Exploiting sparseness in de novo genome assembly.
The very large memory requirements for the construction of assembly graphs for de novo genome assembly limit current algorithms to super-computing environments. In this paper, we demonstrate that constructing a sparse assembly graph which stores only a small fraction of the observed k-mers as nodes and the links between these nodes allows the de novo assembly of even moderately-sized genomes (~500 M) on a typical laptop computer. We implement this sparse graph concept in a proof-of-principle software package, SparseAssembler, utilizing a new sparse k-mer graph structure evolved from the de Bruijn graph. We test our SparseAssembler with both simulated and real data, achieving ~90% memory savings and retaining high assembly accuracy, without sacrificing speed in comparison to existing de novo assemblers.


Non-invasive monitoring of adrenocortical physiology in a threatened Australian marsupial, the western quoll (Dasyurus geoffroii).
Reintroduction has become an increasingly important conservation tool in Australia, yet the effects of stress on species during reintroduction programs have received little attention. The use of enzyme immunoassays to measure faecal glucocorticoid metabolites (FGM) is a useful non-invasive technique to monitor adrenal activity but requires validation before they can be reliably used. As part of a large reintroduction project, the goals of this study were to 1) monitor FGM in 53 western quolls (Dasyurus geoffroii) following capture from the wild and transfer to a holding facility and use this stressor to biologically validate an enzyme immunoassay; 2) determine if biological factors, such as sex, age, weight or source population affect baseline FGM levels; and 3) examine individual variation in the acute adrenal response of quolls to the capture and transfer associated with reintroductions. We successfully validated an assay that targets glucocorticoid metabolites with a 5α-3β,11β-diol structure and found that sex significantly influenced both baseline and peak FGM output in western quolls, whereas age, weight and source population did not. We also observed considerable variation among individuals in the magnitude and duration of their physiological response to capture and transfer. Using the methods described here, FGM analysis may provide further information about the adrenal activity of the western quoll and improve future conservation efforts for this threatened species.


Association of maternal D-dimer level in late pregnancy with birth outcomes in a Chinese cohort.
To investigate the association of D-dimer level during late pregnancy with birth outcomes in a Chinese population. A retrospective observational cohort study of 11,570 pregnant women who delivered in a single central hospital was conducted. Maternal plasma D-dimer levels at hospital admission and pregnancy outcomes were abstracted and analyzed from laboratory information system and hospital records, respectively. Maternal plasma D-dimer levels were associated with higher fetal growth indicators for the highest vs. lowest quartile (Q) of D-dimer (mean birth weight: 145.79 g, mean birth length: 0.11 cm, mean gestational age: 0.30 week). Increase in D-dimer quartiles were associated with an decreased risk for small for gestational age (SGA), low birth weight (LBW) and preterm birth (PTB) neonates, and with an increased risk for large for gestational age (LGA), and macrosomia infants (SGA: OR = 0.52, 95% CI: 0.43, 0.64; LBW: OR = 0.58, 95% CI: 0.38, 0.86; PTB: OR = 0.44, 95% CI: 0.35, 0.55; LGA: OR = 2.37, 95% CI: 2.01, 2.78; macrosomia: OR = 2.59, 95% CI, 2.06, 3.24; for Q4 vs. Q1). Maternal plasma D-dimer levels during late pregnancy were associated with birth outcomes and had risk evaluation value for these outcomes.


Orientation to time as a guide to the presence and severity of cognitive impairment in older hospital patients.
Testing of orientation to time is an important part of mental status examination. The validity of errors in different aspects of temporal orientation was examined in older hospital patients as a guide to the presence of dementia or delirium and as a measure of the severity of dementia, as defined by the Global Deterioration Scale. Inpatients and outpatients attending an acute hospital underwent independent assessments by two doctors on the same day to determine orientation to time and cognitive status. Optimum cut-offs for error scores on the different aspects of temporal orientation were calculated to maximise the sum of sensitivity and specificity for detection of dementia or delirium. Of the 262 patients assessed, 62 (23.7%) had dementia or delirium. The best cut-offs for detection of these disorders were: any error in identifying the year, month, day of the month or day of the week; and an error of more than 1 h in identifying the time of day. Failure to identify the year correctly was the most valuable single sign of dementia or delirium (sensitivity 86% and specificity 94%); failure to identify either year or month correctly was 95% sensitive and 86.5% specific for the detection of cognitive impairment. Severity of temporal disorientation, measured using a number of approaches, was strongly associated with severity of dementia. Disorientation to time is a useful guide to the presence and severity of dementia or delirium in older hospital patients. Failure to identify the year or month correctly is a sufficiently sensitive and specific indicator of dementia or delirium to warrant more detailed cognitive assessment in this population.


Elements of Successful Food Sovereignty Interventions within Indigenous Communities in the United States and Canada: a Systematic Review.
Despite inherent resiliency and strengths, Indigenous Peoples in the United States and Canada have been impacted by colonialism, which has led to a loss of land, culture, and identity. Loss of land in particular has had substantial impacts on Indigenous food system practices. Indigenous food sovereignty (IFS) has been determined to be a mechanism for Indigenous communities to build their capacity to address food insecurity. A systematic review methodology was therefore engaged to gather and analyze the currently published literature to date to identify common elements of successful IFS interventions within Indigenous communities in the United States and Canada. We carried out a systematic search of the following electronic databases: Academic Search Premier, Agricola, PubMed, CINAHL Complete, Indigenous Studies Portal, the Native Health Database, SocIndex, PsycInfo, and Google Scholar. The Mixed Methods Appraisal Tool was used to apply a methodologic quality score to the included articles. We used a 2-stage process for article selection with 2 independent reviewers screening the titles and abstracts of articles identified. Relevant databases were initially searched up to June 2022 with an updated search occurring in January 2023. Content analysis was carried out on the included articles using qualitative analysis software. Twenty articles met the inclusion criteria of the review. Four main categories of successful elements within IFS interventions were identified, including 1) transmission of knowledge and skills within the community through workshops, 2) cultural connectedness through cultivation practices, 3) preparation and consumption of traditional foods through community programs, and 4) community-based partnerships and collaborations. An IFS approach has led to the development of several intervention strategies within Indigenous communities, which have been highlighted in this review. The successful elements identified in this review may serve to support future food sovereignty-related programmatic and intervention development within Indigenous communities. PROSPERO (number: CRD42022342100).


Application of carbon nanotubes in neurology: clinical perspectives and toxicological risks.
Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurological pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrices of neuronal tissue and as delivery systems for the therapy of CNS will be presented.


Identification of fibrosis in hypertrophic cardiomyopathy: a radiomic study on cardiac magnetic resonance cine imaging.
Hypertrophic cardiomyopathy (HCM) often requires repeated enhanced cardiac magnetic resonance (CMR) imaging to detect fibrosis. We aimed to develop a practical model based on cine imaging to help identify patients with high risk of fibrosis and screen out patients without fibrosis to avoid unnecessary injection of contrast. A total of 273 patients with HCM were divided into training and test sets at a ratio of 7:3. Logistic regression analysis was used to find predictive image features to construct CMR model. Radiomic features were derived from the maximal wall thickness (MWT) slice and entire left ventricular (LV) myocardium. Extreme gradient boosting was used to build radiomic models. Integrated models were established by fusing image features and radiomic models. The model performance was validated in the test set and assessed by ROC and calibration curve and decision curve analysis (DCA). We established five prediction models, including CMR, R1 (based on the MWT slice), R2 (based on the entire LV myocardium), and two integrated models (ICMR+R1 and ICMR+R2). In the test set, ICMR+R2 model had an excellent AUC value (0.898), diagnostic accuracy (89.02%), sensitivity (92.54%), and F1 score (93.23%) in identifying patients with positive late gadolinium enhancement. The calibration plots and DCA indicated that ICMR+R2 model was well-calibrated and presented a better net benefit than other models. A predictive model that fused image and radiomic features from the entire LV myocardium had good diagnostic performance, robustness, and clinical utility. • Hypertrophic cardiomyopathy is prone to fibrosis, requiring patients to undergo repeated enhanced cardiac magnetic resonance imaging to detect fibrosis over their lifetime follow-up. • A predictive model based on the entire left ventricular myocardium outperformed a model based on a slice of the maximal wall thickness. • A predictive model that fused image and radiomic features from the entire left ventricular myocardium had excellent diagnostic performance, robustness, and clinical utility.


Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients.
To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ). Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5x2 Gy/wk. Thirty-five patients received concomitant TMZ at 50 mg/m2, and in 8 patients 75 mg/m2 of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only. Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient. Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.


Diffusion-weighted MRI as an adjunct to mammography in women under 50 years of age: an initial study.
To evaluate diffusion-weighted magnetic resonance (DW) imaging as an adjunct to mammography for the detection of small invasive breast cancer. Institutional review board standards were followed for this retrospective study. We performed both breast DW imaging and mammography on 25 women under 50 years of age with pathologically proven T1 breast cancer and on 21 healthy women under 50 years of age. Four offsite radiologists blind to the clinical information independently interpreted the mammograms and DW images and then classified their confidence level regarding the presence of breast cancer. The composite area under receiver operating characteristic curve (AUC), of mammography alone, DW imaging alone, and the combination of DW imaging and mammography (DWI/Cal) were calculated. The AUC of composite ROC curves of mammography, DW imaging, DWI/Cal combination, was 0.79 (95% CI, 0.72-0.87), 0.86 (95% CI, 0.84-0.87), and 0.96 (95% CI, 0.92-1.00), respectively. DW imaging may be a useful adjunct to mammography in the detection of small invasive breast cancer in women under 50 years of age.


Mtss1 is a critical epigenetically regulated tumor suppressor in CML.
Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.


Novel insights into transketolase activation by cofactor binding identifies two native species subpopulations.
Transketolase (TK) cofactor binding has been studied extensively over many years, yet certain mysteries remain, such as a lack of consensus on the cooperativity of thiamine pyrophosphate (TPP) binding into the two active sites, in the presence and absence of the divalent cation, Mg2+. Using a novel fluorescence-based assay, we determined directly the dissociation constants and cooperativity of TPP binding and provide the first comprehensive study over a broad range of cofactor concentrations. We confirmed the high-affinity dissociation constants and revealed a dependence of both the affinity and cooperativity of binding on [Mg2+], which explained the previous lack of consensus. A second, discrete and previously uncharacterised low-affinity TPP binding-site was also observed, and hence indicated the existence of two forms of TK with high- (TKhigh) and low-affinity (TKlow). The relative proportions of each dimer were independent of the monomer-dimer transition, as probed by analytical ultracentrifugation at various [TK]. Mass spectrometry revealed that chemical oxidation of TKlow led to the formation of TKhigh, which was 22-fold more active than TKlow. Finally, we propose a two-species model of transketolase activation that describes the interconversions between apo-/holo-TKhigh and TKlow, and the potential to significantly improve biocatalytic activity by populating only the most active form.


Enzymatic PCL-grafting to NH2-end grouped silica and development of microspheres for pH-stimulated release of a hydrophobic model drug.
This study set out to evaluate novel PCL-based silica containing nanohybrids as the polymer matrix in a hydrophobic drug-loaded microsphere system. Nanohybrids were synthesized by PCL-grafting to NH2-end grouped silica by in situ enzymatic ring opening polymerization of ε-caprolactone. Molecular weight and monomer conversion, PCL grafting percentage, thermal properties and crystallinity of the nanohybrids were determined by 1H NMR, TGA, DSC and XRD. Synthesized nanohybrids had low crystallinity percentage (32 and 39 %) and molecular weight (4800 and 8700 g/mol), promising for controlled drug release applications. The nanohybrids were used for fabrication of trans-chalcone-loaded microspheres by O/W single emulsion solvent evaporation. Mean particle diameter of the microspheres were between 15 and 30 µm. The result of release studies showed that optimum microsphere formulations (AP4 and A2, respectively) had 61 and 64 % encapsulation efficiency. One of the more significant findings to emerge from this investigation is that TC release was extended to 16 and 37 days, in a controlled manner. TC release was significantly enhanced in acidic pH media (pH 3.6 and 5.6) indicating pH-dependent release from nanohybrid microspheres; releasing 80-100 % of the loaded drug in 4-14 days. Drug/polymer interactions and molecular structures were investigated by FT-IR spectroscopy and DSC analysis. According to the results obtained, enzymatically synthesized nanohybrids have potential for pH-dependent release of the model drug, trans-chalcone.


Immunoglobulin-cytokine fusion molecules: the new generation of immunomodulating agents.
Advances in the understanding of genetic engineering, protein expression, and Ig function have come together to allow for the rapid synthesis and production of a novel generation of potent immunomodulating reagents. Selective approaches that allow the isolation of desired specificities will be elucidated through meticulous engineering techniques. This, in turn, may eventually result in the fulfillment of the tremendous potential of engineered proteins for therapeutic and diagnostic applications.


Self-Applied Home Sleep Recordings: The Future of Sleep Medicine.
Sleep disorders form a massive global health burden and there is an increasing need for simple and cost-efficient sleep recording devices. Recent machine learning-based approaches have already achieved scoring accuracy of sleep recordings on par with manual scoring, even with reduced recording montages. Simple and inexpensive monitoring over multiple consecutive nights with automatic analysis could be the answer to overcome the substantial economic burden caused by poor sleep and enable more efficient initial diagnosis, treatment planning, and follow-up monitoring for individuals suffering from sleep disorders.


Conversion of Biowaste Asian Hard Clam (Meretrix lusoria) Shells into White-Emitting Phosphors for Use in Neutral White LEDs.
The increasing volume and complexity of waste associated with the modern economy poses a serious risk to ecosystems and human health. However, the remanufacturing and recycling of waste into usable products can lead to substantial resource savings. In the present study, clam shell waste was first transformed into pure and well-crystallized single-phase white light-emitting phosphor Ca₉Gd(PO₄)₇:Eu2+,Mn2+ materials. The phosphor Ca₉Gd(PO₄)₇:Eu2+,Mn2+ materials were synthesized by the solid-state reaction method and the carbothermic reduction process, and then characterized and analyzed by means of X-ray diffraction (XRD) and photoluminescence (PL) measurements. The structural and luminescent properties of the phosphors were investigated as well. The PL and quantum efficiency measurements showed that the luminescence properties of clam shell-based phosphors were comparable to that of the chemically derived phosphors. Moreover, white light-emitting diodes were fabricated through the integration of 380 nm chips and single-phase white light-emitting phosphors (Ca0.979Eu0.006Mn0.015)₉Gd(PO₄)₇ into a single package of a white light emitting diode (WLED) emitting a neutral white light of 5298 K with color coordinates of (0.337, 0.344).


Environmental stress influences mitochondrial metabolism in vascular cells: consequences for angiogenesis.
While the important and varied roles that vascular cells play in both health and disease is well recognised, the focus on potential therapeutic targets continually shifts as new players emerge. Here, we outline how mitochondria may be viewed as more than simply energy-generating organelles, but instead as important sentinels of metabolic health and effectors of appropriate responses to physiological challenges.


Modeling the topological organization of cellular processes.
The cell as a dynamical system presents the characteristics of having a dynamical structure. That is, the exact phase space of the system cannot be fixed before the evolution and integrative cell models must state the evolution of the structure jointly with the evolution of the cell state. This kind of dynamical systems is very challenging to model and simulate. New programming concepts must be developed to ease their modeling and simulation. In this context, the goal of the MGS project is to develop an experimental programming language dedicated to the simulation of this kind of systems. MGS proposes a unified view on several computational mechanisms (CHAM, Lindenmayer systems, Paun systems, cellular automata) enabling the specification of spatially localized computations on heterogeneous entities. The evolution of a dynamical structure is handled through the concept of transformation which relies on the topological organization of the system components. An example based on the modeling of spatially distributed biochemical networks is used to illustrate how these notions can be used to model the spatial and temporal organization of intracellular processes.


MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma.
NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here, we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs shows that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.


Determination of the pharmacokinetics of 2-amino-7-phosphonoheptanoate in rat plasma and cerebrospinal fluid.
The pharmacokinetics of 2-amino-7-phosphonoheptanoate (AP7) in rat plasma and appearance in cerebrospinal fluid (CSF) are reported. Using high-performance liquid chromatography (HPLC) with fluorescence detection, concentrations of AP7 can be detected as low as 1.0 microM. Peak CSF concentrations (12-15 microM) for both the D-AP7 and D,L-AP7 are observed 10-15 min after i.v. administration and amount to approximately 0.1% of a 1 mmol/kg dose. Significant quantities (3 microM) are present in CSF at 2 h and no AP7 is detectable at 4 h. Following i.v. administration, a monoexponential clearance was observed for D-AP7 clearance from plasma, 15.4 +/- 0.8 S.E.M. ml/min/kg with a t1/2 of 38.9 +/- 0.8 S.E.M. min. However, a biexponential clearance from plasma was observed for D,L-AP7.


Acral lamellar ichthyosis with amino acid substitution in the C-terminus of keratin 2.
Most cases of hereditary ichthyoses present with generalized scaling and skin dryness. However, in some cases skin involvement is restricted to particular body regions as in acral lamellar ichthyosis. We report on the genetic basis of acral ichthyosis in two families presenting with a similar phenotype. Genetic testing was performed by targeted next generation sequencing and whole-exome sequencing. For identity-by-descent analysis, the parents were genotyped and data analysis was performed with the Chromosome Analysis Suite Software. RT-PCR with RNA extracted from skin samples was used to analyse the effect of variants on splicing. Genetic testing identified a few heterozygous variants, but only the variant in KRT2 c.1912 T > C, p.Phe638Leu segregated with the disease and remained the strongest candidate. Pairwise identity-by-descent analysis revealed no indication of family relationship. Phenylalanine 638 is the second last amino acid upstream of the termination codon in the tail of K2, and substitution to leucine is predicted as probably damaging. Assessment of the variant is difficult, in part due to the lack of crystal structures of this region. Altogether, we show that a type of autosomal dominant acral ichthyosis is most probably caused by an amino acid substitution in the C-terminus of keratin 2.


Low dose aminophylline selectively increases upper airway motor activity in normals.
Because certain pharmacologic agents differentially influence upper airway and diaphragm motor activity, we postulated that the adenosine antagonist theophylline might preferentially increase alae nasi activity in human subjects. Using a double-blinded, randomized, placebo controlled design, we studied the effect of low dose aminophylline (1-2 mg/kg) on alae nasi and diaphragm surface electromyographic (EMG) activity. Seven healthy volunteers served as subjects for two trials on separate days. Subjects breathed from a close circuit while end tidal PCO2 was held constant in the eucapnic range. During each trial we recorded EMG signals from the alae nasi and diaphragm before and after intravenous infusion of either aminophylline or placebo. After the administration of aminophylline, the mean alae nasi EMG signal increased 87 +/- 31 (SD)% (P less than 0.005) while the mean diaphragmatic EMG signal did not change. There was no significant change in either the alae nasi or diaphragmatic EMG signal after placebo. There was no change in minute ventilation, tidal volume, or respiratory frequency after either aminophylline or placebo. We speculate that low dose aminophylline produces a selective increase in upper airway muscle activity through stimulation of the reticular activating system.


Evaluation of lymphangiogenesis in premalignant conditions of the head and neck mucosa.
Our aim was to determine whether lymphangiogenesis occurs in the early steps of cancerogenesis of the upper aerodigestive tract. We assessed the number of lymphatics per unit area (lymphatic vascular density [LVD]) and the percent area occupied by the lymphatic vessels (lymphatic vascular area [LVA]) by computer-assisted morphometric analysis in 56 samples immunohistochemically stained with the lymphatic marker D2-40. The results were compared to those obtained in 63 invasive squamous cell carcinomas. No significant difference was observed between normal mucosa, hyperplasia/mild dysplasia, and moderate/severe dysplasia for LVD (p = .8) and LVA (p = .7). Conversely, invasive carcinomas presented a higher LVD than normal mucosa and precancerous lesions (p < .001), whereas there was no difference for LVA (p = .1). Lymphangiogenesis does not occur in premalignant lesions of the upper aerodigestive tract and it is rather a late event associated with the development of an invasive phenotype.


Retracted: Online and Offline Interaction Model of International Chinese Education Based on Few-Shot Learning.
[This retracts the article DOI: 10.1155/2022/8281670.].


Building Hierarchical Microcubes Composed of One-Dimensional CoSe2 @Nitrogen-Doped Carbon for Superior Sodium Ion Batteries.
Designing and synthesizing highly stable anode materials with high capacity is critical for the practical application of sodium ion batteries (SIBs), however, to date, this remains an insurmountable barrier. The introduction of hierarchical architectures and carbon supports is proving an effective strategy for addressing these challenges. Thus, we have fabricated a hierarchical CoSe2 @nitrogen-doped carbon (CoSe2 @NC) microcube composite using the Prussian blue analogue Co3 [Co(CN)6 ]2 as template. The rational combination of the unique hierarchical construction from one to three dimensions and a nitrogen-doped carbon skeleton facilitates sodium ion and electron transport as well as stabilizing the host structure during repeated discharge/charge processes, which contributes to its excellent sodium storage capability. As expected, the as-prepared CoSe2 @NC composite delivered remarkable reversible capacity and ultralong cycling lifespan even at a high rate of 2.0 A g-1 (384.3 mA h g-1 after1800 loops) when serving as the anode material for SIBs. This work shows the great potential of the CoSe2 -based anode for practical application in SIBs, and the original strategy may be extended to other anode materials.


Association between physical activity before diagnosis and the presence of clinical remission in type 1 diabetes - InlipoDiab1 study.
To investigate whether physical activity is associated with the occurrence of remission in adults with type 1 diabetes. Ninety nine adult participants with newly diagnosed type 1 diabetes were enroled into a prospective, observational study. The participants were advised to exercise 2-3 times a week with moderate intensity for a one-year period. Physical activity was assessed by a self-administrated questionnaire on every fourth visit. We counted the months in which participants fulfiled a partial-remission criteria: HbA1c < 6.5%, C-peptide > 0.5 ng/ml, and daily dose of insulin <0.3 U/kg/day. We assigned the participants to two groups: MORE EFFORT and LESS EFFORT, depending on the median value of physical activity in the studied population. The occurrence of the remission achieved statistical significance at 6th month with a greater prevalence in MORE EFFORT group (55% vs. 35% p = 0.047). In multivariate logistic regression analysis for the occurrence of remission at 12th month, physical activity before the diagnosis was the only variable that influences the occurrence of the remission (adjusted odds ratios = 3.32 [95% confidence intervals 1.25-8.80]; p = 0.02). In adults with newly diagnosed type 1 diabetes physical activity before the diagnosis is associated with higher occurrence of remission.


Non-myeloablative bone marrow transplantation in an adult with Wiskott-Aldrich syndrome.
Early bone marrow transplant is now standard treatment for infants with severe immunodeficiencies such as Wiskott-Aldrich Syndrome (WAS), but results in older children and adults are poor. Non-myeloablative transplant has shown promise in the treatment of older children, who are likely to have active infections and organ damage. We describe a non-myeloablative transplant of a 26-year-old man with WAS, undertaken because of severe infections and vasculitis. Partial engraftment and immunorestoration were achieved. The patient is well 1 year post transplantation.


Barriers to prophylactic treatment among patients with haemophilia A in Shandong Province, China: a qualitative study.
Haemophilia A is a rare, hereditary haemorrhagic disease that manifests as induced spontaneous bleeding and leads to disability or premature death in severe cases. Prophylactic treatment is optimal for patients to prevent uncontrolled bleeding and reduce the severity of the injury. However, little is known about the use of prophylactic treatment among patients with haemophilia A in China, especially barriers that predispose them to low or non-adherence. In this study, we explore the barriers to the prophylactic treatment of patients with haemophilia A. We used personal interviews and focus groups to collect the data and analysed the data through thematic analysis. Purposive sampling was employed to recruit our participants. We continued recruiting participants until data saturation was reached from the thematic analysis. Ultimately, we obtained 37 participants, among whom 19 participated in personal interviews and 18 participated in focus groups (i.e., 3 focus groups with 6 participants each). Three themes and nine subthemes were identified from the thematic analysis. Nine subthemes (i.e., perceived barriers) emerged from the analysis, which were further clustered into three themes: (1) poor primary health care, (2) inadequate financial support, and (3) a lack of patient-centred care. The findings presented in this descriptive qualitative study offer a unique view of Chinese patients with haemophilia A and their barriers to prophylactic treatment. Our findings not only provide an in-depth understanding of barriers to prophylactic treatment encountered by Chinese patients with haemophilia A but also address the urgent need to strengthen primary care, provide adequate financial support, and establish patient-centred care for these suffering patients.


The unique axon trajectory of the accessory nerve is determined by intrinsic properties of the neural tube in the avian embryo.
The accessory nerve is a cranial nerve, composed of only motor axons, which control neck muscles. Its axons ascend many segments along the lateral surface of the cervical spinal cord and hindbrain. At the level of the first somite, they pass ventrally through the somitic mesoderm into the periphery. The factors governing the unique root trajectory are unknown. Ablation experiments at the accessory nerve outlet points have shown that somites do not regulate the trajectory of the accessory nerve fibres. Factors from the neural tube that may control the longitudinal pathfinding of the accessory nerve fibres were tested by heterotopic transplantations of an occipital neural tube to the cervical and thoracic level. These transplantations resulted in a typical accessory nerve trajectory in the cervical and thoracic spinal cord. In contrast, cervical neural tube grafts were unable to give rise to the typical accessory nerve root pattern when transplanted to occipital level. Our results show that the formation of the unique axon root pattern of the accessory nerve is an intrinsic property of the neural tube.


Drug abuse in Denmark (Jutland and Funen). A forensic study based upon drugs seized in 1982-1987.
Two thousand fifty-three samples submitted to forensic chemical analysis during the period 1982-1987 were characterized according to their content of narcotics and the year of seizure. Heroin and cannabis dominated the material, but a significant decrease in the number of heroin samples was observed in 1987. Amphetamine, on the contrary, hardly seen during the period 1982-1984, accounted for half of the narcotics submitted in 1987. The misuse of morphine, especially in the form of poppy capsules, was a problem for some years, whereas cocaine has not yet been a drug of abuse in Denmark. The mean concentrations of the heroin and the amphetamine samples were 30% and 44%, respectively, both for retail drugs and the entire material.


Comparison of Iodixanol and Ioxaglate for Coronary Optical Coherence Tomography Imaging.
The impact of contrast type on coronary imaging using optical coherence tomography (OCT) has received limited study. We compared OCT imaging obtained using the non-ionic, iso-osmolar iodixanol with the ionic, low-osmolar ioxaglate. Twenty-two vessels in 20 patients were imaged twice using manual injection of iodixanol and ioxaglate in random order. OCT images were analyzed at 1 mm intervals to determine lumen area, artifact diameter and area, as well as stent strut coverage and malapposition in OCT pullbacks that included stents. There were no complications related to OCT imaging or to contrast administration. A total of 2184 cross-sections (1092 with iodixanol and 1092 with ioxaglate) were analyzed. Compared with iodixanol, imaging using ioxaglate provided similar mean lumen area (6.21 ± 2.83 mm2 vs 6.27 ± 2.83 mm2; Spearman's rho, 0.982), mean minimum lumen diameter (2.47 ± 0.59 mm vs 2.50 ± 0.58 mm; Spearman's rho, 0.939), and mean maximum lumen diameter (2.99 ± 0.71 mm vs 3.01 ± 0.70 mm; Spearman's rho, 0.964), but lower mean artifact area per cross-section (0.099 ± 0.325 mm2 vs 0.068 ± 0.329 mm2; P<.001). Analyses of 3303 stent struts in 388 cross-sections (194 with iodixanol and 194 with ioxaglate) demonstrated similar strut malapposition rates (11.82% vs 13.90%; P=.10) and strut coverage (41.92% vs 40.33%; P=.35). Compared with iodixanol, OCT imaging using ioxaglate provided similar lumen and diameter measurements and stent strut characterization, but smaller area of artifact.


Comparison of the use of endoscopic and radiologic gastrostomy in a single head and neck cancer unit.
Head and neck cancer patients frequently require gastrostomy feeding. Different insertion techniques have been described. The aim of the present study was to compare clinical results of percutaneous endoscopic and radiological gastrostomies in patients treated in a regional head and neck cancer unit. The records of patients who received either percutaneous endoscopic gastrostomy (PEG) or percutaneous radiological gastrostomy (PRG) between August 1997 and February 2001 were reviewed retrospectively. Documented complications (leak, infection, nausea and vomiting, ileus, bleeding, peritonitis) were recorded, compared and evaluated. There were 74 patients (56 PEG, 18 PRG), most with stage III and IV head and neck malignancy. There was a significantly lower incidence of complications in PEG than PRG (11% vs 44%, P = 0.004). There was a delay of feeding due to tube placement in 4% of PEG and 22% of PRG (P < 0.025). Major complications occurred in 3.6% and 5.6% of PEG and PRG, respectively. Generally the complication rate for either form of gastrostomy was comparable with other studies. No procedure-related deaths occurred. Selection bias, technique and tube type appeared to influence the complication rate in the present review. Percutaneous endoscopic gastrostomy will remain the authors' preferred method while PRG will be reserved for those cases for whom endoscopic placement is deemed to be impractical.


Muscle MRI in immune-mediated necrotizing myopathy (IMNM): implications for clinical management and treatment strategies.
Immune-mediated necrotizing myopathy (IMNM) is the most severe idiopathic inflammatory myopathy (IIM) and early aggressive poly-immunotherapy is often required to reduce long-term disability. The aim of this study is to investigate muscle MRI in IMNM as outcome measure for disease activity, severity, progression, response to treatment, and to better characterize the pattern of muscle involvement. This is a retrospective, observational, cross-sectional, and longitudinal study including 22 IMNM patients, divided into three groups based on timing of first MRI and if performed before or under treatment. T1 score and percentage of STIR positive muscles (STIR%) were considered and analyzed also in relation to demographic, clinical and laboratory characteristics. STIR% was higher in untreated patients and in those who performed MRI earlier (p = 0.001). Pelvic girdle and thighs were in general more affected than legs. T1 score was higher in patients with MRI performed later in disease course (p = 0.004) with a prevalent involvement of the lumbar paraspinal muscles, gluteus medius and minimus, adductor magnus and hamstrings. 22% of STIR positive muscles showed fat replacement progression at second MRI. Higher STIR% at baseline correlated with higher risk of fat replacement at follow-up (p = 0.003); higher T1 score correlated with clinical disability at follow-up, with late treatment start and delayed treatment with IVIG (p = 0.03). Muscle MRI is a sensitive biomarker for monitoring disease activity and therapy response, especially when performed early in disease course and before treatment start, and could represent a supportive outcome measure and early prognostic index in IMNM.


Randomised controlled trial of an educational strategy to increase school-based adolescent hepatitis B vaccination.
This study aimed to evaluate a specifically designed hepatitis B education/promotion curriculum package as part of a successful hepatitis B vaccination delivery system to adolescents. A randomised-controlled trial was used to evaluate the effect of the curriculum package (or intervention) on uptake of vaccine. Schools were randomly selected from the metropolitan region of Melbourne to intervention (66 schools or 7,588 students) or control groups (69 schools or 9,823 students). Class teachers administered the intervention to students over 4 class periods before the vaccination course. The difference in mean school uptake between intervention and control was small at 1-2% per dose. 95% confidence intervals around the differences were -5% to 2% per dose and not significant. Intervention schools taught an average of 7 items out of 12 from the curriculum package. Immunisation rates increased by 4-10% per dose between low and high implementation schools, but this trend was not significant. Impact evaluation demonstrated significantly greater knowledge of hepatitis B and vaccination among students in the intervention than the control group. Hepatitis B vaccination of pre-adolescents was not increased by the implementation of a curriculum package that successfully increased knowledge and awareness of hepatitis B in a school-based vaccination program. Additional strategies directed at the education of parents, the cooperative role of schools and pro-active providers might also be required to maximise vaccine uptake in this age group.


Erectile dysfunction due to ectopic penile vein.
A total of 86/260 patients with erectile dysfunction had venous leakage as (joint) etiology. In 5 of 86 patients cavernosography showed pathologic cavernosal drainage only via an ectopic penile vein into the femoral vein. After ligation of this pathologic draining vessel, 4 of 5 patients regained spontaneous erectability. One patient with pathologic bulbocavernosus reflex latencies needed intracavernosal injection of vasoactive drugs for full rigidity.


Geographical psychology.
Geographical psychology is an area of research aimed at mapping the spatial organization of psychological phenomena, identifying the mechanisms responsible for their organization, and understanding how individual characteristics, social entities, and physical features of the environment contribute to their organization. Investigations of geographical variation in personality have revealed geographical differences in personality between and within nations. Three mechanisms that contribute to geographical variation are selective migration, social influence, and ecological influence. Results from studies in North America and Europe indicate that regional differences in personality are linked to political, economic, and health indicators. More work is necessary to understand the causal nature of the links between personality and macro-level outcomes, as well as the scale and impact of person-environment associations over time.


Lower strontium in two different body matrices in neurodevelopmental disorders: A preliminary report.
Environmental factors, including elemental homeostasis, have not been studied sufficiently in neurodevelopmental disorders (NDD). This study aims to compare the status of 13 elements in blood and deciduous teeth dentine of children having an autism spectrum disorder or attention deficit hyperactivity disorder with typically developing controls. Elements including calcium, phosphorus, magnesium, iron, zinc, copper, chromium, manganese, mercury, lead, cadmium, molybdenum, and strontium in both deciduous teeth and blood were analyzed by inductively coupled plasma mass spectrometry. Strontium levels in both blood and teeth samples were found to be significantly lower in the NDD group. Additionally, blood cadmium and mercury levels, and copper/zinc ratio were higher in the NDD group. Our results warrant further investigation in a large series of NDD examining symptom levels and genetic variations associated with elemental homeostasis.


Safety and efficacy of 6-month versus 12-month dual antiplatelet therapy in patients after implantation of multiple biodegradable polymer-coated sirolimus-eluting coronary stents: Insight from the I-LOVE-IT 2 trial.
This study sought to compare the clinical outcomes of 6-month versus 12-month dual antiplatelet therapy (DAPT) in patients receiving multiple biodegradable polymer-coated sirolimus-eluting stents (BP-SES) implants. The clinical outcomes for patients who undergo multiple BP-SES implantation with different DAPT durations are uncertain. In the I-LOVE-IT 2 trial, 907 patients treated with multiple BP-SES (total stent number ≥2) were assigned to receive 6-month (n = 440) or 12-month (n = 467) DAPT. The primary endpoint was 12-month target lesion failure (TLF), which is a composite of cardiac death, target vessel myocardial infarction (MI) or clinically indicated target lesion revascularization. The major secondary endpoints were 12-month net adverse clinical events, a composite of all causes of death, MI, stroke, any revascularization and bleeding. The number of stents per patient between the 6-month and 12-month DAPT group was similar (2.4 ± 0.7 vs. 2.4 ± 0.7, P = 0.47). The incidence of 12-month TLF was comparable in the 6-month and 12-month DAPT groups (9.3% vs.7.5%, Log-rank P = 0.33). However, landmark analysis showed that 12-month DAPT, compared to 6-month DAPT, was associated with a significantly lower risk of TLF (4.8% vs. 2.4%, Log-rank P = 0.049) at a cost of a slightly increased risk of all bleeding events (0.5% vs. 1.7%, Log-rank P = 0.07) between 6 and 12 months. In patients treated with multiple BP-SES, 6- and 12-month DAPT had similar impacts on 12-month clinical outcomes. Additionally, 12-month DAPT might reduce TLF between 6 and 12 months at the cost of a slightly increased risk of all bleeding events. © 2017 Wiley Periodicals, Inc.


Automated glycemic control with a bionic pancreas for type 1 diabetes mellitus: A systematic review and meta-analysis.
The use of a bionic pancreas with automated insulin delivery systems to prevent complications of diabetes mellitus shows conflicting results. We aimed to comprehensively discuss the potential use of a bionic pancreas in patients with type 1 diabetes (T1D). A systematic database search was conducted on October 24, 2022, for articles investigating the use of a bionic pancreas in patients with T1D. The hemoglobin A1c (HbA1c) level, mean glucose level, glucose coefficient of variability, time-in-range (TIR), and adverse events were investigated. Nine studies were included in this review. The data from these studies suggested that the use of a bionic pancreas could reduce the HbA1c (mean difference [MD] = -0.40% [95% confidence interval {CI} = -0.59 to -0.21], I2 = 0%, p < 0.0001) and mean glucose levels (MD = -21.06 [95% CI = -24.66 to -17.46], I2 = 45%, p < 0.00001) and improve the TIR (MD = 14.41% [95% CI = 10.99 to 17.83], I2 = 60%, p < 0.00001). The most common adverse events reported were nausea and vomiting. The use of a bionic pancreas shows potential in preventing complications of T1D by improving the TIR and decreasing the HbA1c and mean glucose levels. Furthermore, serious adverse events with the use of a bionic pancreas and standard of care show insignificant results, suggesting a good safety profile.


Environmental and genotype-by-environment influences on chick size in the Yellow-browed leaf warbler Phylloscopus inornatus.
I investigated genetic and environmental factors affecting fledgling chick size in the Yellow browed leaf warbler Phylloscopus inornatus. The proportion of variation among broods is >45% for both tarsus length and body weight; this can be attributed at least in part to effects of the shared nest environment. A high off-spring-parent regression for weight also appears to be partly due to an environmentally induced correlation and the regression is reduced when effects of laying date are controlled for. A cross-fostering experiment demonstrated a significant nest of origin x nest of rearing interaction. The presence of genotype-environment interaction affecting chick size may be quite general in birds. It is shown how this can account for observed patterns of the dependence of the magnitude of offspringparent regression on prevailing conditions, as has been found in other studies. In P. inornatus the failure to detect significant genetic variance in chick body weight and tarsus length may be due to high standard errors on the estimates, but it may also reflect true low levels of genetic variance in chick size if the genotype-interaction effect described occurs regularly in this species.


Effects of restricted feed intake on blood constituent concentrations in Dorper, Katahdin, and St. Croix sheep from different regions of the USA.
Forty-six Dorper, 47 Katahdin, and 41 St. Croix female sheep (initial BW = 62, 62, and 51 kg, respectively, SEM = 1.43; 3.8 ± 0.18 yr) from farms in Midwest, Northwest, Southeast, and central Texas regions of the USA were used to evaluate effects of feed restriction on blood constituent levels. The amount of feed offered varied in the first 4 wk to achieve stable BW, and that in wk 5-10 was 55% of intake in wk 3-4. Blood was sampled at the end of wk 3, 4, 6, 8, and 10. There were relatively few effects and interactions involving region and no breed × time interactions. Breed affected the concentration of a small number of constituents, including urea N (14.0, 13.7, and 15.4 mg/dl; SEM = 0.31) and creatinine (0.945, 0.836, and 0.809 mg/dl for Dorper, Katahdin, and St. Croix, respectively; SEM = 0.0253). Also, the concentration of triglycerides in wk 4 and 10 was lowest for St. Croix (29.8, 29.5, and 26.7 mg/dl for Dorper, Katahdin, and St. Croix, respectively; SEM = 0.88). There was a trend for a difference (P = 0.051) between wk 4 and 10 in the glucose concentration (51.9 and 54.2 mg/dl; SEM = 0.90), and there were differences (P < 0.05) in lactate (23.9 and 20.3 mg/dl; SEM = 0.89), urea N (16.4 and 13.0 mg/dl; SEM = 0.25), creatinine (0.808 and 0.919 mg/dl; SEM = 0.0165), triglycerides (31.8 and 25.5 mg/dl; SEM = 0.63), and cholesterol (67.5 and 74.7 mg/dl, respectively; SEM = 1.66). In conclusion, similar responses in blood constituent levels of different hair sheep breeds to feed restriction is in accordance with comparable effects on the maintenance energy requirement.


MicroRNA‑144 suppresses aggressive phenotypes of tumor cells by targeting ANO1 in colorectal cancer.
The aim of the present study was to research the mechanism of action of microRNA‑144 (miR‑144) in colorectal cancer (CRC) and its role in tumor progression. It was demonstrated that miR‑144 was downregulated and anoctamin 1 (ANO1) expression was upregulated in CRC. The expression of ANO1 was negatively associated with that of miR‑144 in CRC. The present study indicated that upregulated expression of ANO1 was associated with poor differentiation and advanced tumor‑node‑metastasis stage. It was verified that upregulation of ANO1 expression activated the epidermal growth factor receptor/extracellular signal‑regulated kinase signaling pathway. It was also demonstrated that miR‑144 exerts strong tumor‑inhibiting effects by targeting ANO1. Therefore, miR‑144 may have potential as a prognostic marker or therapeutic target for CRC.


Recent advances in Zn2+ imaging: From organelles to in vivo applications.
Zn2+ is involved in various physiological and pathological processes in living systems. Monitoring the dynamic spatiotemporal changes of Zn2+ levels in organelles, cells, and in vivo is of great importance for the investigation of the physiological and pathological functions of Zn2+. However, this task is quite challenging since Zn2+ in living systems is present at low concentrations and undergoes rapid dynamic changes. In this review, we summarize the design and application of fluorescent probes for Zn2+ imaging in organelles, cells, and live organisms reported over the past two years. We aim to provide inspiration for the design of novel Zn2+ probes for multi-level monitoring and deepen the understanding of Zn2+ biology.


Membrane properties and lipid peroxidation in food restricted animals.
Food restriction (FR) is a well-recognized method of extending mean and maximum longevity of rodents, but the mode of its action remains to be uncovered. This article reviews the effect of FR on the physical-chemical properties and lipid peroxidizability of cellular membranes. FR prevents the age-dependent increase in microviscosity and peroxidizability of cellular membranes. It has been suggested that a decrease in the body temperature occurring in undernourished animals may play a fundamental role in the process. Indeed, the lowering of average body temperature occurring in FR animals may induce a modification in membrane lipid composition, stimulating the cells to counteract the rigidifying effect of lower temperature. Thus, membranes are maintained in a proper functional state by a mechanism similar to that found in poikilotherm animals.


Colorectal cancer spatial pattern in the northeast region of São Paulo, Brazil.
This study examined the spatial pattern of the colorectal cancer (CRC) in the 18 municipalities that compose the Regional Health Department of Barretos (RHD-V), which is in the northeast of the state of São Paulo, Brazil. All incident cases and deaths from CRC between 2002 and 2016 were included. Age-standardized rates (ASR) for incidence and mortality per 100,000 person-years were used to evaluate the spatial distribution for the total and five-year periods. The lethality rates were also assessed. Excess risk maps compared the observed and expected events. Age-standardized net survival was used to evaluate CRC survival. For CRC incidence, the ASR value for the general population over the entire period (2002-2016) was 17.7 (95% CI: 16.7, 18.6), ranging from 16.7 (95% CI: 14.9, 18.4) (2002-2006) to 20.0 (95% CI: 18.3, 21.7) (2012-2016) per 100,000. When males and females were compared, the ASR was 20.1 (95% CI: 18.6, 21.6) and 15.7 (95% CI: 14.5, 17.0) per 100,000, respectively. For CRC mortality (2002-2016), the ASR was 8.2 (95% CI: 7.6, 8.9), ranging from 9.0 (95% CI: 7.8, 10.3) (2002-2006) to 8.2 (95% CI: 7.2, 9.3) (2012-2016) per 100,000. Overall, the excess risk up to 2.0 was more frequent. In terms of survival, municipalities with large port populations had lower survival in comparison with medium port. This study showed a variation in CRC incidence and mortality, with differences considering five-year periods and gender, being the incidence higher in males than females in the entire period, with mortality equivalent to half the incidence. The survival was lower in municipalities with large port populations in comparison with medium port. Knowing spatial patterns of incidence, mortality, lethality, and survival can be necessary to support policymakers to advance or implement effective cancer control programs.


The effect of predation on the structure and invasibility of assembled communities.
Fifty four microcosmic communities were assembled over 4 months from a 28-species source pool of phytoplankton using nine different invasion patterns each replicated six times. Three communities from each set of replicates then were invaded with a cladoceran that feeds on phytoplankton. All communities were then treated identically for an additional 4 months. In all nine invasion categories species richness was greater in predated communities. Predation opened communities to invasion by increasing the representation of infrequently sampled species at the expense of more common species. Invasion rate was four times more influential than predation and over eleven times more important than either invasion order or the timing pattern of interspecific arrivals in determining species richness in this system of communitites.


Acute vasodilator test in pulmonary arterial hypertension: evaluation of two response criteria.
The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH) is to identify patients who have a vasoreactive component that justifies the use of non-selective vasodilators. We tested the ability of two different response criteria to identify such patients studying 34 patients with IPAH. The hemodynamic data from the right heart catheterization were collected at baseline and post-administration of inhaled nitric oxide. We describe the results obtained by two different response criteria: (A) a 20% decrease in indexed pulmonary vascular resistance (PVRi) and in mean pulmonary artery pressure(PAPm)(classic criterion); (B) a fall in PAPm of at least 10 mm Hg to a pressure level of 40 mm Hg or lower (revised criterion). Patients who responded according to the revised criterion showed a higher cardiac index (CI) (3.45+/-1.94 vs. 1.99+/-0.44 L/min/m2; p=0.05) and lower PVRi (1247+/-746 vs. 2437+/-1105 dyn cm-5 s m2; p=0.02) compared to non-responders. Responders according to the classic criterion had a statistically significant lower CI (1.59+/-0.40 vs. 2.43+/-1.14 L/min/m2; p=0.03) and higher PVRI (3130+/-1173 vs. 1958+/-980 dyn cm-5 s m2; p=0.04) also compared to non-responders. We conclude that the revised criterion seems to reflect the degree of vascular remodeling more accurately, identifying patients with better preserved cardiac function, possibly in an earlier phase of the disease.


Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice.
Acetaminophen (APAP) is a widely used analgesic, but also a main cause of acute liver injury in the United States and many western countries. APAP hepatotoxicity is associated with a sterile inflammatory response as shown by the infiltration of neutrophils and monocytes. While the contribution of the immune cells to promote liver repair have been demonstrated, the direct interactions between macrophages or neutrophils with hepatocytes to help facilitate hepatocyte proliferation and tissue repair remain unclear. The purpose of this study was to investigate the relationship between resident macrophages (Kupffer cells) and hepatocytes with a focus on the chemokine receptor CXCR2. C57BL/6J mice were subjected to an APAP overdose (300 mg/kg) and the role of CXCR2 on hepatocytes was investigated using a selective antagonist, SB225002. In addition, clodronate liposomes were used to deplete Kupffer cells to assess changes in CXCR2 expression. Our data showed that CXCR2 was mainly expressed on hepatocytes and it was induced specifically in hepatocytes around the necrotic area 24 h after APAP treatment. Targeting this receptor using an inhibitor caused a delayed liver recovery. Depletion of Kupffer cells significantly prevented CXCR2 induction on hepatocytes. In vitro and in vivo experiments also demonstrated that Kupffer cells regulate CXCR2 expression and pro-regenerative gene expression in surviving hepatocytes through production of IL-10. Thus, Kupffer cells support the transition of hepatocytes around the area of necrosis to a proliferative state through CXCR2 expression.


Posterior interosseous neuropathy due to compression by a soft tissue chondroma of the elbow.
A case of soft tissue chondroma or extraskeletal chondroma is described. The tumour caused compression of the posterior interosseous nerve. Excision and biopsy were performed with complete resolution of the symptoms.


Western blot analysis of the antibody response in patients with Listeria monocytogenes meningitis and septicemia.
The antibody response in patients with Listeria monocytogenes septicemia and/or meningitis was investigated using Western blot analysis (WBA). Protein antigen preparations were produced from two strains of Listeria monocytogenes, representing serogroup 1 and 4, by sonication and differential centrifugation. IgG antibodies from 8 (50%) of 16 patients with culture verified septicemia and/or meningitis due to Listeria monocytogenes reacted with a 93 kDa antigen from serogroup 1, in contrast to IgG antibodies from only 1 (2%) of 51 controls; these controls represented 21 patients with infections caused by other bacteria and 30 apparently healthy blood donors. Furthermore, IgM antibodies from 3 (19%) of the patients with listeric infections bound to a 106 kDa protein antigen in contrast to none of the controls. In 3 (33%) of 9 patients from whom acute and convalescence serum were available, the patients responded by producing antibodies against new protein antigens. Current methods used in routine serological investigations, i.e. complement fixation and O-agglutination tests, were positive in only 4 (24%) of the 16 patients with listeriosis. The results point to the possibility of designing new immunoassays for detection of septicemia and meningitis caused by Listeria monocytogenes.


Efficient ofloxacin degradation via photo-Fenton process over eco-friendly MIL-88A(Fe): Performance, degradation pathways, intermediate library establishment and toxicity evaluation.
The high-throughput production of the eco-friendly MIL-88A(Fe) was achieved under mild reaction conditions with normal pressure and temperature. The as-prepared MIL-88A(Fe) exhibited efficient photo-Fenton catalytic ofloxacin (OFL) degradation upon visible light irradiation with good stability and reusability. The OFL (20.0 mg/L) was completely degraded within 50 min under visible light with the aid of MIL-88A(Fe) (0.25 g/L) and H2O2 (1.0 mL/L) in aqueous solution (pH = 7.0). The hydroxyl radicals (·OH) are the main active species during the photo-Fenton oxidation process. Meanwhile, the degradation intermediates and the corresponding degradation pathways were identified and proposed with the aid of both ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and density functional theory (DFT) calculations. Finally, the degradation product library was firstly established to identify intermediate transformation products (TPs) with their variation of concentration, and their corresponding toxicologic activities were assessed via Toxtree and T.E.S.T software as well. Finally, the MIL-88A is efficient and stable with four cycles' catalysis operations, demonstrating good potential for water treatment.


[Growth of fetal extremities, estimation of gestational age and prenatal diagnosis of malformations by measurement of fetal limb bones by ultrasound in the second trimester].
Fetal extremities were examined in 300 pregnant women between 16th and 24th week of gestation by real-time ultrasound. The limb bones of femur, humerus, tibia-fibula and radius-ulna complexes were measured and correlated to menstrual age and estimated age by ultrasound. The standard curves for limb bone growth show a linear increase with constant standard deviations. As fetal limb bone growth is close correlated to gestational age estimation of gestational age is exact as estimation from menstrual dates. Finding out skeletal malformations can be done very effective in patients of high risk.


[Methemoglobinemia due to prilocaine after plexus anesthesia. Reduction by prophylactic administration of ascorbic acid?].
This study investigated in vivo and in vitro kinetics of o-toluidine-induced methemoglobinemia and the influence of ascorbic acid on resulting methemoglobin concentrations. o-Toluidine is a metabolite of prilocaline and ascorbic acid is recommended for treatment of methemoglobinemia as an alternative to methylene blue. We measured the formation of methemoglobin in vitro in a whole blood culture system of 8 healthy individuals 30, 60, and 360 min after the addition of different concentrations of o-toluidine (0.5, 5, 50 micrograms/ml) with and without addition of ascorbic acid (0.5 and 5 mg/ml). In a prospective randomized clinical study, a total of 72 patients of ASA risk I-III were investigated. The 3 groups of 24 patients received either an axillary, an infraclavicular vertical brachial plexus, or a combined femoral and ischiadic blockade. In each plexus anesthesia group, 12 patients were given 2,000 mg ascorbic acid intravenously before applying the local anesthetics. For surgery of the upper limb the patients received 40 ml 1% prilocaine and 10 ml 0.5% bupivacaine, for surgery of the lower limb they received 60 ml 1% prilocaine and 0.25 mg adrenaline. Blood samples for measurement of methemoglobin concentrations were taken before and 30, 60, 120, 180 and 360 min after the injection of the regional anesthetic. A p < 0.05 was considered to be significant. There was a dose-dependent increase of methemoglobin due to addition of o-toluidine after 360 min in vitro. The application of 0.5 mg/ml ascorbic acid to the whole blood samples with 0.5 and 5 micrograms/ml o-toluidine resulted in a further increase of methemoglobin formation whereas there was no difference in the samples with 50 micrograms/ml. The higher concentration of 5 mg/ml ascorbic acid attenuated the methemoglobin formation only with 50 micrograms/ml o-toluidine. No effect was observed with lower concentrations of o-toluidine. In the in vivo study plexus anesthesia with prilocaine resulted in an increase of the methemoglobin concentration with a maximum after 120-180 min. The highest measured methemoglobin concentration found was 11.3%. The methemoglobin concentration already showed a decrease 360 min after the application of the regional anesthetic 2,000 mg ascorbic acid given intravenously before plexus anesthesia was not able to influence the resulting methemoglobin concentrations. In vitro high concentrations of ascorbic acid are able to reduce the resulting methemoglobin concentration 360 min after addition of 50 micrograms/ml o-toluidine. The application of 2,000 mg ascorbic acid i.v. before plexus anesthesia with prilocaine does not reduce the concentration of methemoglobin.


Anesthetic management for resection of hepatic paraganglioma metastatic from the donor organ in an orthotopic liver transplant recipient: a case report.
This is a case report of the anesthetic management for the hepatic resection of a metastatic paraganglioma in a patient with a history of prior orthotopic liver transplantation. Of interest, the metastatic paraganglioma originated from the donor organ. The patient is an 80-year-old woman with multiple medical problems including a history of cryptogenic cirrhosis who underwent successful orthotopic liver transplantation 9 years prior. She later presented with signs and symptoms of catecholamine excess suggestive of a catecholamine-producing tumor (paraganglioma or pheochromocytoma). Elevated urine catecholamine levels and radiographic evidence of a paraganglioma in the transplanted liver metastatic from the donor organ confirmed the diagnosis. Radiofrequency ablation of the tumor and surgical resection was previously attempted without success. We describe the anesthetic management for the successful resection of the metastatic hepatic paraganglioma, which was complicated by profound intraoperative hypertension and hypotension that necessitated the use of multiple vasoactive infusions, extensive surgical blood loss requiring blood transfusion, and difficult glycemic control in an insulin-dependent diabetic patient. The postoperative course is also described. This unique case presented the anesthesia team with challenges specific to both surgery for hepatic resection as well as for catecholamine-secreting tumors. We are not aware of any reports of paragangliomas of either donor or recipient origin involving a transplanted liver, making this the first such report to the best of our knowledge.


Immobilization and restraint effects on pain reactions in animals.
Acute physical restraint represents a potent stressor in several animal species and is accompanied by a complex pattern of hormonal responses and functional changes in the central nervous system. Repeated immobilization leads to partial blunting of the behavioral and hormonal responses, with transient modifications of neurotransmitter systems in the brain. Pain reactions, as investigated by different kinds of nociceptive tests, are usually attenuated both during and immediately following acute immobilization and the analgesic effect of opiate compounds potentiated; these behavioral alterations may be attributed at least in part to activation of an endogenous opioid system. In some species, restraint may induce a reflex immobility (animal hypnosis or tonic immobility) which is also characterized by suppression of pain reactions in rabbits, probably subserved by different mechanisms. Analysis of available data suggests that pain testing in unanesthetized, restrained animals may involve alterations of the animal's reactivity to noxious stimuli.


A Novel Drug-Drug Cocrystal of Levofloxacin and Metacetamol: Reduced Hygroscopicity and Improved Photostability of Levofloxacin.
Levofloxacin (LVFX), a broad-spectrum antibacterial agent from the fluoroquinolone family, is universally prescribed with antipyretics, including paracetamol (APAP) analogs. In this study, a new drug-drug cocrystal of LVFX and an APAP analog was developed using a grinding and heating approach. Among 9 APAP analogs, only metacetamol (AMAP) was able to form a cocrystal with LVFX, with a stoichiometric ratio of 1:1. This cocrystal was obtained from a eutectic melt of anhydrous LVFX and AMAP after complete desorption of water from LVFX hemihydrate. The crystal structure of the cocrystal was determined by single-crystal X-ray structural analysis. Unlike LVFX hydrates, the LVFX-AMAP cocrystal did not form a channel structure where water molecules reside in LVFX hydrates. Thus, the LVFX-AMAP cocrystal did not undergo hydration under high relative humidity conditions during vapor sorption-desorption analysis and physical stability tests. LVFX photostability was improved by cocrystallization when compared with that of the hemihydrate because of hydrogen bond formation between the hydroxyl group of AMAP and the N-methylpiperazine group of LVFX, which is possibly involved in LVFX photodegradation. The LVFX-AMAP cocrystal, which is superior to LVFX hydrates in both pharmacological and physicochemical properties, is expected to be a useful solid form.


Muscle contributions to support during gait in an individual with post-stroke hemiparesis.
Walking requires coordination of muscles to support the body during single stance. Impaired ability to coordinate muscles following stroke frequently compromises walking performance and results in extremely low walking speeds. Slow gait in post-stroke hemiparesis is further complicated by asymmetries in lower limb muscle excitations. The objectives of the current study were: (1) to compare the muscle coordination patterns of an individual with flexed stance limb posture secondary to post-stroke hemiparesis with that of healthy adults walking very slowly, and (2) to identify how paretic and non-paretic muscles provide support of the body center of mass in this individual. Simulations were generated based on the kinematics and kinetics of a stroke survivor walking at his self-selected speed (0.3 m/s) and of three speed-matched, healthy older individuals. For each simulation, muscle forces were perturbed to determine the muscles contributing most to body weight support (i.e., height of the center of mass during midstance). Differences in muscle excitations and midstance body configuration caused paretic and non-paretic ankle plantarflexors to contribute less to midstance support than in healthy slow gait. Excitation of paretic ankle dorsiflexors and knee flexors during stance opposed support and necessitated compensation by knee and hip extensors. During gait for an individual with post-stroke hemiparesis, adequate body weight support is provided via reorganized muscle coordination patterns of the paretic and non-paretic lower limbs relative to healthy slow gait.


Adult outcome of juvenile idiopathic arthritis: A nationwide population-based retrospective cohort study in Taiwan.
To clarify the development of juvenile idiopathic arthritis (JIA) to adult-onset autoimmune diseases in a population-based study in Taiwan. We analyzed data of 107 433 children born between 1990 and 1997 from the National Taiwan Health Insurance Database. There were 262 JIA patients and 107 171 individuals without JIA who were selected and followed up until December 2013 to investigate their outcomes of adult-onset autoimmune diseases after reaching 16 years of age. The adjusted hazard ratios (aHRs) including 95% confidence intervals (95% CI) of adult-onset autoimmune diseases were calculated using the Cox proportional regression model among different age groups. The incidence rate for patients with a history of JIA was 83.56 per 105 person-months for rheumatoid arthritis (RA), 16.61 for systemic lupus erythematosus (SLE), 58.39 for ankylosing spondylitis (AS), and 33.26 for psoriatic diseases. The aHRs were 29.60 for any autoimmune disease, 129.52 for RA, 10.01 for SLE, 49.62 for AS, and 8.20 for psoriatic diseases. Compared with non-JIA individuals, the aHRs of adult-onset autoimmune diseases were 34.87 (95% CI: 4.85-250.62) at the onset age of 3-5 years, 12.01 (95% CI: 2.99-48.26) at the age of 6-10 years, and 45.80 (95% CI: 29.69-70.64) at the age of 11-15 years. Children with JIA were at an increased risk of developing RA, AS, psoriatic disease, and SLE in adulthood.


Factors influencing the patient education performance of hemodialysis unit nurses.
This study aimed to identify the perceptions, barriers, and facilitators of patient education and factors influencing the performance of patient education among hemodialysis unit nurses. This study used a descriptive correlational design in which a total of 262 nurses from 27 hemodialysis facilities in six provinces in the Republic of Korea participated. Self-administered questionnaires were used to identify the perceptions, barriers, facilitators, and performance of patient education. Data were analyzed using a t-test, one-way ANOVA, Pearson's correlation, and stepwise multiple regression. Factors influencing patient education performance were nurses' total clinical experience, perceptions, working experience in a hemodialysis unit, facilitators, number of nurses in the hemodialysis unit, and barriers. These variables accounted for 37.2 % of the variance in the final model. Nurses' performance in patient education was significantly influenced by perceptions, facilitators, and barriers. Nurses' total clinical experience, working experience in a hemodialysis unit, and number of nurses in the unit also influenced patient education performance. A nurse training program should be developed to reinforce nurses' patient education competency.


New clinically applicable method for visualizing adjacent lung segments using an infrared thoracoscopy system.
Our objective was to attempt a clinical trial of segmentectomy using the infrared thoracoscopy system after intravenous injection of indocyanine green. A total of 8 patients with lung lesions were investigated (5 with primary lung cancer, 2 with metastatic lung tumor, and 1 with inflammatory change). All were scheduled to undergo segmentectomy and had been confirmed to have no allergy to iodine or indocyanine green. Informed consent was obtained from all patients. We identified the dominant pulmonary artery supplying the target segment using reconstructed computed tomography images. The dominant pulmonary artery of the target segment was ligated, and after we had observed the lung using the infrared thoracoscopy system after intravenous injection of indocyanine green (3.0 mg/kg), and marked the white-to-blue transitional zone by electrocautery, we performed segmentectomy. Average operation time was 150 ± 62.1 minutes, and bleeding volume was 68.8 ± 30.5 mL. Under infrared thoracoscopy, the area with a normal blood supply became stained blue 13 seconds after injection of indocyanine green. Maximum staining intensity was attained 28 seconds after dye injection, and the observation duration was 3.5 minutes. A well-defined color zonation was observed in all patients. We had enough time to mark it. No complications attributable to infrared thoracoscopy after intravenous injection of indocyanine green were encountered. Infrared thoracoscopy with indocyanine green makes it possible to identify the target lung segment easily and quickly without the need for inflation. This method will be especially useful for cases associated with severe emphysema or when surgery offers a limited view, as is the case with video-assisted thoracic surgery.


Clinical and radiologic features of malignant neoplasms in organ transplant recipients: cyclosporine-treated vs untreated patients.
The radiologic and clinical features of 37 posttransplantation malignant tumors occurring in 33 organ transplant recipients were reviewed to determine the characteristics of the tumors, particularly in relation to previous treatment (or nontreatment) with cyclosporine. The 37 malignant tumors included lymphomas (eight in patients receiving cyclosporine and four in patients not given cyclosporine) and carcinomas of the skin and lips (11), head and neck (five), colon and rectum (three), uterus (two), vulva (two), lung (one), and urinary bladder (one). The neoplasms of the internal viscera and head and neck were relatively advanced when detected. The neoplasms of the skin, vulva, uterine cervix, and urinary bladder were low-grade malignant tumors. Most of the cyclosporine-induced malignant lesions were lymphomas. The lymphomas in cyclosporine-treated recipients were characterized by early appearance after transplantation; more extensive organ involvement; multiple, homogeneous solid lesions without central low density on CT and sonography; and regression after reduction of cyclosporine dose. We conclude that malignant tumors occurring after transplantation are often advanced and that lymphoma induced by cyclosporine has characteristic features.


Transnational indigenous exchange: rethinking global interactions of indigenous peoples at the 1904 St. Louis Exposition.
When the St. Louis Exposition opened in 1904 it became host to the largest gathering of the world's Indigenous peoples to that date. However, questions about how Native peoples understood these transnational Indigenous interactions have remained largely out of the realm of academic inquiry-a fact often attributed to the "absence" of primary sources. This article counters such assertions by providing a rereading that interrogates colonial assumptions embedded in both archival materials and contemporary scholarly interpretations. By analyzing a candid photograph of two Native women-one Tzoneca, the other Ainu-taken at the fair by Jessie Tarbox Beals and utilizing Frederick Starr's journal, this article ultimately questions whether the Exposition's celebration of empire may have inadvertently served anti-colonial purposes. Namely, by presenting Indigenous participants with opportunities to forge relationships across the globe, a fact that may have served to inform the late 20th century emergence of a global Indigenous consciousness.


Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype.
The neurotransmitter acetylcholine is an important modulator of cognitive functions including attention, learning, and memory. The actions of acetylcholine are mediated by five distinct muscarinic acetylcholine receptor subtypes (M(1)-M(5)). The lack of drugs with a high degree of selectivity for these subtypes has impeded the determination of which subtypes mediate which components of cholinergic neurotransmission relevant to cognitive abilities. The present study examined the behavioral functions of the M(2) muscarinic receptor subtype by utilizing congenic C57BL/6 mice possessing a null-mutation in the M(2) muscarinic receptor gene (M(2)(-/-) mice). Comprehensive assessment of general health and the neurological function found no major differences between M(2)(-/-) and wild-type (M(2)(+/+)) mice. In the tests of learning and memory, M(2)(-/-) mice were impaired in the acquisition (trials to criterion), but not the retention (72h) of a passive avoidance task. In a novel open field, M(2)(-/-) mice were impaired in between-sessions, but not within-session habituation. In a holeboard test of spatial memory, M(2)(-/-) mice committed more errors in working memory than M(2)(+/+) mice. Reference memory did not differ between the genotypes. M(2)(-/-) mice showed no impairments in either cued or contextual fear conditioning. These findings replicate and extend earlier findings in a hybrid strain and solidify the interpretation that the M(2) receptor plays a critical role in specific components of cognitive abilities.


Unsupported liquid-state platform for SERS-based determination of triazophos.
A highly reproducible surface-enhanced Raman scattering (SERS) unsupported liquid-state platform (ULP) was developed for accurate quantitative determination of triazophos. Herein, citrate-reduced Ag NPs suspension was concentrated and placed in a stainless steel perforated template to form the SERS ULP. The relative standard deviation of the SERS measurements was less than 5% (n ≥ 10), and the R2 of the calibration curve was 0.994. The developed SERS ULP was applied for determination of triazophos in spiked agricultural products (rice, cabbage, and apple). Experiment results showed that the coefficient of variation ranged from 5.3 to 6.2% for intra-day and from 5.5 to 6.3% for inter-day (n = 3), which proved excellent SERS reproducibility. Moreover, the results were in good agreement with those from HPLC analysis. As a liquid-state SERS substrate, the highly reproducible ULP can perform precision quantitative analysis without surface modification of NPs, which is a significant improvement. This method provides a new perspective for quantitative SERS analysis of pesticide residues. Graphical abstract.


First genome-wide association study for lymphatic filariasis in a West African population points to a human leukocyte antigen-mediated disease pathophysiology.
Lymphatic filariasis (LF) represents a parasitic disease caused by filarial nematodes. Although some infected individuals present an asymptomatic course, others suffer severe chronic lymphatic pathology, including lymphedema, hydrocele, and elephantiasis. Several studies have shown that host genetic factors influence LF susceptibility and chronic pathology. The current study aimed to conduct the first genome-wide association study to systematically determine LF susceptibility. We analyzed genome-wide single-nucleotide polymorphism data from 1459 LF cases and 1492 asymptomatic controls of West African (Ghanaian) descent. We identified two independent genome-wide significant associated genetic variants near the genes HLA-DQB2 (rs7742085) and HLA-DQA1 (rs4959107) contributing to LF and/or lymphedema susceptibility (P <5.0 × 10-8, odds ratios [ORs] >1.30). We also observed suggestive evidence of LF associations (P <1.0 × 10-6) at two non-HLA loci, near the genes ZFHX4-AS1 (rs79562145) and CHP2 (rs12933387). In contrast, we could not replicate any previously reported LF associations drawn from candidate gene association studies. On the polygenic level, we show that our genome-wide association study data explain 24-42% of LF heritability, depending on an assumed population prevalence of 0.5-5.0%. Our findings point to an involvement of HLA-mediated immune mechanisms in LF pathophysiology.


Chick oviduct progesterone receptor: structure, immunology, function.
Analysis of the purified chick oviduct progesterone receptor using biochemical and immunological approaches indicates that while the 'activated' receptor ('4S') is a mixture of two progestin-binding polypeptides, 'A' (Mr approximately 79 kDa) and 'B' (Mr approximately 110 kDa), the non-activated receptor ('8S') is a population of complexes containing a hormone-binding polypeptide (A or B, but probably not both) bound to a non-hormone-binding protein (Mr approximately 90 kDa). Two molecules of the 90 kDa protein appear to be present in each '8S' receptor molecule. The 90 kDa protein is also associated with the non-activated forms of receptors of other steroid hormones in the chick. Molybdate stabilizes the non-activated receptors, probably by forming weak coordination bonds with radicals provided by the subunits of the '8S' structure. Activation implies separation of the subunits, without a change in their primary structure, and does not require intervention of any protein other than those present in the '8S' receptor form. The presence of ligand at the binding site accelerates the activation process but, in vitro, is not necessary for it to occur. Unlike the non-activated form, activated receptors bind to the cell nuclei. However, histological studies with anti-progesterone receptor antibodies indicate that in the non-hormone-exposed tissue the (non-activated) receptors could be localized in the nuclei.


Functional characterization of opioid receptor ligands by aequorin luminescence-based calcium assay.
A functional assay, based on aequorin-derived luminescence triggered by receptor-mediated changes in intracellular calcium levels, was used to examine relative potency and efficacy of the mu-opioid agonists endomorphin-1, endomorphin-2, morphiceptin, and their position 3-substituted analogs, as well as the delta-agonist deltorphin-II. The results of the aequorin assay, performed on recombinant cell lines, were compared with those obtained in the functional assay on isolated tissue preparations (guinea pig ileum and mouse vas deferens). A range of nine opioid peptide ligands produced a similar rank order of potency for the mu- and delta-opioid receptor agonists in both functional assays. The highest potency at the mu-receptor was observed for endomorphin-1, endomorphin-2, and [D-1-Nal3]morphiceptin, whereas deltorphin-II was the most potent delta-receptor agonist. In the aequorin assay, the mu- and delta-agonist-triggered luminescence was inhibited by the opioid antagonists naloxone and naltrindole, respectively. We can conclude that the use of the aequorin assay for new mu- and delta-receptor-selective opioid analogs gives pharmacologically relevant data and allows high-throughput compound screening, which does not involve radioactivity or animal tissues. This is the first study that validates the application of this assay in the screening of opioid analogs.


Engineering oscillating microtubule bundles.
From motility of simple protists to determining the handedness of complex vertebrates, highly conserved eukaryotic cilia and flagella are essential for the reproduction and survival of many biological organisms. Despite extensive studies, the exact mechanism by which individual components coordinate their activity to produce ciliary beating patterns remains unknown. We describe a novel approach toward studying ciliary beating. Instead of deconstructing a fully functional organelle from the top-down, we describe a process by which synthetic cilia-like structures are assembled from the bottom-up and we present methods for engineering such structures. We demonstrate how simple mixtures of microtubules, kinesin clusters, and a bundling agent assemble into structures that produce spontaneous oscillations, suggesting that self-organized beating may be a generic feature of internally driven bundles. Synthetic cilia-like structures can be assembled at high density, leading to synchronization and metachronal traveling waves, reminiscent of the waves seen in biological ciliary fields.


Cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha.
We report the cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha (fTNF-alpha). Messenger RNA was extracted from feline peritoneal macrophage cultures and used to synthesize cDNA for polymerase chain reaction (PCR) amplification. The PCR products were cloned into the plasmid vector pCRII and sequenced, showing 99.3% homology with a published fTNF-alpha gene sequence. Subcloning into the vector pGEX-2T and subsequent expression resulted in a 43 kDa fusion protein of fTNF-alpha and glutathione S-transferase (GST). Thrombin cleavage of the fusion protein yielded a 17 kDa protein. This protein cross-reacted with a monoclonal anti-human TNF-alpha antibody in Western blotting, but not with a polyclonal anti-murine TNF-alpha serum. Recombinant fTNF-alpha (rfTNF-alpha) and rfTNF-alpha-GST had a CD50 of 15 ng ml-1 and 230 ng ml-1, respectively, in the L929 cytotoxicity assay. Cats given rfTNF-alpha-GST intravenously manifested the typical biological effects of TNF-alpha, including fever, depression, and piloerection. The rfTNF-alpha-GST upregulated IL-2 receptor and MHC-II antigen expression on peripheral blood mononuclear cells stimulated in vitro, but had no effect on TNF-alpha receptor and MHC-I antigen expression.


FebriDx®: A Rapid Diagnostic Test for Differentiating Bacterial and Viral Aetiologies in Acute Respiratory Infections.
FebriDx® is a rapid, point-of-care diagnostic test that is designed to aid in the differentiation of bacterial and viral acute respiratory infections (ARIs), thus helping to guide decisions regarding the prescription of antibiotics in the outpatient setting. FebriDx carries a CE mark for use in the EU and is also approved in several other countries, including Canada, Saudi Arabia and Singapore. It is indicated for use in patients > 2 years old with symptoms consistent with a community-acquired ARI. The test involves the use of an immunoassay on a fingerstick blood sample to provide simultaneous, qualitative measurement of elevated levels of C-reactive protein (CRP) and myxovirus resistance protein A (MxA). In two prospective, multicentre studies in patients with acute upper respiratory tract infections, FebriDx was shown to be both sensitive and specific in identifying patients with a clinically significant infection and in differentiating between infections of bacterial and viral aetiology. The test is simple, requires no additional equipment and produces actionable results in ~ 10 min. As was demonstrated in a small, retrospective analysis, FebriDx results can help guide (improve) antibiotic prescribing decisions. Reducing the unnecessary or inappropriate prescription of antibiotics for ARIs of probable viral aetiology is important for antibiotic stewardship and can also reduce the unnecessary exposure of patients to the risk of antibiotic-related adverse events. FebriDx thus represents a useful diagnostic tool in the outpatient setting.


Occurrence of the toxigenic fungi (producers of aflatoxins and ochratoxin A) in foodstuffs in the Czech Republic 1999-2000.
The occurrence of toxigenic fungi producing aflatoxins and ochratoxin A in foodstuffs was studied in the Czech Republic. Twenty five commodities were collected at twelve collection places in the Czech Republic (300 food samples). The presence of potentially toxigenicAspergillus flavus was observed in 28% of the sampled foods (black pepper, caraway seeds, fruit tea, black tea, oat flakes, fine flour, rolled oat flakes and semolina) in the year 1999, and in 25% of the sampled foods (black pepper, black tea, fine flour) in the year 2000.A tamarii (aflatoxins producer) was found in 3 black pepper samples (25%) in both years. Aflatoxins were detected in black pepper and caraway seed samples in the year 1999 and in sweet red pepper in the year 2000.A parasiticus andA nomius were not isolated. Aspergillus section Nigri (potential producer of ochratoxin A) was detected in some foodstuffs. Ochratoxin A was detected in raisins.Penicillium verrucosum andA ochraceus were not isolated from foodstuffs.


Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells.
Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.


Fistula-in-ano: advances in treatment.
Several techniques have been described for the management of fistula-in-ano, but all carry their own risks of recurrence and incontinence. Technology has evolved over the past 2 decades that may enable surgeons to deal with this troublesome issue with greater success. This review summarizes the history of fistula-in-ano management, the current techniques available, and describes new technologies. Medline searches were performed using the PubMed, Ovid, Embase, Cochrane, and Google Scholar databases to identify articles reporting on fistula-in-ano management using surgery alone, fibrin glues, and fistula plugs. Forty-one articles reporting on the history of fistula-in-ano management and the use of new technologies were included. Conventional fistula surgery techniques have their place, but new technologies such as fibrin glues and the anal fistula plugs offer an alternative approach, with initial studies reporting good success rates. New technologies provide promising alternatives to traditional methods of management. There is, however, a real need for high-quality randomized control trials.


Evaluation of cerebral arterial and venous system in tuberculous meningitis.
Central nervous system infection especially pyogenic results in cerebral venous sinus thrombosis. Tuberculous meningitis (TBM) although associated with infarctions but there is no comprehensive study evaluating the role of CVST contributing in infarction. To evaluate cerebral arterial and venous system using MR angiography (MRA) and MR venography (MRV) in TBM, and correlate with clinical and MRI findings. Consecutive patients with TBM were evaluated clinically and their consciousness was assessed by using Glasgow Coma scale. Cerebrospinal fluid analysis was done. Patients were subjected to MRI, MRA and MRV studies. The severity of TBM was categorized as grades I to III. Presence of infarction on MRI and its cause as arterial or venous was noted based on MRA and MRV abnormalities. Twenty-six patients were included whose median age was 23 years. Seven (26.9%) patients had stage I, 12 (46.2%) stage II and 7 (26.9%) stage III TBM. MRI revealed infarction in 13 (50%) patients and were in tubercular zone (caudate, lentiform nuclei, anterior limb and genu of internal capsule, and anterior thalamus) in all except one. MRA was abnormal in 11/25 (42.3%) patients; 7 had middle cerebral artery, 2 both posterior cerebral artery and middle cerebral artery, and 2 had narrowing of all intracranial vessels. MRV however did not reveal any evidence of CVST although revealed variation in normal anatomy in 14 (53.8%) patients, commonest being hypoplastic transverse sinus. In TBM, infarction occurs in 50% patients, and is of arterial in origin. Cerebral venous system is usually spared in TBM.