to this agonist.


Is Discharge Within a Day Following Total Hip Arthroplasty Safe in the Septuagenarian and Octogenarian Population? A Propensity-Matched Cohort Study.
Limited data exists on whether patients older than 70 can safely be discharged within a day (rapid discharge (RD)) following primary total hip arthroplasty (THA). The purpose of this study was to compare perioperative complications and readmission rates associated with RD in patients ≥70 years compared to longer lengths of stay following THA. A retrospective, propensity-matched cohort study was conducted using the National Surgical Quality Improvement Program database from 2006 to 2020. Patients ≥70 years undergoing RD following THA were propensity matched to patients ≥70 years who had longer hospital stays (nonrapid discharge). Sub-analyses were performed for septuagenarians and octogenarians. Following 1:1 matching, multivariate analyses were performed to compare perioperative complications and readmissions. Following propensity matching, both groups contained 2,192 patients. The RD patients were found to have shorter operative times (P < .001), less bleeding complications (P < .001), and were more likely to have home discharges (P < .001). The 2 cohorts did not differ in the remaining complications or 30-day postoperative period readmissions among all patients and when evaluating septuagenarians and octogenarians. Patients ≥70 years undergoing RD following THA had comparable complication and readmission rates to patients older than 70 undergoing nonrapid discharge. Furthermore, RD patients were more likely to have home discharges and have shorter operations with less bleeding complications. Septuagenarians receiving RD were more likely to have an unplanned readmission. These data suggest that RD following THA can be performed safely in select patients older than 70.


Cancer-Associated Fibroblasts Regulate the Plasticity of Breast Cancer Stemness through the Production of Leukemia Inhibitory Factor.
Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in vitro investigation is conducted to determine the crosstalk between breast cancer cells and fibroblasts. Based on the results, cancer-associated fibroblasts are producers of LIF in the cocultivation system with breast cancer cells. Treatment with the CAF-CM and human LIF protein significantly promoted stemness through the dedifferentiation process and regaining of stem-cell-like properties. In addition, the results indicate that activation of LIFR signaling in breast cancer cells in the existence of CAF-secreted LIF can induce Nanog and Oct4 expression and increase breast cancer stem cell markers CD24-/CD44+. In contrast, suppression of the LIF receptor by human LIF receptor inhibition antibody decreased the cancer stem cell markers. We found that LIF was frequently overexpressed by CAFs and that LIF expression is necessary for dedifferentiation of breast cancer cell phenotype and regaining of cancer stem cell properties. Our results suggest that targeting LIF/LIFR signaling might be a potent therapeutic strategy for breast cancer and the prevention of tumor recurrence.


Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules.
Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO-1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3-3 μM) in a concentration-dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO-1 and SOD1/SOD2) and anti-apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.


[Barium embolisation into the portal vein--a complication of barium enema in Leśniowski-Crohn disease].
Barium embolisation is a very rare complication of barium enema, but carries a mortality of about 50%. We report a case of 70-year-old woman with Lesniowski-Crohn disease, who survived after barium intravasation into the portal circulation produced during a barium enema.


Labdane-type diterpenes: thermal effects on phospholipid bilayers, incorporation into liposomes and biological activity.
Labd-13(E)-ene-8alpha,15-diol (1) and its derivative labd-13(E)-ene-8alpha-ol-15-yl-acetate (2) are water insoluble biological active molecules and their structures were elucidated using NMR and X-ray techniques. Differential scanning calorimetry (DSC) was applied to study the thermal effects of 1 and 2 on DPPC bilayers. Liposomes composed of egg phosphatidylcholine/dipalmytoylphosphatidylglycerol (9:0.1 molar ratio) were prepared by the thin-film hydration method and were used for incorporating 1 and 2. Free and liposomal 1 and 2 were tested for their activity against human cancer cell lines using the sulphorhodamine B assay. The effect of 1 and 2 on DPPC bilayers caused abolition of the pre-transition temperature, lowering of the main phase transition and reduction of the transition enthalpy only in the presence of cholesterol. The liposomes that have been designed and developed offer high incorporation efficiency; 62.4% (0.369 drug/lipid molar ratio) and 99.7% (0.661 drug/lipid molar ratio) for 1 and 2, respectively. Liposomal 2 showed growth-inhibiting activity against the majority of the tested cell lines.


Calicotyle hydrolagi n. sp. (Monogenea: Monocotylidae) infecting the deep-sea Eastern Pacific black ghost shark Hydrolagus melanophasma from the Atacama Trench, with comments on host specificity of Calicotyle spp.
We describe Calicotyle hydrolagi n. sp. (Monogenea: Monocotylidae) infecting the cloaca of deep-water Eastern Pacific black ghost sharks, Hydrolagus melanophasma captured as bycatch at a local fishery for Patagonian toothfish Dissostichus eleginoides, (Nototheniidae) in the Atacama Trench using morphological and nucleotide (LSU rRNA and SSU rRNA) data. This new species is differentiated from its congeners by a number of characters, including the absence of a cecal diverticula, the size and shape of the male copulatory organ and the shape of the vagina, as well as by differences in molecular data (SSU rRNA and LSU rRNA). The suitability of some sclerotized structures such as the male copulatory organ (MCO) as a taxonomic character is discussed; specifically, we found that the relationship between MCO and total length exhibit different trends in members of Calicotyle isolated from sharks, skates and chimaeras. Additional efforts to obtain sample of Calicotyle species and further molecular studies based on ribosomal and mitochondrial genes are necessary to clarify the degree of host specificity in this genus. Additionally, this is the first report of a member of Calicotyle to be reported in the Southeastern Pacific Ocean.


Relationship between c-Kit expression and proliferation in acute myeloblastic leukemia cell lines.
We have proposed that the transmembrane receptor encoded by the c-Kit protooncogene and its ligand play an important role in regulating the proliferation of blasts cells in acute myeloblastic leukemia (AML). To test this hypothesis, immunobeads were used to separate blasts from three Kit-expression positive cell lines into strongly Kit-protein positive and weakly Kit-protein positive fractions. The strongly positive fraction had greater proliferative potential than the weakly positive fraction as assessed both by colony-formation in methylcellulose and growth of clonogenic cells in suspension. The reproducibility of the percentage of each blast population found in the strongly and weakly positive fractions provided evidence that Kit-protein expression is regulated. Kinetic experiments provided evidence for reversible transitions between strong and weak Kit protein expression. Thus regulated expression of the Kit receptor may be a mechanism for controlling blast cell growth in culture.


Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with polycomb repressive marks.
Helicobacter pylori infection can induce CpG island (CGI) hypermethylation in gastric mucosa. Recently, genes occupied by Polycomb proteins in embryonic stem cells were shown to be vulnerable to aberrant DNA hypermethylation in cancers. To explore the relationship between H. pylori infection and DNA methylation changes in neoplastic and non-neoplastic stomach, we analyzed 25 CGIs and repetitive DNA elements from 82 chronic gastritis and 69 gastric carcinomas. Twenty-three CGIs showed significantly higher methylation levels in H. pylori-negative gastric carcinoma (n = 28) than in H. pylori-negative chronic gastritis (n = 39; P < 0.05), indicating cancer-associated methylation. Eight CGIs exhibited significantly higher methylation levels in H. pylori-positive chronic gastritis (n = 43) than in H. pylori-negative chronic gastritis (n = 39; P < 0.05). Six CGIs showed both cancer-associated and H. pylori-associated hypermethylation. Six (75%) of the eight H. pylori-associated hypermethylated genes contained at least one of three repressive marks (Suzl2 occupancy, Eed occupancy, histone H3 K27 trimethylation), whereas 31% of the remaining cancer-associated hypermethylated genes had at least one mark. The findings suggest that H. pylori infection strongly induces CGI hypermethylation in gastric epithelial cells and that susceptibility to H. pylori-induced DNA hypermethylation may be determined by Polycomb repressive marks in stem or progenitor cells.


Learning defense transformations for counterattacking adversarial examples.
Deep neural networks (DNNs) are vulnerable to adversarial examples with small perturbations. Adversarial defense thus has been an important means which improves the robustness of DNNs by defending against adversarial examples. Existing defense methods focus on some specific types of adversarial examples and may fail to defend well in real-world applications. In practice, we may face many types of attacks where the exact type of adversarial examples in real-world applications can be even unknown. In this paper, motivated by that adversarial examples are more likely to appear near the classification boundary and are vulnerable to some transformations, we study adversarial examples from a new perspective that whether we can defend against adversarial examples by pulling them back to the original clean distribution. We empirically verify the existence of defense affine transformations that restore adversarial examples. Relying on this, we learn defense transformations to counterattack the adversarial examples by parameterizing the affine transformations and exploiting the boundary information of DNNs. Extensive experiments on both toy and real-world data sets demonstrate the effectiveness and generalization of our defense method. The code is avaliable at https://github.com/SCUTjinchengli/DefenseTransformer.


Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression.
Although increasing evidence supports a link between epidermal growth factor receptor (EGFR) signaling and resistance to apoptosis, the mechanism by which the EGFR signaling pathway inhibits apoptosis is not well understood. In this study, we found that epidermal growth factor (EGF) stimulation increased the level of expression of the inhibitor of apoptosis protein survivin in breast cancer cells but not in normal mammary epithelial cells. We further demonstrated that activation of survivin gene expression is mediated by oxygen-independent hypoxia-inducible factor (HIF)-1alpha up-regulation in EGF-treated cancer cells. EGFR signaling activated the phosphoinositide 3-kinase/AKT pathway, subsequently increasing the level of HIF-1alpha under normoxic conditions. HIF-1alpha then activated survivin gene transcription through direct binding to the survivin promoter. Furthermore, we found that overexpression of HIF-1alpha small interfering RNA blocks EGF-induced survivin gene up-regulation and increases apoptosis induced by the chemotherapy drug docetaxel. However, transfection of a plasmid expressing HIF-1alpha gene activates survivin gene expression and reduces the apoptotic response. Our results demonstrate a novel pathway for EGFR signaling-mediated apoptosis resistance in human cancer cells. Although the role of HIF-1alpha in regulating cell survival under hypoxic conditions has been studied extensively, our results show that normoxic breast cancer cells utilize cross-talk between EGFR signals and HIF-1alpha to up-regulate the anti-apoptotic survivin gene, providing a strong rationale for the targeting of HIF-1alpha as a therapeutic approach for both hypoxic and normoxic tumor cells. Understanding key molecular events in EGFR signaling-induced apoptosis resistance should provide new information for the development of novel therapeutic agents targeting EGFR, HIF-1alpha, and/or survivin.


Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function.
Signaling of TGFbeta family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFbeta-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.


Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions.
We investigated 45 patients with Kawasaki disease (KD) and report the first simultaneous determination of tumor necrosis factor (TNF), interleukin 2 receptor (IL-2R) and interferon-gamma (IFN-gamma) in the serum during acute phase. Serum levels of TNF were measured by a sandwich enzyme-linked immunosorbent assay. Serum levels of soluble IL-2R and IFN-gamma were measured by a sandwich enzyme immunoassay and radioimmunoassay, respectively. Serum levels of TNF, IL-2R, and IFN-gamma were seen to increase during the acute phase of KD. In KD patients with coronary-artery lesions (CAL), the percentage of positive cases for TNF (greater than or equal to 10 U/ml), IL-2R (greater than or equal to 1056 U/ml), and IFN-gamma (greater than or equal to 0.3 U/ml) was higher than that in patients without CAL. Our results suggest that aggressive activation of immunocompetent cells develops in KD with CAL.


Radioautographic study of the seasonal distribution of leukocytes in turtles Phrynops hilarii (Chelonia Chelidae).
The aim of this study was to present a morphological description of the leukocytes of Phrynops hilarii turtles according to the seasonal distribution of these cells and to show their replacement in the blood circulation using a radioautographic method. Five animals of both sexes weighing 600-1200 g were used. The animal's blood was aspirated, smeared on glass slides, and stained with the Romanowsky stain, and 500 cells of each animal were counted during each season. The results obtained were analyzed statistically by analysis of variance followed by the Bonferroni test (NCSS), with the level of significance set at p<0.05. The radioautographic analysis of turtle blood exposed to 1000 microCi of (3)H-thymidine and developed after 30 days showed a large number of silver grains incorporated into the cells, except for basophils, with cell renewal occurring every seven days. Quantitative data demonstrated a seasonal influence on the distribution of some leukocyte types, with the following "p" values: heterophils (p=0.0007), basophils (p=0.0002), monocytes (p=0.0016), eosinophils (p=0.0073). However, using this statistical method, it was not possible to detect a significant difference related to seasonal influence on lymphocytes (p=0.16295) or thrombocytes (p=0.1046). Using this experimental animal model, a seasonal influence on the distribution of some leukocyte types was observed, and the radioautographic method revealed a cell renewal system occurring every seven days, except for basophils.


The efferent blood flow of early hepatocellular carcinoma and borderline lesions: Demonstration by color Doppler imaging.
We performed waveform analysis of the efferent signal detected within early hepatocellular carcinomas and borderline lesions, in which portal flow was demonstrated. Continuity of this flow with the surrounding vessels was also analyzed. Nine nodules in 7 patients with early hepatocellular carcinomas and borderline lesions were included in this study. Tumor diameter ranged from 1.2 to 3.5 cm; average, 2.1 cm. Waveform of the efferent flow signal from within these nodules was continuous in 5 nodules and biphasic venous in 4 nodules. Outside the nodules, the waveform of the efferent flow signal was that of a biphasic venous wave. All efferent signals were confirmed to continue in the hepatic vein. These findings thus suggest that the draining vessel in early hepatocellular carcinomas and their borderline lesions is the hepatic vein.


Deciphering the role of Th17 cells in human disease.
Since their identification in 2005, T helper (Th)17 cells have been proposed to play important roles in several human diseases, including various autoimmune conditions, allergy, the development and progression of tumors, and the acceptance or rejection of transplanted organs and bone marrow. Focusing on human studies, here we review recent developments regarding Th17 biology and function in each of these fields. Th17 cells actively participate in the pathogenesis of autoimmune disease, allergy and transplantation rejection. Th17 cells contribute to protective antitumor immunity in human epithelial malignancy, whereas Th17-associated cytokines may also be associated with tumor initiation and growth in the context of chronic inflammation and infection. Also discussed is how the in vivo plasticity of Th17 cells may be an important feature of Th17 cell biology in human disease.


Controversies in Sentinel Lymph Node Biopsy for Gynecologic Malignancies.
Sentinel lymph node (SLN) biopsy represents an evolution in the advancement of minimally invasive surgical techniques for gynecologic cancers. Prospective and retrospective studies have consistently shown its accuracy in the detection of lymph node metastases for endometrial and cervical cancers. However, consistent with any emerging surgical technique in the early phases of adoption, new questions have arisen regarding its application and impact. This paper served as a scoping review to identify the key controversies that have arisen in the field of SLN biopsy for endometrial and cervical cancers. Several key controversies were identified, and PubMed, the Cochrane Library (cochranelibrary.com) advanced search function, and the National Comprehensive Cancer Network guidelines were searched for supporting evidence. These included search terms such as "the accuracy of SLN biopsy for high grade endometrial cancer or cervical cancers >2-cm," "cost effectiveness of SLN biopsy for gynecologic cancers," "clinical significance of low volume metastases in endometrial cancer," "morbidity of SLN biopsy for endometrial and cervical cancer," and "impact on cancer survival of SLN biopsy for endometrial and cervical cancer." Studies were selected for review if they included significant numbers of patients, were level I evidence, or were prospective trials. Where this level of evidence failed to exist, seminal observational series that were published in high-quality journals were included. Similar studies were listed and subcategorized and cross-compared, excluding those that included repeated analyses of the same patient populations. The relevant clinical trials or observational studies were clustered and reviewed for each chosen controversy. Adequate evidence supports the accuracy of SLN biopsy in the staging of high-grade endometrial cancer and cervical cancer, and it seems to be a cost-effective strategy for invasive endometrial cancer. Conclusive evidence was lacking with respect to the oncologic outcomes related to SLN biopsy, the impact on patient morbidity, and whether clinicians should treat isolated tumor cells in SLNs with adjuvant therapy. SLN biopsy is an accepted staging strategy for cervical and endometrial cancer surgery; however, controversies remain in how it can be applied with the most safety and efficacy. These ultimately need to be resolved with further clinical trials and observations of larger series of patients.


Experience with a new epimyocardial pacing lead in children.
A new permanent epimyocardial Medtronic 4951 "stab-in" or "fishhook" pacing electrode was implanted in 16 children. Identical technique, with particular attention to the direction of the coronary circulation, was utilized to implant the leads. There were 10 atrial implantations (5 active, 5 redundant) and 18 ventricular implantations (15 active, 3 redundant). Pacing modes were VVI (12), VDD (1), DVI (2), and DDD (1). Experience with the lead covers 280 patient months (3 days to 21.8 months, mean 14 months). Patients were followed monthly via telephonic transmission. With the exception of the single patient who expired three days after implantation, each patient has returned for follow-up analysis including chronic threshold determinations using the programming capabilities of the pulse generators. Only one lead required more than the minimum obtainable voltage output from the pulse generator to effect capture. No other lead required more than 5.0 volts at 0.5 ms pulse width. There have been no lead fractures or dislodgements. In this evaluation the Medtronic 4951 lead performed well in both atrium and ventricle in a group of children with diverse cardiac pathology. The small diameter of the lead and the low profile of the electrode are advantageous for use in pediatric patients.


Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer's disease patients.
The purpose of this study was to examine the levels of cerebrospinal fluid (CSF) apolipoprotein E (apoE) species in Alzheimer's disease (AD) patients. We analyzed two CSF cohorts of AD and control individuals expressing different APOE genotypes. Moreover, CSF samples from the TgF344-AD rat model were included. Samples were run in native- and SDS-PAGE under reducing or non-reducing conditions (with or without β-mercaptoethanol). Immunoprecipitation combined with mass spectrometry or western blotting analyses served to assess the identity of apoE complexes. In TgF344-AD rats expressing a unique apoE variant resembling human apoE4, a ~35-kDa apoE monomer was identified, increasing at 16.5 months compared with wild-types. In humans, apoE isoforms form disulfide-linked dimers in CSF, except apoE4, which lacks a cysteine residue. Thus, controls showed a decrease in the apoE dimer/monomer quotient in the APOE ε3/ε4 group compared with ε3/ε3 by native electrophoresis. A major contribution of dimers was found in APOE ε3/ε4 AD cases, and, unexpectedly, dimers were also found in ε4/ε4 AD cases. Under reducing conditions, two apoE monomeric glycoforms at 36 kDa and at 34 kDa were found in all human samples. In AD patients, the amount of the 34-kDa species increased, while the 36-kDa/34-kDa quotient was lower compared with controls. Interestingly, under reducing conditions, a ~100-kDa apoE complex, the identity of which was confirmed by mass spectrometry, also appeared in human AD individuals across all APOE genotypes, suggesting the occurrence of aberrantly resistant apoE aggregates. A second independent cohort of CSF samples validated these results. These results indicate that despite the increase in total apoE content the apoE protein is altered in AD CSF, suggesting that function may be compromised.


Assembly of G1 and G2 glycoprotein oligomers in Punta Toro virus-infected cells.
We have studied the oligomerization of the membrane glycoproteins of Punta Toro virus (PTV), a member of the Phlebovirus genus of the family Bunyaviridae, and the effect of glycosylation on protein stability and transport. By using sucrose gradient centrifugation, the G1 and G2 glycoproteins in PTV-infected or recombinant-transfected cells were found to sediment as dimers after DSP cross-linking, suggesting that the G 1 and G2 proteins are associated as dimers by non-covalent interactions. Pulse-chase and two-dimensional gel analysis indicate that dimerization occurs between newly synthesized G1 and G2 proteins, and that a small fraction of the G2 proteins is assembled into G2 homodimers. The amounts of G1 and G2 proteins were substantially decreased, while the amounts of nucleocapsid protein remained nearly unchanged, when PTV-infected cells were treated with the glycosylation inhibitor tunicamycin, indicating that the G1 and G2 proteins are unstable if glycosylation is prevented.


Robust attitude control design for spacecraft under assigned velocity and control constraints.
A novel robust nonlinear control design under the constraints of assigned velocity and actuator torque is investigated for attitude stabilization of a rigid spacecraft. More specifically, a nonlinear feedback control is firstly developed by explicitly taking into account the constraints on individual angular velocity components as well as external disturbances. Considering further the actuator misalignments and magnitude deviation, a modified robust least-squares based control allocator is employed to deal with the problem of distributing the previously designed three-axis moments over the available actuators, in which the focus of this control allocation is to find the optimal control vector of actuators by minimizing the worst-case residual error using programming algorithms. The attitude control performance using the controller structure is evaluated through a numerical example.


Differential impact of swine, bovine and poultry manure on the microbiome and resistome of agricultural grassland.
Land spreading of animal manure is an essential process in agriculture. Despite the importance of grassland in global food security the potential of the grass phyllosphere as a reservoir of antimicrobial resistance (AMR) is unknown. Additionally, the comparative risk associated with different manure sources is unclear. Due to the One Health nature of AMR there is an urgent need to fully understand the risk associated with AMR at the agriculture - environmental nexus. We performed a grassland field study to assess and compare the relative and temporal impact of bovine, swine and poultry manure application on the grass phyllosphere and soil microbiome and resistome over a period of four months, using 16S rRNA amplicon sequencing and high-throughput quantitative PCR (HT-qPCR). The soil and grass phyllosphere contained a diverse range of antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs). Manure treatment was found to introduce ARGs belonging to clinically important antimicrobial classes, such as aminoglycoside and sulphonamide into grass and soil. Temporal analysis of ARGs and MGEs associated with manure treatment indicated ARGs patterns were similar across the different manure types in the manure treated soil and grass phyllosphere. Manure treatment resulted in the enrichment in members of the indigenous microbiota and the introduction of manure associated bacteria, with this impact extending past the recommended six-week exclusion period. However, these bacteria were in low relative abundance and manure treatment was not found to significantly impact the overall composition of the microbiome or resistome. This provides evidence that the current guidelines facilitate reduction of biological risk to livestock. Additionally, in soil and grass samples MGEs correlated with ARGs from clinically important antimicrobial classes, indicating the key role MGEs play in horizontal gene transfer in agricultural grassland. These results demonstrate the role of the grass phyllosphere as an under-studied sink of AMR.


Measuring health professionals' perceptions of communication contributing to medication incidents in hospitals - scale development and primary results of weekly perceived communication challenges.
Communication challenges are one of the main contributors for medication incidents in hospitals, but health professionals' perceptions about variety of the contributing communication factors and the factors' occurrence frequencies are studied little. This cross-sectional descriptive study aimed to (1) operationalize a literature-based framework into a scale for measuring health professionals' perceptions of communication factors, which contribute to medication incidents either directly or indirectly in hospitals, (2) to measure the construct validity and internal consistency of the scale and (3) to describe the primary results of the measured weekly perceived communication challenges. The structured online questionnaire with 82 communication related items was developed based on a framework in literature. A content validity index of expert panelists' answers was used for item reduction. Data was collected between November 1st, 2019, and January 31st, 2020, by convenience sampling. The study sample (n = 303) included multiple health professional groups in diverse specialties, unit types and organizational levels in two specialized university hospital districts in Finland. Exploratory factor analysis with Maximum Likelihood method and Oblique rotation produced a six factors scale consisting of 57 items and having acceptable construct validity and internal consistency. The six communication factors contributing to medication incidents concerned (1) medication prescriptions, (2) guidelines and reporting, (3) patient and family, (4) guideline implementation,5) competencies and responsibilities, and 6) attitude and atmosphere. The most frequently perceived communication challenges belonged to the Medication prescription related factor. Detailed item frequencies suggested that the most usual weekly challenges were: (1) lack or unclarity of communication about medication prescriptions, (2) missing the prescriptions which were written outside of the regular physician-ward-rounds and (3) digital software restricting information transfer. The scale can be used for determining the most frequent detailed communication challenges. Confirmatory factor analysis of the scale is needed with a new sample for the scale validation. The weekly perceived communication challenges suggest that interventions are needed to standardize prescribing documentation and to strengthen communication about prescriptions given outside of regular ward-rounds.


Long range correlations in the stride interval of running.
Fluctuations in the stride interval time series of unconstrained walking are not random but exhibit long range correlations that decay as a power law [Hausdorff JM, Peng CK, Ladin Z, Wei JY, Goldberger AL. Is walking a random walk? Evidence for long range correlations in stride interval of human gait. J Appl Physiol 1995;78:349-58]. Here, we examine whether the long range correlations are present in the stride interval time series of running. Recreational female runners ran 8min trials at their preferred running speed as well as 10% and 20% slower and faster than their preferred speed. Both the average time and the amount of variability of the stride interval decreased with increasing speed. Detrended fluctuation analysis (DFA) showed that there were long range correlations present in the stride interval time series and these correlations followed a quasi U-shaped function, with the minimum at the preferred running speed. These results are consistent with the hypothesis that the preferred running speed, falling as it does between the upper and lower limits of possible running speeds, is the speed at which the most dynamical degrees of freedom are available for adaptive control of locomotion.


Long-term survival in a large cohort of patients with venous thrombosis: incidence and predictors.
Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis. 4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well. 736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0-24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0-5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7-4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0-6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories. Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients. Please see later in the article for the Editors' Summary.


Regulation of blood-brain barrier permeability by transient receptor potential type C and type v calcium-permeable channels.
To identify plasma membrane ion channels mediating calcium influx at the blood-brain barrier in response to disrupting stimuli. We examined the expression and function of candidate transient receptor potential channels using reverse transcriptase polymerase chain recation, Fura-2 calcium imaging, and permeability assays. Immortalized mouse brain microvessel endothelial cells expressed multiple transient receptor potential isoforms: transient receptor potential C1, C2, C4, and C7, M2, M3, M4, and M7, and V2 and V4. Similar profiles were observed in freshly isolated cerebral microvessels and primary cultured rat brain endothelial cells. Thrombin-stimulated calcium influx in brain endothelial cells was blocked by transient receptor potential C inhibitors. Transient receptor potential V activating stimuli also increased intracellular calcium. This increase was inhibited by a transient receptor potential V blocker or by removal of extracellular calcium. Barrier integrity was compromised by thrombin, hypo-osmolar stress, and PMA treatment. The increase in barrier permeability induced by transient receptor potential V activators was blocked by transient receptor potential V inhibition, while thrombin effects were inhibited by transient receptor potential C inhibitors. These results demonstrate that transient receptor potential C and transient receptor potential V channels mediate calcium influx at the blood-brain barrier, and as a consequence, may modulate barrier integrity.


Study protocol: realist evaluation of effectiveness and sustainability of a community health workers programme in improving maternal and child health in Nigeria.
Achievement of improved maternal and child health (MCH) outcomes continues to be an issue of international priority, particularly for sub-Saharan African countries such as Nigeria. Evidence suggests that the use of Community Health Workers (CHWs) can be effective in broadening access to, and coverage of, health services and improving MCH outcomes in such countries. In this paper, we report the methodology for a 5-year study which aims to evaluate the context, processes, outcomes and longer-term sustainability of a Nigerian CHW scheme. Evaluation of complex interventions requires a comprehensive understanding of intervention context, mechanisms and outcomes. The multidisciplinary and mixed-method realist approach will facilitate such evaluation. A favourable policy environment within which the study is conducted will ensure the successful uptake of results into policy and practice. A realist evaluation provides an overall methodological framework for this multidisciplinary and mixed methods research, which will be undertaken in Anambra state. The study will draw upon health economics, social sciences and statistics. The study comprises three steps: (1) initial theory development; (2) theory validation and (3) theory refinement and development of lessons learned. Specific methods for data collection will include in-depth interviews and focus group discussions with purposefully identified key stakeholders (managers, service providers and service users), document reviews, analyses of quantitative data from the CHW programme and health information system, and a small-scale survey. The impact of the programme on key output and outcome indicators will be assessed through an interrupted time-series analysis (ITS) of monthly quantitative data from health information system and programme reports. Ethics approvals for this study were obtained from the University of Leeds and the University of Nigeria. This study will provide a timely and important contribution to health systems strengthening specifically within Anambra state in southeast Nigeria but also more widely across Nigeria. This paper should be of interest to researchers who are interested in adapting and applying robust methodologies for assessing complex health system interventions. The paper will also be useful to policymakers and practitioners who are interested in commissioning and engaging in such complex evaluations to inform policies and practices.


Decrease in Choroidal Vascularity Index of Haller's layer in diabetic eyes precedes retinopathy.
The study aimed to evaluate Choroidal Vascularity Index (CVI) of Haller's and Sattler's layers and their relationships with choroidal and retinal thickness, volumes measured on enhanced depth imaging-optical coherence tomography (OCT) scans in the eyes of patients without diabetes, patients with diabetes with no diabetic retinopathy (DR) and patients with diabetes and DR. Retrospective analysis of 165 eyes from 84 Singapore Indian Eye Study-2 study participants (group 1: no diabetes, group 2: diabetes with no DR and group 3: with DR). Groups 1 and 2 were matched by age and gender from group 3. In the eyes of patients with diabetes without DR, the macular CVI of Haller's but not Sattler's layer was significantly reduced compared with eyes of patients without diabetes. Eyes with >5 years of diabetes have significantly decreased CVI of Sattler's layers (mean difference=0.06 ± 0.10, p=0.04) and also decreased subfoveal choroidal volume (mean difference=0.89 ± 0.16 mm3, p=0.02), compared with those with ≤5 years of diabetes. Diabetic eyes without DR had significantly lower CVI of macular Haller's layer than those of healthy controls. With a longer duration of diabetes, CVI of subfoveal Sattler's layer and choroidal volume continue to decrease, irrespective of diabetic control, suggesting that early diabetic choroidopathy mainly affects larger choroidal veins initially before medium-sized arterioles. The CVI of macular Haller's layer could potentially be used as a marker on spectral domain OCT imaging in newly diagnosed patients with diabetes for the onset of DR and as a possible prognostication tool in diabetic eyes. Future prospective longitudinal studies in diabetic eyes would be useful in establishing the relationship between CVIs of Haller's and Sattler's layer with visual acuity as a marker of photoreceptor health and visual prognosis.


Evaluation of surgically excised mitral valves: revised recommendations based on changing operative procedures in the 1990s.
In 1990, 95 mitral valves from 54 women and 41 men (mean age, 61 years; age range, 8 to 85 years) were replaced (76%) or repaired (24%) at the Mayo Clinic. Functionally, 58% of the valves were purely regurgitant (MR), 25% were stenotic and regurgitant (MS-MR), and 17% were purely stenotic (MS). Postinflammatory (presumably rheumatic) disease accounted for 100% of MS cases, 92% of MS-MR cases, and 16% of MR cases. Other causes of pure MR included floppy valves (49%), ischemic heart disease (13%), infective endocarditis (9%), miscellaneous (9%), and indeterminate (4%). Thus, postinflammatory disease represented the major cause of both mitral stenosis (MS and MS-MR) and overall mitral valve disease in our surgical population. In contrast, floppy valves were the most commonly observed cause of pure MR. Among postinflammatory valves, 55% were completely excised and 45% had only the anterior leaflet removed; all were replaced. In contrast, floppy valves were incompletely excised in 96%; 67% were repaired and only 33% were replaced. Because mitral valves frequently are incompletely excised, rendering an accurate etiologic diagnosis requires not only a morphologic assessment of resected tissues but also a knowledge of the clinical history, operative details, and functional state of the valve.


A very large diversity space of synthetically accessible compounds for use with drug design programs.
We have constructed a very large virtual diversity space containing more than 10(13) chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.


Effects of an Escherichia coli exopolysaccharide on human and mouse gut microbiota in vitro.
In this study, an exopolysaccharide (EPS) named EPS-RB was produced when the gene cluster ycjD-fabI-yciW-rnb were overexpressed in E. coli. Monosaccharide composition analysis revealed that EPS-RB is a novel EPS that consisted of L-fucose, L-arabinose, D-galactose/N-acetyl glucosamine, D-glucose, D-xylose, D-ribose, and D-glucuronic acid, and their molecular ratio was approximately 80:3:53:69:1:2:64. The content of carbohydrates, protein, and uronic acids in EPS-RB was 90.35 ± 1.35%, 2.62 ± 0.05% and 8.16 ± 1.00%, respectively. The interaction between EPS-RB and gut microbiota was investigated using an in vitro batch fermentation system. The results showed that ~96% of EPS-RB can be degraded by human fecal microbiota after 72 h fermentation, but few can be degraded by mouse cecal microbiota. Furthermore, high-throughput sequencing showed that EPS-RB regulates the human gut microbiota. The genera Collinsella, Butyricimonas, and Hafnia were enriched in group VIR (EPS-RB as a carbon source) when compared with group VI (no carbon source) and VIS (starch as a carbon source). Short-chain fatty acids (SCFAs) production analysis showed that their concentration was significantly higher in group VIR than groups VI and VIS after 72 h fermentation. In summary, an EPS-RB in E. coli was isolated and its regulatory function on gut microbiota was analyzed.


Chronic hypokalemic nephropathy: a clinical study.
Description of 23 patients (21 women, 2 men) with an average age of 36.6 (19--68) years, who were hypokalemic during 6.5 years on the average (range 1/2--16 years). The cause of the potassium depletion was malnutrition (anorexia nervosa, vomiting) and/or abuse of laxatives and/or diuretics. With increasing duration of potassium depletion renal function deteriorated; in two cases terminal renal failure developed. Histology of the kidneys (9 cases) showed the picture of chronic abacterial interstitial nephritis. Urinalysis was negative or non-specific. The blood pressure levels were normal or low, hypertensive values being exceptional. Aside of hypokalemia a tendency to hyponatriemia, hypochloremia and metabolic alcalosis was observed, the latter turning into hypokalemic normochloremic acidosis with advancing renal insufficiency. Plasma renin activity and aldosterone concentration or excretion frequently were elevated, but no close correlation was found between these parameters or with the blood pressure. Bacterial infection of the urinary tract occured, if at all, in the late phase and seems to be complication rather than the cause of the kidney disease. The discussion of other possible pathogenetic factors leads to the conclusion that the term "chronic kaliopenic nephropathy" is justified. Some diagnostic and therapeutic consequences are mentioned.


[Venous surgery: varicose veins (author's transl)].
varicose veins of the long saphenous vein and short saphenous vein. locally developed varicose veins and all forms of edema. When there is doubt, venography and tracing of the lymphatic vessels should be performed. Preservation of the lymphatic channels: incision in the groin higher than usual. Note the seven variations of the junction of the short saphenous vein. In case of damaged deep veins, operative treatment only if venous pressure curve shows improvement after compression of the superficial varicose veins.


Can ambulatory blood pressure measurements substitute assessment of subclinical cardiovascular damage?
We have previously demonstrated that markers of subclinical organ damage (SOD) improve cardiovascular risk prediction in healthy individuals. We wanted to investigate whether this additive effect of SOD was due to inaccurate blood pressure (BP) measurement or whether ambulatory BP (AMBP) added further to risk prediction. In a population cohort of 1385 Danish individuals free of cardiovascular disease and diabetes, we recorded traditional risk factors, AMBP and pulse wave velocity (PWV), urine albumin/creatinine ratio (UACR), left ventricular mass index (LVMI) and carotid atherosclerotic plaques at baseline. A composite cardiovascular endpoint (CEP) consisting of cardiovascular death and nonfatal myocardial infarction and stroke was recorded in national registries. During a median follow-up of 12.8 years, a total of 119 CEPs occurred. In categorical analysis, presence of SOD as well as masked hypertension increased sensitivity of Systemic Coronary Risk Estimation from 73.9 to 89.1% (P < 0.001) and reduced specificity from 60.1 to 41.8% (P < 0.001). In continuous analysis, logUACR [hazard ratio = 1.20 (95% confidence interval [CI] 1.05-1.38), P = 0.009], atherosclerotic plaques [hazard ratio = 1.82 (95% CI 1.21-2.74), P = 0.004] and 24-h SBP [hazard ratio = 1.34 (95% CI 1.12-1.60), P = 0.002] but not logPWV or LVMI predicted CEP in a model with adjustments for age, sex, conventional BP, total cholesterol and smoking. Compared with a risk model using only traditional risk factors, adding PWV, UACR, plaques, LVMI and 24-h SBP increased C-index significantly from 0.76 to 0.79% and produced a net reclassification improvement of 23.3% (P = 0.001). UACR and plaques predicted cardiovascular events independently of AMBP and improved risk prediction.


Histaminergic mechanisms in clonidine induced analgesia in rat tail-flick test.
The role of neural histamine in clonidine-analgesia and in clonidine-induced potentiation of stress analgesia was studied. Pretreatment of rats with alpha-fluoromethylhistidine (FMH) (200 ug icv/rat; daily for five days) increased the analgesic effect of the alpha 2-agonist clonidine on the spinal reflex of the tail-flick test. Rats subjected to cold-restraint stress (30 min at 4 degrees C) showed increased latency compared to the unstressed rats. The analgesic efficacy of clonidine was significantly greater in rats subjected to cold-restraint with respect to unstressed rats. However, the inhibition of histamine biosynthesis by FMH significantly reduced cold-restraint analgesia in saline-controls, and consistently increased the analgesic efficacy of the alpha 2-agonist, showing a maximum latency. Yohimbine exhibited high affinity as an antagonist for alpha 2-receptors, inducing hyperalgesic effects and antagonizing clonidine analgesia and clonidine-induced potentiation of cold stress analgesia. In FMH-pretreated rats, yohimbine failed to reverse clonidine analgesia and did not block the increased analgesic efficacy of clonidine in cold-restrained FMH-pretreated rats. Results of this study suggest that inhibition of histamine release through alpha 2-adrenoceptors on histaminergic axons may contribute to the analgesic efficacy of systemically injected clonidine, also confirming that neural histaminergic pathways are implicated in the mediation of pain response in particular conditions of stress.


Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous recombinant hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous recombinant hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as recombinant hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of recombinant hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of recombinant hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of recombinant hirudin. Platelet count rose from nadir (median value 60 x 10(9), 15 to 90) to above 100 x 10(9)/L in every patient within 3-6 days (median 5), after discontinuation of heparin. Intravenous administration of recombinant hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.


Nocturnal elevation of intraocular pressure in young adults.
To distinguish 24-hour (circadian) and postural effects on intraocular pressure (IOP) in healthy young adults. Thirty-three volunteers were housed in a sleep laboratory for 1 day under a strictly controlled 16-hour light and 8-hour dark environment. Sleep was encouraged in the dark period. Intraocular pressure was measured in each eye every 2 hours using a pneumatonometer. Researchers used night-vision goggles to perform IOP measurements in the dark, while the subject's light exposure was minimized. In the first group of 12 subjects, measurements were taken with subjects in the sitting position during the light-wake period and supine during the dark period. In the second group of 21 subjects, all IOP measurements were taken with the subjects supine. Average IOP was significantly higher in the dark period than in the light-wake period in both groups. The lowest IOP occurred in the last light-wake measurement, and the peak IOP occurred in the last dark measurement. The trough-peak difference in IOP was 8.2+/-1.4 mm Hg (mean +/- SEM) in the first group. Intraocular pressure changed sharply at the transitions between light and dark. In the second group, the trough-peak IOP difference was 3.8+/-0.9 mm Hg. Intraocular pressure changed gradually throughout the 24-hour period. In comparison with the sitting IOP in the first group, the supine IOP in the second group was significantly higher during the light-wake period. Circadian rhythms of IOP were shown in young adults, with the peaks occurring in the late dark period. A nocturnal IOP elevation can appear independent of body position change, but change of posture from upright to recumbent may contribute to the relative nocturnal IOP elevation.


Sialendoscopy: Getting started, how long does it take?
Dilation of the salivary gland papilla for access is well-recognized as one of the major rate-limiting steps to sialendoscopy and has been shown to be a major challenge for beginners. The purpose of this study was to demonstrate that an algorithm involving multiple techniques for salivary duct access in sialendoscopy results in excellent success rates and acceptable operative times. A retrospective, observational review of 61 patients who underwent sialendoscopy of the parotid or submandibular gland, for a total of 65 papillas accessed (31 parotid, 34 submandibular) with seven different trainees utilizing a standard protocol for duct access, was performed. The time interval from the case start to endoscopic visualization of the ductal lumen was measured. Average values for time to duct access were then calculated. The papilla was identified in all but one case without difficulty. Five submandibular gland cases required sialodochotomy for access. The average time to duct access was 4.2 ± 4.7 minutes (range: 0.67-25 minutes). Exclusion of four difficult cases with access times over 15 minutes yielded an average access time of 3.2 ± 2.2 minutes. This standardized protocol demonstrates high rates of success for salivary duct access via the papilla in a short time interval with infrequent need for sialodochotomy, even in the hands of novice surgeons. 4. Laryngoscope, 126:1083-1085, 2016.


Automated occlusion detection for the diagnosis of acute ischemic stroke: A detailed performance review.
Stroke is a leading cause of adult disability and death worldwide. Automated detection of stroke on brain imaging has promise in a time critical environment. We present a method for the automated detection of intracranial occlusions on dynamic CT Angiography (CTA) causing acute ischemic stroke. We derived dynamic CTA images from CT Perfusion (CTP) data and utilised advanced image processing to enhance and display major cerebral blood vessels for symmetry analysis. We reviewed the performance of the algorithm on a cohort of 207 patients from the International Stroke Perfusion Imaging Registry (INSPIRE), with Large Vessel Occlusion (LVO) and non-LVO strokes. Included in the data were images with chronic stroke, various artefacts, incomplete vessel occlusions, and images of poorer quality. All images were annotated by stroke experts. In addition, each image was graded in terms of the difficulty of the task of occlusion detection. Performance was evaluated on the overall cohort, and with respect to occlusion location, collateral grade, and task difficulty. We also evaluated the impact of including additional perfusion data. Images with a rating of lower difficulty achieved a sensitivity and specificity of 96% and 90%, respectively, while images with a moderate difficulty rating achieved 88% and 50%, respectively. For cases of high difficulty, where more than two experts or additional data were required to reach consensus, sensitivity and specificity was 53% and 11%. The addition of perfusion data to the dCTA images increased the specificity by 38%. We have provided an unbiased interpretation of algorithm performance. Further developments include generalising to conventional CTA and employing the algorithm in a clinical setting for prospective studies.


Magnesium sulphate intravenously reduces tachycardia side-effects of β2-agonists.
Intravenous magnesium sulphate allows safer intravenous β2-agonist delivery in acute-severe and life-threatening asthma attacks https://bit.ly/3veUpfC.


Cath-A-Cyst: a new urinary catheter.
A new disposable catheter assembly using the advantages of the Foley catheter, filiform and followers is presented. This new system obviates emergency urologic consultation or further trauma to a patient with a difficult urethra to catheterize.


Distribution of Bathyarchaeota Communities Across Different Terrestrial Settings and Their Potential Ecological Functions.
High abundance and widespread distribution of the archaeal phylum Bathyarchaeota in marine environment have been recognized recently, but knowledge about Bathyarchaeota in terrestrial settings and their correlation with environmental parameters is fairly limited. Here we reported the abundance of Bathyarchaeota members across different ecosystems and their correlation with environmental factors by constructing 16S rRNA clone libraries of peat from the Dajiuhu Peatland, coupling with bioinformatics analysis of 16S rRNA data available to date in NCBI database. In total, 1456 Bathyarchaeota sequences from 28 sites were subjected to UniFrac analysis based on phylogenetic distance and multivariate regression tree analysis of taxonomy. Both phylogenetic and taxon-based approaches showed that salinity, total organic carbon and temperature significantly influenced the distribution of Bathyarchaeota across different terrestrial habitats. By applying the ecological concept of 'indicator species', we identify 9 indicator groups among the 6 habitats with the most in the estuary sediments. Network analysis showed that members of Bathyarchaeota formed the "backbone" of archaeal community and often co-occurred with Methanomicrobia. These results suggest that Bathyarchaeota may play an important ecological role within archaeal communities via a potential symbiotic association with Methanomicrobia. Our results shed light on understanding of the biogeography, potential functions of Bathyarchaeota and environment conditions that influence Bathyarchaea distribution in terrestrial settings.


Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice.
Degradation of extracellular matrix proteins, such as fibrin, is pivotal to tumor invasion. Inhibition of the interaction between urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and hence pro-u-PA activation, is an attractive approach to anti-invasive cancer therapy. A number of inhibitors exist for the human system, but because of species specificity none of these are efficient in mice. We have recently generated an inhibitory monoclonal antibody (mAb) against mouse u-PAR (mR1) by immunization of u-PAR-deficient mice. To evaluate the effect of mR1 in vivo in a physiological setting sensitive to deregulated fibrinolysis, we have administered mR1 systemically and quantitated the effect on liver fibrin accumulation. Wild-type and tissue-type plasminogen activator (t-PA) deficient mice were administered with mR1, or control antibody, during 6 weeks. Thereafter, the livers were retrieved and the amount of liver fibrin measured by unbiased morphometrical analysis of immunofluorescence signal. Systemic administration of mR1 caused significantly increased fibrin signal in anti-u-PAR treated t-PA-deficient mice compared to mock-treated, which mimics the phenotype of u-PAR;t-PA double-deficient mice. Fibrin and fibronectin accumulated within the sinusoidal space and was infiltrated by inflammatory cells. Analysis of small and rare hepatic fibrin plaques observed in t-PA-deficient mice showed infiltrating macrophages that, contrary to surrounding Kuppfer cells, expressed u-PAR. We show that u-PAR-expressing macrophages are involved in cell-mediated fibrinolysis of liver fibrin deposits, and that the antimouse-u-PAR mAb is effective in vivo and thus suited for studies of the effect of targeting the u-PA/u-PAR interaction in mouse cancer models.


A tribute to John Gibbon.
This article provides an overview of the published research of John Gibbon. It describes his experimental research on scalar timing and his development of scalar timing theory. It also describes his methods of research which included mathematical analysis, conditioning methods, psychophysical methods and secondary data analysis. Finally, it describes his application of scalar timing theory to avoidance and punishment, autoshaping, temporal perception and timed behavior, foraging, circadian rhythms, human timing, and the effect of drugs on timed perception and timed performance of Parkinson's patients. The research of Gibbon has shown the essential role of timing in perception, classical conditioning, instrumental learning, behavior in natural environments and in neuropsychology.


Sildenafil in heart transplant candidates with pulmonary hypertension.
Severe pulmonary hypertension is a usual contraindication to heart transplantation. A few studies have found that sildenafil has a favourable effect on haemodynamic variables in patients with severe left ventricular systolic dysfunction. To report our clinical experience of sildenafil in patients with left ventricular systolic dysfunction and severe pulmonary hypertension. All patients underwent echocardiography, radionuclide angiography, a cardiopulmonary exercise test and right heart catheterization before and after treatment with sildenafil. All patients were clinically stable and were receiving maximal tolerated doses of recommended drugs. We included 18 patients, with a mean±standard deviation age of 47±13 years. After a median of 8.7 months (interquartile range, 4.4-13.5 months) on sildenafil, there was a significant improvement in New York Heart Association classification (P=0.02) and mean right ventricular ejection fraction (from 26±7% to 30±9%; P=0.008), with a decrease in the VE/VCO2 slope (from 52±11 to 44±11; P=0.009) and in pulmonary vascular resistance (from 5.3±1.9 Wood units to 3.3±1.8 Wood units; P=0.01). During follow-up, three patients had urgent heart transplantation, two had non-urgent transplantation and six had left ventricular assist device implantation. All patients with pulmonary vascular resistance<3 Wood units after sildenafil were alive, compared with four in the other subgroup (44% survival). In patients with pulmonary hypertension related to left ventricular systolic dysfunction, sildenafil seems to improve cardiac haemodynamics.


Developing an education and assessment framework for the Foundation Programme.
To develop an education and assessment framework for the second year of the Foundation Programme (F2). A total of 23 PRHOs were recruited to the F2 pilot in August 2003. The training posts included a variety of specialties at 2 hospital trusts plus primary care. Trainee expectations and satisfaction were evaluated using questionnaires administered before and at the end of the pilot. At the end of the pilot, 10 trainees participated in a focus group and 19 trainers participated in a semistructured telephone interview. The majority of trainees (78%) felt that their expectations of the F2 pilot were met and all felt that they had improved their generic skills. Attendance at the generic education programme was 95%. The majority of trainees found the assessment framework useful. The percentage of undecided trainees in terms of career aspirations dropped from 48% to 13%. Trainees valued the breadth of experience provide by the year and the support provided by the programme directors and each other. A need for better communication, administrative support and time for assessment was highlighted by the trainers. Early, focused education on generic skills will benefit both doctors and their patients. More varied career experience will help to ensure that doctors make appropriate and timely career decisions. Pilots are identifying good practice and areas that need improvement.


Functional Response and Intraspecific Competition in the Fall Armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae).
Functional responses of the fall armyworm (FAW) larvae at each stage, and their intraspecific competition associated with cannibalism, provide insights into developing pest management strategies for the FAW. To help use insecticides more sparingly, the functional response and intraspecific competition of the FAW larvae were evaluated under the laboratory conditions. The results showed that all stages of the FAW larvae displayed a type II functional response to diet. Based on Holling's disc equation, the search rate (a) and handling time (Th) of sixth instar larvae (a = 0.493; Th = 0.37 min) were the highest, and the shortest of all larval stages, respectively. Intraspecific competition curves fitted the data for fourth to sixth larval stages of the FAW, and the coefficient of intraspecific competition (m) assessed by the intraspecific competition equation were highest for fifth instar larvae (m = 0.48). The present study indicates that 5th and 6th instar larvae can cause the most plant damage (accounted for 88.9% of larval consumption), and these stages should be the focus of any pest management strategy. Intraspecific competition, especially cannibalism, impacts the feeding patterns of the FAW larvae and needs close attention. Understanding the functional response and intraspecific competition of the FAW larvae contributes greatly to practical applications of insecticides, increasing the effectiveness of chemical sprays and decreasing ecological damage.


Inter- and intraspecific comparisons of antiherbivore defenses in three species of rainforest understory shrubs.
Plants defend themselves against herbivores and pathogens with a suite of morphological, phenological, biochemical, and biotic defenses, each of which is presumably costly. The best studied are allocation costs that involve trade-offs in investment of resources to defense versus other plant functions. Decreases in growth or reproductive effort are the costs most often associated with antiherbivore defenses, but trade-offs among different defenses may also occur within a single plant species. We examined trade-offs among defenses in closely related tropical rain forest shrubs (Piper cenocladum, P. imperiale, and P. melanocladum) that possess different combinations of three types of defense: ant mutualists, secondary compounds, and leaf toughness. We also examined the effectiveness of different defenses and suites of defenses against the most abundant generalist and specialist Piper herbivores. For all species examined, leaf toughness was the most effective defense, with the toughest species, P. melanocladum, receiving the lowest incidence of total herbivory, and the least tough species, P. imperiale, receiving the highest incidence. Although variation in toughness within each species was substantial, there were no intraspecific relationships between toughness and herbivory. In other Piper studies, chemical and biotic defenses had strong intraspecific negative correlations with herbivory. A wide variety of defensive mechanisms was quantified in the three Piper species studied, ranging from low concentrations of chemical defenses in P. imperiale to a complex suite of defenses in P. cenocladum that includes ant mutualists, secondary metabolites, and moderate toughness. Ecological costs were evident for the array of defensive mechanisms within these Piper species, and the differences in defensive strategies among species may represent evolutionary trade-offs between costly defenses.


Low dose of IGF-I increases cell size of skeletal muscle satellite cells via Akt/S6K signaling pathway.
The objective of this study was to investigate the effect of insulin growth factor-I (IGF-I) on the size of pig skeletal muscle satellite cells (SCs). Using microarray, real-time RT-PCR, radioimmunoassay analysis and western blot, we first showed that supplementation of low-dose of IGF-I in culture medium resulted in enlarged cell size of Lantang SCs, only Akt and S6K were up-regulated at both the mRNA and protein levels among almost all of the mTOR pathway key genes, but had no effect on cell number. To elucidate the signaling mechanisms responsible for regulating cell size under low-dose of IGF-I treatment, we blocked Akt and S6K activity with the specific inhibitors MK2206 and PF4708671, respectively. Both inhibitors caused a decrease in cell size. In addition, MK2206 lowered the protein level of p-Akt (Ser473), p-S6K (Thr389), and p-rpS6 (Ser235/236), whereas PF4708671 lowered the protein level of p-S6K (Thr389) and p-rpS6 (Ser235/236). However, low dose of IGF-I didn't affect the protein level of p-mTOR (Ser2448) and p-mTOR (Ser2481). When both inhibitors were applied simultaneously, the effect was the same as that of the Akt inhibition alone. Taken together, we report for the first time that low-dose of IGF-I treatment increases cell size via Akt/S6K signaling pathway.


Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.
Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.


Setting research priorities to achieve long-term national road safety goals in Iran.
Road traffic crashes (RTCs) and its associated injuries are one of the most important public health problems in the world. In Iran, RTCs rank second in terms of mortality. To address this issue, there is a need for research-based interventions. Prioritizing researches using a variety of approaches and frameworks to determine the most effective interventions is a key nodal point in the RTCs' research policy planning cycle. Thus, this study aims to generate and prioritize research questions in the field of RTCs in Iran. By adapting the Child Health and Nutrition Research Initiative (CHNRI) method, this study engaged 25 prominent Iranian academic leaders having role in setting Iran's long-term road safety goals, a group of research funders, and policymakers. The experts' proposed research questions were independently scored on a set of criteria: feasibility, impact on health, impact on the economy, capacity building, and equity. Following the prioritization of Research Questions (RQs), they were all classified using the 5 Pillar frameworks. In total, 145 Research Questions were systematically scored by experts against five criteria. Iran's top 20 road traffic safety priorities were established. The RQs related to "road safety management" and "road and infrastructure" achieved a high frequency. The top 20 research questions in the area of RTCs in Iran were determined by experts. The majority of these RQs were related to "road safety management". The results of this study may contribute to the optimal use of resources in achieving long-term goals in the prevention and control of road traffic crashes and its related injuries. Considering these RQs as research investment options will improve the current status of Road Traffic Injuries (RTIs) at a national level and further advance toward compliance with international goals. If these research priorities are addressed, and their findings are implemented, we can anticipate a significant reduction in the number of crashes, injuries, and deaths.


Cardiac magnetic resonance imaging and transesophageal echocardiography in patients with transcatheter closure of patent foramen ovale.
We studied the value of cardiac magnetic resonance imaging (CMRI) before and after closure of patent foramen ovale (PFO) in patients with cryptogenic ischemic events. Cardiac magnetic resonance imaging is a powerful noninvasive tool for detailed assessment of cardiac anatomy and function. The relevance of CMRI compared with transesophageal echocardiography (TEE) in patients undergoing transcatheter PFO closure has not been evaluated so far. Contrast-enhanced CMRI and TEE were performed in 75 patients before and after PFO closure. Twelve months after PFO closure, both imaging techniques were repeated in 61 patients with contrast application. To determine provokable atrial right-to-left shunting in CMRI, we applied a contrast-enhanced perfusion imaging technique. Detection of atrial septal aneurysm (ASA) was achieved by means of a high-resolution cine imaging technique. Before PFO closure, ASA was seen with CMRI in 28 of 75 cases (37.3%), compared with 47 of 75 (62.7%) cases using TEE. There were a total of 211 CMRI studies with a corresponding TEE performed in 75 patients. No shunt was present in 107 of 211 studies with both techniques. Contrast-enhanced right-to-left shunting was detected by CMRI in 48 of 72 (66.6%) cases with moderate or severe shunts seen with TEE, but only in 6 of 32 (18.8%) studies with mild shunts with TEE. Anomalous venous returns were excluded in all patients. In two patients, coronary anomalies were seen. The present CMRI technique is inferior to TEE in detection of contrast-enhanced right-to-left shunting and identification of ASA.


Anomalous ECG downloads from semi-automatic external defibrillators.
The coincidental print-out by two different Laerdal systems (subsequently called 'system A' and 'system B') of the same medical control module (MCM) for a Laerdal Heartstart 2000 semi-automatic external defibrillator (SAED) led to the discovery of three deficiencies in the information storage and printing processes. First, we noted that the impedance reported via system A was consistently higher. Second, we found the attachment of 'mysterious' ECG samples in the reports from system B, but not from system A. A third problem was the unpredictable (in)ability of system B to print out the information from the MCMs. Further investigations with help from the company suggested that the above-mentioned problems were caused by incompatibilities between the software in the different parts of equipment used (i.e. SAED devices, MCMs, printing systems and a computer program to store the information in a database). These observations demonstrate the need for strict medical supervision on all aspects of a SAED project, and for feed-back from clinicians to manufacturers.


Progress and Prospects in Pediatric Leukemia.
Pediatric leukemia is the single most common malignancy affecting children, representing up to 30% of all pediatric cancers. Dramatic improvements in survival for acute lymphoblastic leukemia (ALL) have taken place over the past 4 decades with outcomes approaching 90% in the latest studies. However, progress has been slower for myeloid leukemia and certain subgroups like infant ALL, adolescent/young adult ALL, and relapsed ALL. Recent advances include recognition of molecularly defined subgroups, which has ushered in precision medicine approaches. We discuss the current understanding of the biology of the various childhood leukemias, recent advances in research, and future challenges in this field.


Boyden's triad in the left lung: an interesting phenomenon.
Boyden's triad of the right lung was first proposed in 2021. Here, we report 5 cases of this malformation found in the left lung. A total of 5280 patients with pulmonary lesions underwent three-dimensional computed tomography bronchography and angiography between January 2019 and January 2021, prior to surgery; 5 cases of this malformation were identified in the left lung. Bronchovascular patterns were analysed in each patient. The incidence rate of Boyden's triad in the left lung was 0.1%. This malformation was further divided into B3 on B4+5 type and B3 on B4 type. In B3 on B4+5 type, B3 was shifted downwards on the common trunk of B4+5, and A3 arose from the common trunk of A4+5 running alongside B3. In B3 on B4 type, B3 was shifted downwards on B4. A4 and A5 appeared separately. A3 arose from A4, running alongside B3; A5 arose from the common trunk of A8 - 10, and there was also an extraordinary 'posterior vein' (V. post): V1+2c. The incidence of V. post was 0.17%. An additional 'fissure' lies longitudinally between S1+2 and S3+4+5, nearly perpendicular to the oblique fissure, dividing the upper lobe into 'two lobes'. The B3 downwards-shifting malformation can be found on both lungs, and this is the first description of Boyden's triad in the left lung; it appears to be much rarer than that in the right lung, with some accompanying unique variations.


Comparison of high spatial resolution respiratory triggered inversion recovery-prepared spoiled gradient echo sequence with standard breathhold T1 sequence MRI of the liver using gadoxetic acid.
To assess if a high resolution respiratory triggered inversion recovery prepared GRE sequence (RT) improved image quality and detection of lesions compared with breathhold GRE T1 weighted MR sequence (BH) in the hepatobiliary uptake phase of MR of the liver using gadoxetic acid (Gd-EOB-DTPA). Thirty-eight consecutive patients from July 2009 to September 2010 who had undergone Gd-EOB-DTPA enhanced liver exams were retrospectively identified. Qualitative assessment performed on reference lesions and background liver by two independent readers. Quantitative assessment performed by one reader. Liver parenchyma signal-to-noise ratio for BH was 90.3 ± 23.9 (mean ± SD) and RT, 106.1 ± 40.4 (P = 0.119). For BH, 320 lesions were detected compared with 257 for RT. Lesion to liver contrast was significantly better on RT sequences (0.26 ± 0.24; mean ± SD) compared with BH sequence (0.21 ± 0.20; P = 0.044). Fifty-seven reference lesions assessed. Both reviewers rated BH better for lesion margin and hepatic vessel sharpness. BH was rated with less artifact (P < 0.05). Lesion to liver contrast on BH was significantly better for one reviewer. BH sequence had better overall image quality than RT in several quantitative and qualitative factors including number of lesions detected and level of artifact.


Triangle retinal detachment- ultrasonic identification of massive periretinal proliferation in eyes with opaque media.
The demonstration of a triangle configuration retinal detachment by B-scan ultrasonography in eyes with opaque media is diagnostic of advanced massive periretinal proliferation. Eyes with this type of retinal detachment have a very poor surgical prognosis even with modern vitrectomy techniques.


Effects of topical application of a recombinant staphylococcal enterotoxin A on DNCB and dust mite extract-induced atopic dermatitis-like lesions in a murine model.
Atopic dermatitis (AD) is a chronic inflammatory skin disease with biphasic T cell-mediated abnormalities. Staphylococcal superantigens contribute to the exacerbation of inflammation in AD. The underlying immunopathological mechanisms are not fully understood. To determine whether epicutaneous application of recombinant staphylococcal enterotoxin A (rSEA) would exacerbate AD-like allergic inflammation induced by 2, 4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model. We first established an AD-like model using BALB/c mice exposed to DNCB/DFE on the ear. Next, Staphylococcus (S.) aureus or rSEA were topically applied to the mice. We evaluated the clinical and histopathological features of the animals. Serum immunoglobulin levels were also measured. In addition, real-time PCR analysis of cytokines produced by T cell subsets in the ears was conducted. Mice treated with S. aureus and rSEA had more severe clinical symptoms, including increased mean dermatitis scores and ear thickness, compared to animals with only AD-like lesions. Total IgE, IgG2a and serum histamine levels were increased in all groups except the normal control group. The S. aureus- and rSEA-treated groups showed increased levels of cytokines such as IL-4, IL-13, INF-γ, IL-17, and IL-18. In particular, increased cytokine expression was more conspicuous in the rSEA-treated group than in mice exposed to S. aureus. The results of this study showed that topical exposure to rSEA as well as SEA-producing S. aureus aggravate atopic skin inflammation. This may be associated with the induction of a mixed Th1/Th2 type dermatitis.


Licensing procedures for immunological veterinary medicinal products in the European Union.
With the adoption of the new authorization system, all regulatory needs for veterinary medicinal products have been fulfilled with the European Union. This system, indeed, provides access to a continent-wide market to innovative products, in particular vaccines, and facilitates access to the markets of the Member States for other products. This should have a clearly favorable impact on the veterinary vaccines industry.


Keratosis follicularis spinulosa decalvans: a rare cause of scarring alopecia in two young Indian girls.
Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked xenodermatosis characterized by scarring alopecia and follicular hyperkeratosis. This condition mainly affects males with females being carriers and will have milder symptoms. We present two sisters with severe form of KFSD, progressing to scarring alopecia.


Abnormalities in the visual system of Xenopus after larval optic nerve section.
One optic nerve was cut in a series of larval Xenopus laevis; in approximately half of these the corresponding eye was also rotated. The resultant primary visual projections were mapped in the adult. Although in most cases the projections were retinotopically normal, some of them were not. These abnormal projections were consistently associated with a very thin optic nerve which reached the tectum via the oculomotor route. Animals with rotated eyes which developed retinotopically organised primary projections had a normal intertectal ipsilateral projection from the rotated eye and a rotated projection from the normal eye, thus confirming earlier findings that a process of binocular interaction determines the formation of intertectal connections. In all frogs with retinotopically abnormal primary projections the intertectal connections from the normal eye were of the type found after enucleation and those from the abnormal side were fragmentary or absent. Since the development of abnormal retinotopic patterns preceded that of intertectal connections the mechanisms of binocular interaction must have broken down in the presence of the abnormal primary projections.


Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue.
Interleukin (IL)-33 is a member of the IL-1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL-33 by 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL-33 mRNA and intracellular IL-33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL-33 was also up-regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y-27632, and by latrunculin B, but statin-induced IL-33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U-46619. The IL-33 promoter was 2.3-fold more accessible in statin-treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin-treated patients IL-33 protein was up-regulated as compared with the hearts of non-statin-treated patients (P = 0.048). As IL-33 was previously shown to exert cardioprotective effects, one could speculate that such up-regulation of IL-33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.