Special AT-rich Sequence-binding Protein 1 (SATB1) Functions as an Accessory Factor in Base Excision Repair.
Base excision repair is initiated by DNA glycosylases that recognize specific altered bases. DNA glycosylases for oxidized bases carry both a glycosylase activity that removes the faulty base and an apyrimidinic/apurinic lyase activity that introduces a single-strand DNA incision. In particular, the CUT domains within the CUX1 and CUX2 proteins were recently shown to interact with the 8-oxoguanine (8-oxoG) DNA glycosylase and stimulate its enzymatic activities. SATB1, which contains two CUT domains, was originally characterized as a T cell-specific genome organizer whose aberrant overexpression in breast cancer can promote tumor progression. Here we investigated the involvement of SATB1 in DNA repair. SATB1 knockdown caused a delay in DNA repair following exposure to H2O2, an increase in OGG1-sensitive oxidized bases within genomic DNA, and a decrease in 8-oxoG cleavage activity in cell extracts. In parallel, we observed an increase in phospho-CHK1 and γ-H2AX levels and a decrease in DNA synthesis. Conversely, ectopic expression of SATB1 accelerated DNA repair and reduced the levels of oxidized bases in genomic DNA. Moreover, an enhanced GFP-SATB1 fusion protein was rapidly recruited to laser microirradiation-induced DNA damage. Using purified proteins, we showed that SATB1 interacts directly with OGG1, increases its binding to 8-oxoG-containing DNA, promotes Schiff base formation, and stimulates its glycosylase and apyrimidinic/apurinic lyase enzymatic activities. Structure/function analysis demonstrated that CUT domains, but not the homeodomain, are responsible for the stimulation of OGG1. Together, these results identify another CUT domain protein that functions both as a transcription factor and an accessory factor in base excision repair.


Association of Montevideo units with uterine rupture in women undergoing a trial of labor.
To determine if an association exists between Montevideo units (MVUs) and uterine rupture in women undergoing trial of labor after cesarean (TOLAC). A case-control study of women who underwent a TOLAC, comparing uterine rupture (n = 9) to successful vaginal birth after cesarean (VBAC) (n = 48) and failed TOLAC (n = 35). MVUs were calculated in 12 10-minute intervals prior to uterine rupture, cesarean delivery, or complete dilation in the VBAC group. MVUs were compared between groups by Wilcoxon rank sum test. The pattern of change of MVUs over time was examined by linear regression mixed models. The MVUs were similar among all groups (medians ranged from 140-175 [VBAC], 145-190 [TOLAC], and 130-195 [ruptures]). The analysis of pattern of change in MVUs over time demonstrated no difference within the VBAC group (p = 0.22) or the failed TOLAC group (p = 0.87), or between groups (VBAC and rupture [p = 0.56], failed TOLAC and rupture [p = 0.37]). A post-hoc power analysis showed a mean difference of 50 MVUs (SD 45) between VBAC and rupture and 55 MVUs (SD 45) between failed TOLAC and rupture can be detected with a power of 80% at a significance of 0.05. There is no association between MVUs and uterine rupture in women undergoing a TOLAC.


Engineering Catalytic Interfaces in Cuδ+/CeO2-TiO2 Photocatalysts for Synergistically Boosting CO2 Reduction to Ethylene.
Photocatalytic CO2 conversion into a high-value-added C2 product is a highly challenging task because of insufficient electron deliverability and sluggish C-C coupling kinetics. Engineering catalytic interfaces in photocatalysts provides a promising approach to manipulate photoinduced charge carriers and create multiple catalytic sites for boosting the generation of C2 product from CO2 reduction. Herein, a Cuδ+/CeO2-TiO2 photocatalyst that contains atomically dispersed Cuδ+ sites anchored on the CeO2-TiO2 heterostructures consisting of highly dispersed CeO2 nanoparticles on porous TiO2 is designedly constructed by the pyrolytic transformation of a Cu2+-Ce3+/MIL-125-NH2 precursor. In the designed photocatalyst, TiO2 acts as a light-harvesting material for generating electron-hole pairs that are efficiently separated by CeO2-TiO2 interfaces, and the Cu-Ce dual active sites synergistically facilitate the generation and dimerization of *CO intermediates, thus lowering the energy barrier of C-C coupling. As a consequence, the Cuδ+/CeO2-TiO2 photocatalyst exhibits a production rate of 4.51 μmol-1·gcat-1·h-1 and 73.9% selectivity in terms of electron utilization for CO2 to C2H4 conversion under simulated sunlight, with H2O as hydrogen source and hole scavenger. The photocatalytic mechanism is revealed by operando spectroscopic methods as well as theoretical calculations. This study displays the rational construction of heterogeneous photocatalysts for boosting CO2 conversion and emphasizes the synergistic effect of multiple active sites in enhancing the selectivity of C2 product.


Prediction and prevention of schizophrenia: what has been achieved and where to go next?
In modern medicine, vigorous efforts are being made in the prediction and prevention of diseases. Mental disorders are suitable candidates for the application of this program. The currently known neurobiological and psychosocial risk indicators for schizophrenia do not have a predictive power sufficient for selective prevention in asymptomatic patients at risk. However, once predictive basic and later pre-psychotic high risk symptoms of psychosis develop into the five-year initial prodrome, the impending outbreak of the disease can be predicted with high accuracy. Research findings suggest a differential strategy of indicated prevention with cognitive behavioral therapy in early initial prodromal states and low dosage atypical antipsychotics in late initial prodromal states. The most important future tasks are the improvement of the predictive power by risk enrichment and stratification, as well as the confirmation of the existing and the development of new prevention strategies, with a stronger focus on the etiology of the disorder. In addition, the prediction and prevention approach would benefit from the inclusion of risk symptoms in the DSM-5 criteria.


Spatial segregation between wild ungulates and livestock outside protected areas in the lowlands of Nepal.
Understanding how wildlife interacts with human activities across non-protected areas are critical for conservation. This is especially true for ungulates that inhabit human-dominated landscapes outside the protected area system in Nepal, where wildlife often coexists with livestock. Here we investigated how elevation, agricultural land, distance from roads, and the relative abundance of livestock (goats, sheep, cow and buffalo) influenced wild ungulate chital (Axis axis), nilgai (Boselaphustrago camelus), wild boar (Sus scrofa) and sambar (Rusa unicolor) abundance and occurrence. We counted all individuals of wild ungulates and livestock along 35 transects conducted between November 2017 and March 2018 in community forests of Bara and Rautahat distracts in the lowlands of Nepal. We assessed abundance and occurrence relation to covariates using Generalized Linear Models. We found that livestock outnumbered wild ungulates 6.6 to 1. Wild boar was the most abundant wild ungulate, followed by nilgai, chital, and sambar. Elevation and livestock abundance were the most important covariates affecting the overall abundance of wild ungulates and the distribution of each individual ungulate species. Our results suggest spatial segregation between wild ungulates, which occur mainly on high grounds (> 300 m.a.s.l.), and livestock that concentrate across low ground habitats (< 300 m.a.s.l.). Our results provide a critical first step to inform conservation in community forest areas of Nepal, where wildlife interacts with people and their livestock. Finding better strategies to allow the coexistence of ungulates with people and their livestock is imperative if they are to persist into the future.


Barrier-limited, microsecond folding of a stable protein measured with hydrogen exchange: Implications for downhill folding.
Folding experiments are conducted to test whether a covalently cross-linked coiled-coil folds so quickly that the process is no longer limited by a free-energy barrier. This protein is very stable and topologically simple, needing merely to "zipper up," while having an extrapolated folding rate of k(f) = 2 x 10(5) s(-1). These properties make it likely to attain the elusive "downhill folding" limit, at which a series of intermediates can be characterized. To measure the ultra-fast kinetics in the absence of denaturant, we apply NMR and hydrogen-exchange methods. The stability and its denaturant dependence for the hydrogen bonds in the central part of protein equal the values calculated for whole-molecule unfolding. Like-wise, their closing and opening rates indicate that these hydrogen bonds are broken and reformed in a single cooperative event representing the folding transition from the fully unfolded state to the native state. Additionally, closing rates for these hydrogen bonds agree with the extrapolated barrier-limited folding rate observed near the melting transition. Therefore, even in the absence of denaturant, where DeltaG(eq) approximately -6 kcal.mol(-1) (1 cal = 4.18 J) and tau(f) approximately 6 mus, folding remains cooperative and barrier-limited. Given that this prime candidate for downhill folding fails to do so, we propose that protein folding will remain barrier-limited for proteins that fold cooperatively.


Correlation of ABO Blood Group Phenotype and Rhesus Factor with Periodontal Disease: An Observational Study.
The knowledge of the ABO blood group phenotype of the patients and their correlation with the periodontal disease maybe important in the development of early treatment strategies, and it would be helpful to target non-responding areas to periodontal therapy of the susceptible individuals. The present study was conducted to determine whether there was any correlation between periodontal diseases and ABO blood groups and Rh factor. This study was carried out on 537 subjects attending Faculty of Dental Sciences OPD in BHU. Subjects were divided into three groups: group I (healthy subjects), group II (subjects with gingivitis), and group III (subjects with periodontitis) based on periodontal examination (Gingival index, Bleeding Index, Probing pocket depth and clinical attachment level). ABO Blood grouping were done and correlated with the periodontal status of study subjects. Statistical Analysis: Data was analyzed using the statistical software namely Statistical Package for the Social Sciences (SPSS, Version 16, IBM Analytics) and Systat 8.0. In this study, there was a greater prevalence of gingivitis in blood group O and periodontitis in blood group B. The blood group AB showed the least prevalence of periodontal diseases. Similarly gingivitis and peridontitis were significantly higher among Rhesus positive groups when compared with Rhesus negative groups. Considering the results of this study, it can be concluded that ABO blood groups and Rh factor could be a risk factor for the development of periodontal disease.


ISOC1 is a novel potential tumor suppressor in hepatocellular carcinoma.
Isochorismatase domain-containing 1 (ISOC1) plays a carcinogenic role in various tumors. However, its expression and role in hepatocellular carcinoma (HCC) have not been elucidated. This is the first study to investigate the involvement of ISOC1 in HCC growth and migration. ISOC1 expression was analyzed using public databases and clinical samples, and clinical specimens were analyzed by real-time quantitative polymerase chain reaction, western blotting, and immunohistochemistry. ISOC1 was also overexpressed in two HCC cell lines (Huh7 and HepG2) to explore how ISOC1 affects HCC cells. Finally, a nude mouse xenograft tumor model was used to investigate the role of ISOC1 in HCC cell tumorigenicity. ISOC1 was downregulated in HCC tissues compared to that in matched paracancerous tissues, and low ISOC1 expression was associated with a poor prognosis. The proliferation and single-cell colony-forming ability of the ISOC1-overexpressing cell lines Huh7 and HepG2 were significantly inhibited. Moreover, ISOC1 overexpression suppressed the migration and invasion abilities of HCC cells in vitro, and ISOC1 upregulation hindered tumor growth in the xenograft tumor model in vivo. Therefore, ISOC1 is a potential HCC suppressor protein.


Long-term results of non-fludarabine versus fludarabine-based stem cell transplantation without total body irradiation in Fanconi anemia patients.
Hematopoietic cell transplantation (HCT) is the only therapeutic modality capable of correcting the hematologic manifestations of Fanconi anemia (FA). The development of well-tolerated immunosuppressive conditioning regimens for FA patients undergoing HCT has proven to be a challenging task for hematologists. Retrospective, patients referred to the hematology, oncology and stem cell transplantation research center. We analyzed the outcome of 53 FA patients who had undergone HCT between 1992 and 2010. The median age at transplantation was 9 years. Patients received transplants from an HLA-identical sibling (n=39) or matched relative (n=9) and one-antigen locus mismatched other relative/sibling (n=5). All of the patients underwent transplantation with fludarabine and non-fludarabine-based conditioning regimens. No radiation therapy was given. The median follow-up period for survivors was 13.5 months (range, 3 months-13.5 years). The 3-year overall survival (OS) was 60.6%. The 3-year OS for patients who did or did not receive fludarabine-based preparative regimens for the allograft was 36.4%, and 70%, respectively. However, there were no statistically significant differences in OS rates between these two groups (P=.112). Graft failure occurred in 4 patients (7.5%). All of these 4 patients had received fludarabine-based conditioning regimens. The incidence of acute GVHD after fludarabine-based regimens was 45% versus 79% in non-fludarabine-based regimens (P=.03). Despite the high incidence of acute GVHD (78.6%) in the non-fludarabine group, which resulted in the death of some patients, the OS rate was significantly better than in fludarabine recipients. Therefore, in spite of the fact that recent studies advocate the fludarabine-based conditioning regimens, we propose to conduct a multicenter, prospective study to evaluate the outcomes of regimens employed in FA patients.


Agrococcus lahaulensis sp. nov., isolated from a cold desert of the Indian Himalayas.
The taxonomic position of a lemon-yellow-pigmented actinobacterium, strain K22-21(T), isolated from a soil sample from Lahaul-Spiti Valley in the Indian Himalayas, was determined using a polyphasic approach. The strain had phenotypic and chemical properties that were consistent with its classification in the genus Agrococcus. Alignment of the 16S rRNA gene sequence of strain K22-21(T) with sequences from Agrococcus jenensis DSM 9580(T), Agrococcus baldri DSM 14215(T) and Agrococcus citreus DSM 12453(T) revealed similarities of 98.5, 96.8 and 96.6 %, respectively. However, the level of DNA-DNA relatedness between strain K22-21(T) and A. jenensis was 55.1 %. The novel strain could be distinguished from type strains of the three species of the genus Agrococcus using DNA-DNA relatedness and phenotypic data. Based on these differences, strain K22-21(T) (=MTCC 7154(T)=DSM 17612(T)) should be classified as the type strain of a novel species of Agrococcus, for which the name Agrococcus lahaulensis sp. nov. is proposed.


Recurrent malignant fibrous histiocytoma with expression of cytokeratin.
A case of locally recurrent malignant fibrous histiocytoma was documented in a 70-year-old man. He first noticed a subcutaneous nodule forty years previously. The tumor was surgically removed four times during the last four years with local recurrence on every occasion. In the recurrent tumors, the tumor cells almost completely replaced the whole dermis and invaded skeletal muscles. They were composed of pleomorphic spindle cells arranged in a storiform pattern and bizarre histiocytic cells, which were present principally in the deeper portions of the tumor. Both types of tumor cells showed marked nuclear atypicality. In the primary tumor, surrounding a large necrotic area, spindle-shaped cells were arranged in a storiform pattern. These tumor cells exhibited only mild nuclear atypia. The recurrent tumor was strongly positive for vimentin and alpha-1-antichymotrypsin. Most tumor cells were also weakly positive for KL1, a monoclonal antibody for keratin. A Western-blot analysis revealed the presence of two bands (62 and 69 Kd) reacting with KL1 in the fractions which were obtained from the tumor according to the method for keratin extraction.


Undetectable triglycerides related to the combined intake of ascorbic acid and tacrolimus.
Management of triglyceride (TG) levels is essential in intensive care units (ICU), especially to manage the risk of pancreatitis induced by propofol. However, some therapeutics in ICU such as intravenous ascorbic acid protocol, especially used in the context of Covid-19 could lead to false decrease of triglycerides by analytical disruption of Trinder reaction. We report here the case of a sample with unmeasurable triglyceride levels partly due to high plasma ascorbic acid levels. However, repeated measure on the same sample four days later revealed that interference mechanism on TG was still present whereas the level of ascorbic acid was very reduced by oxidation degradation. Hence, additional interference mechanism was suspected. After clinical investigation, we found that the patient had also received high doses of tacrolimus due to a transplant. As previous studies reported that tacrolimus treatment lead to a decrease of the measured plasma activity of lipoprotein lipase (LPL), we hypothesized that tacrolimus or related metabolites could also interfere by direct inhibition of LPL involved in TG analytical method used.


Differences in psychological perception of lung cancer between patients, medical staff and medical students.
In clinical practice, medical staff is often unaware that what they think about patient's disease differs much from the perceptions and feelings of the patient. The aim of the study was to analyse the differences in psychological perception of lung cancer between patients treated with combined regimen for lung cancer (n = 30), medical staff (n = 94) and medical students (n = 303). A total of 427 persons were enrolled in this questionnaire study using Imagination and Perception of Illness Scale (IPIS) by Sak. The IPIS scale items described: loss of motivation to carry out specific activities (eight items), mental sphere destruction (six items), physical sphere destruction (eight items), pessimism (four items), being a burden to others (three items) and loss of control over the illness (three items). A seven-point scale from '0', meaning the choice of maximum positive feature, to '6', meaning the choice of maximum negative feature, was used. The higher result obtained within a given factor signified the more negative perception of the illness. In all IPIS items, the results among patients were significantly lower than among medical staff or students (P = 0.018 and P = 0.001, respectively). Medical staff and students perceive lung cancer as causing more profound destruction in patient's mental and physical spheres than patients do. Patients treated for lung cancer with combined regimen perceive their disease more optimistically than what is imagined by medical staff and students, and may underestimate the threat. It may be explained by psychological adaptation of patients to their disease during prolonged treatment. We believe that informing lung cancer patients in detail about their illness should be recommended to enhance self-awareness and doctor-patient cooperation.


Trench Foot or Non-Freezing Cold Injury As a Painful Vaso-Neuropathy: Clinical and Skin Biopsy Assessments.
Trench foot, or non-freezing cold injury (NFCI), results from cold exposure of sufficient severity and duration above freezing point, with consequent sensory and vascular abnormalities which may persist for years. Based on observations of Trench foot in World War II, the condition was described as a vaso-neuropathy. While some reports have documented nerve damage after extreme cold exposure, sensory nerve fibres and vasculature have not been assessed with recent techniques in NFCI. To assess patients with chronic sensory symptoms following cold exposure, in order to diagnose any underlying small fibre neuropathy, and provide insight into mechanisms of the persistent pain and cold hypersensitivity. Thirty soldiers with cold exposure and persistent sensory symptoms (>4 months) were assessed with quantitative sensory testing, nerve conduction studies, and skin biopsies. Immunohistochemistry was used to assess intraepidermal (IENF) and subepidermal (SENF) nerve fibres with a range of markers, including the pan-neuronal marker protein gene product 9.5 (PGP 9.5), regenerating fibres with growth-associated protein 43 (GAP43), and nociceptor fibres with transient receptor potential cation channel subfamily V member 1 (TRPV1), sensory neuron-specific receptor (SNSR), and calcitonin gene-related peptide (CGRP). von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) were used for assessing blood vessels, and transient receptor potential cation channel, subfamily A member 1 (TRPA1) and P2X purinoceptor 7 (P2X7) for keratinocytes, which regulate nociceptors via release of nerve growth factor. Clinical examination showed pinprick sensation was abnormal in the feet of 20 patients (67%), and between 67 and 83% had abnormalities of thermal thresholds to the different modalities. 7 patients (23%) showed reduced sensory action potential amplitude of plantar nerves. 27 patients (90%) had decreased calf skin PGP 9.5 IENF (p < 0.0001), the remaining 3 patients had decreased nerve markers in subepidermis or foot skin. There were marked increases of all vascular markers (for vWF in calf skin, p < 0.0001), and increased sensory or regenerating SENF (for calf skin, GAP43, p = 0.002). TRPA1 (p = 0.0012) and P2X7 (p < 0.0001) were increased in basal keratinocytes. A range of skin biopsy markers and plantar nerve conduction studies are useful objective assessments for the diagnosis of peripheral neuropathy in NFCI. Our results suggest that an increase in blood vessels following tissue ischaemia/hypoxia could be associated with disproportionate and abnormal nerve fibres (irritable nociceptors), and may lead to NFCI as a "painful vaso-neuropathy."


Metabolomic Impact of Lidocaine on a Triple Negative Breast Cancer Cell Line.
Background: Metabolomics and onco-anesthesia are two emerging research fields in oncology. Metabolomics (metabolites analysis) is a new diagnostic and prognostic tool that can also be used for predicting the therapeutic or toxic responses to anticancer treatments. Onco-anesthesia studies assess the impact of anesthesia on disease-free and overall survival after cancer surgery. It has been shown that local anesthetics (LA), particularly lidocaine (LIDO), exert antitumor properties both in vitro and in vivo and may alter the biologic fingerprints of cancer cells. As LA are known to impair mitochondrial bioenergetics and byproducts, the aim of the present study was to assess the impact of LIDO on metabolomic profile of a breast cancer cell line. Methods: Breast cancer MDA-MB-231 cells were exposed for 4 h to 0.5 mM LIDO or vehicle (n = 4). The metabolomic fingerprint was characterized by high resolution magic angle spinning NMR spectroscopy (HRMAS). The multivariate technique using the Algorithm to Determine Expected Metabolite Level Alteration (ADEMA) (Cicek et al., PLoS Comput. Biol., 2013, 9, e1002859), based on mutual information to identify expected metabolite level changes with respect to a specific condition, was used to determine the metabolites variations caused by LIDO. Results: LIDO modulates cell metabolites levels. Several pathways, including glutaminolysis, choline, phosphocholine and total choline syntheses were significantly downregulated in the LIDO group. Discussion: This is the first study assessing the impact of LIDO on metabolomic fingerprint of breast cancer cells. Among pathways downregulated by LIDO, many metabolites are reported to be associated with adverse prognosis when present at a high titer in breast cancer patients. These results fit with the antitumor properties of LIDO and suggest its impact on metabolomics profile of cancer cells. These effects of LIDO are of clinical significance because it is widely used for local anesthesia with cutaneous infiltration during percutaneous tumor biopsy. Future in vitro and preclinical studies are necessary to assess whether metabolomics analysis requires modification of local anesthetic techniques during tumor biopsy.


Sand dollar: a weight belt for the juvenile.
Juvenile sand dollars (Dendraster excentricus) selectively ingest heavy sand grains from the substrate and store them in an intestinal diverticulum which may function as a weight belt, assisting the young animal to remain in the shifting sandy environment. The sand disappears from the diverticulum when the animal reaches the length of 30 millimeters.


[Regional citrate anticoagulation for continuous renal replacement therapy].
Regional citrate anticoagulation (RCA) is currently the recommended anticoagulation modality for continuous renal replacement therapy. Indeed, compared with systemic heparinization, RCA is associated with a lower risk of bleeding, a longer circuit lifespan and a decrease nursing workload. However, RCA requires a strict protocol to be followed, as it might be associated with potentially severe complications, such as citrate accumulation. Citrate accumulation is rare and usually associated with specific situations : severe circulatory shock, liver failure and mitochondrial dysfunction. According to centers' expertise, these situations might represent contra-indications to RCA. This review presents RCA, its mode of action, associated risks and proposes an algorithm for patients' selection.


Visual laser ablation of the prostate (VLAP): an effective alternative treatment of benign prostatic hyperplasia.
A total of 75 patients suffering from benign prostatic hyperplasia (BHP) were treated with visual laser ablation of the prostate (VLAP) using the Nd-Yag laser. Preoperative evaluation consisted in determination of urinary flow and residual urine, assessment of voiding symptoms and urodynamic evaluation. Postoperatively, the same evaluation was performed at 3 and at 6 months. VLAP is a relatively simple technique with a low perioperative morbidity and short time results are comparable to classical transurethral resection of the prostate. Therefore VLAP seems to be an effective alternative treatment method for BPH which may replace classical transureteral resection of the prostate in a selected number of cases.


Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1.
Adherence of mature Plasmodium falciparum parasitized erythrocytes (PRBCs) to microvascular endothelium contributes directly to acute malaria pathology. We affinity purified molecules from detergent extracts of surface-radioiodinated PRBCs using several endothelial cell receptors known to support PRBC adherence, including CD36, thrombospondin (TSP), and intercellular adhesion molecule 1 (ICAM-1). All three host receptors affinity purified P. falciparum erythrocyte membrane protein 1 (PfEMP1), a very large malarial protein expressed on the surface of adherent PRBCs. Binding of PfEMP1 to particular host cell receptors correlated with the binding phenotype of the PRBCs from which PfEMP1 was extracted. Preadsorption of PRBC extracts with anti-PfEMP1 antibodies, CD36, or TSP markedly reduced PfEMP1 binding to CD36 or TSP. Mild trypsinization of intact PRBCs of P. falciparum strains shown to express antigenically different PfEMP1 released different (125)I-labeled tryptic fragments of PfEMP1 that bound specifically to CD36 and TSP. In clone C5 and strain MC, these activities resided on different tryptic fragments, but a single tryptic fragment from clone ItG-ICAM bound to both CD36 and TSP. Hence, the CD36- and TSP-binding domains are distinct entities located on a single PfEMP1 molecule. PfEMP1, the malarial variant antigen on infected erythrocytes, is therefore a receptor for CD36, TSP, and ICAM-1. A therapeutic approach to block or reverse adherence of PRBCs to host cell receptors can now be pursued with the identification of PfEMP1 as a malarial receptor for PRBC adherence to host proteins.


Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial.
After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN: Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY: BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.


Enveloped virus but not bacteria block IL-13 responses in human cord blood T cells in vitro.
Infections that occur early in life may have a beneficial effect on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4(+) T cell-derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4(+) T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL-5 and IL-13) compared with cord myeloid DC and to adult DC. When adding microbes to these cultures, bacteria and virus differed in two major respects; Firstly, all enveloped viruses, but none of the bacteria, blocked Th2 (IL-13) production by cord CD4(+) cells. Secondly, all Gram-positive bacteria, but none of the virus, induced IL-12p40 responses, but the IL-12p40 responses did not affect Th1 cytokine production (IFN-γ). Instead, Th1 responses were correlated with the capacity to induce IFN-α secretion, which in cord cells were induced by S. aureus and influenza virus alone. These data imply that enveloped virus can deviate Th2 responses in human cord T cells.


Contrast-enhanced ultrasound for imaging blunt abdominal trauma - indications, description of the technique and imaging review.
Patients with blunt abdominal trauma are initially imaged with ultrasound (US) for the evaluation of free abdominal fluid. However, lacerations of solid organs can be overlooked. Although computed tomography (CT) is the gold standard technique for abdominal trauma imaging, overutilization, ionizing radiation, need to transport the patient and potential artifacts are well known disadvantages. Contrast-enhanced US (CEUS) can be used as an imaging tool between the two methods. It can easily and reliably reveal solid abdominal organ injuries in patients with low-energy localized trauma and decrease the number of CT scans performed. It can be rapidly performed at the patient's bedside with no need for transportation. There are only very few contraindications and anaphylactoid reactions are extremely rare. Altogether, CEUS has proved to be very helpful for the initial imaging of traumatic lesions of the liver, kidney and spleen, as well as for patient follow-up.


Effects of 2-nicotinamidethyl nitrate (SG-75) and/or nitroglycerin on systemic hemodynamics and coronary blood flow in conscious dogs.
The effect of 2-nicotinamidethyl nitrate (SG-75), a newly synthesized nitroester, on hemodynamics and coronary circulation was studied in conscious dogs, comparing it with nitroglycerin (NG). Dogs were previously instrumented with catheters in the aorta and left atrium and a Doppler flow probe on the left circumflex coronary artery. Percent increases in coronary flow rate were 11 (10 micrograms/kg), 20 (50 micrograms/kg), 71 (100 micrograms/kg) and 169% (200 micrograms/kg) in SG-75 and 3 (1 microgram/kg), 28 (5 microgram/kg), 65 (10 micrograms kg) and 99% (20 micrograms/kg) in NG, thus the dose ratio for an equivalent increase in mean coronary flow is about 10:1 between SG-75 and NG. The duration of coronary flow increase was also dose dependent and 2.1 min in 200 micrograms/kg SG-75 and 1.3 min in 20 micrograms/kg NG. Comparable changes in heart rate increase and pressure reduction were noted both in SG-75 and NG. The peculiar difference between two drugs was their time course of coronary flow increase: SG-75 showed monophasic increase while NG showed bipeaked increase in flow. The results suggest that the reflex increase in heart rate elicited by pressure drop after SG-75 did not influence the envelope of coronary flow increase such as observed upon NG administration.


Jingzhaotoxin-IX, a novel gating modifier of both sodium and potassium channels from Chinese tarantula Chilobrachys jingzhao.
Tarantula Chilobrachys jingzhao is one of the most venomous species distributed in China. In this study, we have isolated and characterized a novel neurotoxin named Jingzhaotoxin-IX (JZTX-IX) from the venom of the tarantula. JZTX-IX is a C-terminally amidated peptide composed of 35 amino acid residues. The toxin shows 74% sequence identity with CcoTx3 from southeastern Africa tarantula Ceratogyrus cornuatus. JZTX-IX was found to interact with multiple types of ion channels including voltage-gated sodium channels (both tetrodotoxin-resistant and tetrodotoxin-sensitive isoforms) and Kv2.1 channel. The toxin had no effect on delayed rectifier potassium channel Kv1.1, 1.2 and 1.3. JZTX-IX shifted the voltage dependence of channel activation to more positive voltages, but binding of toxin to ion channels was not reversible by extreme depolarization. In addition, JZTX-IX could bias the activities of ion channels towards closed state because the time constant for decay (channel deactivation) of tail currents became faster in the presence of toxin. Taken together with the finding that 10 microM JZTX-IX completely blocked ion channels at resting potential without pulsing, we propose that JZTX-IX is a gating modifier showing low selectivity for ion channel types and trapping voltage sensor at closed state.


Selective Sensing of Phosphates by a New Bis-heteroleptic RuII Complex through Halogen Bonding: A Superior Sensor over Its Hydrogen-Bonding Analogue.
The selective phosphate-sensing property of a bis-heteroleptic RuII complex, 1[PF6 ]2 , which has a halogen-bonding iodotriazole unit, is demonstrated and is shown to be superior to its hydrogen-bonding analogue, 2[PF6 ]2 . Complex 1[PF6 ]2 , exploiting halogen-bonding interactions, shows enhanced phosphate recognition in both acetonitrile and aqueous acetonitrile compared with its hydrogen-bonding analogue, owing to considerable amplification of the RuII -center-based metal-to-ligand charge transfer (MLCT) emission response and luminescence lifetime. Detailed solution-state studies reveal a higher association constant, lower limit of detection, and greater change in lifetime for complex 1 in the presence of phosphates compared with its hydrogen-bonding analogue, complex 2. The 1 H NMR titration study with H2 PO4- ascertains that the binding of H2 PO4- occurs exclusively through halogen-bonding or hydrogen-bonding interactions in complexes 1[PF6 ]2 and 2[PF6 ]2 , respectively. Importantly, the single-crystal X-ray structure confirms the first ever report on metal-assisted second-sphere recognition of H2 PO4- and H2 P2 O72- with 1 through a solitary C-I⋅⋅⋅anion halogen-bonding interaction.


Emerging Roles of miRNAs in Brain Development and Perinatal Brain Injury.
In human beings the immature brain is highly plastic and depending on the stage of gestation is particularly vulnerable to a range of insults that if sufficiently severe, can result in long-term motor, cognitive and behavioral impairment. With improved neonatal care, the incidence of major motor deficits such as cerebral palsy has declined with prematurity. Unfortunately, however, milder forms of injury characterized by diffuse non-cystic white matter lesions within the periventricular region and surrounding white matter, involving loss of oligodendrocyte progenitors and subsequent axonal hypomyelination as the brain matures have not. Existing therapeutic options for treatment of preterm infants have proved inadequate, partly owing to an incomplete understanding of underlying post-injury cellular and molecular changes that lead to poor neurodevelopmental outcomes. This has reinforced the need to improve our understanding of brain plasticity, explore novel solutions for the development of protective strategies, and identify biomarkers. Compelling evidence exists supporting the involvement of microRNAs (miRNAs), a class of small non-coding RNAs, as important post-transcriptional regulators of gene expression with functions including cell fate specification and plasticity of synaptic connections. Importantly, miRNAs are differentially expressed following brain injury, and can be packaged within exosomes/extracellular vesicles, which play a pivotal role in assuring their intercellular communication and passage across the blood-brain barrier. Indeed, an increasing number of investigations have examined the roles of specific miRNAs following injury and regeneration and it is apparent that this field of research could potentially identify protective therapeutic strategies to ameliorate perinatal brain injury. In this review, we discuss the most recent findings of some important miRNAs in relation to the development of the brain, their dysregulation, functions and regulatory roles following brain injury, and discuss how these can be targeted either as biomarkers of injury or neuroprotective agents.


Demonstration of a compact wavelength tracker using a tunable silicon resonator.
Here, we demonstrate a chip-scale integrated optical wavelength tracker with fast response and compact format. By exploiting the electro-optic(EO) effect on a thermally controlled silicon micro-ring resonator filter, the proposed tracker can operate over a wide wavelength range according to the thermo-optic (TO) effect; meanwhile, the tracker's response speed is greatly improved through the EO effect (i.e. tracking within 1 ns), as compared to the traditional TO controlled methods (typical ~10 μs). With the integration of a photodiode onto the photonics chip, the compact chip is with a footprint of 0.5 mm × 1.5 mm. This tracker has potential applications for wavelength tacking in advanced DWDM network systems, tunable laser sources, and high performance optical sensors.


Human resting energy expenditure in relation to dietary potassium.
This study investigates the putative effect of potassium on energy expenditure. Eight young adult men were submitted to two different normocaloric mixed diets in a randomized order, containing either 163 +/- 9 or 69 +/- 2 mmol potassium/d. On the fifth day of each diet, after an overnight fast, resting metabolic rate (RMR) was measured over a 1-h period. After these measurements, either a potassium load (50 mmol) or a placebo were given to subjects submitted to the low- or the high-potassium diet, respectively. RMR was then measured again for 3 h and the last hour was kept for further analysis. Results showed that acute and chronic variations in potassium intake do not induce significant changes in RMR, and chronic but not acute changes in serum potassium concentration were significantly correlated with changes in energy expenditure (r = 0.74, P less than 0.05) by mechanisms that remain to be elucidated.


Magnetic Cellulose-Chitosan Nanocomposite for Simultaneous Removal of Emerging Contaminants: Adsorption Kinetics and Equilibrium Studies.
The presence of pharmaceuticals in water systems threatens both terrestrial and aquatic life across the globe. Some of such contaminants are β-blockers and anticonvulsants, which have been constantly detected in different water systems. Various methodologies have been introduced for the removal of these emerging pollutants from different waters. Among them, adsorption using nanomaterials has proved to be an efficient and cost-effective process for the removal of pharmaceuticals from contaminated water. In this this study, a firsthand/time approach applying a recyclable magnetic cellulose-chitosan nanocomposite for effective simultaneous removal of two β-blockers (atenolol (ATN)) and propranolol (PRP) and an anticonvulsant (carbamazepine (CBZ)) is reported. A detailed characterization of the eco-friendly, biocompatible cellulose-chitosan nanocomposite with magnetic properties was performed at various rates of synthesis using X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), and Fourier transform infrared (FTIR) spectroscopy. A N2c adsorption-desorption test showed that the prepared nanocomposite is mesoporous, with a BET area of 112 m2 g-1. The BET isotherms results showed that the magnetic cellulose-chitosan nanocomposite has a pore size of 24.1 nm. The adsorption equilibrium of PRP and CBZ fitted with the Langmuir isotherm was consistent with the highest coefficient of determination (R2 = 0.9945) and (R2 = 0.9942), respectively, while the Sips model provided a better fit for ATN, with a coefficient of determination R2 = 0.9956. The adsorption rate was accompanied by a pseudo-second-order kinetics. Moreover, the swelling test showed that up to 100 percent swelling of the magnetic cellulose-chitosan nanocomposite was achieved.


Medium-term follow-up on use of freeze-dried, irradiated donor fascia for sacrocolpopexy and sling procedures.
The aim of this study was to document longer-term follow-up of patients in a previously reported series who underwent either sacrocolpopexy (SCP) or suburethral sling procedures utilizing freeze-dried, irradiated donor fascia. Subjects from the initial series of 67 SCPs and 35 slings were included in this retrospective chart review of postoperative follow-up where surgical follow-up longer than 3 months from the procedure was available. Subjects undergoing SCP were examined at the time of any clinical visit and their pelvic organ support evaluated utilizing the POP-Q system. The SCP procedure was considered to be unsuccessful if any anterior vaginal wall point (Aa or Ba) was at the hymen or beyond, or if the vaginal apical point (C or D) descended to a point at least halfway to the hymen from a position of perfect apical support. Subjects who did not return for clinical examination after their 3-month postoperative visit but who had been in telephone contact with the clinic stating that they had experienced symptomatic recurrence of their POP were also included as having unsuccessful SCP procedures. Those similarly in contact with the office by telephone, but not clinically examined, who indicated no subjective return of their POP, were coded as successful. The outcome of the sling procedure was primarily evaluated subjectively, with the patient indicating that stress incontinence symptoms were present or absent. Follow-up was available for 75 patients, who had undergone 54 SCP and 27 sling procedures (6 patients had undergone both SCP and sling procedures). When failure was defined according to any of the criteria listed in the methods section, 45 (83%) patients experienced SCP failure at a median of 12 months after surgery. A total of 14 (52%) sling procedures were failures, with recurrent SUI symptoms experienced from 2 weeks to 24 months (median 3 months) after the procedure. One year after surgery, 23 (43%) SCPs were known to be failures, and 11 (41%) slings were known to be failures. The remaining 13 (48%) slings were subjectively successful when last seen 7-51 months after surgery. We reoperated on 21 (40%) patients. At the time of repeat SCP (chosen by 16 patients) we found graft between the sacrum and vagina in just 3 patients (19%). The use of freeze-dried, irradiated donor fascia for both SCP and sling procedures was associated with an unacceptably high failure rate in our series.


[Gemcitabine concurrent with radiation for locally advanced pancreatic cancer].
Gemcitabine (GEM) concurrent with radiation is clinically not well defined. We herein report four cases of chemo-radiotherapy against locally advanced pancreatic cancer using low-dose GEM concurrent with extra-beam radiation. A total of eight cases entered the study. Three were resected and five were non-resected cases. Intraoperative radiation was carried out in every case using an 8 or 10 centimeter cone with a radiation dose of 25 Gy. Postoperative radiation was 2 Gy per day on weekdays for 5 weeks. Four cases were concurrent with low-dose GEM (40 mg/m2) twice a week, whereas the other four were radiation only. With the use of GEM concurrent with radiation, tumor markers decreased more than 80 percent regardless of the tumor resection. CT scan confirmed a necrotic change and the decrease of the tumor size. In conclusion, low dose GEM concurrent with radiation therapy may be a promising therapeutic choice for the local control of advanced pancreatic cancers.


[Pleurodesis using autologous blood plus OK-432 for intractable spontaneous pneumothorax with high surgical risk].
Air leakage persisted from the lung in three cases of spontaneous pneumothorax. Pleurodesis with autologous blood ended in failure. Autologous blood plus OK-432 was instilled into the thoracic cavity from the chest drainage tube. Air leakage was stopped without serious side effects and the chest tube was removed uneventfully. Although the long-term outcome of this treatment is not known, pleurodesis using autologous blood plus OK-432 may be an effective way of treatment for spontaneous pneumothorax in cases with high surgical risk.


System identification of the low-dose kinetics of p-aminohippuric acid.
The renal clearance of p-aminohippuric acid, due to tubular secretion in addition to glomerular filtration, can only be determined by kinetic experiments. Maximal information can be gained from observed temporal marker concentration profiles by fitting dynamic mathematical models of the processes involved, such as absorption, distribution, and elimination, to the kinetic data. Thereby the values of the system constants, such as fractional elimination or fractional distribution rates, and their accuracy measures are determined by methods which are based firstly on measured time-dependent data elicited in an individual test object by perturbing inputs and secondly, on mathematical formulations of prior knowledge of the underlying physiological system. Such methods of model adaptation are called system identification. In this context a computer-based method of system identification and error estimation for the system constants of two-compartment models matched a dynamic concentration profiles of p-aminohippuric acid is presented. The method is used of single-injection experiments to demonstrate that such a technique is able to correctly estimate the clearance of p-aminohippuric acid if sufficiently long experimental protocols are chosen, and to ascertain the sufficient length of a protocol for an individual subject. The renal clearance of p-aminohippuric acid is known to exhibit concentration-dependence generally, but to achieve its maximal value when low doses are applied. The present study deals with the low-dose kinetics of p-aminohippuric acid.


4-Spiro[2.n]alkyl cations and their rearrangements.
A series of 4-spiro[2.n]alkanols, where n = 3-7, were ionized in either FSO3H x SbF5/SO2ClF or SbF5/SO2ClF at -78 degrees C and -130 degrees C. The resulting solutions were studied by 13C NMR spectroscopy over the temperature range of -130 degrees C to -10 degrees C. The 4-spiro[2.5]octanol gave the expected static 4-spiro[2.5]octyl cation, which can be considered as a long-lived secondary cyclohexyl cation stabilized by an adjacent spirocyclopropane ring. The same spiro[2.5]octyl cation was also obtained by ionization of isomeric bicyclo[4.2.0]octan-1-ol and bicyclo[4.1.0]heptyl-1-methanol. The static spiro[2.5]-octyl cation was found to rearrange to the equilibrating 1-bicyclo[3.3.0]octyl cation above -10 degrees C. On the other hand, the 4-spiro[2.4]heptanol gave the rearranged 1-methylcyclohexenyl cation. The spiro[2.6]nonanol gave directly the equilibrating 1-bicyclo[4.3.0]nonyl cation. The other 4-spiro[2.n]-alkanols (n = 3 and 7) gave unidentifiable polymeric products. The ionization of 3-spirocyclopropyl-2-norbornanol yields only the rearranged 2-methylbicyclo[3.2.1]oct-3-ene-2-yl cation.


Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics.
The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.


Ascorbic acid and copper in linoleate oxidation. 3. Catalysts in combination.
In promoting oxidation of 0.02 m potassium linoleate in a buffered (pH 7.0) aqueous dispersion at 37 degrees C, ascorbic acid at low concentrations (1.8 x 10(-6) and 1.8 x 10(-5) m) in combination with copper (1.3 x 10(-7) to 1.3 x 10(-3) m) had greater catalytic activity than the additive activity of the two catalysts individually. Possible explanations for the enhanced catalysis include reduction of copper by ascorbic acid to the cuprous form, increased concentration of semidehydroascorbic acid radical, and formation of a metal-ascorbic acid-oxygen complex. Some combinations of ascorbic acid (1.8 x 10(-4) and 1.8 x 10(-3) m) and copper (1.3 x 10(-6) and 1.3 x 10(-3) m) inhibited the formation of conjugated dienes but not the oxidation of ascorbic acid, and caused rapid loss of part of the conjugated dienes that were already present. It is suggested that free-radical inhibitors formed by the combination of catalysts inhibit initiation of lipid oxidation but not copper-catalyzed oxidation of ascorbic acid. Effects of the inhibitory combinations on changes in UV absorption by conjugated dienes, and absorbance in the TBA test, indicate the presence of at least two conjugated dienes that differ in stability.


Development and Evaluation of an In-House ELISA to Detect Anti-FcεR1α IgG Autoantibodies in Chronic Spontaneous Urticaria Patients.
Association between chronic spontaneous urticaria (CSU) and autoimmunity has been well documented. Autologous serum skin testing could support the autoimmune etiology of CSU, whereas it is difficult to interpret and could not be performed on antihistamine omitted patients. It was found that immunoglobulin G (IgG) autoantibodies (autoAbs) against high-affinity IgE receptor (FcεR1) were suggested as a potential trigger in the pathogenesis of CSU. Although many ELISA protocols have been developed to detect these autoAbs, they lacked validation or a reliable cut-off point. We, therefore, aimed to develop a validated ELISA with a reliable cut-off point to quantitate IgG anti-FcεR1α autoAbs for CSU. We developed an in-house ELISA to quantitate IgG anti-FcεR1α autoAbs. Sera from 233 CSU patients and 25 healthy people were used to test with ELISA. The cut-off point was obtained from the results subjected to analyze with receiver operating characteristic (ROC) analysis. ELISA was validated with 116 CSU patients and 150 healthy donors. ELISA revealed that healthy people had a basal level of IgG anti-FcεR1α autoAbs, whereas their levels were significantly lower than autoAbs levels in CSU patients. ROC analysis of ELISA determined the cut-off point at 936.7 ng/ml. Our ELISA was validated and provided excellent sensitivity and specificity at 98.28% and 92.67%, respectively. Our ELISA could detect significant levels of IgG anti-FcεR1α autoAbs in CSU, supporting that these autoAbs were associated with CSU etiology. Our validated ELISA with the reliable cut-off point provided excellent accuracy at 95.11% (98.28% sensitivity and 92.67% specificity). Our ELISA could be an alternative test benefit for the patient who is unable to omit antihistamine treatment.


[A questionnaire survey of asthma in children with co-morbid allergic rhinitis].
Bronchial asthma is often complicated with allergic rhinitis (AR). To investigate the relationship between the upper and lower airway diseases in children with asthma, we performed a questionnaire survey at 6 centers in Kinki area in Japan. A questionnaire was filled out by parents of 333 asthmatic children (0-16 years, median age 7). It included questions concerning nasal symptoms, onset ages of rhinitis and asthma, correlation between nasal symptoms and asthma symptoms, and family history of allergic diseases. One hundred and fifty five (46.5%) subjects answered to have any nasal diseases; 20 with sinusitis, 46 with seasonal AR, and 119 (35.7%) with perennial AR. To further clarify the relationship of asthma and concomitant AR, we focused on patients with perennial AR and compared the clinical characteristics with patients with no nasal diseases. Percentage of non-atopic asthma was significantly lower in patients with comorbid AR than those without. Severity of asthma tended to be milder and family history of perennial AR was more often in the former than the latter group. Interestingly, asthmatic children with comorbid AR were more likely to have cold air-induced asthma exacerbations. In the subjects with comorbid AR, concomitant exacerbation of the upper and lower airways occurred in 38.7%. The median age of onset of asthma and nasal symptoms was 2 and 4 years, respectively. In 43.9% of them, upper airway symptoms started either before or simultaneously with asthma. The attention should be paid to the nasal symptoms in children with asthma, especially they have atopic asthma and positive family history of perennial allergic rhinitis. It is important that an appropriate diagnosis and treatment of nasal symptoms to better control asthma in children.


Classifying Crystals of Rounded Tetrahedra and Determining Their Order Parameters Using Dimensionality Reduction.
Using simulations we study the phase behavior of a family of hard spherotetrahedra, a shape that interpolates between tetrahedra and spheres. We identify 13 close-packed structures, some with packings that are significantly denser than previously reported. Twelve of these are crystals with unit cells of N = 2 or N = 4 particles, but in the shape regime of slightly rounded tetrahedra we find that the densest structure is a quasicrystal approximant with a unit cell of N = 82 particles. All 13 structures are also stable below close packing, together with an additional 14th plastic crystal phase at the sphere side of the phase diagram, and upon sufficient dilution to packing fractions below 50-60% all structures melt. Interestingly, however, upon compressing the fluid phase, self-assembly takes place spontaneously only at the tetrahedron and the sphere side of the family but not in an intermediate regime of tetrahedra with rounded edges. We describe the local environment of each particle by a set of l-fold bond orientational order parameters q̅l, which we use in an extensive principal component analysis. We find that the total packing fraction as well as several particular linear combinations of q̅l rather than individual q̅l's are optimally distinctive, specifically the differences q̅4 - q̅6 for separating tetragonal from hexagonal structures and q̅4-q̅8 for distinguishing tetragonal structures. We argue that these characteristic combinations are also useful as reliable order parameters in nucleation studies, enhanced sampling techniques, or inverse-design methods involving odd-shaped particles in general.


Increased endothelin-1 production in diabetic patients after cardioplegic arrest and reperfusion impairs coronary vascular reactivity: reversal by means of endothelin antagonism.
Evidence has accrued to suggest that diabetic patients face an increased risk of ischemic events and low output syndrome and might mount an inordinate response to ischemia and reperfusion. Because hyperglycemia is a potent stimulus for endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 in diabetes might represent an important mediator of endothelial dysfunction in patients with that disease. To this aim, we compared the effects of cardioplegic arrest and reperfusion on coronary sinus effluent endothelin-1 levels and atrial arteriolar vascular responses in diabetic and case-matched nondiabetic patients undergoing coronary artery bypass grafting. In study 1 coronary sinus effluent endothelin-1 levels were assessed at baseline and at 1 and 10 minutes after reperfusion in 13 diabetic and 12 nondiabetic patients matched for age, ejection fraction, Parsonnet score, and crossclamp time. In study 2 vascular responses of atrial arterioles subjected to perioperative ischemia-reperfusion were evaluated with videomicroscopy. Atrial microvessels (from appendages) were obtained before and after removal of the aortic crossclamp, and vascular responses to exogenously administered endothelin-1 (10(-10) mol/L) and substance P (10(-8) mol/L) were studied in the presence or absence of BQ-123, an endothelin A receptor antagonist. Diabetic patients elaborated more endothelin-1 at 1 and 10 minutes after reperfusion (P =.01). Endothelin-1-mediated vasoconstriction was similar in diabetic and nondiabetic atrial microvessels before cardioplegic arrest and cardiopulmonary bypass. After cardiopulmonary bypass and reperfusion, endothelin-1-mediated vasoconstriction was enhanced in both groups; however, this response was greater in microvessels from diabetic patients (P =.02). BQ-123, the endothelin A antagonist, attenuated the effects of bypass and reperfusion on endothelin-1-mediated vasoconstriction in both groups (P =.01). Substance P-mediated vasodilatation was similar in diabetic and nondiabetic atrial microvessels before bypass. After bypass and reperfusion, substance P-mediated vasodilatation was diminished in both groups; however, this response was more pronounced in the diabetic group (P =.003). BQ-123 coincubation restored substance P-mediated vasodilatation in both groups. We determined the following: (1) the coronary effluent release of endothelin-1 is higher in diabetic than in nondiabetic patients after cardiopulmonary bypass and reperfusion; (2) diabetic coronary microvessels respond to bypass and reperfusion with greater endothelin-1-mediated vasoconstriction and diminished nitric oxide-mediated vasodilatation; and (3) these effects are attenuated by endothelin antagonism. Endothelin-1 might be an important mediator of ischemia-reperfusion injury in patients with diabetes. Furthermore, use of endothelin receptor antagonists might be a novel strategy for improving the resistance of the diabetic heart to cardioplegic arrest and reperfusion.


BRAF V600K vs. BRAF V600E: a comparison of clinical and dermoscopic characteristics and response to immunotherapies and targeted therapies.
A number of mutations related to malignant melanoma (MM) have been identified, and of the mutated genes, BRAF has been found to be altered in > 50% of cases. Most of these have been BRAF V600E mutations, whereas the incidence of BRAF V600K may vary from 10% to 30%. Little is known about the clinical prognostic correlations of BRAF V600K MMs. We evaluated the clinical and dermoscopic features, incidence, therapy response and outcomes in the medium to long term. To compare the clinical and dermoscopic characteristics, the response to systemic therapies and the prognosis among MMs with BRAF V600E and BRAF V600K mutations. We retrieved the data of patients tested in our centre for MM from 2012 to 2015, including clinical features, dermoscopic pictures, clinical history and tumour mutations. Only patients with BRAF V600E and BRAF V600K mutations were included. Any MMs positive for BRAF V600K mutation were collected, and the number of V600K cases and their features were used to extract the same number of patients with BRAF V600E from our database using a matching method. The clinical and dermoscopic presentation, therapy response and disease progression of the two groups were then evaluated. In total, 132 cases of BRAF V600E-mutated MMs were identified, and then randomized with a propensity-score method to match the 10 retrieved cases of BRAF V600K mutation. Both groups had a nodular appearance to the tumours and an advanced disease stage, and no significant differences in dermoscopic features were highlighted. During the follow-up period, four patients with BRAF V600K died of disease-specific causes. Moreover, we found a higher frequency of metastasis, a faster disease progression and more rapid mortality in patients with BRAF V600K. Despite the small size of this study, the results show similar clinical and dermoscopic characteristics between V600E and V600K mutations, but compared with BRAF V600E MMs, BRAF V600K MMs seem to be less responsive to therapy and have a worse prognosis.


Evaluation of the impact of the natural forest protection program on rural household livelihoods.
In this study, we estimated the impact on local household livelihoods of the Natural Forest Protection Program (NFPP), which is the largest logging-ban program in the world, which aims to protect watersheds and conserve natural forests. In doing so, we used a series of microeconometric policy-evaluation techniques to assess the impacts of the NFPP on two interrelated facets of household livelihoods: income and off-farm labor supply. We found that the NFPP has had a negative impact on incomes from timber harvesting but has actually had a positive impact on total household incomes from all sources. Furthermore, we found that off-farm labor supply outside the village has increased more rapidly in NFPP than in non-NFPP areas. Based on these results, policy implications for household livelihoods were drawn and are presented herein.


Reverse transcription - 3' rapid amplification of cDNA ends-nested PCR of ACT1 and SAP2 mRNA as a means of detecting viable Candida albicans in an in vitro cutaneous candidiasis model.
The presence of viable cells of Candida albicans, in broth or in a reconstructed living skin equivalent, was determined by the detection of amplicons of partial mRNA sequences of the genes encoding fungal actin (ACT1) and secreted aspartyl proteinase 2 (SAP2). The mRNA of both genes were amplified by reverse transcription-3' rapid amplification of cDNA ends-nested polymerase chain reaction. Single bands of ACT1 (315 bp) and SAP2 (162 bp) mRNA were amplified from total RNA extracts of C. albicans grown in yeast carbon base-albumin broth or in living skin equivalent tissue; only the former was amplified from Sabouraud broth-grown organisms. Primer pairs targeted for ACT1 and SAP2 were Candida genus-specific and C. albicans-specific, respectively. The sensitivity limits of the assay were 100 fg of total RNA or 10 cells of C. albicans, by ethidium bromide staining. When C. albicans-infected living skin equivalent was exposed to amorolfine, amplicons of ACT1 and SAP2 mRNA were not detected in total RNA extracts. Non-amplification of the mRNA correlated with the absence of C. albicans growth in Sabouraud agar cultures of living skin equivalent samples. Reverse transcription-3' rapid amplification of cDNA ends-nested polymerase chain reaction of the mRNA encoding specific proteins of an organism has potential application in determining the viability of the organism in tissue, thus monitoring the efficacy of an antimicrobial therapy, and in detecting mRNA expressed in very little amounts in tissue.


[Changes in laboratory parameters of peripheral blood reflect cell and protein content of the immune system in bone resorption].
The aim of this study was to investigate dynamic changes in the laboratory parameters of peripheral blood, reflecting cellular and protein composition of the immune system in bone resorption. The study involved 108 patients with degenerative-dystrophic and posttraumatic disorders of the hip joint before and after joint replacement surgery. Half of the cases resulted in bone resorption. Dynamic monitoring was performed up to 7.5 years. It included flow cytometry (Coulter Epics XL, USA) and enzyme immunoassay to determine the amount of immunocompetent cells, immunoglobulin class M, A, G, E, cytokines, acute phase proteins (C-reactive protein, fibrinogen, albumin, ceruloplasmin, haptoglobin), parameters of neutrophil functional activity (lactoferrin cationic protein, myeloperoxidase, superoxide anion production). The results of the study revealed the leading role of haptoglobin, albumin, and IL-1b in bone resorption. The use of multiple regression analysis made it possible to propose criteria for prediction of bone resorption. In particular, the Ig G concentration one month after operation at a value of 13 or less g/l with a probability of 86.8% suggests a high risk of bone tissue destruction in the operated area of the joint (diagnostic sensitivity and diagnostic specificity of 85.7% and 86.9%, respectively). Determination of the IL-1b level also has a good predictive power: its concentration exceeding 191.2 pg/ml six month after surgery with the probability of 87.4% suggests destruction of bone tissue in the operated area of the joint (diagnostic sensitivity and diagnostic specificity of 87.2% and 88.1%, respectively).


Prediction of diagnosis in acute and subacute oligoarthritis of unknown origin.
A total of 146 consecutive patients between 18 and 60 yr of age with oligoarthritis of unknown origin (< or = 6 active joints, < or = 8 weeks duration) were examined by a variety of clinical, laboratory and microbiological investigations, and followed longitudinally for 24 weeks. Reactive arthritis was diagnosed in 46 patients (19 induced by Chlamydia trachomatis, 27 by enterobacteria), 62 had undifferentiated arthritis, eight other inflammatory arthritic diseases, 15 acute sarcoid arthritis and 15 non-inflammatory joint diseases. Group differences were found for many baseline variables, but with considerable overlap between the groups. A set of four clinical and laboratory variables (elevated CRP, genitourinary symptoms, metatarsophalangeal joint involvement. HLA B27) could predict reactive arthritis with a sensitivity of 69.2% and a specificity of 93.5%. A wide range of clinical and laboratory examinations are required to determine the final diagnosis in oligoarthritis, but individual and sets of clinical and laboratory measures may give helpful clues for the correct diagnosis.


Understanding COVID-19 Vaccine Hesitancy Among Students in Health Professions: A Cross-Sectional Analysis.
Vaccine hesitancy (VH), delay in acceptance, and/or refusal to vaccinate is influenced by complacency, confidence, unmet safety, and efficacy concerns. A survey was conducted among U.S. healthcare students to identify factors contributing to COVID-19 vaccine hesitancy. The World Health Organization 2014 vaccine hesitancy guidelines informed development of a 37-item survey. This cross-sectional survey was distributed to students in 10 randomly selected nursing, pharmacy, and medical programs. Descriptive statistics and logistic regression were used to identify factors contributing to COVID-19 vaccine hesitancy. Of the 902 participants who started the survey, 398 completed all COVID-19 questions. Survey respondents were primarily from private schools (84%) and consisted of medical students (49%), female (71%), and millennials (57%). Students believed COVID-19 vaccine was important and protection of vulnerable communities more important than individual protection. Students in general agreed getting the vaccine was necessary to protect others (school and healthcare facilities) (77.4%); only one-third (33.7%) disagreed that they planned to wait and want to see how vaccine affected others before receiving it. Logistic regression results suggest significant differences based on program and political affiliation. Engagement of healthcare students may help reach student peers who are vaccine hesitant and help reduce the spread of COVID-19.


Long-term surveillance of liver histological changes in chronic hepatitis C patients completing pegylated interferon-α plus ribavirin therapy: an observational cohort study.
For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored. This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63-7.54). In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n = 77), cases achieving sustained virological response (SVR) (n = 52) had a significantly lower rate of fibrosis progression than non-SVR cases (n = 25) (3.8% versus 24.0%, p = 0.012). Among the entire cohort (n = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases (n = 59) was significantly higher than that in non-SVR cases (n = 26) (94.9% versus 65.4%, p = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p = 0.049) and activity response (OR = 17.741, p = 0.047), respectively. Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment.


A case of truncus arteriosus type II.
A case of truncus arteriosus type II is reported. Truncus arterious is an uncommon congenital cardiac defect where a single great vessel exits the heart. Truncus arteriosus is usually fatal, if untreated. This defect occurs when the conus arteriosus and the truncus divide erroneously in the embryo. Palliative surgery in truncus arteriosus has been unsuccessful. Pulmonary banding has been tried and was ineffective and usually fatal. We operated on a nine-month-old (6200 g) male infant with a type II (Edwards-Collett) defect and a large ventricular septal defect. The pulmonary artery average pressure was 51 mmHg. We performed a cardiopulmonary bypass in the usual manner. Pulmonary arteries were resected from the truncal root, and primary end-to-end anastomosis of the truncal root to the ascending aorta was performed. Right ventricle to pulmonary artery continuity was provided using a valveless Gore-Tex graft. We lost our patient due to intractable pulmonary hypertension on the first postoperative day.


[Treatment of Graves' disease].
This is a commentary on a retrospective study on the pros and cons of the treatment options in new-onset Graves' hyperthyroidism, including antithyroid drugs, radioactive iodine treatment and thyroidectomy. We discuss a number of methodological concerns limiting the interpretability and clinical impact of this study. We furthermore provide a short overview of the current state of the field and knowledge gaps.


Randomized controlled trial of a dose consolidation program.
To evaluate the effectiveness and financial impact of a drug dose consolidation (optimization) program using letter intervention. This pilot program in a large, mid-Atlantic health plan utilized a randomized controlled trial research design. A review of adjudicated pharmacy claims records was performed monthly for 3 consecutive months from November 2002 through February 2003 to identify inefficient (i.e., >once-daily) regimens for any one of 68 dosage strengths of 37 single-source maintenance drugs with once-daily dosing recommendations. Prescribers who had prescribed one or more inefficient regimens were identified and randomized to one of the 2 intervention arms or a control arm. Prescribers in both intervention arms were sent personalized letters with information on their patients. inefficient regimens and suggested dose consolidation options. Patients of prescribers in one intervention arm received a complementary, patient-oriented letter. Pharmacy claims for patients in all arms were examined at 180 days after the date of the letter mailing for conversion to an efficient (once-daily) regimen. Financial modeling analysis calculated net savings as changes in pharmacy expenditures minus administrative costs. A total of 2,614 inefficient regimens, representing 6.7% of claims for the targeted medications, were identified. The rate of consolidation to a suggested dosing option was lower for the Physician Letter arm (7.3%) than for the Physician/Member Letter arm (10.2%) (P = 0.046). Both intervention arms had higher consolidation rates than the Control arm (3.9%) (P = 0.018 and P = 0.000, respectively.). Approximately 30% of the regimens in each study arm were never refilled after being targeted. Financial modeling indicated that a dose consolidation intervention could save 0.03 dollars to 0.07 dollars per member per month (PMPM) in 2003 dollars with full medication compliance but only 0.02 dollars to 0.03 dollars PMPM when savings were calculated with realistic, partial compliance rates. Subanalyses performed at the drug therapy class level revealed few opportunities to justify implementing a dose consolidation program. After taking into consideration program administrative costs, high rates of refill discontinuation, and dose consolidation that occurs naturally without intervention, the results indicated that a letter-based dose consolidation program did not appreciably decrease pharmacy expenditures.


Impact of the Quality of Postpartum Sleep and its Health Determinants on Human Milk Volume.
To examine the impact of postpartum sleep disturbance on 24-hour milk volume and breastfeeding during the early postpartum period. Factors associated with postpartum sleep disturbance also were examined. A descriptive, correlational design was used. The sample included 29 first-time mothers exclusively breastfeeding healthy, full-term newborns. A home visit was conducted to collect self-report data for sleep, stress, fatigue, depression, and anxiety at 2 weeks postpartum. Infant test weights as an estimate of 24-hour milk volume also were performed. At 1 month, a phone interview was conducted for breastfeeding status. Pearson's correlation and hierarchical regression were used for data analysis. All mothers were breastfeeding at 2 weeks and at 1 month postpartum. Most (69.2%) reported significant sleep disturbance. Higher degree of stress was associated with more disturbed sleep (β = .59, p = .001), and sleep disturbance was associated with more symptoms of fatigue (r = .70, p = - .001), depression (r = .58, p = .001), and anxiety (r = .52, p = - .01). Poor sleep quality was the only significant predictor for lower milk volume (β = - .70, p = .02). Clinically significant sleep disturbance is common during the early postpartum period and may have a negative impact on human milk production and other important maternal health indicators. A better understanding of postpartum sleep disturbance and its impact on breastfeeding and maternal health is needed.


Variations in Genes Related to Sleep Patterns in Children With Autism Spectrum Disorder.
Sleep disturbance is a frequent comorbidity in children with autism spectrum disorder (ASD), affecting an estimated 40-80% of cases. Previous reports have shown relationships between several circadian rhythm-related genes and sleep problems in ASD. The purpose of the present study was to relate variation in and around melatonin synthesis and suprachiasmatic nucleus genes to sleep problems in a large sample of children with ASD. This secondary analysis used existing genotypic and phenotypic data for 2,065 children, aged 4-18 years, from the Simons Simplex Collection (SSC). Sleep problems were measured with the SSC Sleep Interview. Expression quantitative trait loci and single nucleotide polymorphisms in 25 circadian genes were chosen primarily for their impact on expression levels of target genes in the brain. Associations between variants and composite sleep problems, nighttime problems, daytime problems, and sleep duration problems were calculated using logistic regression analysis. Age, sex, nonverbal IQ, ASD severity, gastrointestinal distress, seizures, and ancestry were included as covariates. Transmission disequilibrium tests were performed to test for overtransmission of alleles in the same variants. No significant associations or transmission disequilibrium were found between gene variants and sleep problems in this sample of children with ASD. Variation in expression of investigated genes in the melatonin synthesis and suprachiasmatic nucleus pathways did not have notable impacts on sleep problems in this large sample of children with ASD. Future research could explore translational and posttranslational effects of these genes or the effects of genes in other sleep-homeostasis pathways on sleep patterns.


A high-current electron gun for the electron beam ion trap at the National Superconducting Cyclotron Laboratory.
The Electron Beam Ion Trap (EBIT) in NSCL's reaccelerator ReA uses continuous ion injection and accumulation. In order to maximize capture efficiency and minimize breeding time into high charge states, the EBIT requires a high-current/high current-density electron beam. A new electron gun insert based on a concave Ba-dispenser cathode has been designed and built to increase the current transmitted through the EBIT's superconducting magnet. With the new insert, stable EBIT operating conditions with 0.8 A of electron beam have been established. The design of the electron gun is presented together with calculated and measured perveance data. In order to assess the experimental compression of the electron beam, a pinhole CCD camera has been set up to measure the electron beam radius. The camera observes X-rays emitted from highly charged ions, excited by the electron beam. Initial tests with this camera setup will be presented. They indicate that a current density of 640 A/cm(2) has been reached when the EBIT magnet was operated at 4 T.


[Plasma homocysteine concentration in patients with ischaemic stroke caused by large or small vessel disease].
Homocysteine is known risk factor for the development of atherosclerosis, but its contribution to the different etiologies of ischaemic stroke remains unclear. Comparison of homocysteine, folic acid and vitamin 812 plasma concentrations in patients with ischaemic stroke due to large vessel disease (LVD), small vessel disease (SVD) and in controls. We studied 71 patients with ischaemic stroke (including 30 patients with LVD and 41 patients with SVD) as well as 30 control subjects. Aetiology of ischaemic stroke was established according to the TOAST criteria using computed tomography of the head, EKG, carotid ultrasound and echocardiography. In patients being 3-12 months after stroke we registered age, sex and the presence of common risk factors for stroke. The serum concentrations of homocysteine, folic acid, and vitamin 812 were measured in venous blood samples drawn after the overnight fasting. Serum homocysteine concentrations were similar in patients with LVD, SVD, and in controls (19.5 +/- 8.9, 18.6 +/- 6.6, and 16.8 +/- 6.4 micromol/l, respectively) (p = 0.36, ANOVA). Vitamin 812 concentrations did not differ significantly among patients with LVD, SVD, and in controls (377 +/- 143, 414 +/- 179, and 412 +/- 173 pg/ml, respectively) (p = 0.66, ANOVA). Patients with LVD, SVD, and controls were also similar regarding the concentrations of folic acid (7.1 +/- 4.0, 6.4 +/- 2.7, and 7.6 +/- 4.0 ng/ml, respectively) (p = 0.38, ANOVA). Serum concentrations of homocysteine, vitamin 812, and folic acid are similar in patients with stroke due to LVD, SVD, and in control subjects.


Solid waste management practices in wet coffee processing industries of Gidabo watershed, Ethiopia.
The financial and social contributions of coffee processing industries within most coffee export-based national economies like Ethiopia are generally high. The type and amount of waste produced and the waste management options adopted by these industries can have negative effects on the environment. This study investigated the solid waste management options adopted in wet coffee processing industries in the Gidabo watershed of Ethiopia. A field observation and assessment were made to identify whether the operational characteristics of the industries have any effect on the waste management options that were practiced. The investigation was conducted on 125 wet coffee processing industries about their solid waste handling techniques. Focus group discussion, structured questionnaires, key informant interview and transect walks are some of the tools employed during the investigation. Two major types of wastes, namely hull-bean-pulp blended solid waste and wastewater rich in dissolved and suspended solids were generated in the industries. Wet mills, on average, released 20.69% green coffee bean, 18.58% water and 60.74% pulp by weight. Even though these wastes are rich in organic matter and recyclables; the most favoured solid waste management options in the watershed were disposal (50.4%) and industrial or household composting (49.6%). Laxity and impulsive decision are the driving motives behind solid waste management in Gidabo watershed. Therefore, to reduce possible contamination of the environment, wastes generated during the processing of red coffee cherries, such as coffee wet mill solid wastes, should be handled properly and effectively through maximisation of their benefits with minimised losses.


Importance of within subject variation in levodopa pharmacokinetics: a 4 year cohort study in Parkinson's disease.
The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson's disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72 hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V1), peripheral volume (V2), clearance (CL) and inter-compartmental clearance (CL(ic)) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V2 27.3 l/70 kg (0.27), and CL(ic) 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V1, 0.13 CL, 0.15 V(2), 0.28 CL(ic), within trial variability (WTV) which was 0.16 V1, 0.13 CL, 0.08 V2, 0.18 CL(ic) and between trial variability (BTV) which was 0.40 V1, 0.17 CL, 0.21 V2, 0.34 CL(ic.) Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.


Lack of effect of a purified bran preparation in men with low HDL cholesterol.
In 21 men who had been on a lipid-lowering diet for several years, the serum triglyceride and cholesterol levels had become normal on that treatment. In spite of this they all had low levels of cholesterol in the high density lipoproteins (HDL). In an effort to normalize this they were given a purified concentrated bran product (FiberformR, 3.5 g) three times daily for 6 weeks. The cross-over study was double-blind, placebo-controlled, and with a wash-out period between the treatment periods. There were no statistically significant changes in body weight, serum triglycerides and cholesterol or HDL triglycerides and cholesterol in association with the bran treatment. It is concluded that wheat bran in moderately large doses that are convenient to take does not offer a therapeutic alternative for increasing subnormal HDL cholesterol levels in normocholesterolaemic men.


Klumpfuss controls FMRFamide expression by enabling BMP signaling within the NB5-6 lineage.
A number of transcription factors that are expressed within most, if not all, embryonic neuroblast (NB) lineages participate in neural subtype specification. Some have been extensively studied in several NB lineages (e.g. components of the temporal gene cascade) whereas others only within specific NB lineages. To what extent they function in other lineages remains unknown. Klumpfuss (Klu), the Drosophila ortholog of the mammalian Wilms tumor 1 (WT1) protein, is one such transcription factor. Studies in the NB4-2 lineage have suggested that Klu functions to ensure that the two ganglion mother cells (GMCs) in this embryonic NB lineage acquire different fates. Owing to limited lineage marker availability, these observations were made only for the NB4-2 lineage. Recent findings reveal that Klu is necessary for larval neuroblast growth and self-renewal. We have extended the study of Klu to the well-known embryonic NB5-6T lineage and describe a novel role for Klu in the Drosophila embryonic CNS. Our results demonstrate that Klu is expressed specifically in the postmitotic Ap4/FMRFa neuron, promoting its differentiation through the initiation of BMP signaling. Our findings indicate a pleiotropic function of Klu in Ap cluster specification in general and particularly in Ap4 neuron differentiation, indicating that Klu is a multitasking transcription factor. Finally, our studies indicate that a transitory downregulation of klu is crucial for the specification of the Ap4/FMRFa neuron. Similar to WT1, klu seems to have either self-renewal or differentiation-promoting functions, depending on the developmental context.


Real-world effectiveness of airway clearance techniques in children with cystic fibrosis.
Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean±sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV1) (mean effect size 0.23 (95% CI 0.19-0.27) FEV1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV1 between them (mean effect size 0.02 (95% CI -0.01-0.05) FEV1 % pred per treatment). ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.


Dreaming in agenesis of the corpus callosum: laboratory and home assessment of four cases.
Laboratory and home dream recall was studied in four subjects with agenesis of the corpus callosum and in four control subjects who were matched for age, gender, and handedness. In addition, the structural and emotional content of home dreams was compared for these two groups. Results indicate that acallosal subjects recalled fewer dreams in the laboratory than did control subjects, but recalled the same number of dreams at home. They also reported more contentless dreams in both situations. Furthermore, although acallosal subjects used fewer words to describe their dream content in both contexts, the number of content categories they reported differed little from the number reported by control subjects. However, some trends were found for acallosal's home dreams to differ from those of controls, i.e. more dreams with known characters and fewer dreams with unknown characters, animals, and colours. Differences in emotional contents were few; acallosals reported more distress than controls. The shorter length of acallosals' dreams might be explained, in part, by their lower verbal IQs. Other characteristics of dream content (e.g. more distress, fewer dreams with unknown and animal characters) may reflect limited social experiences in this group. However, the greater frequency of contentless dreams and the lower frequency of dreams with colour are trends consistent with the possibility that the corpus callosum may be implicated in processes of dream production and dream recall.


Cutaneous Intravascular NK/T-cell lymphoma mimic panniculitis clinically, case report and literature brief review.
Intravascular large cell lymphoma is a rare subtype of extranodal large cell lymphoma characterized by the presence of neoplastic cells within the lumina of small vessels. Most cases of intravascular large cell lymphoma have a B-cell phenotype. To date, 12 cases of intravascular natural killer (NK/)/T-cell lymphoma (IVNKL) have been reported. Our case is A 47-year-old female presented with erythematous patches and plaques on the lower extremities mimicking panniculitis clinically. A skin biopsy revealed intravascular lymphoma (IVL) with a NK/T cell phenotype (positive for CD3, and granzyme B and negative for CD20, CD4, CD8, CD5). The lymphoma cells were also positive for Epstein-Barr virus by Epstein-Barr virus-encoded RNA in situ hybridization test. Because this type of lymphoma is extremely rare, our case is documented and compared with the previously reported cases.


Gut Fermentation of Dietary Fibres: Physico-Chemistry of Plant Cell Walls and Implications for Health.
The majority of dietary fibre (DF) originates from plant cell walls. Chemically, DF mostly comprise carbohydrate polymers, which resist hydrolysis by digestive enzymes in the mammalian small intestine, but can be fermented by large intestinal bacteria. One of the main benefits of DF relate to its fermentability, which affects microbial diversity and function within the gastro-intestinal tract (GIT), as well as the by-products of the fermentation process. Much work examining DF tends to focus on various purified ingredients, which have been extracted from plants. Increasingly, the validity of this is being questioned in terms of human nutrition, as there is evidence to suggest that it is the actual complexity of DF which affects the complexity of the GIT microbiota. Here, we review the literature comparing results of fermentation of purified DF substrates, with whole plant foods. There are strong indications that the more complex and varied the diet (and its ingredients), the more complex and varied the GIT microbiota is likely to be. Therefore, it is proposed that as the DF fermentability resulting from this complex microbial population has such profound effects on human health in relation to diet, it would be appropriate to include DF fermentability in its characterization-a functional approach of immediate relevance to nutrition.


Determination of amines in the presence of excess ammonia by ion chromatography-mass spectrometry.
A new method for the simultaneous determination of several amines in the presence of an excess of ammonia by ion chromatography-mass spectrometry detection was developed. Current methods using ion chromatography with suppressed conductivity detection are not selective enough to determine small amines at the required level of 10 microg/L or preferably lower in the presence of a large excess of ammonia (approximately 1 mg/L) without resorting to time-consuming sample pre-treatment techniques. By using mass spectrometric detection, which is capable of resolving eluting compounds on their m/z values, an additional dimension of confirmation is added to the analysis. Detection based on the analytes m/z value overcomes problems such as co-elution or background interferences that complicate the quantification when using conductivity detection. The optimal conditions for mass spectrometry detection of amines in the presence of an excess of ammonia were investigated by a four-factor central composite design. The four factors investigated were scan time, cone voltage, probe temperature, and needle voltage. Evaluation of the obtained experimental data showed that detection limits were up to a factor of 100 lower when using mass spectrometry as the detection technique instead of the conventional suppressed conductivity detection. Detection limits of 1 microg/L and lower can be achieved for the six amines investigated in the presence of a large excess of ammonia (approximately 1 mg/L).


The photoluminescent graphene oxide serves as an acceptor rather than a donor in the fluorescence resonance energy transfer pair of Cy3.5-graphene oxide.
We have systematically studied the fluorescence resonance energy transfer (FRET) efficiency between the photoluminescent graphene oxide (GO) and Cy3.5 dye by controlling the donor-acceptor distance with a double stranded DNA and demonstrated that the GO serves as an acceptor rather than a donor in this FRET system.


Palladium-catalyzed isobenzofuran generation under neutral conditions via oxidative addition to lactol methyl ether.
A novel method for generation of isobenzofuran is developed from lactol methyl ether using palladium catalysts. This reaction can be carried out under neutral conditions and hence improves on the precedent methods under acidic or basic conditions and at high temperatures. Furthermore, this Pd-catalyzed isobenzofuran generation suggests the involvement of oxidative addition of Pd catalyst into benzylic or allylic methyl ethers. [reaction: see text]