Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.
The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy.


Sprouting of mossy fibers and presynaptic inhibition by group II metabotropic glutamate receptors in pilocarpine-treated rat hippocampal slice cultures.
Mossy fibre sprouting (MFS) is a phenomenon observed in the epileptic hippocampus. We have studied MFS, in 7, 14 and 21 day in vitro (DIV) organotypic slice cultures, or in slice cultures treated with pilocarpine (0.5 mM) or pilocarpine and atropine (0.1 mM or 0.5 mM) for 48-72 h at 5 DIV and tested at 21 DIV. Acute application of pilocarpine directly activated hilar neurons and elicited epileptic-like discharges in CA3 pyramids and mossy cells of 5-8 DIV cultures, without causing substantial cell death, as assessed by lactate dehydrogenase measurements. Timm staining revealed increases in MFS in chronic pilocarpine-treated cultures, which was prevented by prior application of atropine. Extracellular synaptic responses were recorded in the granule cell layer and elicited by antidromic mossy fibre stimulation. The GABA(A) antagonist 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid (1 microM) induced a greater increase in the coastline bursting index in pilocarpine-treated cultures than in 21 DIV controls. However, there was no significant increase in the frequency of spontaneous or miniature synaptic events recorded in granule cells from pilocarpine-treated cultures. Granule cells were filled with biocytin and morphometric analysis revealed that the length of axon collaterals in the granule and molecular layer was longer in pilocarpine-treated cultures than in 21 DIV controls. Dual recordings between granule cells and between granule and hilar neurons showed that pilocarpine-treated cultures had a larger proportion of monosynaptic and polysynaptic connections. The group II metabotropic glutamate receptor (mGluR) agonist LY354740 (0.5 microM) suppressed excitatory but not inhibitory monosynaptic currents. LY354740 also inhibited antidromically evoked action currents in granule cells from pilocarpine- and to a lesser extent in pilocarpine and atropine-treated cultures, suggesting that group II mGluRs can reside along the axon and suppress action potential invasion. We provide direct evidence for the development of functional MFS and suggest a novel, axonal mechanism by which presynaptic group II mGluRs can inhibit selected synapses.


Peyronie's disease following radical prostatectomy: incidence and predictors.
Both prostate cancer and Peyronie's disease (PD) are prevalent in men after their fifth decade of life. The evidence to support or refute a link between radical prostatectomy (RP) and PD is limited. To define the incidence of PD in men who had RP and determine possible predictors of PD development after RP. A review of a prospectively built sexual medicine database, years 2002-2008, looking at subjects who had RP as a monotherapy for localized prostate cancer. We identified and characterized subjects who developed PD within 3 years after RP and compared them with subjects who did not. The incidence of PD among men who attended a sexual medicine clinic after they had RP, predictors of PD development after RP. The study population included 1,011 subjects, and PD incidence in this population was 15.9%. Mean time to develop PD after RP was 13.9 +/- 0.7 months. Mean curvature magnitude was 31 + 17 degrees. On univariate analysis, younger age (mean age of 59 + 7 in men with PD vs. 60 + 7 years in men without PD, P = 0.006) and white race (vs non-white, 18% vs. 7%, P < 0.001) were predictive of PD development after RP, but post-op erectile function was not a predictor of PD development. On multivariate analysis, younger age (odds ratio (OR) = 1.3, for 5-year decrease in age) and white race (OR = 4.1, vs. non-white) remained independent significant predictors. Men presenting with sexual dysfunction after RP have higher PD incidence then the general population. Therefore, they should be routinely evaluated for PD. Younger men and men of white race are at increased risk for PD. Prospective controlled studies are needed to elucidate the incidence of PD following RP and to conclude if RP has a causative role in the pathogenesis of PD.


Classification of MSH6 Variants of Uncertain Significance Using Functional Assays.
Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.


Nurses' Remaining in Everyday Nursing Practice-A Comprehensive Model.
Previous theoretical and empirical models of nurses' remaining in everyday nursing practice are explained by elements such as intent to stay and desire to stay. This study provides a model that expands or expresses an increased understanding of the comprehensiveness of the issue by pointing to the qualitative worth of different desires. The aim of this study is to describe a comprehensive model of nurses' remaining in everyday nursing practice. This study was designed in three sequential stages: first, the empirical foundation of the model; second, the development of the model; and third, the description of the model. The described model is derived from a previous qualitative study's comprehensive understanding of empirical findings. That original study was based on a hermeneutical approach, the aim of which was to understand what is of significance for nurses to remain in everyday practice. The collected data consisted of qualitative interviews and qualitative follow-up interviews with 13 nurses. The research context was the primary and secondary somatic and psychiatric health service. The present comprehensive model is stated in a simple structure, which nonetheless provides a relevant framework for constituent elements of nurses' remaining in everyday practice. Horizons of identity and self-understanding have been identified as constituent elements or key concepts involved in remaining. By focusing on a deepened and broader understanding, the model highlights that remaining may be constituted through a process of identification and taking standpoints, which in turn has a potential to empower nurses to realize themselves.


Upregulation of the Suppressors of Cytokine Signaling 1 and 3 Is Associated with Arrest of Phosphorylated-STAT1 Nuclear Importation and Reduced Innate Response in Denguevirus-Infected Macrophages.
To clarify whether the suppressors of cytokine signaling (SOCS) are associated with denguevirus (DENV) evasion of the antiviral response, we analyzed the expression kinetics of SOCS1 and SOCS3 and of the antiviral genes MxA and OAS during DENV infection of U937 macrophages that were or not treated with interferon (IFN)-α. DENV infection produced a viral titer three times higher in untreated than in IFN-α-treated cells (p < 0.001 at 72 h postinfection [p.i.]). Partial inhibition of DENV replication was associated with reduced expression of MxA and OAS antiviral genes as well as higher SOCS1 and SOCS3 expression in DENV-infected cells than in cells treated only with IFN-α. Complete loss of phosphorylated-signal transducer and activator of transcription (p-STAT)2 and reduced nuclear importation of p-STAT1 were observed in DENV-infected cells compared to IFN-α treatment that induced p-STAT1 and p-STAT2. Our data thus suggest that overexpression of SOCS1 and SOCS3 induced by DENV infection leads to impairment of antiviral response through the inhibition of STAT functionality.


Resilience is strongly associated with health-related quality of life but does not buffer work-related stress in employed persons 1 year after acute myocardial infarction.
Resilience may facilitate the adaptation after experiencing a severe disease such as acute myocardial infarction (AMI) and attenuate the negative effects of stress on health-related quality of life (HRQOL). However, it is unclear so far whether resilience moderates a negative association between work-related stress and HRQOL in employed patients after AMI. Patients with confirmed AMI and regular paid employment admitted to a hospital in the study region of the MONICA/KORA Myocardial Infarction Registry, Germany (04/2014-06/2017) were included and completed questionnaires during their hospital stay and 6 and 12 months after discharge. The Resilience Questionnaire (RS-11) and the Effort-Reward Imbalance (ERI) Questionnaire were used to assess trait resilience and ERI, respectively. HRQOL was measured by the Short Form 36 Health Survey (SF-36) mental and physical component summary scales. Generalized estimating equations (GEE) adjusted for relevant potential confounding variables (demographic, social, stress-related, and clinical) were used to determine the association between resilience and HRQOL in the study course. From the 346 patients enrolled in the study, 270 patients (78.0%) had completed all surveys. High baseline trait resilience was significantly and independently associated with high physical HRQOL (ß = 0.15, p < 0.0001) and high mental HRQOL (ß = 0.37, p < 0.0001) 1 year post AMI. No significant interaction effects between trait resilience and ERI were found in the physical HRQOL GEE model (ß = 0.05, p = 0.7241) and in the mental HRQOL model (ß = 0.05, p = 0.3478). The results demonstrated that trait resilience is independently and strongly related with post-AMI HRQOL but does not moderate the association between ERI and HRQOL.


Long-term effects of directed forgetting.
The intention to forget reduces the accessibility of information in memory, which is commonly explained with temporary retrieval difficulties. Long-term effects have rarely been studied, and results are inconsistent. The present study re-assessed the long-term effects of directed forgetting (DF). Participants encoded a first list of items (L1), and were then instructed to forget or to remember this list. Immediately afterwards, all participants were presented with a second list to remember. In Experiment 1, memory for L1 and L2 was assessed after a 24-h delay. The forget cue reduced the number of items that were recalled from L1. Experiment 2 implemented a 12-h delay between encoding and test that was either filled with day-time wakefulness or night-time sleep. Replicating the findings of Exp. 1, recall of L1 was reduced in the forget in comparison to the remember condition. Sleep in comparison to wakefulness significantly strengthened L1 memory in the remember group only. Taken together, the present study shows that the intention to forget can have long-lasting consequences. This suggests that different mechanisms underlie the short- and long-term effects of DF, with long-term effects potentially reflecting the preferential consolidation of information that has been identified as important during encoding.


QuadraPure-supported palladium nanocatalysts for microwave-promoted Suzuki cross-coupling reaction under aerobic condition.
Cross-linked resin-captured palladium (XL-QPPd) was readily prepared by simple physical adsorption onto the high loading QuadraPure macroporous resin and a subsequent reduction process. To enhance the mechanical stability, entrapped palladium nanocatalysts were cross-linked with succinyl chloride. Both transmission electron microscopy images and X-ray diffraction analysis revealed that the palladium nanoparticles were well dispersed with diameters ranging in 4-10 nm. The catalyst performed good catalytic activity in microwave-promoted Suzuki cross-coupling reactions in water under aerobic condition with mild condition by using various aryl halides and phenylboronic acid. In addition, the catalyst showed an excellent recyclability without significant loss of catalytic activity.


The Transcriptional Effects of PCB118 and PCB153 on the Liver, Adipose Tissue, Muscle and Colon of Mice: Highlighting of Glut4 and Lipin1 as Main Target Genes for PCB Induced Metabolic Disorders.
Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved.


Joint distraction using a purpose-built device for knee osteoarthritis: a prospective 2-year follow-up.
Knee distraction treatment for end-stage osteoarthritis successfully postpones arthroplasty for years. Studies performed thus far used general intended use, patient-personalised or custom-made devices. In this study, for the first time, a device specifically designed for knee distraction is evaluated. 65 patients (≤65 years) with end-stage knee osteoarthritis indicated for arthroplasty received knee distraction. Before, 1-year and 2-year post-treatment, questionnaires were filled out and knee radiographs made. Adverse events and self-reported pain medication were registered. Forty-nine patients completed 2-year follow-up: one patient did not complete treatment, three patients received arthroplasty in the first and four patients in the second year follow-up. Eight patients were lost to follow-up in the second year. The total Western Ontario and McMaster Universities Osteoarthritis Index score showed a clinically relevant improvement at 1 and 2 years (+26 and +24 points), as did all subscales (all p<0.001). The minimum radiographic joint space width improved over 1 (+0.5 mm; p<0.001) and 2 (+0.4 mm; p=0.015) years, as did the physical Short-Form 36 (+10 points; p<0.001). The most common adverse event was pin tract infection, experienced by 66% of patients, in 88% successfully treated with oral antibiotics. In two cases, hospitalisation and/or intravenous antibiotics were needed. Eight patients experienced device-related complications. None of the complications influenced 2-year outcomes. Before treatment, 42% of patients used pain medication, which had nearly been halved 1 (23%; p=0.02) and 2 years (29%; p=0.27) post-treatment. Patients treated with a general applicable, for knee distraction purpose-built device showed, despite adverse events, significant clinical and structural improvement over 2 years. NL7986.


Application of radial ray based segmentation to cervical lymph nodes in CT images.
The 3D-segmentation of lymph nodes in computed tomography images is required for staging and disease progression monitoring. Major challenges are shape and size variance, as well as low contrast, image noise, and pathologies. In this paper, radial ray based segmentation is applied to lymph nodes. From a seed point, rays are cast into all directions and an optimization technique determines a radius for each ray based on image appearance and shape knowledge. Lymph node specific appearance cost functions are introduced and their optimal parameters are determined. For the first time, the resulting segmentation accuracy of different appearance cost functions and optimization strategies is compared. Further contributions are extensions to reduce the dependency on the seed point, to support a larger variety of shapes, and to enable interaction. The best results are obtained using graph-cut on a combination of the direction weighted image gradient and accumulated intensities outside a predefined intensity range. Evaluation on 100 lymph nodes shows that with an average symmetric surface distance of 0.41 mm the segmentation accuracy is close to manual segmentation and outperforms existing radial ray and model based methods. The method's inter-observer-variability of 5.9% for volume assessment is lower than the 15.9% obtained using manual segmentation.


Intraoperative use of diffusion tensor imaging fiber tractography and subcortical mapping for resection of gliomas: technical considerations.
Resection of lesions involving motor or language areas or pathways requires the intraoperative identification of functional cortical and subcortical sites for effectively and safe guidance. Diffusion tensor (DT) imaging and fiber tractography are MR imaging techniques based on the concept of anisotropic water diffusion in myelinated fibers, which enable 3D reconstruction and visualization of white matter tracts and provide information about the relationship of these tracts to the tumor mass. The authors routinely used DT imaging fiber tractography to reconstruct various tracts involved in the motor and/or language system in a large series of patients with lesions involving the motor and/or language areas or pathways. The DT imaging fiber tractography data were loaded into the neuronavigational system and combined intraoperatively with those obtained from direct electrical stimulation applied at the subcortical level. In this paper the authors report the results of their experience, describing the findings for each tract and discussing technical aspects of the combined use as well as the pitfalls.


Pneumomediastinum from acute inhalation of chlorine gas in 2 young patients.
Trichloroisocyanuric acid is a high-efficiency and-low toxicity fungicide and bleach. It is commonly used as disinfectant for industrial circulating water, swimming pools, restaurants, and other public places in China. When trichloroisocyanuric acid is put into water, chlorine gas is produced. Chlorine gas is a potent pulmonary irritant that causes acute damage in both the upper and lower respiratory tracts (J Toxicol Clin Toxicol. 1998;36(1-2):87-93). Pneumomediastinum is a rare complication in patients with acute chlorine gas poisoning. A small amount of gas can be asymptomatic, but a large amount of gas entering the mediastinum suddenly will lead to respiratory and circulatory disorder, mediastinal swing, or even cardiopulmonary arrest. Severe chlorine gas poisoning patients usually need mechanical ventilation; if the pneumomediastinum is not found on time, threat to life would be greatly increased. It requires a high index of suspicion for diagnosis and rapid treatment. The proper use of ventilator, timely and effective treatment of original disease, and multiple system organ support had significant impact on the prognosis. The pneumomediastinum case secondary to inhalation of chlorine gas that we report here should remind all emergency department physicians to maintain a high index of suspicion for this disease and seek immediate and proper intervention when treating patients with acute chlorine gas poisoning, once diagnosed, especially in younger patients.


Thyroseq V3 Molecular Profiling for Tailoring the Surgical Management of Hürthle Cell Neoplasms.
Hürthle cell predominant thyroid nodules often confound the diagnostic utility of fine needle aspiration biopsy (FNAB) with cytology often interpreted as a Hürthle cell lesion with an indeterminate risk of malignancy, Bethesda category (BC) III or IV. Molecular diagnostics for Hürthle cell predominant nodules has also been disappointing in further defining the risk of malignancy. We present a case of a slowly enlarging nodule within a goiter initially reported as benign on FNAB, BC II but on subsequent FNAB suspicious for a Hürthle cell neoplasm, BC IV. The patient had initially requested a diagnostic lobectomy for a definitive diagnosis despite a higher risk of malignancy based on the size of the nodule > 4 cm alone. To better tailor this patient's treatment plan, a newer expanded gene mutation panel, ThyroSeq® v3 that includes copy number alterations (CNAs) and was recently found to have greater positive predictive value (PPV) for identifying Hürthle cell carcinoma (HCC), was performed on the FNAB material. Molecular profiling with ThyroSeq® v3 was able to predict a greater risk of carcinoma, making a more convincing argument in favor of total thyroidectomy. Surgical pathology confirmed a Hürthle cell carcinoma with 5 foci of angioinvasion and foci of capsular invasion.


Top Ten Tips Palliative Care Clinicians Should Know About Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Rapidly proliferating leukemic cells cause symptoms and increase the risk of infection. While individuals may initially benefit from supportive measures, disease-directed therapy may ultimately be required for symptom management, even at the end of life, although this may also inadvertently increase symptom burden. This unpredictable illness trajectory complicates prognostic uncertainty and the timing of hospice referral, which may prohibit access to palliative therapies and lead to recurrent hospitalizations. However, emerging evidence demonstrates that early palliative care (PC) integration with standard leukemia care results in improved quality of life, psychological outcomes, and greater participation in advance care planning. To orient PC clinicians asked to care for patients with AML, this article highlights 10 salient considerations.


Visual marking and visual change.
Five experiments investigated the types of changes that disrupt the preview effect--the benefit gained in difficult search tasks from presenting some distractors earlier in time. A shape change with or without an overall luminance change at the location of an old item was found to disrupt the preview effect, whereas an equivalent luminance change alone or an isoluminant color change was not disruptive. Results suggest that (a) relatively low-level visual changes may not be sufficient to abolish the benefit, (b) the benefit most likely occurs through inhibition applied to locations within a location master map, and (c) inhibition need not be applied to surface features of objects.


The transmembrane domains of hepatitis C virus envelope glycoproteins E1 and E2 play a major role in heterodimerization.
Oligomerization of viral envelope proteins is essential to control virus assembly and fusion. The transmembrane domains (TMDs) of hepatitis C virus envelope glycoproteins E1 and E2 have been shown to play multiple functions during the biogenesis of E1E2 heterodimer. This makes them very unique among known transmembrane sequences. In this report, we used alanine scanning insertion mutagenesis in the TMDs of E1 and E2 to examine their role in the assembly of E1E2 heterodimer. Alanine insertion within the center of the TMDs of E1 or E2 or in the N-terminal part of the TMD of E1 dramatically reduced heterodimerization, demonstrating the essential role played by these domains in the assembly of hepatitis C virus envelope glycoproteins. To better understand the alanine scanning data obtained for the TMD of E1 which contains GXXXG motifs, we analyzed by circular dichroism and nuclear magnetic resonance the three-dimensional structure of the E1-(350-370) peptide encompassing the N-terminal sequence of the TMD of E1 involved in heterodimerization. Alanine scanning results and the three-dimensional molecular model we obtained provide the first framework for a molecular level understanding of the mechanism of hepatitis C virus envelope glycoprotein heterodimerization.


Incidence of abnormal RNA studies and dysrhythmias in patients with blunt chest trauma.
The incidence and significance of myocardial contusion and subsequent cardiac complications have recently been debated. A prospective study of patients with blunt chest trauma was undertaken at a Regional Trauma Unit between January 1, 1989 and March 31, 1990. One hundred ninety-one patients were entered into the study; 72-hour Holter monitoring was performed in 183 patients, and radionuclide angiography (RNA) was performed on 163 patients. All patients had CPK levels (with CPK-mb fractions) measured, and serial electrocardiographs. There were seven patients with abnormal RNA studies; five of the seven abnormal studies were attributable to previously undiagnosed coronary artery disease or myocardial infarction. Nine patients were diagnosed as having atrial fibrillation, seven of whom were in atrial fibrillation on admission. Ventricular dysrhythmias were classified by the number of premature ventricular contractions (PVCs) per hour or the presence of ventricular tachycardia. Twelve patients developed short runs of ventricular tachycardia, and clinically insignificant PVCs were common. Only one patient with ventricular dysrhythmias (frequent PVCs) was treated and there were no hemodynamically significant dysrhythmias. The incidence of clinically significant dysrhythmias or hemodynamically significant myocardial contusion appears to be low in this patient population. Aggressive investigation and monitoring solely for cardiac complications may not be indicated.


Effect of transfused reticulocytes on iron exchange.
A animal model was developed whereby reticulocyte-rich blood was introduced into normal rats by exchange transfusion. Measurements of plasma iron turnover was made at similar plasma iron concentrations before and after exchange transfusions. High reticulocyte blood obtained from animals rendered iron deficient by diet or by treatment with phenylhydrazine resulted in a mean increase of 86% in internal iron exchange, while the plasma iron turnover was unaffected by exchange with normal red cells. Since iron input from reticuloendothelial cells could have increased due to breakdown of transfused cells, iron absorption was also measured. Within 1 hr and for a least 6 hr after exchange with high reticulocyte blood, mean absorption in six groups of animals was increased over control animals by 50%-130%. The increased plasma iron turnover and absorption was not mediated by a decrease in plasma iron or an increase in unsaturated iron-binding capacity. Indeed, a higher plasma iron and transferrin saturation augmented the movement of iron into the plasma from iron-donating tissues. It is proposed that the donation of iron by transferrin in some way immediately facilitates the procurement of more iron by transferrin.


Deriving in Vivo Bioconcentration Factors of a Mixture of Fragrance Ingredients Using a Single Dietary Exposure and Internal Benchmarking.
Chemicals in mixtures that are hydrophobic with Log KOW > 4 are potentially bioaccumulative. Here, we evaluate an abbreviated and benchmarked in vivo BCF measurement methodology by exposing rainbow trout to a mixture of eight test chemicals found in fragrance substances and three benchmark chemicals (musk xylene (MX), hexachlorobenzene (HCB) and PCB52) via a single contaminated feeding event followed by a 28-day depuration period. Concentrations of HCB and PCB52 in fish did not decline significantly (their apparent depuration rate constants, kT, were close to zero), whereas kT for MX was 0.022 d-1. The test chemicals were eliminated much more rapidly than the benchmark chemicals ( kT > 0.117 d-1). The bioconcentration factors (BCFA) for the test chemicals were in the range of 273 L kg-1 (8-cyclohexadecen-1-one (globanone)) to 1183 L kg-1 (α-pinene); the benchmarked BCFs (BCFG) calculated relative to HCB ranged from 238 L kg-1 (globanone) to 1147 L kg-1 (α-pinene). BCFG were not significantly different from BCFA but had smaller standard errors. BCFs derived here agreed well with values previously measured using the OECD 305 test protocol. We conclude that it will be feasible to derive BCFs of chemicals in mixtures using a single dietary exposure and chemical benchmarking.


Stereoselective synthesis of 4 alpha-hydroxy-8,12-guaianolides from santonin
Hydroxyester 2, easily obtained from santonin (1), has been transformed into 10 alpha-hydroxyguai-3-en-8,12-olide 6, a good intermediate for the synthesis of natural 8,12-guaianolides. Compound 6 was obtained from 2 by photochemical rearrangement of its acetyl derivative 7, stereoselective hydrogenation on Pd/C, reduction, regioselective elimination, hydrolysis, and lactonization. The synthesis of the natural guaianolides 3-5 was carried out in two sequences in which the regioselective elimination of a hydroxyl group at C10 with triflic anhydride or SOCl2 to afford, respectively, the endo or exo double bond on C10 and the regioselective opening of the C3-C4 alpha-epoxide were the key steps.


Discovery of 2-aryl and 2-pyridinylbenzothiazoles endowed with antimicrobial and aryl hydrocarbon receptor agonistic activities.
Benzothiazole is a privileged scaffold in medicinal chemistry present in diverse bioactive compounds with multiple pharmacological applications such as analgesic, anticonvulsant, antidiabetic, anti-inflammatory, anticancer and radioactive amyloidal imagining agents. We reported in this work the study of sixteen functionalized 2-aryl and 2-pyridinylbenzothiazoles as antimicrobial agents and as aryl hydrocarbon receptor (AhR) modulators. The antimicrobial activity against Gram-positive (S. aureus and M. luteus) and Gram-negative (P. aeruginosa, S. enterica and E. coli) pathogens yielded MIC ranging from 3.13 to 50 μg/mL and against the yeast C. albicans, the benzothiazoles displayed MIC from 12.5 to 100 μg/mL. All compounds showed promising antibiofilm activity against S. aureus and P. aeruginosa. The arylbenzothiazole 12 displayed the greatest biofilm eradication in S. aureus (74%) subsequently verified by fluorescence microscopy. The ability of benzothiazoles to modulate AhR expression was evaluated in a cell-based reporter gene assay. Six benzothiazoles (7, 8-10, 12, 13) induced a significant AhR-mediated transcription and interestingly compound 12 was also the strongest AhR-agonist identified. Structure-activity relationships are suggested herein for the AhR-agonism and antibiofilm activities. Furthermore, in silico predictions revealed a good ADMET profile and druglikeness for the arylbenzothiazole 12 as well as binding similarities to AhR compared with the endogenous agonist FICZ.


The presence of a virulence locus discriminates Fusarium oxysporum isolates causing tomato wilt from other isolates.
Fusarium oxysporum is an asexual fungus that inhabits soils throughout the world. As a species, F. oxysporum can infect a very broad range of plants and cause wilt or root rot disease. Single isolates of F. oxysporum, however, usually infect one or a few plant species only. They have therefore been grouped into formae speciales (f.sp.) based on host specificity. Isolates able to cause tomato wilt (f.sp. lycopersici) do not have a single common ancestor within the F. oxysporum species complex. Here we show that, despite their polyphyletic origin, isolates belonging to f.sp. lycopersici all contain an identical genomic region of at least 8 kb that is absent in other formae speciales and non-pathogenic isolates, and comprises the genes SIX1, SIX2 and SHH1. In addition, SIX3, which lies elsewhere on the same chromosome, is also unique for f.sp. lycopersici. SIX1 encodes a virulence factor towards tomato, and the Six1, Six2 and Six3 proteins are secreted in xylem during colonization of tomato plants. We speculate that these genes may be part of a larger, dispensable region of the genome that confers the ability to cause tomato wilt and has spread among clonal lines of F. oxysporum through horizontal gene transfer. Our findings also have practical implications for the detection and identification of f.sp. lycopersici.


Development an electronic nose to recognize pesticides in groundwater.
Timely detection of Groundwater pollution is essential to protect human health, especially for pesticide pollution. To solve this issue, we proposed a novel solution to realize the prediction of pesticide in groundwater by using the electronic nose (e-nose). The main work of this paper was divided into three steps: 1) checking whether sample was polluted by pesticides, 2) further predicting the pesticide type, brand and pollution degree when the sample was polluted by pesticides, and 3) optimizing the sensor array. Random forest was used to complete the first step, which had the best accuracy and sensitivity of 100 %. Support vector machine was applied to complete the second step, and the accuracy reaching 98.08 %. As for the third step, recursive feature elimination was used to optimize the sensor array. After optimization, the number of sensors was reduced from 26 to 8. In addition, the e-nose developed in this paper was compared with a commercial e-nose. The results showed that the cost of the developed e-nose was much lower than that of the commercial e-nose despite its slightly weaker prediction performance. Thus, this e-nose can be employed to recognize the pesticides in groundwater, and even can be integrated into the while drilling technology to realize the in-situ detection of groundwater.


Determination of the Pharmacokinetics and Pharmacodynamics of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in a Cross-Over Cynomolgus Macaque Model of Mycobacterium tuberculosis Infection.
Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of Mycobacterium tuberculosis (M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-γ ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs.


Inhibition of Biofilm Formation by the Synergistic Action of EGCG-S and Antibiotics.
Biofilm, a stress-induced physiological state, is an established means of antimicrobial tolerance. A perpetual increase in multidrug resistant (MDR) infections associated with high mortality and morbidity have been observed in healthcare settings. Multiple studies have indicated that the use of natural products can prevent bacterial growth. Recent studies in the field have identified that epigallocatechin gallate (EGCG), a green tea polyphenol, could disrupt bacterial biofilms. A modified lipid-soluble EGCG, epigallocatechin-3-gallate-stearate (EGCG-S), has enhanced the beneficial properties of green tea. This study focuses on utilizing EGCG-S as a novel synergistic agent with antibiotics to prevent or control biofilm. Different formulations of EGCG-S and selected antibiotics were used to study their combinatorial effects on biofilms produced by five potential pathogenic bacteria, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and Mycobacterium smegmatis. The crystal violet (CV) assay and the sensitive fluorescence-based resazurin biofilm viability assay were used to assess the biofilm production. Our results identified optimal formulation for each bacterium, effectively inhibiting biofilm formation to an extent of 95-99%. Colony-forming unit (CFU) and cell viability analyses showed a decrease of viable bacteria. These results depict the potential of EGCG-S as a synergistic agent with antibiotics and as an anti-biofilm agent.


Selective detection of complementarity-determining regions of monoclonal antibody by limiting protease access to the substrate: nano-surface and molecular-orientation limited proteolysis.
We report a novel method for the selective proteolysis by limiting protease access to the substrate, which we have named nano-surface and molecular-orientation limited (nSMOL) proteolysis. We focus on the identification of the Fab and quantitation of antibodies. This method successfully performed limited proteolysis on the Fab.


Youth perspectives on mobile health adherence interventions: A qualitative study guided by the supportive accountability model.
We applied a Supportive Accountability Model lens to understand how youth view remote human coaching versus automated reminders targeting medication adherence. We used thematic analysis to interpret (N = 22) youths' responses to semi-structured interviews after 12 weeks of mobile health intervention. Participants reported that both coaching and automated reminders prompted them to take medication, improving their adherence. Participants found coaching helpful because they developed routines and strategies, were motivated to avoid disappointing their coach, and felt their coach cared for them. Automated support could be motivational for some but demanded less engagement. Participants described phone calls as disruptive to their daily lives, but conducive to developing a personal connection with their coach, whereas texts were easier and more flexible. Youth emphasized that individual preferences often differ. Human coaching was viewed as a more potent, engaging adherence intervention than automated reminders, although individual needs and preferences differed. Phone calls may enhance the experience of supportive accountability for adherence, but also pose greater acceptability and usability barriers than texting. Intervention developers should provide opportunities for youth to make personal connections with human adherence supporters and attend to youth preferences for communication modality.


Effects of Proximity between Companion Dogs and Their Caregivers on Heart Rate Variability Measures in Older Adults: A Pilot Study.
Heart rate variability (HRV) is a noninvasive tool used to evaluate autonomic nervous system function and is affected by age, stress, postural changes, and physical activity. Dog ownership has been associated with higher 24-hr HRV and increased physical activity compared to nonowners. The current pilot study was designed to evaluate the effects of proximity to a dog in real time (minute-by-minute) on older dog caregivers' HRV measures and stress index during normal daily life over a 24-hr period. Eleven caregivers (56-83 years of age) wore ActiGraph GT9X Link accelerometers and camntech electrocardiogram monitors, and 11 dogs wore PetPace Collars and ActiGraph monitors to determine (a) proximity (absence or presence of Received Signal Strength Indicator, RSSI), (b) heart rate and HRV measures, (c) position (lying vs. sitting vs. standing), and (d) physical activity in the 11 dyads. Twenty-four hour HRV (SDNN index) and physical activity in the caregivers and dogs were related. Stress index was lower, and HRV parameters (SDNN, rMSDD, high frequency power (HF)) were higher when an RSSI signal was detected (presence of dog) compared to no RSSI signal (absence of dog) in the caregivers while inactive (lying + sitting + standing combined). HRV parameters (rMSDD and HF) were lower in the caregivers while standing and sitting compared to lying. The results from this pilot study support the hypothesis that spending time in the presence of a companion dog increases caregivers' HRV throughout the day and suggest that proximity to a dog may contribute to overall improvements in 24-hr HRV and cardiac health in dog caregivers.


Arrangement of water molecules and high proton conductivity of tunnel structure phosphates, KMg1-x H2x (PO3)3·yH2O.
A fast proton conductor was investigated in a mixed-valence system of phosphates with a combination of large cations (K+) and small cations (Mg2+), which resulted in a new phase with a tunnel structure suitable for proton conduction. KMg1-x H2x (PO3)3·yH2O was synthesized by a coprecipitation method. A solid solution formed in the range of x = 0-0.18 in KMg1-x H2x (PO3)3·yH2O. The structure of the new proton conductor was determined using neutron and X-ray diffraction measurements. KMg1-x H2x (PO3)3·yH2O has a tunnel framework composed of face-shared (KO6) and (MgO6) chains, and PO4 tetrahedral chains along the c-direction by corner-sharing. Two oxygen sites of water molecules were detected in the one-dimensional tunnel, one of which exists as a coordination water of K+ sites. Multi-step dehydration was observed at 30 °C and 150 °C from thermogravimetric/differential thermal analysis measurements, which reflects the different coordination environments of the water of crystallization. Water molecules are connected to PO4 tetrahedra by hydrogen bonds and form a chain along the c-axis in the tunnel, which would provide an environment for fast proton conduction associated with water molecules. The KMg1-x H2x (PO3)3·yH2O sample with x = 0.18 exhibited high proton conductivity of 4.5 × 10-3 S cm-1 at 150 °C and 7.0 × 10-3 S cm-1 at 200 °C in a dry Ar gas flow and maintained the total conductivity above 10-3 S cm-1 for 60 h at 150 °C under N2 gas atmosphere.


Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.
Synthesis of normal human hemoglobin A, alpha 2 beta 2, is based upon balanced expression of genes in the alpha-globin gene cluster on chromosome 16 and the beta-globin gene cluster on chromosome 11. Full levels of erythroid-specific activation of the beta-globin cluster depend on sequences located at a considerable distance 5' to the beta-globin gene, referred to as the locus-activating or dominant control region. The existence of an analogous element(s) upstream of the alpha-globin cluster has been suggested from observations on naturally occurring deletions and experimental studies. We have identified an individual with alpha-thalassemia in whom structurally normal alpha-globin genes have been inactivated in cis by a discrete de novo 35-kilobase deletion located approximately 30 kilobases 5' from the alpha-globin gene cluster. We conclude that this deletion inactivates expression of the alpha-globin genes by removing one or more of the previously identified upstream regulatory sequences that are critical to expression of the alpha-globin genes.


Are ions involved in the gating of calcium channels?
The rates of activation and deactivation of the currents carried by calcium, strontium, or barium ions through the voltage-sensitive calcium channel of Paramecium are different. The differences cannot be attributed to complications due to internal ion concentration, calcium channel inactivation, potassium current activation, surface charge effects, or incomplete space clamping. The findings indicate participation of the divalent cations in the voltage-driven calcium channel gating process.


In vitro genotoxicity and in silico Docking Analyses of the Essential Oils of Thuja orientalis.
Two main objectives were pursued to assess the reliability of Thuja orientalis essential oils (TOEO). The first objective was to extract TOEO, analyze them by GC-MS, and determine their in vitro genotoxicity against selected plants using the RAPD-PCR method. The second objective was to evaluate the in-silico toxicity of TOEO. The binding sites and energies of each content was calculated against B-DNA. In-silico analyses were performed using a simulation program, AutoDock Vina, and Toxicity Estimation Software Tools. 3-carene, cedrol, and 2-pinene were identified as the predominant components. In vitro studies showed that the TOEO had a more significant impact on reducing genomic stability in wheat compared to the amaranth. The lowest stability was determined as 39.78% in wheat and 53.58% in amaranth. Cedrol (-5,7 kcal/mol) and selinene (-5,6 kcal/mol) exhibited the highest binding affinity. The toxicity test indicated that components other than cyclohexene may have toxic effects, none of them were predicted to be mutagenic, and LD50 (mol/kg) values could vary between 1.33 and 1.55.


Introduction to the 2019 Philadelphia Prostate Cancer Consensus Program: 'Implementation of Genetic Testing for Inherited Prostate Cancer'.
In 2017 the Sidney Kimmel Cancer Center of Thomas Jefferson University held the first international consensus conference on the role of genetic testing for inherited prostate cancer risk. This article outlines the key elements of our 2017 consensus meeting and discusses the rationale and design of our follow up 2019 Philadelphia Prostate Cancer Consensus titled the 'Implementation of Genetic Testing for Inherited Prostate Cancer.'


Frequent premature ventricular contractions in an orbital spaceflight participant.
Commercial spaceflight participants on orbital flights typically are older than career astronauts and they often have medical conditions that have not been studied at high g or in microgravity. This is a case report of a 56-yr-old orbital spaceflight participant with essential tremor and frequent premature ventricular contractions that occurred at rates up to 7000 per day. Before training and spaceflight, he was required to complete extensive clinical investigations to demonstrate normal cardiac structures and the absence of cardiac pathology. The evaluation included signal averaged ECG, transthoracic stress echocardiography, exercise tolerance tests, electrophysiological studies, cardiac MRI, electron beam CT, Holter monitoring, and overnight oximetry. While no cardiac pathology was demonstrated, the Russian medical team required that the PVCs be treated prior to training and spaceflight. For the initial flight, a selective beta-1 receptor beta blocker was used and for the second a calcium channel blocker was used in combination with a nonselective beta blocker for tremor control. Analogue environment testing assured that this combination of medications was compatible. The spaceflight participant's PVCs were incompletely suppressed with a low-dose selective beta-1 blocker, but were well suppressed by a calcium channel blocker. He tolerated in-flight periodic use of a nonselective beta blocker in combination with a calcium channel blocker. In-flight ECG and blood pressure monitoring results were normal, and an ECG obtained midmission and on landing day showed successful PVC suppression. He did not have any cardiac difficulty with launch, on-orbit operations, entry, or recovery


A study of silent disengagement and distressing emotion in psychotherapy.
Fifty-two psychotherapy sessions were coded for silences that reflect processes of client disengagement (e.g., withdrawal, resistance). The study examined the presence of these silences and clients' reports of in-session emotion and symptom change. Results indicated that disengagement predicted poorer proximal and distal outcome as measured by the Beck Depression Inventory for Primary Care (BDI-PC) and poorer proximal outcome on the Symptom Checklist-5, but it was not significantly predictive of Outcome Questionnaire-45 scores. Interitem analyses revealed that disengagement had a significant proximal effect on depressive mood and negative self-evaluative items assessed by the BDI-PC, but across time these effects were sustained for the negative self-evaluative items only.


Effect of initial sarcomere length on sarcomere kinetics and force development in single frog atrial cardiac cells.
We studied sarcomere performance in single isolated intact frog atrial cells using techniques that allow direct measurement of sarcomere length and force. The purpose of this investigation was to determine whether length-dependent alterations in contractile activation occur in the single isolated cardiac cell. This was accomplished by determining the effect of initial sarcomere length on the time course of sarcomere shortening and force development during auxotonic twitch contractions. The results presented in this paper demonstrate that the velocity of sarcomere shortening, the rate of force development, and the magnitude of force development during auxotonic twitch contractions all increase as initial sarcomere length increases over the range of about 2 micrometers to greater than 3 micrometers. These results indicate that the level of contractile activation increases as initial sarcomere length increases. Also, results are presented that indicate that the rate of increase of contractile activation during a twitch contraction also increases as initial sarcomere length increases. These length-dependent effects on contractile activation in conjunction with the slow time course of contractile activation cause the force-velocity-length relationship to be time-dependent: i.e., the velocity of sarcomere shortening at a given sarcomere length and load depends on the time during the contraction when the sarcomere reaches that length. The results suggest that length-dependent alterations in contractile activation may play a major role in the improved contractile performance that accompanies an increase in initial sarcomere length in cardiac muscle.


Solitary Pulmonary Fibroleiomyomatous Hamartoma on 18 F-FDG PET/CT.
Solitary pulmonary fibroleiomyomatous hamartoma is a very rare benign tumor. A 57-year-old man presented with dry cough over 1 month. A CT showed an irregular nodule in the left upper lobe of the lung. A malignant tumor was suspected, and further investigation with 18 F-FDG PET/CT showed the pulmonary nodule with slightly increased FDG uptake. Thoracoscopic resection was performed. Subsequent histopathological and immunohistochemical tests confirmed the diagnosis of fibroleiomyomatous hamartoma.


Interferon-gamma inhibits the intrahepatocytic development of malaria parasites in vitro.
In this study, we examined the activity of recombinant interferon (IFN)-gamma against Plasmodium berghei exoerythrocytic forms (EEF) grown in vitro within the highly differentiated human hepatoma cell line HEPG2. We assayed the effect of IFN-gamma on parasite growth by DNA hybridization using a P. berghei specific DNA probe. The specific activity of IFN-gamma against EEF is very high, and depends upon the time of lymphokine addition. When IFN-gamma is added to HEPG2 cells containing intracellular EEF, 6 hr after sporozoite invasion, parasite DNA replication is inhibited by approximately 75% at 10(3) U/ml and 50% at 1 U/ml. This treatment can either abolish or greatly reduce the infectivity of EEF for mice. When added earlier, 3 hr after completion of sporozoite invasion, IFN-gamma inhibits parasite replication to an even greater degree. The highest levels of inhibition were obtained when IFN-gamma was added 6 hr prior to sporozoite invasion (100% inhibition at 10(2) U/ml, approximately 55% inhibition at 0.1 U/ml, and 17% inhibition at 0.001 U/ml). We found that HEPG2 cells express approximately 44,000 surface receptors for IFN-gamma. These data are consistent with the view that IFN-gamma exerts its antimalarial activity by binding to surface receptors on hepatocytes and inducing intracellular changes unfavorable for parasite development. Tryptophan starvation does not appear to be involved in this process. These findings also support the idea that IFN-gamma, released from immune T cells upon encountering sporozoite antigen, may be an important effector mechanism in sterile immunity to sporozoite challenge.


Atypical scanning strategies of emotional faces for individuals with high autistic traits.
Autism has become one of the primary diseases causing disability in children, and the incidence has risen rapidly in recent years. The preclinical study on individuals with high autistic traits is extremely important to reduce genetic risks of autism because high autistic traits is the susceptibility marker of autism. However, few studies explored the face scanning pattern of people with high autistic traits in typical developing populations. In this study, we designed a facial emotion recognition experiment including four emotions (happy, neutral, sad, angry) and three angles (0°, 45°, 90°) , and informed the participants to identify the facial emotion. Forty-two college students with typical development were recruited and divided into high autistic traits (HAT) group and low autistic traits (LAT) group by the Autism-Spectrum Quotient, and we collected the eye movement data using eye-tracking technology when they performed the task. The response time, recognition accuracy, AOI based proportional fixation time and pupil diameter were computed and analyzed for both groups. HATs showed significantly lower recognition accuracy and lower pupil diameter than LATs when recognizing negative emotions (P<0.05) , indicating HATs kept poor autonomic nervous arousal. What ' s more, the proportional fixation time of HATs were significantly more in mouth area but less in eye area than that of LAT group (P<0.05) , revealed HATs had an atypical emotional faces scanning strategies that paid less attention to eyes and more attention to mouth. Our research provides a feasible objective biomarker for screening high autistic traits population.


The leukocyte nuclear envelope proteome varies with cell activation and contains novel transmembrane proteins that affect genome architecture.
A favored hypothesis to explain the pathology underlying nuclear envelopathies is that mutations in nuclear envelope proteins alter genome/chromatin organization and thus gene expression. To identify nuclear envelope proteins that play roles in genome organization, we analyzed nuclear envelopes from resting and phytohemagglutinin-activated leukocytes because leukocytes have a particularly high density of peripheral chromatin that undergoes significant reorganization upon such activation. Thus, nuclear envelopes were isolated from leukocytes in the two states and analyzed by multidimensional protein identification technology using an approach that used expected contaminating membranes as subtractive fractions. A total of 3351 proteins were identified between both nuclear envelope data sets among which were 87 putative nuclear envelope transmembrane proteins (NETs) that were not identified in a previous proteomics analysis of liver nuclear envelopes. Nuclear envelope localization was confirmed for 11 new NETs using tagged fusion proteins and antibodies on spleen cryosections. 27% of the new proteins identified were unique to one or the other of the two leukocyte states. Differences in expression between activated and resting leukocytes were confirmed for some NETs by RT-PCR, and most of these proteins appear to only be expressed in certain types of blood cells. Several known proteins identified in both data sets have functions in chromatin organization and gene regulation. To test whether the novel NETs identified might include those that also regulate chromatin, nine were run through two screens for different chromatin effects. One screen found two NETs that can recruit a specific gene locus to the nuclear periphery, and the second found a different NET that promotes chromatin condensation. The variation in the protein milieu with pharmacological activation of the same cell population and consequences for gene regulation suggest that the nuclear envelope is a complex regulatory system with significant influences on genome organization.


Reliability and validity of a reactive agility test for Australian football.
The aim of this study was to test the reliability and construct validity of a reactive agility test (RAT), designed for Australian Football (AF). Study I tested the reliability of the RAT, with 20 elite junior AF players (17.44 +/- 0.55 y) completing the test on two occasions separated by 1 wk. Study II tested its construct validity by comparing the performance of 60 participants (16.60 +/- 0.50 y) spread over three aged-matched population groups: 20 athletes participating in a State Under-18 AF league who had represented their state at national competitions (elite), 20 athletes participating in the same league who had not represented their state (subelite), and 20 healthy males who did not play AF (controls). Test-retest reliability reported a strong correlation (0.91), with no significant difference (P = .22) between the mean results (1.74 +/- 0.07 s and 1.76 +/- 0.07 s) obtained (split 2+3). Nonparametric tests (Kruskal-Wallis and Mann-Whitney) revealed both AF groups performed significantly faster on all measures than the control group (ranging from P = .001 to .005), with significant differences also reported between the two AF groups (ranging from P = .001 to .046). Stepwise discriminant analyses found total time discriminated between the groups, correctly classifying 75% of the participants. The RAT used within this study demonstrates evidence of reliability and construct validity. It further suggests the ability of a reactive component within agility test designs to discriminate among athletes of different competition levels, highlighting its importance within training activities.


Enhancing Enterprise Credit Risk Assessment with Cascaded Multi-level Graph Representation Learning.
The assessment of Enterprise Credit Risk (ECR) is a critical technique for investment decisions and financial regulation. Previous methods usually construct enterprise representations by credit-related indicators, such as liquidity and staff quality. However, indicators of many enterprises are not accessible, especially for the small- and medium-sized enterprises. To alleviate the indicator deficiency, graph learning based methods are proposed to enhance enterprise representation learning by the neighbor structure of enterprise graphs. However, existing methods usually only focus on pairwise relationships, and overlook the ubiquitous high-order relationships among enterprises, e.g., supply chain connecting multiple enterprises. To resolve this issue, we propose a Multi-Structure Cascaded Graph Neural Network framework (MS-CGNN) for ECR assessment. It enhances enterprise representation learning based on enterprise graph structures of different granularity, including knowledge graphs of pairwise relationships, homogeneous and heterogeneous hypergraphs of high-order relationships. To distinguish influences of different types of hyperedges, MS-CGNN redefine new type-dependent hyperedge weight matrices for heterogeneous hypergraph convolutions. Experimental results show that MS-CGNN achieves state-of-the-art performance on real-world ECR datasets.


Effects of the Metal Ion on the Mechanism of Phosphodiester Hydrolysis Catalyzed by Metal-Cyclen Complexes.
In this study, mechanisms of phosphodiester hydrolysis catalyzed by six di- and tetravalent metal-cyclen (M-C) complexes (Zn-C, Cu-C, Co-C, Ce-C, Zr-C and Ti-C) have been investigated using DFT calculations. The activities of these complexes were studied using three distinct mechanisms: (1) direct attack ( DA ), (2) catalyst-assisted ( CA ), and (3) water-assisted ( WA ). All divalent metal complexes (Zn-C, Cu-C and Co-C) coordinated to the BNPP substrate in a monodentate fashion and activated its scissile phosphoester bond. However, all tetravalent metal complexes (Ce-C, Zr-C, and Ti-C) interacted with BNPP in a bidentate manner and strengthened this bond. The DA mechanism was energetically the most feasible for all divalent M-C complexes, while the WA mechanism was favored by the tetravalent complexes, except Ce-C. The divalent complexes were found to be more reactive than their tetravalent counterparts. Zn-C catalyzed the hydrolysis with the lowest barrier among all M-C complexes, while Ti-C was the most reactive tetravalent complex. The activities of Ce-C and Zr-C, except Ti-C, were improved with an increase in the coordination number of the metal ion. The structural and mechanistic information provided in this study will be very helpful in the development of more efficient metal complexes for this critical reaction.


Fat elimination in parenterally fed low birth weight infants during the first two weeks of life.
Eighteen low birth weight infants (27-34 wk gestation) were given supplementary parenteral nutrition via peripheral veins of a maximal dose of 8.5 g glucose, 2.5 g amino acids (Aminovenös päd 10%) and 2 g soybean oil egg lecithin emulsion (Intralipid 10%) kg body weight/24 hr. The fat emulsion was infused continuously at a rate of 0.084 g/kg body weight/hr. The elimination of Intralipid from the blood stream was controlled by enzymatic determination of serum triglyceride concentrations, and the fatty acid pattern of the serum lipids was determined by gas chromatography. The serum triglyceride concentrations were 0.60 +/- 0.16 mmol/liter on the 1st day, increased to 0.96 +/- 0.29 mmol/liter up to the 5th day, and approached a level around 0.90 mmol/liter in the further course. No hypertriglyceridemia was noted. The fatty acid pattern of the serum lipids showed a linoleic acid fraction of 8.1 +/- 4.0% in the beginning, which was followed by a continuous increase up to 27.8 +/- 4.8% on the 7th day. No significant changes were noticed thereafter. The levels were within the normal limits as found in 2-wk-old enterally fed preterm infants of comparative maturity (25.6 +/- 3.4%). We conclude that the preterm infants can eliminate Intralipid from the blood stream if maximal dosage and infusion rate, as described above, are applied.


Genetic variations in two seahorse species (Hippocampus mohnikei and Hippocampus trimaculatus): evidence for middle Pleistocene population expansion.
Population genetic of seahorses is confidently influenced by their species-specific ecological requirements and life-history traits. In the present study, partial sequences of mitochondrial cytochrome b (cytb) and control region (CR) were obtained from 50 Hippocampus mohnikei and 92 H. trimaculatus from four zoogeographical zones. A total of 780 base pairs of cytb gene were sequenced to characterize mitochondrial DNA (mtDNA) diversity. The mtDNA marker revealed high haplotype diversity, low nucleotide diversity, and a lack of population structure across both populations of H. mohnikei and H. trimaculatus. A neighbour-joining (NJ) tree of cytb gene sequences showed that H. mohnikei haplotypes formed one cluster. A maximum likelihood (ML) tree of cytb gene sequences showed that H. trimaculatus belonged to one lineage. The star-like pattern median-joining network of cytb and CR markers indicated a previous demographic expansion of H. mohnikei and H. trimaculatus. The cytb and CR data sets exhibited a unimodal mismatch distribution, which may have resulted from population expansion. Mismatch analysis suggested that the expansion was initiated about 276,000 years ago for H. mohnikei and about 230,000 years ago for H. trimaculatus during the middle Pleistocene period. This study indicates a possible signature of genetic variation and population expansion in two seahorses under complex marine environments.


[Immunomodulatory effect of pentoxifylline in Graves ophthalmopathy].
In the pathomechanism of the thyroid associated ophthalmopathy (TAO) the inflammatory cytokines produced by infiltrating lymphocytes of the retroorbital tissues are involved. The activated lymphocytes have been shown to secrete a number of cytokines including tumour necrosis factor-alpha, interleukin-1 and interferon-gamma. The widely used immunosuppressive therapies have potential serious side effects. The pentoxifylline (Ptx) is known to have effect on production of cytokines. The aim of this study was to investigate the effect of Ptx on expression of HLA-DR molecules and production of glycosaminoglycan of human retroorbital tissue cultures and potential efficacy in patients with TAO. It was found that pentoxifylline (Ptx) was able to inhibit significantly the HLA-DR expression and glycosaminoglycan synthesis induced by inflammatory cytokines including TNF-alpha, IFN-gamma and IL-1. Ten patients with untreated moderate severe ophthalmopathy (8 female and 2 male) were excluded from steroid treatment due diabetes mellitus and psychiatric disease. Classification of eye changes was made by NOSPECS categories and total eye score. All patients were euthyroid during the study and was no remarkable difference in thyroid function and eye symptoms. Before and during Ptx therapy the laboratory parameters were also determined including glycosaminoglycan. TNF-alpha, anti-TSH-receptor, anti-eye muscle, anti-thyroglobulin and anti-thyroid peroxidase antibodies in the patients'sera. It was found a remarkable improvement in the eye symptoms in eight of ten patients. The levels of glycosaminoglycan (uronic acid) and TNF-alpha gradually decreased in eight patients who considered to be responders. The levels of uronic acid in plasma of the responders were found to be significantly lower after Ptx treatment. Before Ptx therapy the TNF-alpha in the sera was not different remarkably in non-responders and responders. After 4 weeks Ptx treatment the TNF-alpha decreased significantly in responders compared to non-responders (20.9 +/- 4.8 pg/ml v. s. 28.3 +/- 6.1 pg/ml) (p < 0.01). The titre of anti-eye muscle antibodies were found to be lower at the end of observation, however, the anti-thyroid antibodies were not changed remarkably. It was concluded that Ptx in the majority of patients (8/10) has a beneficial effect on inflammatory symptoms of TAO and laboratory parameters and suggested to use as an additive therapy, however, further comparative studies are required for final evaluation of Ptx in the treatment of TAO.


Interhemispheric transfer in high-functioning children and adolescents with autism spectrum disorders: a controlled pilot study.
Autism is a neurodevelopmental disorder with strong genetic influences. Clinical experience and limited empirical evidence support the view that autism may be associated with aberrant interhemispheric information transfer. This empirical controlled study examined whether, at neuropsychological testing, children with autism showed problems with interhemispheric information transfer. The study included auditory, visual, and motor measures covering information transfer within, as well as across, modalities. Thirty children (24 males, 6 females; mean age 12 years 8 months, SD 2 years 8 months; range 9 years 5 months to 17 years 5 months) without learning disability but with autism spectrum disorders were compared with 30 children from a mainstream school matched for age, sex, and IQ>75. Children with autism spectrum disorder performed significantly worse than the comparison group on most of the tests (p=0.02 for auditory perception and attention, p=0.005 for visual perception, p=0.0001 for motor control, p=0.04 for tactile perception). Results support the notion that aberrant interhemispheric transfer may be involved in the pathogenesis or clinical course of autism. The findings were not accounted for by lower IQ in the group with autism.


Saturation transfer ratio imaging in invasive ductal carcinomas of the breast.
A prospective study was performed to investigate the correlations between saturation transfer ratio (STR) and histologic parameters of invasive ductal carcinomas in human breast. The histologic parameters investigated were the extent of fibrosis in the intercellular matrix, dysplastic changes of nuclei, and mitotic index. Twenty-seven patients with breast carcinoma were examined using an off-resonance saturation pulse in conjunction with conventional field-echo T(1)-weighted imaging at frequency offsets of 448 Hz and 1200 Hz from water resonance. The values of STR at frequency offset of 1200 Hz (STR(1200)) increased from non-scirrhous carcinoma to scirrhous carcinoma. Although STR(1200) showed correlation with the extent of fibrosis in the intercellular matrix (p<0.01, n = 27), they did not correlate with the dysplastic changes of nuclei or mitotic index. On the other hand, the values of STR at frequency offset of 448 Hz (STR(448)) demonstrated close correlation to dysplastic changes of nuclei and mitotic index (p<0.01, n = 27). STR(1200) correlates with the structural characteristics and STR(448) correlates with the nature of malignant cells with regard to nuclear dysplasia and mitotic potential.


Laboratory testing in hemophilia: Impact of factor and non-factor replacement therapy on coagulation assays.
The advent of extended half-life (EHL) recombinant clotting factors and innovative non-factor replacement therapeutics, such as emicizumab, offers several advantages over existing products for the prophylactic treatment of people living with hemophilia (PwH). These include low annual bleeding rates with less frequent dosing, higher trough plasma concentrations, and a more convenient route of administration. However, increasing use of these therapies poses challenges to clinicians and coagulation laboratories due to the lack of standardized assays for monitoring of hemostatic parameters, and the potential for misinterpretation of test results, which may jeopardize patient safety. Definitive diagnosis of hemophilia and treatment monitoring is reliant on demonstrating factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B) deficiency using a functional coagulation assay. The most frequently used assays are based on activated partial thromboplastin time, using a one-stage or two-stage process. While one-stage and chromogenic assays have performed well with human-derived FVIII and FIX and full-length recombinant products, EHL recombinant factors are heterogeneous in structure and mode of action and therefore show wide variation in activity levels between different one-stage assays, and between one-stage and chromogenic assays. In the context of the recommended stepwise approach for laboratory diagnosis of hemophilia, we examine the diagnostic challenges associated with the use of EHL factors and novel non-factor therapeutics and consider the optimal diagnostic approach in PwH who are receiving these treatments. Ultimately, accurate diagnostic solutions are a prerequisite for personalized therapy to minimize treatment burden and improve quality of life in PwH.


Low-Frequency Protein Motions Coupled to Catalytic Sites.
This review examines low-frequency vibrational modes of proteins and their coupling to enzyme catalytic sites. That protein motions are critical to enzyme function is clear, but the kinds of motions present in proteins and how they are involved in function remain unclear. Several models of enzyme-catalyzed reaction suggest that protein dynamics may be involved in the chemical step of the catalyzed reaction, but the evidence in support of such models is indirect. Spectroscopic studies of low-frequency protein vibrations consistently show that there are underdamped modes of the protein with frequencies in the tens of wavenumbers where overdamped behavior would be expected. Recent studies even show that such underdamped vibrations modulate enzyme active sites. These observations suggest that increasingly sophisticated spectroscopic methods will be able to unravel the link between low-frequency protein vibrations and enzyme function.


Can experienced surgeons predict the additional value of a CT scan in patients with displaced intra-articular distal radius fractures?
There are no clear guidelines when an additional CT scan should be obtained for the treatment of displaced intra-articular distal radius fractures (DRF). This study aimed to investigate whether surgeons can predict the usefulness of CT scans to facilitate choice of treatment plan and/or pre-operative planning for DRF. Four surgeons evaluated 51 patients with displaced DRF. The choice of treatment (operative or nonoperative) was based on conventional radiographs. Subsequently, the surgeons were asked whether they would have requested an additional CT scan to determine this treatment choice, and also whether they required a CT scan for pre-operative planning. After 4 weeks, the additional CT scan was provided and the cases were assessed again. Based on these data, we calculated the number needed to scan (NNS) and number needed to harm (NNH) for two decision models. Model 1: Only provide a CT scan if the surgeon requested one based on their judgment of the X-rays. Model 2: CT scans for all displaced intra-articular DRF. For choice of treatment, the NNS was lower for model 1 than for model 2 (2.6 vs. 4.3) and the NNH is higher for model 1 (3.1 vs. 1.3). For pre-operative planning, the NNS (1.3 vs. 1.4) and NNH (3.7 vs. 3.4) were comparable for both models. Surgeons are able to predict the usefulness of an additional CT scan for intra-articular displaced DRF for OR indication. However, for pre-operative planning the usefulness of a CT scan is much harder to predict.


Extracorporeal Membrane Oxygenation Uses in Refractory Cardiogenic Shock After Open-Heart Surgery.
Extracorporeal membrane oxygenation (ECMO) is the first-line therapy for temporary mechanical circulatory support allowing cardiac and pulmonary recovery or as a bridge to further therapeutic alternatives. The aim of this study was to report clinical outcomes in adult patients with refractory cardiac failure after open-heart surgery undergoing ECMO in a single center with an ECMO unit in Chile. We retrospectively analyzed adults with refractory cardiac failure after open-heart surgery who required a venoarterial (VA) ECMO between 2016 and 2021. Of 16 patients with VA ECMO, 60% were men (n=10), 90% had hypertension (n=14), 69% had < 30% of left ventricular ejection fraction (n=11), and the mean European System for Cardiac Operative Risk Evaluation II score was 12 ± 11%. ECMO support with central cannulation accounts for 81% (n=13), and an intra-aortic balloon pump was used in nine patients (56%). The mean time of support was 4.7 ± 2.6 days (1.5 - 12 days). ECMO weaning was achieved in 88% of patients, and in-hospital mortality was 44% (n=7) after discharge. The freedom from all-cause mortality at one year of follow-up of the entire cohort was 38% (n=6). VA ECMO is now a well-known life-saving therapeutic option, but mortality and morbidity remain high. Implementation of an ECMO program with educational training is mandatory in order to find the proper balance between patient benefits, ethical considerations, and public health financial input in South America.


Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial.
Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event-free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0.0007). Event-free survival was significantly improved with dexamethasone (84.2% vs. 75.6% at 5 years; P = 0.01), with no evidence of differing effects in any subgroup of patients. The use of 6.5 mg/m(2) dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk-groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.


Meson structure in a relativistic many-body approach
Results from an extensive relativistic many-body analysis utilizing a realistic effective QCD Hamiltonian are presented for the meson spectrum. A comparative numerical study of the BCS, Tamm-Dancoff (TDA), and RPA treatments provides new, significant insight into the condensate structure of the vacuum, the chiral symmetry governance of the pion, and the meson spin, orbital, and flavor mass splitting contributions. In contrast to a previous glueball application, substantial quantitative differences are computed between TDA and RPA for the light quark sector with the pion emerging as a Goldstone boson only in the RPA.


ASAS centennial paper: net energy systems for beef cattle--concepts, application, and future models.
Development of nutritional energetics can be traced to the 1400s. Lavoisier established relationships among O(2) use, CO(2) production and heat production in the late 1700s, and the laws of thermodynamics and law of Hess were discovered during the 1840s. Those discoveries established the fundamental bases for nutritional energetics and enabled the fundamental entity ME = retained energy + heat energy to be established. Objectives became: 1) to establish relationships between gas exchange and heat energy, 2) to devise bases for evaluation of foods that could be related to energy expenditures, and 3) to establish causes of energy expenditures. From these endeavors, the basic concepts of energy partitioning by animals were developed, ultimately resulting in the development of feeding systems based on NE concepts. The California Net Energy System, developed for finishing beef cattle, was the first to be based on retained energy as determined by comparative slaughter and the first to use 2 NE values (NE(m) and NE(g)) to describe feed and animal requirements. The system has been broadened conceptually to encompass life cycle energy requirements of beef cattle and modified by the inclusion of numerous adjustments to address factors known to affect energy requirements and value of feed to meet those needs. The current NE system remains useful but is empirical and static in nature and thus fails to capture the dynamics of energy utilization by diverse animals as they respond to changing environmental conditions. Consequently, efforts were initiated to develop dynamic simulation models that captured the underlying biology and thus were sensitive to variable genetic and environmental conditions. Development of a series of models has been described to show examples of the conceptual evolution of dynamic, mechanistic models and their applications. Generally with each new system, advances in prediction accuracy came about by adding new terms to conceptually validated models. However, complexity of input requirements often limits general use of these larger models. Expert systems may be utilized to provide many of the additional inputs needed for application of the more complex models. Additional information available from these systems is expected to result in an ever-increasing range of application. These systems are expected to have increased generality and the capability to be integrated with other models to allow economic evaluation. This will eventually allow users to compute solutions that allow development of optimal production strategies.


Pharmacokinetics of nicotine in kidney failure.
Smoking is an important risk factor for cardiovascular and cerebrovascular complications in patients with chronic kidney failure. Very high plasma nicotine concentrations have been reported in patients with severe kidney failure, indicating that the disposition of nicotine in these patients may be different. The purpose of this study was to assess the pharmacokinetics of intravenously administered nicotine in healthy subjects and in patients with kidney failure. Nine healthy subjects (glomerular filtration rate [GFR], 84 to 143 mL/min/1.73 m2), four patients with mild kidney failure (GFR, 63 to 73 mL/min/1.73 m2), five patients with moderate kidney failure (GFR, 18 to 36 mL/min/1.73 m2), and six patients with severe kidney failure (GFR, 1 to 10 mL/min/1.73 m2) were recruited. Three patients were treated with continuous ambulatory peritoneal dialysis. An intravenous infusion of nicotine (0.028 mg/kg) was given for 10 minutes. Nicotine and cotinine concentrations were measured in plasma, urine, and peritoneal dialysate from 0 to 24 hours after start of infusion There were significant correlations between GFR and total clearance, nonrenal and renal clearance of nicotine, area under the plasma concentration-time curve extrapolated to infinity, terminal elimination half-life, and mean residence time. Nonrenal clearance was 1303 mL/min and 661 mL/min in healthy subjects and patients with severe kidney failure, respectively. Only 1% to 2% of the nicotine dose was excreted unchanged in a 24-hour collection of peritoneal dialysate. The elimination of cotinine was also decreased in patients with kidney failure. Progressive kidney failure is associated with a gradual decrease of renal and nonrenal elimination of nicotine.


A study to estimate the prevalence of upper respiratory tract papillomatosis in patients with genital warts.
Respiratory tract papillomas are associated with human papillomavirus (HPV) types 6 and 11; these HPV types are also commonly associated with genital warts (condyloma acuminata). Although most commonly seen in young children, the incidence of respiratory tract papillomas in young adults is increasing. It has been postulated that orogenital contact is the means of transmission in this age group. We performed a survey of adults with genital warts to assess the prevalence of respiratory tract papillomatosis in relation to sexual behaviour and other factors. Fifty-three adult patients (35 male, 18 female) with genital warts attending a genitourinary medicine clinic agreed to examination of the mouth and throat, including indirect laryngoscopy. Seventy per cent of the group had participated in oral sex. Two patients (3.8%) had lesions attributable to HPV infection of the oropharynx and larynx (one with laryngeal keratosis, one with papilloma of the pharynx). There was no specific risk factor identified to predict respiratory tract disease. In view of the high infectivity of genital warts, it is interesting to note the low prevalence of oropharyngeal warts in adults indulging in orogenital contact. Since malignant transformation is known in respiratory tract papillomas, we would recommend that any patient with genital warts who develops unexplained hoarseness has a specialist examination of the upper respiratory tract.


Flagella-independent surface motility in Salmonella enterica serovar Typhimurium.
Flagella are multiprotein complexes necessary for swimming and swarming motility. In Salmonella enterica serovar Typhimurium, flagella-mediated motility is repressed by the PhoP/PhoQ regulatory system. We now report that Salmonella can move on 0.3% agarose media in a flagella-independent manner when experiencing the PhoP/PhoQ-inducing signal low Mg(2+). This motility requires the PhoP-activated mgtA, mgtC, and pagM genes, which specify a Mg(2+) transporter, an inhibitor of Salmonella's own F1Fo ATPase, and a small protein of unknown function, respectively. The MgtA and MgtC proteins are necessary for pagM expression because pagM mRNA levels were lower in mgtA and mgtC mutants than in wild-type Salmonella, and also because pagM expression from a heterologous promoter rescued motility in mgtA and mgtC mutants. PagM promotes group motility by a surface protein(s), as a pagM-expressing strain conferred motility upon a pagM null mutant, and proteinase K treatment eliminated motility. The pagM gene is rarely found outside subspecies I of S. enterica and often present in nonfunctional allelic forms in organisms lacking the identified motility. Deletion of the pagM gene reduced bacterial replication on 0.3% agarose low Mg(2+) media but not in low Mg(2+) liquid media. Our findings define a form of motility that allows Salmonella to scavenge nutrients and to escape toxic compounds in low Mg(2+) semisolid environments.


Overweight and obesity among children and adolescents with fetal alcohol spectrum disorders.
Because prenatal alcohol exposure is associated with growth deficiency, little attention has been paid to the potential for overweight and obesity in children with fetal alcohol spectrum disorders (FASD). This study examined the prevalence of overweight/obesity (body mass index [BMI]) in a large clinical sample of children with FASD. Children, aged 2 to 19 years, who were evaluated for FASD at University Clinics, included 445 with an FASD diagnosis and 171 with No-FASD diagnosis. Prevalence of overweight/obesity (BMI ≥ 85 percentile) was compared to national and state prevalence. BMI was examined in relation to FASD diagnosis, gender, and age. Dietary intake data were examined for a young subsample (n = 42). Thirty-four percent with any FASD diagnosis were overweight or obese, which did not differ from the No-FASD group or U.S. prevalence. Underweight was prevalent in those with fetal alcohol syndrome (FAS) (17%). However, increased rates of overweight/obesity were seen in those with partial FAS (40%). Among adolescents, those with any FASD diagnosis had increased overweight/obesity (42%), particularly among females (50%). The rate in adolescent females with FASD (50%) was nearly 3 times higher than state prevalence for adolescent females (17 to 18%), p < 0.001. In the young subsample, those who were overweight/obese consumed more calories, protein, and total fat per day than those who were not overweight or obese. Rates of overweight/obesity are increased in children with partial FAS. In adolescents, rates are increased for any FASD diagnosis (particularly in females). Results are suggestive of possible metabolic/endocrine disruption in FASD-a hypothesis for which there is evidence from animal models. These data suggest that clinicians may consider prenatal alcohol exposure as a risk factor for metabolic/endocrine disruption, should evaluate diet as a risk in this population, and may need to target interventions to females prior to puberty to effect changes in overweight-related outcomes.


Modification of esterified cell wall phenolics increases vulnerability of tall fescue to herbivory by the fall armyworm.
Feruloylation of arabinoxylan in grass cell walls leads to cross-linked xylans. Such cross-linking appears to play a role in plant resistance to pathogens and insect herbivores. In this study, we investigated the effect of ferulate cross-linking on resistance to herbivory by fall armyworm (Spodoptera frugiperda) making use of genetically modified tall fescue [Schedonorus arundinaceus (Festuca arundinacea)] expressing a ferulic acid esterase gene. Mature leaves of these plants have significant reduced levels of cell wall ferulates and diferulates but no change in acid detergent lignin. These reduced levels of esterified cell wall ferulates in transgenic plants had a positive effect on all measures of armyworm larval performance examined. More larvae survived (89 vs. 57 %) and grew faster (pupated 2.1 days sooner) when fed transgenic leaves with reduced levels of cell wall ferulates, than when fed control tall fescue leaves where levels of cell wall ferulates were not altered. Overall, mortality, growth and food utilization were negatively associated with level of esterified cell wall ferulates and diferulates in leaves they were fed. This study is the first to use transgenic plants with modified level of cell wall esterified ferulates to test the role of feruloylation in plant resistance to insects. It is concluded that the accumulation of ferulates and the cross-linking of arabinoxylans via diferulate esters in the leaves of tall fescue underlies the physical barrier to insect herbivory. Reducing ferulate cross-linking in grass cell walls could increase susceptibility of these plants to insect folivores.


Machine Learning Prediction of Foodborne Disease Pathogens: Algorithm Development and Validation Study.
Foodborne diseases, as a type of disease with a high global incidence, place a heavy burden on public health and social economy. Foodborne pathogens, as the main factor of foodborne diseases, play an important role in the treatment and prevention of foodborne diseases; however, foodborne diseases caused by different pathogens lack specificity in clinical features, and there is a low proportion of clinically actual pathogen detection in real life. We aimed to analyze foodborne disease case data, select appropriate features based on analysis results, and use machine learning methods to classify foodborne disease pathogens to predict foodborne disease pathogens that have not been tested. We extracted features such as space, time, and exposed food from foodborne disease case data and analyzed the relationship between these features and the foodborne disease pathogens using a variety of machine learning methods to classify foodborne disease pathogens. We compared the results of 4 models to obtain the pathogen prediction model with the highest accuracy. The gradient boost decision tree model obtained the highest accuracy, with accuracy approaching 69% in identifying 4 pathogens including Salmonella, Norovirus, Escherichia coli, and Vibrio parahaemolyticus. By evaluating the importance of features such as time of illness, geographical longitude and latitude, and diarrhea frequency, we found that they play important roles in classifying the foodborne disease pathogens. Data analysis can reflect the distribution of some features of foodborne diseases and the relationship among the features. The classification of pathogens based on the analysis results and machine learning methods can provide beneficial support for clinical auxiliary diagnosis and treatment of foodborne diseases.


Directional biases reveal utilization of arm's biomechanical properties for optimization of motor behavior.
Strategies used by the CNS to optimize arm movements in terms of speed, accuracy, and resistance to fatigue remain largely unknown. A hypothesis is studied that the CNS exploits biomechanical properties of multijoint limbs to increase efficiency of movement control. To test this notion, a novel free-stroke drawing task was used that instructs subjects to make straight strokes in as many different directions as possible in the horizontal plane through rotations of the elbow and shoulder joints. Despite explicit instructions to distribute strokes uniformly, subjects showed biases to move in specific directions. These biases were associated with a tendency to perform movements that included active motion at one joint and largely passive motion at the other joint, revealing a tendency to minimize intervention of muscle torque for regulation of the effect of interaction torque. Other biomechanical factors, such as inertial resistance and kinematic manipulability, were unable to adequately account for these significant biases. Also, minimizations of jerk, muscle torque change, and sum of squared muscle torque were analyzed; however, these cost functions failed to explain the observed directional biases. Collectively, these results suggest that knowledge of biomechanical cost functions regarding interaction torque (IT) regulation is available to the control system. This knowledge may be used to evaluate potential movements and to select movement of "low cost." The preference to reduce active regulation of interaction torque suggests that, in addition to muscle energy, the criterion for movement cost may include neural activity required for movement control.


[Adhesive properties of microorganisms colonizing rheumatoid arthritis and systemic lupus erythematosus patients].
Evaluation of adhesive properties of microorganisms colonizing rheumatoid arthritis and systemic lupus erythematosus patients. Nose mucosa and urinal microflora from 62 rheumatoid patients (32--rheumatoid arthritis and 30--systemic lupus erythematosus patients) was studied. 57 opportunistic microorganisms were isolated: including representatives of Staphylococcus, Escherichia, Klebsiella, Morganella, Enterobactergenera. Adhesive properties on erythrocyte model of microorganisms isolated in patients with rheumatoid disease, museum cultures and clinical strains were analyzed by using standard technique. Bacteria isolated in rheumatoid disease patients were characterized by pronounced adhesive potential. Bacteria of Enterobacteriaceae family have shown significantly higher adhesive properties. Heterogeneity of adhesive properties levels, and genera and species adhesive potential of bacteria was determined. Microorganisms colonizing rheumatoid disease patients have a high adhesive potential that can increase the risk of patient infections.


Beekeeping Management Practices Are Associated with Operation Size and Beekeepers' Philosophy towards in-Hive Chemicals.
Management by beekeepers is of utmost importance for the health and survival of honey bee colonies. Beekeeping management practices vary from low to high intervention regarding the use of chemicals, hive manipulations, and supplemental feeding of colonies. In this study, we use quantitative data from the Bee Informed Partnership's national survey to investigate drivers of management practices among beekeepers in the United States. This is the first study to quantitatively examine these variables to objectively describe the management practices among different groups of beekeepers in the United States. We hypothesized that management practices and goals among beekeepers are different based on the beekeeper's philosophy (as determined by their willingness to use chemicals to control pests and pathogens) and the size of the beekeeping operation. Using a multiple factor analysis, we determined that beekeepers use a continuum of management practices. However, we found that beekeepers' willingness to use in-hive chemicals and the number of colonies in their operation are non-randomly associated with other aspects of beekeeping management practices. Specifically, the size of the beekeeping operation was associated with beekeepers' choices of in-hive chemicals, while beekeepers' philosophy was most strongly associated with choices of in-hive chemicals and beekeeping goals. Our results will facilitate the development of decision-making tools for beekeepers to choose management practices that are appropriate for the size of their operations and their beekeeping philosophy.