Morphological analysis of 3d atom probe data using Minkowski functionals.
We present a morphological analysis of atom probe data of nanoscale microstructural features, using methods developed by the astrophysics community to describe the shape of superclusters of galaxies. We describe second-phase regions using Minkowski functionals, representing the regions' volume, surface area, mean curvature and Euler characteristic. The alloy data in this work show microstructures that can be described as sponge-like, filament-like, plate-like, and sphere-like at different concentration levels, and we find quantitative measurements of these features. To reduce user decision-making in constructing isosurfaces and to enhance the accuracy of the analysis a maximum likelihood based denoising filter was developed. We show that this filter performs significantly better than a simple Gaussian smoothing filter. We also interpolate the data using natural cubic splines, to refine voxel sizes and to refine the surface. We demonstrate that it is possible to find a mathematically well-defined, quantitative description of microstructure from atomistic datasets, to sub-voxel resolution, without user-tuneable parameters.


Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.
Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.


[Late primary abdominal pregnancy. Case report].
Abdominal advanced pregnancy is an obstetric complication that put at risk maternal and fetal life. We report a case of advanced abdominal pregnancy with intact ovaries and fallopian tubes, without ureteroperitoneal fistulae and, late prenatal diagnosis, in a multiparous patient without risk factors, with alive newborn, and whose pregnancy was attended at Unidad Medica de Alta Especialidad, Hospital de Gineco-Obstetricia, Centro Medico Nacional de Occidente del IMSS, Guadalajara, Jalisco, México.


Processing, mixing, and particle size reduction of forages for dairy cattle.
Adequate forage amounts in both physical and chemical forms are necessary for proper ruminal function in dairy cows. Under conditions in which total amounts of forage or particle size of the forage are reduced, cows spend less time ruminating and have a decreased amount of buoyant digesta in the rumen. These factors reduce saliva production and allow ruminal pH to fall, depressing activity of cellulolytic bacteria and causing a prolonged period of low ruminal pH. Insufficient particle size of the diet decreases the ruminal acetate-to-propionate ratio and reduces ruminal pH. The mean particle size of the diet, the variation in particle size, and the amount of chemical fiber (i.e., NDF or ADF) are all nutritionally important for dairy cows. Defining amounts and physical characteristics of fiber is important in balancing dairy cattle diets. Because particle size plays such an important role in digestion and animal performance, it must be an important consideration from harvest through feeding. Forages should not be reduced in particle size beyond what is necessary to achieve minimal storage losses and what can be accommodated by existing equipment. Forage and total mixed ration (TMR) particle sizes are potentially reduced in size by all phases of harvesting, storing, taking out of storage, mixing, and delivery of feed to the dairy cow. Mixing feed causes a reduction in size of all feed particles and is directly related to TMR mixing time; field studies show that the longest particles (>27 mm) may be reduced in size by 50%. Forage and TMR particle size as fed to the cows should be periodically monitored to maintain adequate nutrition for the dairy cow.


Opioid treatment programs, telemedicine and COVID-19: A scoping review.
Background: Methadone and buprenorphine are effective medications for opioid use disorder (MOUD) that are highly regulated in the United States. The on-going opioid crisis, and more recently COVID-19, has prompted reconsideration of these restrictions in order to sustain and improve treatment access, with renewed interest in telemedicine. We reviewed the evidence on use of telemedicine interventions and applicability to MOUD policy changes in the post-COVID-19 treatment landscape. Methods: Ovid MEDLINE and the Cochrane Database of Systematic Reviews databases were searched from inception to April 2021 and reference lists were reviewed to identify additional studies. Studies were eligible if they examined telemedicine interventions and reported outcomes (e.g. treatment initiation, retention in care). Randomized trials and controlled observational studies were prioritized; other studies were included when stronger evidence was unavailable. One investigator abstracted key information and a second investigator verified data. We described the results qualitatively. Results: We identified nine studies: three controlled trials (two randomized), and six observational studies. Three studies evaluated patients treated with methadone and six studies with buprenorphine, including one study of pregnant women with OUD. All studies showed telemedicine approaches associated with similar outcomes (treatment retention, positive urine toxicology) compared to treatment as usual. Trials were limited by small samples sizes, lack of reporting harms, and most were conducted prior to the COVID-19 pandemic; observational studies were limited by failure to control for confounding. Conclusions: Limited evidence suggests that telemedicine may enhance access to MOUD with similar effectiveness compared with face-to-face treatment. Few studies have been published since COVID-19, and it is unclear the potential impact of these interventions on the existing racial/ethnic disparities in treatment. The COVID-19 pandemic and need for social distancing led to temporary policy changes for prescribing of MOUD that could inform additional research in this area to support comprehensive policy reforms.


Empirically supported psychological treatments: the challenge of evaluating clinical innovations.
Clear and transparent standards are required to establish whether a therapeutic method is "evidence based." Even when research demonstrates a method to be efficacious, it may not become available to patients who could benefit from it, a phenomenon known as the "translational gap." Only 30% of therapies cross the gap, and the lag between empirical validation and clinical implementation averages 17 years. To address these problems, Division 12 of the American Psychological Association published a set of standards for "empirically supported treatments" in the mid-1990s that allows the assessment of clinical modalities. This article reviews these criteria, identifies their strengths, and discusses their impact on the translational gap, using the development of a clinical innovation called Emotional Freedom Techniques (EFT) as a case study. Twelve specific recommendations for updates of the Division 12 criteria are made based on lessons garnered from the adoption of EFT within the clinical community. These recommendations would shorten the cycle from the research setting to clinical practice, increase transparency, incorporate recent scientific advances, and enhance the capacity for succinct comparisons among treatments.


Relax from the holiday on the edge of the lagoon : turquoise waters and red legs !
We report a case of livedo reticularis of the lower limbs in a 30-year-old woman scuba diver after a diving session. Consideration of the differential diagnoses, the clinical picture, and the course of the symptoms led to a diagnosis of cutaneous decompression sickness. This accident, which resolved favorably in this scuba diver without any right-to-left shunt, is an alarm signal that calls for her to comply strictly with safety rules before resuming scuba diving, to avoid a more serious accident.


CXCR2 is a novel cancer stem-like cell marker for triple-negative breast cancer.
Breast cancer is the leading cause of mortality from cancer in women worldwide, and cancer stem-like cell (CSC) is responsible for failure treatment of breast cancer. It plays an important role in resistant disease and metastasis. CD44/CD24 and ALDH are well-accepted protein markers of breast CSC, and it was reported that distinct subtypes of breast CSC were identified by the 2 markers. It is possible that there are various kinds of breast CSC which could be identified by different markers, and CSC markers utilized at present are not enough to fully understand breast CSC. Finding out more novel CSC markers is necessary. CXCR2 is involved in breast cancer metastasis, treatment resistance, and recurrence and has positive cross-talk with known breast CSC protein markers. It can be concluded that CXCR2 is related to breast CSC, and further study is in need. In this study, we assessed expression of CXCR2 with immunohistochemistry in breast cancer tissues from 37 patients and discovered that level of CXCR2 was significantly lower in triple-negative breast cancer (TNBC) compared with non-TNBC. CXCR2 expression decreased in estrogen receptor-negative or HER2-negative breast cancer, but not progesterone receptor-negative counterparts. By immunofluorescence, we observed high coexpression rate of CXCR2 and CSC-related proteins, including NANOG and SOX2. To prove our speculation that CXCR2 was a novel CSC marker for TNBC, we used 4T1 cell, which is a TNBC cell line, to analyze CXCR2-positive subpopulations and observed that CXCR2-positive 4T1 cells showed characteristics of CSC, including resistance to cisplatinum, radiation, and hypoxia, low proportion (around 1%), much more tumor xenografts, tumor spherule formation, and higher levels of CSC-related mRNA compared with CXCR2-negative cells. CXCR2 is an acceptable and newly discovered CSC marker for only TNBC.


[Idiopathic cholestasis in Hodgkin's disease].
The authors present the development of a intrahepatic Cholestasis in a Hodgkin's disease. The cholestasis was characterized with the biochemical signs of total bile duct obstruction. There were also signs of cholestasis at liver biopsy, while non hepatic involvement was detected. No biliary tract obstruction was proved. Chemotherapy produced remission of cholestasis. They also went over the different theories on the etiology and physiopathogeny of the idiopathic cholestasis in this disease, which are still uncertain, and they especially remark the need of discarding the idiopatic cholestasis in a Hodgkin's disease with jaundice.


Amplification of a reactive oxygen species signal in axotomized retinal ganglion cells.
Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury. Elucidation of the sequence of intracellular events proximal to caspase activation may allow development of effective neuroprotective strategies. In this study, we explored the role that reactive oxygen species may have in signaling RGC apoptosis after axonal injury. Using the fluorescent probe dihydroethidium, we were able to measure intracellular superoxide anion production. We found that axotomized RGCs exposed to oxidative stress exhibited a secondary superoxide burst. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone did not block the burst, suggesting it is proximal to caspase activation, but it was inhibited by cycloheximide, consistent with a requirement for protein synthesis. These results are consistent with RGC axotomy inducing synthesis of one or more proteins that mediate oxidative amplification. This could be an early event in signaling of RGC apoptosis after axonal injury.


A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling.
The Wnt gene family encodes proteins that serve key roles in differentiation and development. Wnt proteins interact with seven transmembrane receptors of the Frizzled family and activate a signaling pathway leading to the nucleus. A primary biochemical effect of Wnt-1 signaling is the stabilization of cytoplasmic (beta)-catenin which, in association with transcription factors of the Lef/tcf family, regulates gene expression. The recent identification of a new class of secreted proteins with similarity to the extracellular, ligand-binding domain of Frizzled proteins, soluble Frizzled related proteins (sFRP), suggested that additional mechanisms could regulate Wnt signaling. Here we demonstrate that FrzA, a sFRP that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to Wnt-1 protein, but not Wnt-5a protein, and modulates Wnt-1 signaling. FrzA associated with Wnt-1 either when expressed in the same cell or when soluble FrzA was incubated with Wnt-1-expressing cells. FrzA efficiently inhibited the Wnt-1 mediated increase in cytoplasmic (beta)-catenin levels as well as the Wnt-1 induction of transcription from a Lef/tcf reporter gene. The effects of FrzA on (beta)-catenin levels could be demonstrated when co-expressed with Wnt-1 or when individual cells expressing FrzA and Wnt-1 were co-cultured. These data demonstrate the existence of a negative regulatory mechanism mediated by the selective binding of FrzA to Wnt-1 protein.


Organization of axonal projections from the anterolateral area of the bed nuclei of the stria terminalis.
The anterolateral group of the bed nuclei of the stria terminalis (BSTalg) contains four distinct cell groups embedded within an undifferentiated anterolateral area (BSTal) that architectonically resembles a subjacent subcommissural zone (BSTsc). The overall distributions of axonal projections from various regions of the BSTal and from the BSTsc were determined with the Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracer method and found to be identical. The BSTal and BSTsc share dense bidirectional connections, and also project heavily within the BST to the rhomboid and fusiform nuclei and the anteroventral and anterodorsal areas. They project less densely to the juxtacapsular, oval, magnocellular, ventral, and interfascicular BST nuclei. Outside the BST, brain areas receiving strong to moderate inputs from the BSTal and BSTsc fall into several functional groups: somatomotor system (nucleus accumbens, substantia innominata, ventral tegmental area, and retrorubral area and adjacent midbrain reticular nucleus), central autonomic control system (central amygdalar nucleus, dorsal lateral hypothalamic area, ventrolateral periaqueductal gray, parabrachial nucleus, and nucleus of the solitary tract), neuroendocrine system (paraventricular and supraoptic nuclei, hypothalamic visceromotor pattern generator network), and thalamocortical feedback loops (midline, medial, and intralaminar nuclei). The results indicate that the BSTal and BSTsc are parts of the same cell group (dorsal and ventral to the anterior commissure), which plays a role in coordinating visceral and somatic motor responses (during ingestive behaviors, for example), especially in response to noxious stimuli (learned anorexia associated with noxious stimuli). BSTal projections are distinct from those of the adjacent juxtacapsular, oval, fusiform, and rhomboid nuclei.


A zinc complex of a neutral pyridine-based amphiphile: a highly efficient and potentially therapeutic bactericidal material.
The alarming rise in antibiotic-resistant pathogenic bacteria demands a prudent approach in the generation of therapeutic antibacterials. The present study illustrates the development of a potent amphiphilic bactericidal material tailored to leverage interactions with metal-reactive groups (MRGs) present in the bacterial cell surface envelope. Complexation of Zn(ii) with a neutral pyridine-based synthetic amphiphile (C1) generated the cationic C1-Zn, which exhibited manyfold higher membrane-directed bactericidal activity compared to the neutral C1, or the cationic amphiphile bearing two pyridinium head groups (C2). The relevance of MRGs in C1-Zn-bacteria interactions was validated by amphiphile-bacteria binding studies and metal protection assays performed with Mg(ii). C1-Zn retained its bactericidal activity even in simulated gastric fluid (SGF) and the enhanced membrane-directed bactericidal activity of C1-Zn could be garnered in adjuvant applications to increase the efficacy of the therapeutic antibiotic erythromycin. Given the relevance of Zn(ii) in S. aureus biofilm formation, the antibiofilm potential of the amphiphile C1 realized through Zn(ii) complexation could be demonstrated. The lack of resistance in target bacteria coupled with a favorable therapeutic index (IC50/MIC) and non-toxic nature hold significant implications for C1-Zn as a potential antibacterial therapeutic material.


Learning continuous trajectories in recurrent neural networks with time-dependent weights.
This paper is concerned with a general learning (with arbitrary criterion and state-dependent constraints) of continuous trajectories by means of recurrent neural networks with time-varying weights. The learning process is transformed into an optimal control framework, where the weights to be found are treated as controls. A new learning algorithm based on a variational formulation of Pontryagin's maximum principle is proposed. This algorithm is shown to converge, under reasonable conditions, to an optimal solution. The neural networks with time-dependent weights make it possible to efficiently find an admissible solution (i.e., initial weights satisfying state constraints) which then serves as an initial guess to carry out a proper minimization of a given criterion. The proposed methodology may be directly applicable to both classification of temporal sequences and to optimal tracking of nonlinear dynamic systems. Numerical examples are also given which demonstrate the efficiency of the approach presented.


Cell-mediated amplification and down regulation of cytotoxic immune response against autologous human cancer.
The cytotoxic host immune response toward autologous human cancer may be regulated by the immunoregulatory network. Here we show that helper T cells, cloned from peripheral blood lymphocytes that were sensitized in vitro against an autologous human malignant paraganglioma, proliferated against and made interleukin 2 when cocultured with the tumor-associated antigen in the presence of autologous accessory cells. Furthermore, the helper cell clones amplified cytotoxic immune response by peripheral blood lymphocytes against the paraganglioma cells in coculture with the blood lymphocytes and the paraganglioma cells. An autologous T cell line bearing suppressor phenotype, established from a lymph node that had been infiltrated with the paraganglioma tumor cells, in contrast to the helper cells, selectively suppressed the cytotoxic immune response by the blood lymphocytes against the paraganglioma cells in identical coculture. These results, therefore, demonstrate the existence of cell-mediated immunologic regulations of the cytotoxic immune response (concurrent amplification and suppression in the same host) against an autologous human tumor.


Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model.
Direct conversion from fibroblasts to generate hepatocyte like-cells (iHeps) bypassing the pluripotent state has been described in previous reports as an attractive method acquiring hepatocytes for cell-based therapy. The limited proliferation of iHeps, however, has hampered it uses in cell-based therapy. Since hepatic stem cells (HepSCs) possess self-renewal and bipotency with the capacity to differentiate into both hepatocytes and cholangiocytes, they have therapeutic potential for treating liver disease. Here, we investigated the therapeutic effects of induced HepSCs (iHepSCs) on a carbon tetrachloride (CCl4)-induced liver fibrosis model. We demonstrate that Oct4 and Hnf4a are sufficient to convert fibroblasts into expandable iHepSCs. Hepatocyte-like cells derived from iHepSCs (iHepSC-HEPs) exhibit the typical morphology of hepatocytes and hepatic functions, including glycogen storage, low-density lipoprotein (LDL) uptake, Indocyanine green (ICG) detoxification, drug metabolism, urea production, and albumin secretion. iHepSCs-derived cholangiocyte-like cells (iHepSC-CLCs) expressed cholangiocyte-specific markers and formed cysts and tubule-like structures with apical-basal polarity and secretory function in three-dimensional culture condition. Furthermore, iHepSCs showed anti-inflammatory and anti-fibrotic effects in CCl4-induced liver fibrosis. This study demonstrates that Oct4 and Hnf4α-induced HepSCs show typical hepatic and biliary functionality in vitro. It also presents the therapeutic effect of iHepSCs in liver fibrosis. Therefore, directly converting iHepSCs from somatic cells may facilitate the development of patient-specific cell-based therapy for chronic liver damage.


Epidermal growth factor receptor number decreases during rat liver regeneration.
The potential role of epidermal growth factor (EGF) in the regulation of rat liver regeneration was examined by assessing the binding of 125I-EGF to hepatic membranes isolated at various times after partial hepatectomy. The results demonstrated a fall in 125I-EGF binding detectable as early as 8 h after partial hepatectomy. The nadir in EGF binding, less than 40% of that observed in sham-operated control rats, was seen 36 and 48 h after partial hepatectomy. Scatchard analysis showed that the decrease in binding capacity was due to a fall in receptor number. The specificity of the observed loss of EGF receptors was substantiated in parallel studies of 125I-insulin and 125I-wheat germ lectin binding; the binding of these ligands did not decrease appreciably during liver regeneration. The data are consistent with the hypothesis that EGF or a similar substance is one component of the complex humoral signal that regulates liver regeneration.


Longitudinal and Cross-Sectional Sampling of Serpentovirus (Nidovirus) Infection in Captive Snakes Reveals High Prevalence, Persistent Infection, and Increased Mortality in Pythons and Divergent Serpentovirus Infection in Boas and Colubrids.
The aim of this study of serpentovirus infection in captive snakes was to assess the susceptibility of different types of snakes to infection and disease, to survey viral genetic diversity, and to evaluate management practices that may limit infection and disease. Antemortem oral swabs were collected from 639 snakes from 12 US collections, including 62 species, 28 genera, and 6 families: Pythonidae (N = 414 snakes; pythons were overrepresented in the sample population), Boidae (79), Colubridae (116), Lamprophiidae (4), Elapidae (12), and Viperidae (14). Infection was more common in pythons (38%; 95% CI: 33.1-42.4%), and in boas (10%; 95% CI: 5.2-18.7%) than in colubrids (0.9%, 95% CI: <0.01-4.7%); infection was not detected in other snake families (lamprophiids 0/4, 95% CI: 0-49%; elapids 0/12, 95% CI: 0-24.2%; and vipers 0/14, 95% CI: 0-21.5%), but more of these snakes need to be tested to confirm these findings. Clinical signs of respiratory disease were common in infected pythons (85 of 144). Respiratory signs were only observed in 1 of 8 infected boas and were absent in the single infected colubrid. Divergent serpentoviruses were detected in pythons, boas, and colubrids, suggesting that different serpentoviruses might vary in their ability to infect snakes of different families. Older snakes were more likely to be infected than younger snakes (p-value < 0.001) but males and females were equally likely to be infected (female prevalence: 23.4%, 95% CI 18.7-28.9%; male prevalence: 23.5%, 95% CI 18-30.1%; p-value = 0.144). Neither age (p-value = 0.32) nor sex (p-value = 0.06) was statistically associated with disease severity. Longitudinal sampling of pythons in a single collection over 28 months revealed serpentovirus infection is persistent, and viral clearance was not observed. In this collection, infection was associated with significantly increased rates of mortality (p-value = 0.001) with death of 75% of infected pythons and no uninfected pythons over this period. Offspring of infected parents were followed: vertical transmission either does not occur or occurs with a much lower efficiency than horizontal transmission. Overall, these findings confirm that serpentoviruses pose a significant threat to the health of captive python populations and can cause infection in boa and colubrid species.


Sequence design for magnetic resonance spectroscopic imaging of prostate cancer at 3 T.
Magnetic resonance spectroscopic imaging (MRSI) has proven to be a powerful tool for the metabolic characterization of prostate cancer in patients before and following therapy. The metabolites that are of particular interest are citrate and choline because an increased choline-to-citrate ratio can be used as a marker for cancer. High-field systems offer the advantage of improved spectral resolution as well as increased magnetization. Initial attempts at extending MRSI methods to 3 T have been confounded by the J-modulation of the citrate resonances. A new pulse sequence is presented that controls the J-modulation of citrate at 3 T such that citrate is upright, with high amplitude, at a practical echo time. The design of short (14 ms) spectral-spatial refocusing pulses and trains of nonselective refocusing pulses are described. Phantom studies and simulations showed that upright citrate with negligible sidebands is observed at an echo time of 85 ms. Studies in a human subject verified that this behavior is reproduced in vivo and demonstrated that the water and lipid suppression of the new pulse sequence are sufficient for application in prostate cancer patients.


Uncombable hair syndrome is a rare hair shaft anomaly presenting in childhood with blond, frizzy, and unruly hair. This case report presents a 9-year-old boy with remarkable hair where the mother, after reading a medical paper on hair shaft anomalies, suspected uncombable hair syndrome. She reached out to the author group, and the employment of molecular genetics later confirmed the diagnosis of uncombable hair syndrome. This case report serves as an example of how digital access enables the attention of patients and relatives to be directed towards rare conditions.


Synthesis of Thiazoloindole α-Amino Acids: Chromophores Amenable to One- and Two-Photon Induced Fluorescence.
Thiazoloindole α-amino acids have been synthesized in four steps from tryptophan using a dual-catalytic thiolation reaction and a copper-mediated intramolecular N-arylation process. Late-stage diversification of the thiazoloindole core with electron-deficient aryl substituents produced chromophores that on one-photon excitation displayed blue-green emission, mega-Stokes shifts, and high quantum yields. The thiazoloindole amino acids could also be excited via two-photon absorption in the near-infrared, demonstrating their potential for biomedical imaging applications.


Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia.
Patients with heterozygous familial hypercholesterolemia (n = 12) were treated either with pravastatin, a specific inhibitor of HMG-CoA reductase, or cholestyramine, followed by a period of combined treatment with both drugs. Initially, these patients had increased serum levels of low density lipoprotein (LDL) cholesterol (8.77 +/- 0.48 mmol/l; SEM), lathosterol (5.32 +/- 0.60 mg/l), and ubiquinone (0.76 +/- 0.09 mg/l), while the serum dolichol concentration was in the normal range. Cholestyramine treatment (n = 6) decreased the levels of LDL cholesterol (-32%) and increased lathosterol (+125%), but did not change dolichol or ubiquinone levels in a significant manner. Pravastatin treatment (n = 6) decreased LDL cholesterol (-27%), lathosterol (-46%), and ubiquinone (-29%). In this case, the amount of dolichol in serum also showed a small but statistically insignificant decrease (-16%) after 12 weeks of treatment. Combined treatment with cholestyramine and pravastatin (n = 6) resulted in changes that were similar to, but less pronounced than, those observed during pravastatin treatment alone. In no case was the ratio between ubiquinone and LDL cholesterol reduced. Possible effects on hepatic cholesterol, ubiquinone, and dolichol concentrations were studied in untreated (n = 2), cholestyramine-treated (n = 2), and pravastatin-treated (n = 4) gallstone patients and no consistent changes could be observed. The results indicate that treatment with pravastatin in familial hypercholesterolemia decreases serum ubiquinone levels in proportion to the reduction in LDL cholesterol.


Use of high-throughput enzyme-based assay with xenobiotic metabolic capability to evaluate the inhibition of acetylcholinesterase activity by organophosphorous pesticides.
The inhibition of acetylcholinesterase (AChE) has pharmaceutical applications as well as potential neurotoxic effects. The in vivo metabolites of some chemicals including organophosphorus pesticides can become more potent AChE inhibitors compared to their parental compounds. To account for the effects of biotransformation, we have developed and characterized a high-throughput screening method for identifying AChE inhibitors that become active or more potent following xenobiotic metabolism. In this study, an enzyme-based assay was developed in 1536-well plates using recombinant human AChE combined with human or rat liver microsomes. The AChE activity was measured by two methods with different readouts: colorimetric and fluorescent. The assay exhibited exceptional performance characteristics including large assay signal window, low well-to-well variability and high reproducibility. The performance of the assays with microsomes was characterized by testing a group of known AChE inhibitors including parent compounds and their metabolites. Large potency differences between the parent compounds and the metabolites were observed in the assay with microsome addition. Both assay readouts were required for maximal sensitivity. These results demonstrate that this platform is a promising method to profile large numbers of chemicals that require metabolic activation for inhibiting AChE activity.


Vibroacoustic stimulation for fetal assessment in labour in the presence of a nonreassuring fetal heart rate trace.
Fetal vibroacoustic stimulation is a simple, non-invasive technique where a device is placed on the maternal abdomen over the region of the fetal head and sound is emitted at a predetermined level for several seconds. It is hypothesized that the resultant startle reflex in the fetus and subsequent fetal heart rate acceleration or transient tachycardia following vibroacoustic stimulation provide reassurance of fetal well-being. This technique has been proposed as a tool to assess fetal well-being in the presence of a non-reassuring cardiotocographic trace during the first and second stages of labour. To evaluate the clinical effectiveness and safety of vibroacoustic stimulation in the assessment of fetal well-being during labour, compared with mock or no stimulation for women with a singleton pregnancy exhibiting a non-reassuring fetal heart rate pattern. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 September 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2004), MEDLINE (January 1966 to January 2005), EMBASE (January 1966 to January 2005) and reference lists of all retrieved articles. We sought unpublished trials and abstracts submitted to major international congresses and contacted expert informants. All published and unpublished randomised trials that compared maternal and fetal/neonatal/infant outcomes when vibroacoustic stimulation was used to evaluate fetal status in the presence of a non-reassuring cardiotocographic trace during labour, compared with mock or no stimulation. Two independent review authors identified potential studies from the literature search and assessed them for methodological quality and appropriateness of inclusion, using a data extraction form. Attempts to contact study authors for additional information were unsuccessful. The search strategies yielded six studies for consideration of inclusion. However, none of these studies fulfilled the requirements for inclusion in this review. There are currently no randomised controlled trials that address the safety and efficacy of vibroacoustic stimulation used to assess fetal well-being in labour in the presence of a non-reassuring cardiotocographic trace. Although vibroacoustic stimulation has been proposed as a simple, non-invasive tool for assessment of fetal well-being, there is insufficient evidence from randomised trials on which to base recommendations for use of vibroacoustic stimulation in the evaluation of fetal well-being in labour in the presence of a non-reassuring cardiotocographic trace.


Accuracy of artificial intelligence model for infectious keratitis classification: a systematic review and meta-analysis.
Infectious keratitis (IK) is a sight-threatening condition requiring immediate definite treatment. The need for prompt treatment heavily depends on timely diagnosis. The diagnosis of IK, however, is challenged by the drawbacks of the current "gold standard." The poorly differentiated clinical features, the possibility of low microbial culture yield, and the duration for culture are the culprits of delayed IK treatment. Deep learning (DL) is a recent artificial intelligence (AI) advancement that has been demonstrated to be highly promising in making automated diagnosis in IK with high accuracy. However, its exact accuracy is not yet elucidated. This article is the first systematic review and meta-analysis that aims to assess the accuracy of available DL models to correctly classify IK based on etiology compared to the current gold standards. A systematic search was carried out in PubMed, Google Scholars, Proquest, ScienceDirect, Cochrane and Scopus. The used keywords are: "Keratitis," "Corneal ulcer," "Corneal diseases," "Corneal lesions," "Artificial intelligence," "Deep learning," and "Machine learning." Studies including slit lamp photography of the cornea and validity study on DL performance were considered. The primary outcomes reviewed were the accuracy and classification capability of the AI machine learning/DL algorithm. We analyzed the extracted data with the MetaXL 5.2 Software. A total of eleven articles from 2002 to 2022 were included with a total dataset of 34,070 images. All studies used convolutional neural networks (CNNs), with ResNet and DenseNet models being the most used models across studies. Most AI models outperform the human counterparts with a pooled area under the curve (AUC) of 0.851 and accuracy of 96.6% in differentiating IK vs. non-IK and pooled AUC 0.895 and accuracy of 64.38% for classifying bacterial keratitis (BK) vs. fungal keratitis (FK). This study demonstrated that DL algorithms have high potential in diagnosing and classifying IK with accuracy that, if not better, is comparable to trained corneal experts. However, various factors, such as the unique architecture of DL model, the problem with overfitting, image quality of the datasets, and the complex nature of IK itself, still hamper the universal applicability of DL in daily clinical practice.


High muscle co-contraction does not result in high joint forces during gait in anterior cruciate ligament deficient knees.
The mechanism of knee osteoarthritis development after anterior cruciate ligament injuries is poorly understood. The objective of this study was to evaluate knee gait variables, muscle co-contraction indices and knee joint loading in young subjects with anterior cruciate ligament deficiency (ACLD, n = 36), versus control subjects (n = 12). A validated, electromyography-informed model was used to estimate joint loading. For the involved limb of ACLD subjects versus control, muscle co-contraction indices were higher for the medial (p = 0.018, effect size = 0.93) and lateral (p = 0.028, effect size = 0.83) agonist-antagonist muscle pairs. Despite higher muscle co-contraction, medial compartment contact force was lower for the involved limb, compared to both the uninvolved limb (mean difference = 0.39 body weight, p = 0.009, effect size = 0.70) as well as the control limb (mean difference = 0.57 body weight, p = 0.007, effect size = 1.14). Similar observations were made for total contact force. For involved versus uninvolved limb, the ACLD group demonstrated lower vertical ground reaction force (mean difference = 0.08 body weight, p = 0.010, effect size = 0.70) and knee flexion moment (mean difference = 1.32% body weight * height, p = 0.003, effect size = 0.76), during weight acceptance. These results indicate that high muscle co-contraction does not always result in high knee joint loading, which is thought to be associated with knee osteoarthritis. Long-term follow-up is required to evaluate how gait alterations progress in non-osteoarthritic versus osteoarthritic subjects. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.


Lipids and Atherogenic Indices Fluctuation in Rheumatoid Arthritis Patients on Long-Term Tocilizumab Treatment.
Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events, and the chronic inflammatory state may generate quantitative and qualitative changes in lipoprotein fractions. The anti-IL-6 receptor tocilizumab (TCZ), even if effective in inflammation and joint damage prevention, determined significant alterations to RA patients' lipid levels in randomized controlled trials, but real-world data are lacking. We evaluated the changes in lipid fraction levels and disease activity in a longitudinal cohort of RA patients on long-term treatment with tocilizumab (TCZ) in a community setting. We retrospectively selected 40 naïve-biologic RA patients on treatment with intravenous TCZ compared to 20 RA patients on methotrexate treatment as the control group. Total cholesterol (Tot-Chol), low-density lipoproteins (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured at the baseline and at 12, 24, and 52 weeks thereafter. At the same points, 28-joint disease activity score (DAS28), clinical disease activity index (CDAI), and EULAR clinical responses were also assessed. During the first 24 weeks, we observed in TCZ-treated patients a progressive statistically significant (p < 0.001) increase in Tot-Chol, LDL, HDL, and TG, which returned close to the baseline at 52 weeks. But no changes in the lipid-related CV risk indices Tot-Chol/HDL and LDL/HDL ratios and the atherogenic index (log10 TG/HDL) were detectable. Notably, we observed a statistically significant negative correlation between changes in lipid fractions and DAS28 or CDAI. The prolonged treatment with TCZ was associated to a transient increase in cholesterol's fractions during the first 6 months of treatment, with inverse correlation to disease activity, but with no impact on surrogate lipid indices of atherogenic risk. These findings may aid clinicians in interpreting the RA patient's lipid profile in daily clinical practice.


Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects. It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function. In an effort to recapitulate the effects of IGF-1, as well as increase the likelihood of translating these findings to the clinic, the small molecule therapeutic Roscovitine, is being tested. Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues. Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2)/M phase, as demonstrated by flow cytometry. In contrast, mice treated with radiation exhibit no differences in the percentage of cells in G(2)/M when compared to unirradiated controls. Similar to previous studies utilizing IGF-1, pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells. Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells, which is suppressed by pretreatment with Roscovitine. Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands, both acutely and chronically, as measured by salivary output. These studies suggest that induction of transient G(2)/M cell cycle arrest by Roscovitine allows for suppression of apoptosis, thus preserving normal salivary function following targeted head and neck irradiation. This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues.


High glycolate oxidase activity is required for survival of maize in normal air.
A mutant in the maize (Zea mays) Glycolate Oxidase1 (GO1) gene was characterized to investigate the role of photorespiration in C4 photosynthesis. An Activator-induced allele of GO1 conditioned a seedling lethal phenotype when homozygous and had 5% to 10% of wild-type GO activity. Growth of seedlings in high CO2 (1%-5%) was sufficient to rescue the mutant phenotype. Upon transfer to normal air, the go1 mutant became necrotic within 7 d and plants died within 15 d. Providing [1-14C]glycolate to leaf tissue of go1 mutants in darkness confirmed that the substrate is inefficiently converted to 14CO2, but both wild-type and GO-deficient mutant seedlings metabolized [1-14C]glycine similarly to produce [14C]serine and 14CO2 in a 1:1 ratio, suggesting that the photorespiratory pathway is otherwise normal in the mutant. The net CO2 assimilation rate in wild-type leaves was only slightly inhibited in 50% O2 in high light but decreased rapidly and linearly with time in leaves with low GO. When go1 mutants were shifted from high CO2 to air in light, they accumulated glycolate linearly for 6 h to levels 7-fold higher than wild type and 11-fold higher after 25 h. These studies show that C4 photosynthesis in maize is dependent on photorespiration throughout seedling development and support the view that the carbon oxidation pathway evolved to prevent accumulation of toxic glycolate.


Phytochrome control and anoxia effect on the activity and expression of soybean seedling lipoxygenases 1 and 2.
The effects of different light irradiations and anoxia treatment on the activity and expression of the lipoxygenases 1 (LOX-1) and 2 (LOX-2) of soybean seedlings have been investigated. A phytochrome-mediated decrease of the specific activities of both isoenzymes was found which was due to the regulation of the gene expression at the transcriptional level. The anoxia treatment of the seedlings led to a decrease of both lipoxygenase specific activities as well, but this effect was attributable to the reduction of the amount of the two isoenzymes, without changes in the steady-state levels of specific mRNAs. Therefore, light and anoxia are both regulators of soybean lipoxygenases, but their mechanism of action at the molecular level is different.


Valve-in-Valve Transcatheter Mitral Valve Replacement: A Large First-in-Human 13-Year Experience.
Favourable early outcomes have been reported following valve-in-valve transcatheter mitral valve replacement (TMVR). However, reports of long-term outcomes are lacking. We aimed to evaluate early and late outcomes in a large first-in-human valve-in-valve TMVR 13-year experience. All patients undergoing valve-in-valve TMVR in our centre from 2008 to 2021 were included. Clinical and echocardiographic outcomes, defined according to the Mitral Valve Academic Research Consortium, were reported. A total of 119 patients were analysed: mean age 76.8 ± 10.2 years, mean Society of Thoracic Surgeons score 10.7 ± 6.8%, 55.4% female, 63.9% transapical access. Thirty-day mortality was 2.5% for the total population and 0.0% after transseptal TMVR. Maximum follow-up was 13.1 years. During a median follow-up of 3.4 years (interquartile range 1.8-5.3 years), 55 patients (46.2%) died, mainly from noncardiovascular causes. Valve hemodynamics were acceptable at 5 years, with 2.5% structural dysfunction. Patients treated from 2016 on (n = 68; 57.1%), following the advent of routine use of the Sapien 3 valve, CT screening, and transseptal access, were compared with those treated before 2016 (n = 51; 42.9%). Patients from 2016 on had a higher technical success rate (100.0% vs 94.1%; P = 0.04), shorter hospitalisation (P < 0.001), trending lower 30-day mortality (1.5% vs 3.9%; P = 0.4) and better 5-year survival (74.7% vs 41.1%; P = 0.03). Valve-in-valve TMVR can be performed with little morbidity and low mortality. Mid- to long-term survival remains limited owing to advanced age and comorbidities. Structural bioprosthetic valve dysfunction was rare and redo TMVR feasible in selected patients. Outcomes continue to improve, but the role for valve-in-valve TMVR in lower surgical risk patients remains unclear.


The stem cells as a potential treatment for neurodegeneration.
Cell degeneration and death, be it extensive and widespread, such as in metabolic disorders, or focal and selective as in Parkinson's disease (PD), is the underlying feature of many neurological diseases. Thus, the replacement of cells lost by injury or disease has become a central tenet in strategies aiming at the development of novel therapeutic approaches for neurodegenerative disorders. In addition to the in vivo recruitment of endogenous cells, which is now emerging as a promising novel strategy, the transplantation of new, exogenously generated brain cells is probably the most extensively studied methodology for cell replacement in the central nervous system, with the initial experimental clinical studies in PD dating back to the early 1970s (Bjorklund, A. and Stenevi, U., 1984, Intracerebral neural implants: neuronal replacement and reconstruction of damaged circuitries. Annu Rev Neurosci 7, 279-308; Snyder, B. J. and Olanow, C. W., 2005, Stem cell treatment for Parkinson's disease: an update for 2005. Curr Opin Neurol 18, 376-85). The need to generate the cells to be transplanted in large quantities and in a reproducible, steady, and safe fashion has long represented one of the major issues in this field, regardless of whether one was trying to produce specific cell subtypes or uncommitted and highly plastic neural precursors, which would respond to local, instructive cues, upon transplantation into the damaged area. Neural stem cells (NSCs), with their capacity for long-term expansion in vitro and their extensive functional stability and plasticity, allow now for the establishment of cultures of mature neural cells as well as highly undifferentiated precursors and are emerging as one of the most amenable cell sources for neural transplantation (Gage, F. H., 2000, Mammalian neural stem cells. Science 287, 1433-8; McKay, R., 1997, Stem cells in the central nervous system. Science 276, 66-71). This chapter illustrates the basic aspect of the handling and preparation of NSCs for experimental transplantation in two animal models of neurodegenerative disorders, namely, postcontusion spinal cord injury and multiple sclerosis.


Classification accuracy of individual and combined executive functioning embedded performance validity measures in mild traumatic brain injury.
The development of more sophisticated performance validity measures is important due to concerns with coaching as well as providing clinicians with a greater variety of options when assessing performance validity. Examinees with noncredible performance may find it more difficult to elude detection by PVTs derived from arithmetical summation or logistic regression. The present study evaluated the classification accuracy of several executive functioning (EF) variables as PVTs both individually and when combined into derived variables. The current study evaluated a simple mathematic summation of embedded PVT scores and a logistic regression-based formula based on embedded PVTs from executive function measures. A total of 155 consecutive patients completed neuropsychological evaluation after sustaining a mild traumatic brain injury (MTBI) were studied and were placed into a PVT-PASS (N = 95, mean age = 44.9, SD = 12.55, mean education = 13.45, SD = 2.23, 38% male, 97% Caucasian) or PVT-FAIL group (N = 60, mean age = 44.1, SD = 15.47, mean education = 13.05, SD = 2.58, 55% male, 92% Caucasian). Trail Making Test B, Wisconsin Card Sorting Test, and Stroop Color Word Test were summed and also used in logistic regression to predict whether patients had credible performance. Both the mathematical summation and the logistic regression methods achieved excellent classification accuracy (summation AUC = .79; logistic regression AUC = .82) with higher sensitivity than individual PVTs.


Esophageal motility after laparoscopic Roux-en-Y gastric bypass: the manometry should be preoperative examination routine?
Our goal was to identify the changes of esophageal motility, lower esophageal sphincter (LES) function, and eating adaptation before and after Roux-en-Y gastric bypass (RYGBP) and whether manometry should be a routine examination in patients who undergo this procedure. A total of 81 patients underwent manometry before surgery and 1 year after surgery. The control group consisted of 10 nonobese volunteers. Patients were classified as presenting with vomiting and without vomiting 1 year after surgery. Manometric variables were compared before and after surgery. Statistical analysis was performed using Wilcoxon and Mann-Whitney test. The patients (45.6%) had preoperative manometric findings, 29.8% had LES hypertonia, 18.9% LES hypotonia, 43.2% increase in wave amplitude of contraction, and three 8.1% abnormal peristalsis. One year after surgery manometry was abnormal in 62.9% of patients, 11.7% with hypertonia and 15.7% with hypotonia of the LES, 53% with changes in amplitude contraction and 19.6% with abnormal peristalsis. The control group showed no manometric abnormalities. Chronic vomiting was noted in 21% of patients. When comparing all variables between the pre and postoperative periods, there was no significant difference for all of them except for peristalsis. Comparing the results of manometric findings between the vomiting and non-vomiting groups, no significant changes were found in the variables studied. There was an association between RYGBP and motor abnormalities in the esophagus but no differences in postoperative feeding adaptation. Thus, we conclude that esophageal manometry is not necessary as a routine preoperative examination.


Confirmatory factor analysis of the health literacy in dentistry scale (HeLD) in the Australian population.
To determine the psychometric properties of both the long- and short-form versions of the Health Literacy in Dentistry (HeLD) instrument in a large sample of the Australian adult population. Data were from a subset of the National Dental Telephone Interview Survey 2013. Both the long (HeLD-29) and short-form (HeLD-14) were utilised, each of which comprises items from 7 conceptual domains: access, understanding, support, utilization, economic barriers, receptivity and communication. Confirmatory Factor Analysis was performed through structural equation modelling to determine factorial validity, where the Χ²/df, comparative fit, goodness of fit and root mean square error of approximation were used as indices of goodness of fit. Convergent validity was estimated from the average variance extracted (AVE) and composite reliability (CR), while internal consistency was estimated by Cronbach standardized alpha. The dataset comprised 2,936 Australian adults aged 18+ years. The kurtosis and skewness values indicated an approximation to a normal distribution. Adequate fit was demonstrated for HeLD-14, but not for HeLD-29. Estimates of ≥ 0.50 for AVE and ≥ 0.70 for CR were demonstrated across all factors for both HeLD-29 and HeLD-14, indicating acceptable convergent validity for both forms. Discriminant validity was also demonstrated for both forms. Internal consistency was adequate in the seven conceptual domains for both HeLD forms, with Cronbach's alpha for all subscales being ≥0.70. The psychometric properties of the HeLD instrument in a large sample of the Australian adult population were confirmed. The short form HeLD-14 was more parsimonious than the long-form (HeLD-29).


Rationale, design and baseline characteristics of the MyoVasc study: A prospective cohort study investigating development and progression of heart failure.
Heart failure (HF) is a poly-aetiological syndrome with large heterogeneity regarding clinical presentation, pathophysiology, clinical outcome and response to therapy. The MyoVasc study (NCT04064450) is an epidemiological cohort study investigating the development and progression of HF. The primary objective of the study is (a) to improve the understanding of the pathomechanisms of HF across the full spectrum of clinical presentation, (b) to investigate the current clinical classifications of HF, and (c) to identify and characterize homogeneous subgroups regarding disease development using a systems-oriented approach. Worsening of HF, that is, the composite of transition from asymptomatic to symptomatic HF, hospitalization due to HF, or cardiac death, was defined as the primary endpoint of the study. During a six-year follow-up period, all study participants receive a highly standardized, biannual five-hour examination in a dedicated study centre, including detailed cardiovascular phenotyping and biobanking of various biomaterials. Annual follow-up examinations are conducted by computer-assisted telephone interviews recording comprehensively the participants´ health status, including subsequent validation and adjudication of adverse events. In total, 3289 study participants (age range: 35 to 84 years; female sex: 36.8%) including the full range of HF stages were enrolled from 2013 to 2018. Approximately half of the subjects (n=1741) presented at baseline with symptomatic HF (i.e. HF stage C/D). Among these, HF with preserved ejection fraction was the most frequent phenotype. By providing a large-scale, multi-dimensional biodatabase with sequential, comprehensive medical-technical (sub)clinical phenotyping and multi-omics characterization (i.e. genome, transcriptome, proteome, lipidome, metabolome and exposome), the MyoVasc study will help to advance our knowledge about the heterogeneous HF syndrome by a systems-oriented biomedicine approach. ClinicalTrials.gov; NCT04064450.


Surface Roughness of Different Composite Resins after Application of 15% Carbamide Peroxide and Brushing with Toothpaste: An In-Vitro Study.
This study aimed to evaluate the effect of toothbrushing after application of 15% carbamide peroxide (CP) on the surface roughness of three types of composite resins. Twenty samples, measuring 4 mm in height and diameter, were fabricated of three composite resins namely microfilled (MF) Heliomolar HB, nanohybrid (NH) IPS Empress Direct and microhybrid (MH) Tetric Ceram HB. After polishing, the initial surface roughness was measured with a profilometer. The tray technique was used to apply 15% CP gel for 6 hours. Then, cleaning was carried out with an Oral-B electric toothbrush for 3 minutes in a tank containing a freshly mixed toothpaste. These procedures were repeated for 21 days. Then, the surface roughness was measured again and compared with the initial values. A mixed-design ANOVA model was used for the analysis of data (P<0.05). The baseline roughness was significantly lower in MF compared to the NH and MH composites (P<0.001). Roughness increased in all study groups during the intervention period; however, this increase was not significant in the MH group (P=0.17). Furthermore, the increase in roughness in MF was smaller than that in NH (P<0.001) and MH (P=0.02) groups. The effect of intervention was more pronounced on NH and MH groups. Surface roughness changes were minor in MF composite resin.


Recent findings on the structure and function of teleost IgT.
As key effector molecules of jawed vertebrate's adaptive immune system, immunoglobulins are produced by B lymphocytes, either as a secretory form (antibody) or as a membrane form (B cell receptor). Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD. In addition, IgM in these species was thought to be the only immunoglobulin isotype responding to pathogens both in systemic or mucosal compartments. However, the unexpected discovery of IgT, a new teleost immunoglobulin unearthed in 2005, has provided for new opportunities to analyze further roles of teleost immunoglobulins in these two physiologically distinct compartments. The smoke about the potential function of IgT has cleared recently with the finding that this immunoglobulin appears to be specialized in gut mucosal immunity. Significantly, the new capability of measuring not only IgM but also IgT responses will greatly facilitate the evaluation and understanding of fish immune responses as well as the protective effects of fish vaccines. The purpose of this review is to summarize the molecular characterization of new IgT orthologs and subtypes in teleosts, as well as to describe the new findings concerning the protein structure of IgT, the B cells producing it, and its role in mucosal immunity.


Ischemic exercise and the muscle metaboreflex.
In exercising muscle, interstitial metabolites accumulate and stimulate muscle afferents. This evokes the muscle metaboreflex and raises arterial blood pressure (BP). In this report, we examined the effects of tension generation on muscle metabolites and BP during ischemic forearm exercise in humans. Heart rate (HR), BP, P(i), H(2)PO(4)(-), and pH ((31)P-NMR spectroscopy) data were collected in 10 normal healthy men (age 23 +/- 1 yr) during rhythmic handgrip exercise. After baseline measurements, the subjects performed rhythmic handgrip for 2 min. At 2 min, a 250-mmHg occlusion cuff was inflated, and ischemic handgrip exercise was continued until near fatigue (Borg 19). Measurements were continued for an additional 30 s of ischemia. This protocol was performed at 15, 30, 45, and 60% of the subjects' maximum voluntary contraction (MVC) in random order. As tension increased, the time to fatigue decreased. In addition, mean arterial pressure and HR were higher at 60% MVC than at any of the other lower tensions. The NMR data showed significantly greater increases in H(2)PO(4)(-), P(i), and H(+) at 60% than at 15 and 30% MVC. Therefore, despite the subjects working to the same perceived effort level, a greater reflex response (represented by BP and HR data) was elicited at 60% MVC than at any of the other ischemic tensions. These data are consistent with the hypothesis that, as tension increases, factors aside from insufficient blood flow contribute to the work effect on muscle metabolites and the magnitude of the reflex response.


The achilles heel of ErbB-2/HER2: regulation by the Hsp90 chaperone machine and potential for pharmacological intervention.
Signal transduction mediated by ErbB/HER receptor tyrosine kinases is crucial for the development and maintenance of epithelial tissues, and aberrant signaling is frequently associated with malignancies of epithelial origin. This review focuses on the roles played by the Hsp90 chaperone machinery in the regulation of signaling through the ErbB/HER network, and discusses potential therapeutic strategies that disrupt chaperone functions. Hsp90 and its associated cochaperones regulate ErbB signal transduction through multiple mechanisms. The chaperone system controls the stability of the nascent forms of both ErbB-1 (EGF-receptor) and ErbB-2/HER2, while regulation of the mature form is restricted to ErbB-2. Regulation by the Hsp90 complex extends to downstream effectors of ErbB signaling, namely Raf-1, Pdk-1 and Akt/PKB. Disrupting the function of Hsp90 results in the degradation of both the receptors and their effectors, thereby inhibiting tumor cell growth. The importance of an Hsp90-recognition motif located within the kinase domain of ErbB-2 is discussed, as well as a direct role for Hsp90 in regulating tyrosine kinase activity. In light of recent observations, we emphasize the ability of specific tyrosine kinase inhibitors to selectively target ErbB-2 to the chaperone-mediated degradation pathway. ErbB-specific drugs are already used to treat cancers, and clinical trials are underway for additional compounds that intercept ErbB signaling, including drugs that target Hsp90. Hence, the dependence of ErbB-2 upon Hsp90 reveals an Achilles heel, which opens a window of opportunity for combating cancers driven by the ErbB/HER signaling network.


[Is there a connection between biodiversity and the greenhouse effect].
It was discussed the role of biodiversity in ecosystems capacity to control CO2 in atmosphere as the main reason not only of "greenhouse effect" but "greenhouse catastrophe". The necessity to perfect the preventive measures has been defined by time factor. This time may be so little for completing the evolution theory and models of biosphere management. The temps of contemporaneous species extinction exceed two orders as minimum ones how it has been known from planet history. It doesn't permit to discharge that evolutional process will be successful to create organisms which have been capable to stabilize biosphere in conditions of its changing status. It's possible that such change may be provocated with the crisis in civilization-biosphere interrelations.


The effect of exercise on behavioral and psychological symptoms of dementia: towards a research agenda.
Behavioral and psychological symptoms of dementia (BPSD) are common and are core symptoms of the condition. They cause considerable distress to the person with dementia and their carers and predict early institutionalization and death. Historically, these symptoms have been managed with anxiolytic and antipsychotic medication. Although potentially effective, such medication has been used too widely and is associated with serious adverse side-effects and increased mortality. Consequently, there is a need to evaluate non-pharmacological therapies for behavioral and psychological symptoms in this population. One such therapy is physical activity, which has widespread health benefits. The aim of this review is to summarize the current findings of the efficacy of physical activity on BPSD. Published articles were identified using electronic and manual searches. Rather than systematically aggregating data, this review adopted a rapid critical interpretive approach to synthesize the literature. Exercise appears to be beneficial in reducing some BPSD, especially depressed mood, agitation, and wandering, and may also improve night-time sleep. Evidence of the efficacy of exercise on improving other symptoms such as anxiety, apathy, and repetitive behaviors is currently weak or lacking. The beneficial effect of exercise type, its duration, and frequency is unclear although some studies suggest that walking for at least 30 minutes, several times a week, may enhance outcome. The methodological shortcomings of current work in this area are substantial. The research and clinical implications of current findings are discussed.


[Pathogenesis of posterior capsular opacification after extracapsular cataract extraction].
Rabbit eyes were enucleated and examined by light and electronic microscope immediately after extracapsular surgery, and one day, one week, two weeks, one month and 6 months postoperatively. In addition, the technique of autoradiography was used to examine the status of cell hyperplasia of the lens epithelium. The results showed that posterior capsular opacification was due to migration of the lens epithelial cells onto the posterior capsule and transformation into fibroblasts. Fibrin exudate from postoperative uveitis was also a contributing factor.


Atomic force microscopy of biological samples.
The ability to evaluate structural-functional relationships in real time has allowed scanning probe microscopy (SPM) to assume a prominent role in post genomic biological research. In this mini-review, we highlight the development of imaging and ancillary techniques that have allowed SPM to permeate many key areas of contemporary research. We begin by examining the invention of the scanning tunneling microscope (STM) by Binnig and Rohrer in 1982 and discuss how it served to team biologists with physicists to integrate high-resolution microscopy into biological science. We point to the problems of imaging nonconductive biological samples with the STM and relate how this led to the evolution of the atomic force microscope (AFM) developed by Binnig, Quate, and Gerber, in 1986. Commercialization in the late 1980s established SPM as a powerful research tool in the biological research community. Contact mode AFM imaging was soon complemented by the development of non-contact imaging modes. These non-contact modes eventually became the primary focus for further new applications including the development of fast scanning methods. The extreme sensitivity of the AFM cantilever was recognized and has been developed into applications for measuring forces required for indenting biological surfaces and breaking bonds between biomolecules. Further functional augmentation to the cantilever tip allowed development of new and emerging techniques including scanning ion-conductance microscopy (SICM), scanning electrochemical microscope (SECM), Kelvin force microscopy (KFM) and scanning near field ultrasonic holography (SNFUH).


Determining the role of phonology in silent reading using event-related brain potentials.
The goal of the present study was to delineate phonology's role in silent reading using event-related brain potential (ERP) techniques. Terminal endings of high cloze sentences were manipulated in four conditions in which the terminal word was: (1) the high cloze ending and thus orthographically, phonologically and semantically congruent (e.g., The gambler had a streak of bad luck.); (2) a pseudohomophone that was orthographically incongruent, but was phonologically congruent to the anticipated ending (e.g., The ship disappeared into the thick phog [fog].); (3) a word that was orthographically, phonologically and semantically incongruent to expectations (e.g., The dog chased the cat up the Queen [tree].); or (4) a nonword and consequently orthographically, phonologically and semantically incongruent to expectations (e.g., The gas station is about two miles down the bole [road].). A N270 was elicited by orthographically incongruent words and nonwords (conditions 2, 3 and 4), likely reflecting violations of orthographic form expectations, while the presence of the N400 to semantically incongruent words and nonwords (conditions 3 and 4) reflected violations of semantic expectations. The relative absence of the N400 response to pseudohomophones (condition 3) indicates that integrating word meaning with sentential context is influenced by the phonological representation of the presented letter string. The implication of these results for theories of word recognition is discussed.


How habitat-modifying organisms structure the food web of two coastal ecosystems.
The diversity and structure of ecosystems has been found to depend both on trophic interactions in food webs and on other species interactions such as habitat modification and mutualism that form non-trophic interaction networks. However, quantification of the dependencies between these two main interaction networks has remained elusive. In this study, we assessed how habitat-modifying organisms affect basic food web properties by conducting in-depth empirical investigations of two ecosystems: North American temperate fringing marshes and West African tropical seagrass meadows. Results reveal that habitat-modifying species, through non-trophic facilitation rather than their trophic role, enhance species richness across multiple trophic levels, increase the number of interactions per species (link density), but decrease the realized fraction of all possible links within the food web (connectance). Compared to the trophic role of the most highly connected species, we found this non-trophic effects to be more important for species richness and of more or similar importance for link density and connectance. Our findings demonstrate that food webs can be fundamentally shaped by interactions outside the trophic network, yet intrinsic to the species participating in it. Better integration of non-trophic interactions in food web analyses may therefore strongly contribute to their explanatory and predictive capacity.


Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease.
This double-blind, randomized controlled trial compared the safety and efficacy of subcutaneous epoetin alfa-epbx, an epoetin alfa biosimilar, with the reference product, epoetin alfa, in hemodialysis patients with end-stage kidney disease (ESKD) and anemia who were receiving epoetin alfa maintenance treatment. Eligible patients (n = 320) were randomized (1:1) to subcutaneous epoetin alfa-epbx or epoetin alfa in a titration phase; patients who demonstrated stable subcutaneous dosing (n = 246) were re-randomized to receive subcutaneous epoetin alfa-epbx or epoetin alfa 1 to 3 times per week in a 16-week maintenance phase. Co-primary endpoints were least-squares mean difference between treatments in mean weekly hemoglobin concentration and mean weekly epoetin dose per kilogram body weight (BW) during the last 4 weeks of treatment in the maintenance phase. The least-squares mean difference (95% confidence interval [CI]) between treatments in weekly hemoglobin was 0.04 g/dl (-0.17 to 0.24 g/dl) and weekly epoetin dose/kg BW was -2.34 U/kg per week (-14.51 to 9.82 U/kg per week). The 95% CIs were contained within the prespecified equivalence margins of ±0.5 g/dl (weekly hemoglobin) and ±45 U/kg per week (weekly epoetin dose/kg BW). In the epoetin alfa-epbx and epoetin alfa groups, respectively, 4.0% and 4.1% of patients required blood transfusions, 69.7% and 70.5% reported adverse events, 18.9% and 27.0% reported serious adverse events, and 3 and 2 deaths were reported. Five patients were confirmed positive for anti-recombinant human erythropoietin antibody, 2 of whom tested positive at baseline. All patients tested negative for neutralizing antibodies. This comparative clinical trial demonstrated equivalence in efficacy and similar safety of subcutaneously administered epoetin alfa-epbx to epoetin alfa.


Polyprenol phosphate as an acceptor of mannose from guanosine diphosphate mannose in Aspergillus niger.
Growth of Aspergillus niger in the presence of [2-(14)C]mevalonate and (32)P(i) led to the formation of a lipid, containing (14)C (0.14% of dose) and (32)P (0.009% of dose), that had chromatographic properties identical with those of exo-methylene-hexahydropolyprenol phosphate. When a particulate enzyme preparation from the thallus of A. niger was incubated with GDP-[(14)C]mannose, the main radioactive products were mannose 1-phosphate (57% of products) and mannose (18%). In addition radioactive mannan (8%) and a mannolipid (2%) were formed. The latter was identified as exo-methylene-hexahydropolyprenol phosphate mannose on the basis of its chromatographic properties, acid lability and on the increase in formation of the mannolipid when the phosphate of exo-methylene-hexahydropolyprenols was added to the incubation mixture. The phosphates of ficaprenols and cetyl alcohol caused no corresponding increase. These observations are interpreted as evidence that the thallus of A. niger contains a mannose transferase that uses the phosphate of exo-methylene-hexahydropolyprenols as an acceptor. This situation is discussed in the light of the analogous involvement of a prenol phosphate mannose as an intermediate in the biosynthesis of bacterial wall mannan.


Evolution of anti-parkinsonian activity of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol in various in vivo models.
It has been found recently that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Diol) demonstrates high antiparkinsonian activity in some animal models. We carried out an extended study of the antiparkinsonian activity of Diol in a set of relevant animal models. Diol (20mg/kg) exhibited an anticataleptogenic effect in the haloperidol-induced catalepsy model and restored motor activity in animals in the reserpine-induced model of oligokinesia. The ability of Diol singly administered before MPTP injection to reduce rigidity comparable to that of activity of L-DOPA (100mg/kg) was found using the model of Parkinsonian syndrome (PS) induced by single injection of MPTP (30mg/kg) to C57BL/6 mice. In the model of PS induced by subchronic administration of MPTP (4 × 20mg/kg), Diol at a dose of 20mg/kg reduced rigidity with effectiveness comparable to that of L-DOPA, while being superior to L-DOPA in terms of its effect on motor activity. It was found using the model of PS induced by systemic administration of rotenone that subchronic daily oral administration of Diol prior to rotenone injection reduced severity of PS in rats. Assessment of the effects of chronic administration of Diol (20mg/kg) and L-DOPA to animals with 6-OHDA-induced PS showed that administration of Diol alleviated the symptoms of sensorimotor deficit in right limbs in rats. Thus, the potent antiparkinsonian activity of Diol was demonstrated in all the used rodent models experiments. Diol (20mg/kg) is as effective as the comparator agent L-DOPA administered at doses of 50-100mg/kg.


A systematic review comparing hysterectomy with less-invasive treatments for abnormal uterine bleeding.
To compare hysterectomy with less-invasive alternatives for abnormal uterine bleeding (AUB) in 7 clinically important domains. Systematic review. Randomized clinical trials comparing bleeding, quality of life, pain, sexual health, satisfaction, need for subsequent surgery, and adverse events between hysterectomy and less-invasive treatment options. Women with AUB, predominantly from ovulatory disorders and endometrial causes. Systematic review of the literature (from inception to January 2011) comparing hysterectomy with alternatives for AUB treatment. Eligible trials were extracted into standardized forms. Trials were graded with a predefined 3-level rating, and the strengths of evidence for each outcome were evaluated with the Grades for Recommendation, Assessment, Development and Evaluation system. Nine randomized clinical trials (18 articles) were eligible. Endometrial ablation, levonorgestrel intrauterine system, and medications were associated with lower risk of adverse events but higher risk of additional treatments than hysterectomy. Compared to ablation, hysterectomy had superior long-term pain and bleeding control. Compared with the levonorgestrel intrauterine system, hysterectomy had superior control of bleeding. No other differences between treatments were found. Less-invasive treatment options for AUB result in improvement in quality of life but carry significant risk of retreatment caused by unsatisfactory results. Although hysterectomy is the most effective treatment for AUB, it carries the highest risk for adverse events.


Brainstem enkephalinergic projections to spinal autonomic nuclei.
The present studies in the rat employed a combined retrograde transport-immunocytochemical technique to determine the origin in the brainstem of enkephalin (Enk) projections to spinal sympathetic nuclei, including the intermediolateralis nucleus, pars principalis (ILp). We found that Enk projections to the ILp nucleus are found in such serotonergic-containing areas as the raphe obscurus; raphe pallidus; gigantocellular reticular nucleus, pars alpha; paragigantocellular lateral nucleus; raphe magnus; and the rostral extension of the raphe magnus nucleus. The adrenergic-containing rostroventrolateral reticular nucleus as well as the noradrenergic-containing areas A5, A7, ventral locus coeruleus, subcoeruleus, and fiber pathway linking the locus coeruleus and A5/A7 send Enk projections to ILp. In the pons, a large contralateral Enk projection to spinal sympathetic nuclei was found medial to the facial nerve and medial to the motor nucleus of the trigeminal nerve. These observations show the existence of a large number of Enk brainstem regions that can influence spinal autonomic centers via descending supraspinal projections.


In the complex family of heat stress transcription factors, HsfA1 has a unique role as master regulator of thermotolerance in tomato.
We generated transgenic tomato plants with altered expression of heat stress transcription factor HsfA1. Plants with 10-fold overexpression of HsfA1 (OE plants) were characterized by a single HsfA1 transgene cassette, whereas plants harboring a tandem inverted repeat of the cassette showed cosuppression (CS plants) by posttranscriptional silencing of the HsfA1 gene connected with formation of small interfering RNAs. Under normal growth conditions, major developmental parameters were similar for wild-type (WT), OE, and CS plants. However, CS plants and fruits were extremely sensitive to elevated temperatures, because heat stress-induced synthesis of chaperones and Hsfs was strongly reduced or lacking. Despite the complexity of the plant Hsf family with at least 17 members in tomato, HsfA1 has a unique function as master regulator for induced thermotolerance. Using transient reporter assays with mesophyll protoplasts from WT tomato, we demonstrated that plasmid-encoded HsfA1 and HsfA2 were well expressed. However, in CS protoplasts the cosuppression phenomenon was faithfully reproduced. Only transformation with HsfA2 expression plasmid led to normal expression of the transcription factor and reporter gene activation, whereas even high amounts of HsfA1 expression plasmids were silenced. Thermotolerance in CS protoplasts was restored by plasmid-borne HsfA2, resulting in expression of chaperones, thermoprotection of firefly luciferase, and assembly of heat stress granules.


PEGylation of Terminal Ligands as a Route to Decrease the Toxicity of Radiocontrast Re6-Clusters.
The development of novel radiocontrast agents, mainly used for the visualization of blood vessels, is still an emerging task due to the variety of side effects of conventional X-ray contrast media. Recently, we have shown that octahedral chalcogenide rhenium clusters with phosphine ligands-Na2H14[{Re6Q8}(P(C2H4COO)3)6] (Q = S, Se)-can be considered as promising X-ray contrast agents if their relatively high toxicity related to the high charge of the complexes can be overcome. To address this issue, we propose one of the most widely used methods for tuning the properties of proteins and peptides-PEGylation (PEG is polyethylene glycol). The reaction between the clusters and PEG-400 was carried out in acidic aqueous media and resulted in the binding of up to five carboxylate groups with PEG. The study of cytotoxicity against Hep-2 cells and acute toxicity in mice showed a twofold reduction in toxicity after PEGylation, demonstrating the success of the strategy chosen. Finally, the compound obtained has been used for the visualization of blood vessels of laboratory rats by angiography and computed tomography.


Isolation and toxicity of Bacillus thuringiensis from potato-growing areas in Bolivia.
Bacillus thuringiensis was isolated from 116 samples collected in high altitude potato-growing areas in Bolivia. In these regions, main potato pests are the potato tuberworm Phthorimaea operculella, and the Andean weevils Premnotrypes latithorax and Rhigopsidius tucumanus. B. thuringiensis was found in 60% of the samples. The main percentage of samples with B. thuringiensis was found in larvae of R. tucumanus (78%). Bioassays were performed with 112 isolates. None resulted toxic to either larvae or adults of the two Andean weevils. However, 18 isolates from this study showed more toxicity against the beet armyworm Spodoptera exigua than the standard strain var. kurstaki isolated from DELFIN. Among these isolates, three were also effective against P. operculella, conferring better or equal protection to the tubers than the reference strain HD-1 isolated from DIPEL. The most toxic strains against S. exigua and P. operculella were characterized in terms of serotyping, crystal morphology, protein profile, and cry gene content. PCR was performed with primers amplifying genes from the cry1, cry2, cry3, cry4, cry7, 8, and cry9Aa families. The toxic strains presented bipyramidal crystals, at least a band of 130kDa in SDS-PAGE, and showed an amplification product with cry1 family primers. One of the isolates did not amplify with any specific primer belonging to known cry1 genes. Restriction Fragment Length Polymorphism (RFLP) confirmed the presence of a novel gene and sequence comparison showed that this gene had homology to cry1G.


Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs.
When exposed to prolonged stress, rats develop gastric ulceration, enhanced colon motility with depletion of its mucin content and signs of physiological and behavioral arousal. In this model, we tested whether antidepressants (fluoxetine and bupropion), anxiolytics (diazepam and buspirone) or the novel nonpeptide corticotropin-releasing hormone (CRH) type-1 receptor (CRH-R1) antagonist, antalarmin, modify these responses. Fluoxetine, bupropion, diazepam and antalarmin all suppressed stress-induced gastric ulceration in male Sprague-Dawley rats exposed to four hours of plain immobilization. Antalarmin produced the most pronounced anti-ulcer effect and additionally suppressed the stress-induced colonic hypermotility, mucin depletion, autonomic hyperarousal and struggling behavior. Intraperitoneal CRH administration reproduced the intestinal but not the gastric responses to stress while vagotomy antagonized the stress-induced gastric ulceration but not the intestinal responses. We conclude that brain CRH-R1 and vagal pathways are essential for gastric ulceration to occur in response to stress and that peripheral CRH-R1 mediates colonic hypermotility and mucin depletion in this model. Nonpeptide CRH-R1 antagonists may therefore be prophylactic against stress ulcer in the critically ill and therapeutic for other pathogenetically related gastrointestinal disorders such as peptic ulcer disease and irritable bowel syndrome.


Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukemia treated with nilotinib.
Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1IS at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov identifier: 01061177).


Establishment of mouse embryonic fibroblast cell lines that promote ex vivo expansion of human cord blood CD34+ hematopoietic progenitors.
The development of culture systems that facilitate ex vivo maintenance and expansion of transplantable hematopoietic progenitor cells (HPC) is vital to stem cell transplantation. The use of a monolayer of stromal cells on which to grow HPC in direct contact allows high efficiency ex vivo expansion of HPC. Here, we report an establishment of three murine embryonic fibroblast stromal cell lines from adherent cells of day-12 mouse embryos. Among them, HYMEQ-5 was most efficient in supporting long-term maintenance of human umbilical cord blood (CB) CD34(+) cells. Human CB CD34(+) cells cultured on HYMEQ-5 in the presence of stem cell factor (SCF), thrombopoietin, and flk-ligand (FL) showed high expansion of CD34(+)CD38(-) cells and highly proliferative potential-colony forming cells (HPP-CFC). Direct cell-to-cell contact between CD34(+) cells and HYMEQ-5 was important for this expansion. RT-PCR analysis showed that HYMEQ-5 produced FL, SCF, interleukin-6, and macrophage colony-stimulating factor (M-CSF). Expanded CB CD34(+) cells efficiently reconstituted hematopoiesis in nonobese diabetic/severe combined immunodeficient disease (NOD/SCID) mice. These findings suggest that HYMEQ-5 provides a milieu that supports long-term human hematopoiesis as well as ex vivo expansion of human CB CD34(+) HPC. This cell line may facilitate elucidation of the mechanism of cellular interactions between HPC and stromal cells.


Cystic fibrosis and neuroblastoma.
Two cases of coexistent cystic fibrosis and infantile thoracic neuroblastoma are presented. In one patient, neuroblastoma was congenital, and diagnosis of cystic fibrosis was made at 3 months of age; in the other, the diagnosis of cystic fibrosis was made at 7 months of age, preceding that of neuroblastoma by 4 months. In both infants, surgical resection of the tumors have been successful. Recent advances in the genetic aspects of neuroblastoma, including translocation and activation of the oncogene N-myc, are discussed. Current recombinant DNA technology, which can identify translocation of N-myc and allow localization of the cystic fibrosis gene if the translocation occurs near the cystic fibrosis allele, is being applied to these cases.


Excited-State Triplet Equilibria in a Series of Re(I)-Naphthalimide Bichromophores.
We present the synthesis, structural characterization, electronic structure calculations, and the ultrafast and supra-nanosecond photophysical properties of a series of five bichromophores of the general structural formula [Re(5-R-phen)(CO)3(dmap)](PF6), where R is a naphthalimide (NI), phen = 1,10-phenanthroline, and dmap is 4-dimethylaminopyridine. The NI chromophores were systematically modified at their 4-positions with -H (NI), -Br (BrNI), phenoxy (PONI), thiobenzene (PSNI), and piperidine (PNI), rendering a series of metal-organic bichromophores (Re1-Re5, respectively) featuring variability in the singlet and triplet energies in the pendant NI subunit. Five closely related organic chromophores as well as [Re(phen)(CO)3(dmap)](PF6) (Re6) were investigated in parallel to appropriately model the photophysical properties exhibited in the bichromophores. The excited state processes of all molecules in this study were elucidated using a combination of transient absorption spectroscopy and time-resolved photoluminescence (PL) spectroscopy, revealing the kinetics of the energy transfer processes occurring between the appended chromophores. The spectroscopic analysis was further supported by electronic structure calculations which identified the origin of many of the experimentally observed electronic transitions.


Active suppression of immunoglobulin allotype synthesis. 3. Identification of T cells as responsible for suppression by cells from spleen, thymus, lymph node, and bone marrow.
Thymus-derived cells (T cells) that actively suppress production of IgG2a immunoglobulins carrying the Ig-1b allotype have been found in adult (SJL x BALB/c)F(1) mice exposed to anti-Ig-1b early in life. The suppression is specific for Ig-1b. The allelic product, Ig-1a, is unaffected. Spleen, lymph node, bone marrow, or thymus cells from suppressed mice suppress production of Ig-1b by syngeneic spleen cells from normal F(1) mice. When a mixture of suppressed and normal cells is transferred into lethally irradiated BALB/c mice, there is a short burst of Ig-1b production after which Ig-1b levels in the recipient fall rapidly below detectability. Pretreatment of the cells from the suppressed mice with antiserum specific for T cells (anti-Thy-1b) plus complement before mixture destroys the suppressing activity. Similar results with suppressor cells were obtained in vitro using Mishell-Dutton cultures. Mixture of spleen cells from suppressed animals with sheep erythrocyte (SRBC)-primed syngeneic normal spleen before culture suppresses Ig-1b plaque-forming cell (PFC) formation while leaving Ig-1a PFC unaffected. Treatment of the suppressed spleen with anti-Thy-1b before transfer removes the suppressing activity.


[E-bikers are more often seriously injured in bicycle accidents: results from the Groningen bicycle accident database].
Analysing injury types, injury severity and mortality in victims of accidents with electric bicycles in comparison with conventional bicycles. Prospective cohort study. Data of patients treated at the Accident & Emergency Department of the University Medical Center Groningen after a bicycle accident are being entered in a database since 2014. We have analysed this database for accidents with electric bicycles (e-bikes) and conventional bicycles occurring among adult patients for the period of July 2014 to May 2016. 'Propensity score matching' was used to match e-bikers to conventional cyclists, based on age, gender and the presence of comorbidities. 107 of the 475 included victims were riding an e-bike. Average age of e-bikers and conventional cyclists was 65 years and 39 years respectively. Comorbidity was more common in e-bikers. E-bikers were injured significantly more severely than conventional cyclists. They had more severe injuries of the head and face, and upper and lower extremities. E-bikers were also admitted to the hospital more often, and for longer periods, and they underwent surgery more often. Mortality was the same. Propensity score matching revealed that e-bikers had multiple severe injuries (ISS > 15) twice as often as conventional cyclists, that they had more severe head injuries and were admitted for longer periods than conventional cyclists. E-bikers who had a bicycle accident had more severe injuries, more frequently had multiple injuries and had more severe head injuries than conventional cyclists. This resulted in a greater need for care. Preventive measures such as riding lessons and helmet use should be encouraged. Care providers should pay extra attention to the possibility of severe injuries when a patient had a bicycle accident with an e-bike.


Launching nurse-initiated HIV rapid testing in Veterans Affairs primary care: a comprehensive overview of a self-sustaining implementation.
Our objectives were to use foundational pilot findings to guide the implementation of an HIV rapid testing (RT) intervention at one Veterans Affairs outpatient clinic and to evaluate the success and sustainability of this intervention over the course of one year. Policy modifications were drafted and adopted to enable nurses to order, administer, interpret and document HIV RTs. Staff enrolled in a two-part training sessions designed to teach pre- and post-test counselling techniques and the mechanics of administering, interpreting and coding test results in the patients' medical records. They were subsequently evaluated on their efforts at: (1) increasing HIV RT, (2) sustaining this effort one year post-launch. Enabling nurses to carry out HIV RT resulted in a significant increase in not only HIV RT, but also HIV testing rates overall at this facility, measured over the first year of this implementation. Our findings indicate that targeted strategies, aimed at increasing HIV RT rates, worked to increase testing rates overall, and also, that our initial testing strategies were independently sustainable, which is in contrast to findings in the literature on implementation science.


How to run far: multiple solutions and sex-specific responses to selective breeding for high voluntary activity levels.
The response to uniform selection may occur in alternate ways that result in similar performance. We tested for multiple adaptive solutions during artificial selection for high voluntary wheel running in laboratory mice. At generation 43, the four replicate high runner (HR) lines averaged 2.85-fold more revolutions per day as compared with four non-selected control (C) lines, and females ran 1.11-fold more than males, with no sex-by-linetype interaction. Analysis of variance indicated significant differences among C lines but not among HR for revolutions per day. By contrast, average speed varied significantly among HR lines, but not among C, and showed a sex-by-linetype interaction, with the HR/C ratio being 2.02 for males and 2.45 for females. Time spent running varied among both HR and C lines, and showed a sex-by-linetype interaction, with the HR/C ratio being 1.52 for males but only 1.17 for females. Thus, females (speed) and males (speed, but also time) evolved differently, as did the replicate selected lines. Speed and time showed a trade-off among HR but not among C lines. These results demonstrate that uniform selection on a complex trait can cause consistent responses in the trait under direct selection while promoting divergence in the lower-level components of that trait.


Effect of vascular cadherin knockdown on zebrafish vasculature during development.
Vascular endothelial cadherin (VE-cad) is essential for endothelial barrier integrity and vascular sprouting. However, the role of this important protein in cardiovascular development is only recently becoming apparent. To characterize the role of VE-cadherin in cardiovascular development, we analyzed cardiovascular development in a zebrafish VE-cad knockdown model. Embryos deficient in VE-cad show profoundly impaired cardiac development despite having apparently normal peripheral vasculature. Initial formation of the heart proceeds normally in knockdown embryos, but subsequent looping morphogenesis is impaired. Consistent with these results, VE-cad knockdown embryos demonstrate impaired cardiac function and early circulatory arrest. Histologic examination of knockdown embryos shows persistent, abnormal separation of the endocardial and myocardial layers. Using transmission electron microscopy, we demonstrate that endocardial junctions form poorly in VE-cad knockdown embryos, with resulting leak across the endothelial layer and reduction in the density of the cardiac jelly. Our results demonstrate a significant role for VE-cadherin in cardiac development independent of its effects on the formation of the peripheral vasculature.


Genetic analysis of Aralia cordata Thunb by RAPD.
In the research, genetic analysis of Aralia cordata Thunb. (Araliaceae) was conducted using randomly amplified polymorphism DNA (RAPD). 161 loci were detected with 12 RAPD primers. Percentage of Polymorphic Band (PPB) varied from 34.78% to 63.35%. All the samples were respectively collected from the eight provinces richest in Aralia cordata Thunb resources in China, including Hunan, Yunnan, Zhejiang, Sichuan, Jiangxi, Anhui, Shanxi and Gansu. The results showed that Hunan Province enjoyed the highest level of genetic differentiation and Gansu was the lowest. The total genetic diversity (H(T)) of RAPD, intraspecific genetic diversity (H(S)) and genetic diversity (D(ST)) of the various places was respectively 26.33%, 11.14%, and 49.36%. The differentiation among the species accounted for 98.76% of total genetic diversity (G(ST)). Based on the cluster results of genetic distance, the 8 samples were classified into three groups. It is concluded that Hunan Province enjoyed the highest level of genetic differentiation of Aralia cordata Thunb and Gansu was the lowest, which provides a basis for the taxonomic identification and germplasm resource research of Aralia cordata Thunb in the future.