Improved hydrophilic interaction chromatography LC/MS of heparinoids using a chip with postcolumn makeup flow.
Heparan sulfate (HS) and heparin are linear, heterogeneous carbohydrates of the glycosaminoglycan (GAG) family that are modified by N-acetylation, N-sulfation, O-sulfation, and uronic acid epimerization. HS interacts with growth factors in the extracellular matrix, thereby modulating signaling pathways that govern cell growth, development, differentiation, proliferation, and adhesion. High-performance liquid chromatography (HPLC)-chip-based hydrophilic interaction liquid chromatography/mass spectrometry has emerged as a method for analyzing the domain structure of GAGs. However, analysis of highly sulfated GAG structures decasaccharide or larger in size has been limited by spray instability in the negative-ion mode. This report demonstrates that addition of postcolumn makeup flow to the amide-HPLC-chip configuration permits robust and reproducible analysis of extended GAG domains (up to degree of polymerization 18) from HS and heparin. This platform provides quantitative information regarding the oligosaccharide profile, degree of sulfation, and nonreducing chain termini. It is expected that this technology will enable quantitative, comparative glycomics profiling of extended GAG oligosaccharide domains of functional interest.


Benign nocturnal alternating hemiplegia of childhood: two cases with positive evolution.
Benign nocturnal alternating hemiplegia (BNAH) of childhood is distinct from the classic form of malignant alternating hemiplegia of childhood [1]. It is characterized by hemiplegic attacks occurring exclusively during sleep [2]. It can be misdiagnosed as migraine, nocturnal frontal lobe epilepsy, benign rolandic epilepsy, Panayiotopoulos syndrome, or sleep-related movement disorder [1-4]. Only nine patients have been described to date, with typically, a normal development [1,5-7]. In order to insist about the benignity of the affection, we report two cases: a new three-year-old boy suffering from BNAH and a patient already published to show positive evolution at fourteen years of age. BNAH is a rare disorder but may be underdiagnosed. Making an early diagnosis can help to describe to the parents the good prognosis without treatment.


A gene signature of bone metastatic colonization sensitizes for tumor-induced osteolysis and predicts survival in lung cancer.
Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-β signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis.


Preclinical Immunopharmacologic Assessment of KPL-404, a Novel, Humanized, Non-Depleting Antagonistic Anti-CD40 Monoclonal Antibody.
The CD40/CD40L pathway plays a major role in multiple inflammatory processes involving different immune and stromal cells. Abnormal activation of this pathway has been implicated in pathogenesis of complex autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, Graves' disease, and Sjogren's Syndrome. We completed in vitro and in vivo preclinical characterization of KPL-404, a novel humanized anti-CD40 IgG4 monoclonal antibody, to demonstrate its potency, efficacy, and pharmacokinetic profile; safety was also assessed. In vitro, KPL-404 bound recombinant human and cynomolgus monkey CD40 with comparable affinity in the nanomolar range. KPL-404 binding to cell surface CD40 did not induce antibody- or complement-mediated cytotoxicity of CD40-expressing cells. Pharmacological antagonistic activity of KPL-404 was demonstrated in vitro by inhibition of CD40-mediated downstream NF-kB activation. In the in vivo study with cynomolgus monkeys, KPL-404, administered intravenously as a single dose (10 mg/kg) or two monthly doses of 1 or 5 mg/kg, did not elicit observable safety findings, including thrombocytopenia over 8 weeks. KPL-404 engaged CD40 expressed on peripheral B cells for 2 and 4 weeks after a single administration of 5 or 10 mg/kg IV, respectively, without depletion of peripheral B cells. At 5 mg/kg IV, KPL-404 blocked both primary and secondary responses to T-cell dependent antibody responses to test antigens, KLH, and tetanus toxoid. These data illustrated the relationship between KPL-404 serum concentration and pharmacodynamic effects of CD40-targeting in circulation and in lymphoid tissues. These data support clinical development of KPL-404 in autoimmune diseases. SIGNIFICANCE STATEMENT: We aimed to develop a potent and efficacious CD40 antagonist. In vitro and in vivo findings show that KPL-404 blocks the anti-CD40 antibody that potently inhibits primary and secondary antibody responses at pharmacologically relevant concentrations, has a favorable pharmacokinetic profile, and does not deplete B cells by antibody-dependent cellular cytotoxicity or apoptosis ("nondepleting"). These findings support clinical development of KPL-404 as a potential therapeutic in autoimmune diseases.


The intercarpal ligaments of the equine midcarpal joint, Part 3: Clinical observations in 32 racing horses with midcarpal joint disease.
To characterize the clinical features of intercarpal ligament pathology and to determine the relationship among palmar intercarpal ligament tearing, dorsomedial intercarpal ligament (DMICL) hypertrophy, and other intraarticular lesions. Prospective clinical observations. Twenty-eight thoroughbred and four standardbred race horses. Clinical, radiographic, and arthroscopic examination of 53 midcarpal joints of 32 horses. Palmar intercarpal ligament tearing was observed in 30 joints of 22 horses. Some tearing of the medial palmar intercarpal ligament (MPICL) was present in 27 joints of 20 horses, and tearing of the lateral palmar intercarpal ligament in 9 joints of 7 horses. There was no correlation between the severity of clinical signs recorded and the degree of MPICL tearing. Joints with grade 2-4 MPICL tearing had significantly less cartilage and bone damage than joints with grade 1 or no ligament damage (P < .05). There was a significant inverse relationship between the number and size of intra-articular fractures, as assessed radiographically, and ligament damage (R = -.31). The DMICL was identified in all joints, and in 18 joints the ligament was enlarged. There was a significant correlation between MPICL damage and hypertrophy of the DMICL (R = .35). There was no correlation between DMICL hypertrophy and articular cartilage damage or subchondral bone damage. Severe subchondral bone and MPICL damage rarely occur in the same joint and DMICL hypertrophy may be associated with, rather than a cause of, joint disease. There are no clinical or radiographic findings that will differentiate intercarpal ligament injury from other carpal injuries. Diagnosis is only possible by arthroscopic examination of the midcarpal joint.


[Effect of the macrocyclic polyether 15-crown-5 on the ionic permeability of excitable membranes].
The macrocyclic polyether 15-crown-5 at a concentration of 5 . 10(-5)-10(-3) M reduced the frequency of the contractions of an isolated rat auricle, increasing the refractory period of the contractions. The polyether lowered the rate of activation of the slow input current of rat spinal ganglionic neurons and blocked the sodium channels of the electroexcitable membrane without disturbing the function of activation and inactivation mechanisms. The compound under study considerably delayed the onset of and decelerated reactivation of the sodium input current. These actions were calcium-dependent, becoming more demonstrable with reduction of Ca2+ concentration outside the cell. 15-Crown-5 interfered with the action of Ca2+ on the lipid bilayer membrane potential. It is assumed that all the effects described are determined by the formation of 15-crown-5-Ca2+ complexes, thereby leading to the impairment of the packing of the membrane lipoprotein matrix.


Leveraging a Safety Event Management System to Improve Organizational Learning and Safety Culture.
Safety event management systems (SEMS) are rich sources of patient safety information, which can be used to improve organizational safety culture. An ideal SEMS can accomplish this when the system is improved with the intention of increasing learning and engagement across the organization. To support a global aim of improving overall patient safety and becoming a highly reliable learning health system, focus was directed toward increasing event review and follow-up completion and using this information to drive resource allocation and improvement efforts. A new integrated SEMS was customized, tested, and implemented based on identified organizational need. Revised policies were developed to define expectations for event review and follow-up. The new SEMS incorporated a closed-loop communication process which ensured information from events was shared with the event submitters and facilitated shared learning. The expected impacts, improved event reporting, and follow-up were studied and guided ongoing improvements. After transitioning to a new SEMS, we experienced increased overall reporting by 8.6% and improved event follow-up, demonstrated by documentation on specified system forms, by 53.7%. By implementing a new, efficient, and standardized SEMS, which decentralized event management processes, the organization saw increased reporting and better engagement with patient safety event review and follow-up. Overall, these results demonstrated a stronger reporting culture, which allowed for local problem solving and improved learning from every event reported. A robust reporting culture positively impacted the overall organizational culture of safety.


Non-invasive imaging of acute allograft rejection after rat renal transplantation using 18F-FDG PET.
The number of patients with end-stage renal disease, and the number of kidney allograft recipients continuously increases. Episodes of acute cellular allograft rejection (AR) are a negative prognostic factor for long-term allograft survival, and its timely diagnosis is crucial for allograft function (1). At present, AR can only be definitely diagnosed by core-needle biopsy, which, as an invasive method, bares significant risk of graft injury or even loss. Moreover, biopsies are not feasible in patients taking anticoagulant drugs and the limited sampling site of this technique may result in false negative results if the AR is focal or patchy. As a consequence, this gave rise to an ongoing search for new AR detection methods, which often has to be done in animals including the use of various transplantation models. Since the early 60s rat renal transplantation is a well-established experimental method for the examination and analysis of AR (2). We herein present in addition small animal positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) to assess AR in an allogeneic uninephrectomized rat renal transplantation model and propose graft FDG-PET imaging as a new option for a non-invasive, specific and early diagnosis of AR also for the human situation (3). Further, this method can be applied for follow-up to improve monitoring of transplant rejection (4).


Identification of Haynaldia villosa chromosomes added to wheat using a sequential C-banding and genomic in situ hybridization technique.
Genomic in situ hybridization (GISH) offers a convenient and effective method for cytological detection, but can not determine the identity of the chromosomes involved. We integrated C-banding with GISH to identify Haynaldia villosa chromosomes in a wheat background. All chromosomes of H. villosa showed C-bands, either in telomeric regions or in both telomeric and centromeric regions, which allowed unequivocal identification of each H. villosa chromosome. The seven pairs of H. villosa chromosomes were differentiated as 1-7 according to their characteristic C-bands. Using a sequential C-banding and GISH technique, we have analyzed somatic cells of F3 plants from the amphiploid Triticum aestivum-H. villosa x 'Yangmai 158' hybrids. Three plants (94009/5-4,94009/5-8 and 94009/5-9) were shown to contain H. villosa chromosome(s). 94009/5-4 (2n = 45) had three H. villosa chromosomes (2, 3 and 4); 94009/5-8 (2n = 45) possessed one chromosome 4 and a pair of chromosome 5, and 94009/5-9 (2n = 43) was found to have one chromosome 6 of H. villosa. The combination of GISH with C-banding described here provides a direct comparison of the cytological and molecular landmarks. Such a technique is particularly useful for identifying and localizing alien chromatin and DNA sequences in plants.


Effects of Microglial Activation and Polarization on Brain Injury After Stroke.
Stroke is one of the most common causes of death worldwide. The subsequent development of neuroinflammation and brain edema dramatically increases the risks associated with stroke, leading to a substantial increase in mortality. Although considerable progress has been made in improving cerebral perfusion in the acute phase of stroke, effective treatment options for the subacute and chronic phases associated with cerebral infarction are limited. Microglia, the innate immune cells of the central nervous system (CNS), can be activated and polarized to take on different phenotypes in response to stimulations associated with stroke, including pro-inflammatory and anti-inflammatory phenotypes, which affect the prognosis of stroke. Therefore, investigation of the activation and polarizing mechanisms of microglia plays a critical role in treating stroke. The aim of this article was to investigate the significance of microglial phenotype regulation in stroke treatment by summarizing the activation, polarizing mechanisms, and general microglia characteristics.


The Long Intergenic Noncoding RNA 00707 Sponges MicroRNA-613 (miR-613) to Promote Proliferation and Invasion of Gliomas.
Glioma is one of the most deadly malignant tumors in humans. Long non-coding RNA (lncRNA) plays a key role in the occurrence, development and invasion of tumors by regulating oncogenic and tumor suppressor pathways. However, the role and action mechanism of long intergenic non-coding RNA 00707 (LINC00707) in gliomas have not been elucidated. This study aimed to investigate the interaction between LINC00707 and miR-613 as well as its role in gliomas. The expression levels of LINC00707 and miR-613 were detected by qRT-PCR. The chi-square test was used to analyze the correlation between LINC00707 expression and clinicopathological parameters. CCK-8 and colony formation assays were used to detect glioma cell proliferation; and wound healing and transwell assays were used to detect glioma cell migration and invasion. The relationship between LINC00707 and miR-613 was predicted by Starbase, and verified by qRT-PCR and dual luciferase reporter gene assay. LINC00707 was up-regulated in gliomas. Up-regulated LINC00707 increased the proliferation, migration and invasion of glioma cells, and silenced LINC00707 reduced these abilities. The increase of the expression level of LINC00707 down-regulated miR-613 in glioma cells, while the inhibition of the expression level of LINC00707 up-regulated miR-613 in glioma cells. The high expression of LINC00707 was related to the Karnofsky performance status (KPS) score and WHO staging. LINC00707 could offset the ability of miR-613 to inhibit glioma proliferation and invasion. LINC00707 promotes proliferation and invasion of glioma cells by sponging miR-613. The regulatory axis of LINC00707/miR-613 provides new insights into the mechanism and treatment of gliomas.


Allenoate Prenucleophiles: A Triply Diastereoselective Approach to β-Hydroxy Esters Containing All-Carbon α-Quaternary Centers.
Allenyl esters activated by titanium(IV) underwent additions to a wide range of aldehydes in high regio- and diastereoselectivities leading to products containing an all-carbon quaternary center bearing an α-vinyl group that was installed with high selectivity for the Z-geometry. An aldol product was also converted to an indanone offering a new route to this important compound class. Product triple diastereoselectivity has been rationalized using a concerted transition-state model.


The free groin flap in the rat: a model for improving microsurgical skills and for microvascular perfusion studies.
The goal of this study was to evaluate the free groin flap in the rat transplanted to the neck as a tool for extending microsurgical skills and to assess its suitability as a model for microvascular perfusion studies following secondary venous ischaemia. An analysis of 60 consecutive groin flap transplantations was performed in male Sprague Dawley rats with special regard to anatomy and operation times (Part I, animals No. 1-60). Following flap transplantation, the animals No. 10-30 (n = 21) were used for the determination of the critical time period of a complete venous stasis of the free groin flap resulting in a total flap loss (Part II). The flaps of animals No. 31-41 (n = 11) were used for assessing the feasibility and reproducibility of intra-vital video microscopy (IVM) of the flaps (Part III). The mean total operation time decreased from 166 (± 26) minutes ins the first 10 animals to 126 (± 21) minutes and 130 (± 12) minutes in the latter two groups of 10 animals, respectively. After a critical period of 35 minutes of a complete artificial venous stasis a complete flap necrosis occurred. IVM detected a higher functional capillary density of the skin of the transplanted groin flaps in the animals in which the flaps were rinsed with 1 ml of Ringer's lactated solution prior to I/R. In conclusion, this model is simple and reliable. The model may be a useful tool for evaluating and comparing the effects of various anticoagulants or vasomotor drugss on microvascular perfusion in critically compromised free flaps.


Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes.
Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support Gs-protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT- membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.


Biomolecular Simulations in the Time of COVID19, and After.
COVID19 has changed life for people worldwide. Despite lockdowns globally, computational research has pressed on, working remotely and collaborating virtually on research questions in COVID19 and the virus it is caused by, SARS-CoV-2. Molecular simulations can help to characterize the function of viral and host proteins and have the potential to contribute to the search for vaccines and treatments. Changes in the modus operandi of research groups include broader adoption of the use of preprint servers, earlier and more open sharing of methods, models, and data, the use of social media to rapidly disseminate information, online seminars, and cloud-based virtual collaboration. Research funders and computing providers worldwide recognized the need to provide rapid and significant access to computational architectures. In this review, we discuss how the interplay of all of these factors is influencing the impact - both potential and realized - of biomolecular simulations in the fight against SARS-CoV-2.


Phosphorylation of CBX2 controls its nucleosome-binding specificity.
Chromobox 2 (CBX2), a component of polycomb repressive complex 1 (PRC1), binds lysine 27-methylated histone H3 (H3K27me3) via its chromodomain (CD) and plays a critical role in repressing developmentally regulated genes. The phosphorylation of CBX2 has been described in several studies, but the biological implications of this modification remain largely elusive. Here, we show that CBX2's phosphorylation plays an important role in its nucleosome binding. CBX2 is stably phosphorylated in vivo, and domain analysis showed that residues in CBX2's serine-rich (SR) region are the predominant phosphorylation sites. The serine residues in an SR region followed by an acidic-residue (AR) cluster coincide with the consensus target of casein kinase II (CK2), and CK2 efficiently phosphorylated the SR region in vitro. A nucleosome pull-down assay revealed that CK2-phosphorylated CBX2 had a high specificity for H3K27me3-modified nucleosomes. An electrophoretic mobility-shift assay showed that CK2-mediated phosphorylation diminished CBX2's AT-hook-associated DNA-binding activity. Mutant CBX2 lacking the SR region or its neighboring AR cluster failed to repress the transcription of p21, a gene targeted by PRC1. These results suggest that CBX2's phosphorylation is critical for its transcriptional repression of target genes.


Deep venous valvular function assessed with intramuscular pressure recording.
Intramuscular pressures were measured in the anterior tibial muscle with the microcapillary infusion method in 10 patients (11 limbs) with deep venous valvular insufficiency. The results were compared with pressure measurements in healthy controls (n = 8) and in patients with only superficial venous insufficiency (n = 7). The technique could differentiate patients with deep venous reflux from patients with superficial venous reflux and healthy controls. In contrast to the other two groups studied, patients with deep venous reflux were characterized by a small decrease of muscle relaxation pressure during exercise followed by a short recovery time. The method described provides a potential for evaluating regional deep venous valvular function. However, besides deep venous reflux other factors such as rate of arterial inflow, venous capacity and muscle pump function also might influence the results obtained with intramuscular pressure recordings.


Biomechanical Implications of Training Volume and Intensity in Aging Runners.
Running speed is slower in middle-age compared with younger runners due to reduced ankle but not hip and knee kinetic output. Running-specific training helps attenuate age-related declines in measures of endurance, muscle strength, and gait speed. Considering the adaptability of the human body in response to imposed stresses, maintaining training volume and intensity may play a role in modifying running biomechanics in middle-age runners. To compare running biomechanics between young and middle-age runners when controlling for the confounding effects of training volume and intensity. Fifteen middle-age runners, 15 young runners with similar training volume as the middle-age group and, 15 young runners with similar preferred training paces (i.e., intensity) as the middle-age runners participated in the study. Lower-limb joint kinetics were calculated from kinematic and ground reaction force data during overground running at a submaximal speed and compared among groups. Middle-age runners ran with similar peak ankle power compared with volume-matched younger runners although peak plantarflexor moment was 10.5% lower in the middle age group (P = 0.046; Cohen d = 0.78). Middle-age runners ran with similar ankle plantarflexor moment and joint power compared with training pace-matched young runners. As expected, no age-related differences were observed in hip and knee kinetics when training volume or pace were matched between age groups. These results suggest that training pace may be more effective in attenuating age-related declines in plantarflexor kinetics in middle-age runners. From these findings, we propose the hypothesis that both training volume and training pace may play a role in maintaining plantarflexor kinetics but that training pace may have a greater impact on ankle plantarflexor kinetics in middle-age runners.


Long-Term Clinical Course in Eyes With Peters Anomaly.
Peters anomaly (PA) is known to be a primary cause of congenital corneal opacity. The aim of this study is to report the long-term clinical course and visual achievement of patients with PA who did not undergo keratoplasty. This retrospective study involved 15 eyes of 9 infants with PA less than 5 months of age at initial presentation at the Kyoto Prefectural University of Medicine who were followed up without keratoplasty for more than 6 years after presentation. In each subject, visual acuity, intraocular pressure (IOP), presence of congenital glaucoma, and change of corneal opacity were retrospectively investigated. At initial presentation, the mean patient age was 2.3 months (SD: 1.3; range: 0-4 mo), and the mean follow-up period was 7.9 years (SD: 1.8; range: 6.5-11.3 yrs). Of the 9 patients, 6 were affected bilaterally. Thirteen eyes of 7 patients were found to have glaucoma. Over the follow-up period, corneal opacity gradually decreased in 4 eyes, 1 eye each of 2 unilateral patients without glaucoma and both eyes of 1 bilaterally affected patient with good IOP control during the follow-up period. Visual acuity in the unilateral case with intensive amblyopia treatment gradually increased along with decreasing corneal opacity. The findings of this study show that a natural decrease of corneal opacity can occur in eyes with PA. In cases of unilateral PA without IOP elevation and no enlargement of the corneal diameter, strict amblyopia treatment is vital to obtain a favorable visual prognosis.


Role of systemic and local IGF-I in the effects of estrogen on growth and epithelial proliferation of mouse uterus.
IGF-I is a critical regulator of uterine growth, and locally produced uterine IGF-I could mediate the effects of 17beta-E2 on growth and cellular proliferation. We used IGF-I knockout (KO) mice and tissue grafting to determine the roles of local and systemic IGF-I in uterine growth and E2 responsiveness. Uteri from adult KO mice and neonatal and adult wild-type (WT) mice were grown under the renal capsule of female athymic mice for 4 wk. Initial uterine weights of adult KO and neonatal WT mice were 5% or less of those of adult WT uteri. Weights of adult WT uterine grafts did not increase during grafting. Weights of adult KO and neonatal WT uteri exposed to normal systemic levels of IGF-I in athymic hosts increased 20- to 30-fold to equal or exceed those of adult WT grafts. Uterine epithelial height, reduced in KO mice, was restored to WT levels in KO uteri grafted into athymic hosts. The absence of local IGF-I production in KO uteri did not impair E2- induced epithelial proliferation in KO uterine grafts. Neonatal WT uteri grafted into KO hosts showed minimal growth, providing evidence that local uterine IGF-I production is insufficient to support uterine growth in the absence of systemic IGF-I. E2 treatment of KO females produced minimal uterine growth, confirming that lack of IGF-I, rather than E2, caused the uterine hypoplasia. In summary, systemic IGF-I supports normal uterine growth and E2 response in the absence of local IGF-I. Local IGF-I is not a direct mediator of E2 action in uterus, and systemic IGF-I may be more important than previously thought for growth of the uterus and other tissues.


Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease.
The aim of this study was to ascertain whether coronary microvascular dysfunction (CMD) and inflammation are related in cardiac syndrome X (CSX). CMD can lead to CSX, defined as typical angina and transient myocardial ischemia despite normal coronary arteriograms. Inflammation has been suggested to play a role in the pathogenesis of myocardial ischemia in CSX. We assessed 21 CSX patients (age 52 ± 10 years; 17 women) without traditional cardiovascular risk factors and 21 matched apparently healthy control subjects. Positron emission tomography was used to measure myocardial blood flow (MBF) and coronary flow reserve (CFR) in response to intravenous adenosine, whereas high-sensitivity C-reactive protein (CRP) was measured to assess inflammation. Patients were subdivided a priori into 2 groups according to CRP concentrations at study entry (i.e., ≤3 or >3 mg/l). There were no differences in resting (1.20 ± 0.23 ml/min/g vs. 1.14 ± 0.20 ml/min/g; p = 0.32) or hyperemic MBF (3.28 ± 1.02 ml/min/g vs. 3.68 ± 0.89 ml/min/g; p = 0.18) between CSX patients and the control group, whereas CFR was mildly reduced in CSX patients compared with the control group (2.77 ± 0.80 vs. 3.38 ± 0.80; p = 0.02). Patients with CRP >3 mg/l had more severe impairment of CFR (2.14 ± 0.33 vs. 3.16 ± 0.76; p = 0.001) and more ischemic electrocardiographic changes during adenosine administration than patients with lower CRP, and a negative correlation between CRP levels and CFR (r = -0.49, p = 0.02) was found in CSX patients. CSX patients with elevated CRP levels had a significantly reduced CFR compared with the control group, which is indicative of CMD. Our study thus suggests a role for inflammation in the modulation of coronary microvascular responses in patients with CSX.


Phospholipid degradation in frozen plant cells associated with freezing injury.
A striking degradation of phosphatidylcholine into phosphatidic acid was observed in the cortical tissues of less hardy poplar (Poplus euramericani cv. gelrica), when the tissues were frozen below a lethal temperature. No change in phospholipids was detected during freezing or even after thawing in the cortical tissues of hardy poplar which survived slow freezing to -30 C or even immersion in liquid N(2) after prefreezing to -50 C. The degradation of phosphatidylcholine during freezing appears to be intimately associated with freezing injury.


Diversity of animal models of aggression: their impact on the putative alcohol/aggression link.
Many attempts have been made to "model" the putative link between alcohol and "aggression" using a variety of situations employing a wide range of animal species. In general, these attempts have proved somewhat disappointing. One reason for this appears to be the fact that the different "aggression" tests tap varied mixtures of offensive, defensive and predatory motivations (i.e., they are not homogenous). Indeed, one can make the claim that the majority of examples of "aggression" associated with alcohol-ingesting humans are inappropriate (nonadaptive) responses whereas many animal models tap adaptive territorial or socially competitive actions. A further problem is that alcohol has very wide-ranging effects on neurophysiology and endocrine functioning. Recent evidence from studies on infra-human animals and clinical situations suggests that some of alcohol's effects on social conflict are expressed by actions in signaling and perception rather than motivation. This aspect is briefly examined in some studies with laboratory mice.


Desmoplastic small round cell tumor of the lung.
An extra-abdominal desmoplastic small round cell tumor (DSRCT) of the lung with immunohistochemical, ultrastructural, and cytogenetic evidence of multidirectional differentiation is reported. We demonstrate that DSRCTs of the lung and pleura show morphologic, molecular, genetic, and ultrastructural features similar to DSRCTs arising in other sites. The tumor showed coexpression of cytokeratins (AE1/3, epithelial membrane antigen, CAM 5.2) and mesenchymal markers (vimentin, desmin, neuron-specific enolase), as well as WT1. Ultrastructurally, intracytoplasmic whorls of intermediate filaments, similar to previous descriptions of DSRCT in nonthoracic sites, were also demonstrated in this case. EWS-WT1 gene fusion characteristic of DSRCT with the t(11;22)(q13;q12) translocation was demonstrated in this tumor.


ELISA-based coproantigen in human strongyloidiaisis: a diagnostic method correlating with worm burden.
In order to overcome the false negative diagnosis of strongyloidiasis in the absence of rhabditiform larvae in stools, an ELISA-based Strongyloides stercoralis-specific coproantigen detection assay in stools of infected patients was evaluated. In a sandwich ELISA, a rabbit hyperimmune serum against S. stercoralis ES (excretory/secretory) adult antigen succeeded in capturing S. stercoralis coproantigen from infected patients and did not react with coproantigens prepared from the stool samples of patients infected with Schistosoma mansoni, Fasciola gigantica and Capillaria philippenensis. Coproantigen was able to detect anti-S. stercoralis IgG antibodies in sera of infected patients at the same OD level as produced with S. stercoralis E/S worm antigen using an indirect ELISA did not cross-react with sera from patients with S. mansoni, F. gigantica and C. philippenensis. S. stercoralis coproantigen detection proved a sensitive, simple, reliable and inexpensive ELISA-based, and an alternative to coproscopical methods in copropositive (with larvae in stool) and copronegative (without larvae in stool) stool samples. Fecal ELISA showed a positive relationship between copro-Ag and worm burdens, and considered a starting point for the development of species-specific copro-immunological diagnostic assays using monoclonal antibodies and dipstick technology.


Disturbances in the cerebral perfusion of human immune deficiency virus-1 seropositive asymptomatic subjects: a quantitative tomography study of 18 cases.
Quantitative measurements of cerebral blood flow (CBF) by xenon-133 (133Xe) tomography, together with magnetic resonance imaging (MRI), electroencephalography (EEG), psychometric tests, and laboratory analyses were performed on 18 human immunodeficiency virus 1 (HIV-1) seropositive asymptomatic subjects. Abnormalities of cerebral perfusion were observed in 16 cases (88%). These abnormalities were particularly frequent in the frontal regions (77% of cases). MRI demonstrated leucoencephalopathy in only two cases. EEG showed only induced diffuse abnormalities in two cases. Psychometric tests showed restricted moderate disturbances in 55% of patients. These disturbances mostly concerned those sectors involved in cognitive functions and memorization. These results indicate that quantitative measurements of CBF by 133Xe-SPECT is capable of detecting abnormalities of cerebral perfusion at a very early stage (Phase II) of HIV-1 infection. These abnormalities are indications of disturbances resulting from unidentified metabolic or vascular lesions. This technique appears to be superior to MRI at this stage of the disease's development. It could provide objective information leading to earlier treatment, and prove useful in evaluating potential antiviral chemotherapy.


Hazy Image Decolorization with Color Contrast Restoration.
It is challenging to convert a hazy color image into a gray-scale image because the color contrast field of a hazy image is distorted. In this paper, a novel decolorization algorithm is proposed to transfer a hazy image into a distortionrecovered gray-scale image. To recover the color contrast field, the relationship between the restored color contrast and its distorted input is presented in CIELab color space. Based on this restoration, a nonlinear optimization problem is formulated to construct the resultant gray-scale image. A new differentiable approximation solution is introduced to solve this problem with an extension of the Huber loss function. Experimental results show that the proposed algorithm effectively preserves the global luminance consistency while represents the original color contrast in gray-scales, which is very close to the corresponding ground truth gray-scale one.


Intelligent Diagnosis of Rolling Element Bearing Based on Refined Composite Multiscale Reverse Dispersion Entropy and Random Forest.
Rolling bearings are the vital components of large electromechanical equipment, thus it is of great significance to develop intelligent fault diagnoses for them to improve equipment operation reliability. In this paper, a fault diagnosis method based on refined composite multiscale reverse dispersion entropy (RCMRDE) and random forest is developed. Firstly, rolling bearing vibration signals are adaptively decomposed by variational mode decomposition (VMD), and then the RCMRDE values of 25 scales are calculated for original signal and each decomposed component as the initial feature set. Secondly, based on the joint mutual information maximization (JMIM) algorithm, the top 15 sensitive features are selected as a new feature set and feed into random forest model to identify bearing health status. Finally, to verify the effectiveness and superiority of the presented method, actual data acquisition and analysis are performed on the bearing fault diagnosis experimental platform. These results indicate that the presented method can precisely diagnose bearing fault types and damage degree, and the average identification accuracy rate is 97.33%. Compared with the refine composite multiscale dispersion entropy (RCMDE) and multiscale dispersion entropy (MDE), the fault diagnosis accuracy is improved by 2.67% and 8.67%, respectively. Furthermore, compared with the RCMRDE method without VMD decomposition, the fault diagnosis accuracy is improved by 3.67%. Research results prove that a better feature extraction technique is proposed, which can effectively overcome the deficiency of existing entropy and significantly enhance the ability of fault identification.


The experiences of older adults with a diagnosed functional mental illness, their carers and healthcare professionals in relation to mental health service delivery: An integrative review.
To analyse the experiences of older people with a diagnosed functional mental illness and their carers in relation to mental health service delivery and analyse the experiences of health and social care professionals who care for and treat older people who have a diagnosed functional mental illness. The prevalence of functional mental illness in older adults is notable but to date has received less research attention than dementia. Older adults with functional mental illness have life expectancy of up to 20 years less than the rest of the population. Therefore, the experiences of older adults with functional mental illness, their carers and healthcare professionals, in relation to mental health services, need further exploration. Integrative literature review. A five-stage process was informed by Whittemore and Knafl. MeSH was used. Keyword searches of MEDLINE, CINAHL, Cochrane Library, PsycINFO, EMBASE and AMED were conducted between January 2000-October 2017. Titles were screened, and data were extracted manually and analysed using narrative synthesis. The PRISMA checklist was used. A total of 342 articles were deemed potentially relevant to this review. Once inclusion and exclusion criteria were applied, 28 articles were included. The literature presented an overarching theme "determinants influencing older people with functional mental illness use of services." The overarching theme is supported by two main themes: inevitable consequences of ageing and variations of the availability of healthcare services for older people with functional mental illness. Several determinants influence use of services by older people with functional mental illness. Older people with functional mental illness often perceived they did not have a mental health need. Within the literature, there was little acknowledgement of the experiences of older people with functional mental illness regarding their support needs. This integrative review has highlighted that some older people with functional mental illness do not seek mental health support because they believe that functional mental illness is an inevitable consequence of ageing; this is mirrored at times by healthcare professionals and carers. In addition to this finding, different views prevail regarding the impact that ageless and age-defined mental health service delivery models have on the needs of older people with functional mental illness. Further research is required to understand these findings.


Family of Ebf/Olf-1-related genes potentially involved in neuronal differentiation and regional specification in the central nervous system.
Two novel mouse genes, Ebf2 and Ebf3, have been identified which show high similarity to the rodent Ebf/Olf-1 and the Drosophila collier genes. The strong conservation of the protein regions corresponding to the DNA binding and dimerisation domains previously defined in Ebf strongly suggests that Ebf2 and Ebf3 also constitute DNA sequence-specific transcription factors. Determination of the chromosomal locations of the two genes indicated that the different members of this novel mouse multigene family are not clustered. A detailed analysis of the expression of each of the three Ebf genes in the developing central nervous system revealed partially overlapping patterns with two salient features: 1) In the region extending from the midbrain to the spinal cord, the expression of the three genes correlated with neuronal maturation, with a general activation in early post-mitotic cells, followed by specific patterns of extinction also consistent with the neurogenic gradient. 2) In the forebrain area, although the patterns of expression of the Ebf genes also reflected neuronal maturation, they appeared in addition to be region specific. These data suggest that Ebf genes may be involved in the control of neuronal differentiation in the CNS and in enforcing regional diversity in populations of post-mitotic forebrain neurons.


The effect of the COVID-19 pandemic on non-COVID respiratory ED visits in Israel.
The COVID 19 pandemic has had a crucial effect on the patterns of disease and treatment in the healthcare system. This study examines the effect of the COVID-19 pandemic on respiratory ED visits and admissions broken down by age group and respiratory diagnostic category. Data on non-COVID related ED visits and hospitalizations from the ED were obtained in a retrospective analysis for 29 acute care hospitals, covering 98% of ED beds in Israel, and analyzed by 5 age groups: under one-year-old, 1-17, 18-44, 45-74 and 75 and over. Diagnoses were classified into three categories: Upper respiratory tract infections (URTI), pneumonia, and COPD or asthma. Data were collected for the whole of 2020, and compared for each month to the average number of cases in the three pre-COVID years (2017-2019). In 2020 compared to 2017-2019, there was a decrease of 34% in non-COVID ED visits due to URTI, 40% for pneumonia and a 35% decrease for COPD and asthma. Reductions occurred in most age groups, but were most marked among infants under a year, during and following lockdowns, with an 80% reduction. Patients over 75 years old displayed a marked drop in URTI visits. Pediatric asthma visits fell during lockdowns, but spiked when restrictions were lifted, accompanied by a higher proportion admitted. The percent of admissions from the ED visits remained mostly stable for pneumonia; the percent of young adults admitted with URTI decreased significantly from March to October. Changing patterns of ED use were probably due to a combination of a reduced rate of viral diseases, availability of additional virtual services, and avoidance of exposure to the ED environment. Improved hygiene measures during peaks of respiratory infections could be implemented in future to reduce respiratory morbidity; and continued provision of remote health services may reduce overuse of ED services for mild cases.


Targeting LMW-PTP to sensitize melanoma cancer cells toward chemo- and radiotherapy.
Tumor resistance to apoptosis is one the main causes of anticancer treatment failure. Previous studies showed that LMW-PTP overexpression enhances resistance of cancer cells to traditional anticancer drugs. Today, the role of LMW-PTP in inducing resistance to apoptosis in melanoma cells remains to be elucidated. Experimental setting include MTT assay, Annexin V/Pi method, and colony assay to assess whether silencing of LMW-PTP improves the sensitivity of A375 to dacarbazine, 5-FU, and radiotherapy. Pharmacological targeting of LMW-PTP was obtained using Morin, a LMW-PTP inhibitor. The ability of Morin to improve the effectiveness of anticancer drugs and radiotherapy was also studied. Moreover, PC3 cells were used as an alternative cellular model to confirm the data obtained with melanoma cells. We found that LMW-PTP silencing improves the effectiveness of dacarbazine, 5-FU, and radiotherapy. Identical results were obtained in vivo when Morin was used to target LMW-PTP. We demonstrated that Morin synergizes with dacarbazine, improving its cytotoxic activity. However, we showed that the combined treatment, Morin-anticancer drug, does not affect the viability of noncancerous cells. Knockdown of LMW-PTP sensitizes also PC3 cells to docetaxel and radiotherapy. In conclusion, we showed that LMW-PTP targeting improves effectiveness of anticancer drugs used for treatment of melanoma. Moreover, our results suggest that Morin could be used as adjuvant to improve the outcome of patients affected by metastatic melanoma.


Conceptual metaphorical mapping in chimpanzees (Pan troglodytes).
Conceptual metaphors are linguistic constructions. Such a metaphor is humans' mental representation of social rank as a pyramidal-like structure. High-ranked individuals are represented in higher positions than low-ranked individuals. We show that conceptual metaphorical mapping between social rank and the representational domain exists in our closest evolutionary relatives, the chimpanzees. Chimpanzee participants were requested to discriminate face identities in a vertical arrangement. We found a modulation of response latencies by the rank of the presented individual and the position on the display: a high-ranked individual presented in the higher and a low-ranked individual in the lower position led to quicker identity discrimination than a high-ranked individual in the lower and a low-ranked individual in the higher position. Such a spatial representation of dominance hierarchy in chimpanzees suggests that a natural tendency to systematically map an abstract dimension exists in the common ancestor of humans and chimpanzees. DOI:http://dx.doi.org/10.7554/eLife.00932.001.


Prevalence of snoring in college students.
Snoring in college students may be the earliest presentation of adult sleep-disordered breathing, yet the literature contains few studies that demonstrate its effects on learning or whether early diagnosis leads to interruption of disease progression or prevention of comorbidities. The authors conducted this study in January-April 2004 to assess the prevalence of snoring in college students (N = 2,200). They developed a questionnaire on sleep behaviors and distributed it to 18- to 25-year-old undergraduates at a California university. Almost one-third (30%) of participants reported snoring. The prevalence of snoring was higher among men than women (42% and 25%, respectively). The prevalence of self-reported snoring was highest in Asian students (37%). Snoring is highly prevalent in college students; prevalence is higher in men than women, correlates with body mass index, and varies by ethnicity.


Insulator Leakage Current Prediction Using Hybrid of Particle Swarm Optimization and Gene Algorithm-Based Neural Network and Surface Spark Discharge Data.
This study proposes a new superior hybrid algorithm, which is the particle swarm optimization (PSO) and gene algorithm (GA)-based neural network to predict the leakage current of insulators. The developed algorithm was utilized for the online monitoring systems, which were completely installed on the 69 kV and 161 kV transmission towers in Taiwan. This hybrid algorithm utilizes the local meteorological data as input parameters combined with the extracted enhanced data: the percentage of spark discharge areas and the brightness change in the image of the discharge phenomenon. These data with a high correlation with the leakage current are utilized as input vectors to improve the accuracy and effectiveness of the developed hybrid model. The performance of the developed algorithm is compared with a traditional PSO-based neural network and backpropagation neural network (BPNN) to evaluate and analyze. The comparative simulation results prove the effectiveness of the combination of hybrid PSO-GA-based neural network and surface discharge data, which achieved a maximum improvement of 38.54% MSE, 10.62% MAPE, and 3.41% R square for 161 kV data and 39.28% MSE, 12.62% MAPE, and 1.61% R square for 69 kV data. Moreover, the data with enhanced inputs outperform the traditional data in most benchmark factors, improving the accuracy and effectiveness in defining the deteriorative insulators. The developed methodology with a noticeable improvement was utilized in the online monitoring system to reduce the operational and maintenance cost of transmission lines in Taiwan Power Company.


18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin).
A qualitative assessment of conventional bone scintigraphy with 99mTc methylene diphosphonate is perceived as an insensitive method for monitoring the treatment response of bone metastases, and we postulated that semi-quantitative 18F-fluoride positron emission tomography (PET) might serve as a suitable alternative biomarker of the treatment response. Five patients with castrate-resistant prostate cancer and bone metastases with no known soft tissue disease received 100 kBq/kg of radium-223 (223Ra)-chloride (Alpharadin) therapy at 0 and 6 weeks and had whole body 18F-fluoride PET scans at baseline, 6 and 12 weeks with concurrent prostatic-specific antigen (PSA) and alkaline phosphatase (ALP) measurements. A qualitative comparison of the PET scans was performed blinded to the PSA and ALP results. A semi-quantitative comparison was made by measuring the maximum standardised uptake values (SUVmax) in five bone metastases in each patient. The means of the five SUVmax measurements in each subject were used as a quantitative measure of global metastatic activity at each time point. Three patients showed a PSA decline at 12 weeks (-44%, -31%, -27% reduction) whilst two patients showed PSA increases (+10%, +17%). All five patients showed a reduction in ALP of greater than 25%. The qualitative assessment of the 18F-fluoride scans recorded a stable disease in each case. However, the semi-quantitative assessment showed agreement with the PSA decline in three patients (-52%, -75%, -49%) and minimal change (+12%, -16%) in two patients with increased PSA at 12 weeks. Four patients showed similar reductions in mean SUVmax and ALP at 12 weeks. The semi-quantitative 18F-fluoride PET is more accurate than the qualitative comparison of scans in assessing response in bone metastases, correlating with the PSA response and ALP activity and offering a potential imaging biomarker for monitoring treatment response in bone metastases following treatment with 223Ra-chloride.


Biased Agonism of the Angiotensin II Type I Receptor.
Angiotensin II (AngII) type I receptor (AT1R) recognizes AngII, a cardiovascular peptide hormone that acts as a terminal effector of the renin-angiotensin system (RAS). AT1R belongs to the rhodopsin-like peptidergic family of G protein-coupled receptors (GPCRs) and serves as a therapeutic target for the treatment of cardiovascular diseases, such as hypertension, cardiac hypertrophy and heart failure. Classically, AT1R was considered to signal only through G proteins. However, recent studies have revealed that AT1R is capable of activating G protein-independent signaling that is mediated by β-arrestins. β-arrestin is a cytosolic scaffold that is recruited to the activated GPCRs. In vitro and ex vivo studies have demonstrated that the activation of the AT1R-β-arrestin pathway stimulates contractility and exerts prosurvival effects in cardiomyocytes. TRV027, a potent synthetic β-arrestin-biased ligand for AT1R, specifically activates AT1R-β-arrestin signaling without stimulating G proteins. In preclinical studies, TRV027 not only produced vasodilation by antagonizing the AT1R-Gαq pathway but also enhanced cardiac performance by activating AT1R-β-arrestin signaling. Because of this unique pharmacological profile, TRV027 is now being evaluated in a phase II clinical trial as a novel therapeutic for acute heart failure (AHF).


Risk assessment of dietary exposure to aluminium in the Chinese population.
In order to address the issue of excessive intake of aluminium (Al) from Al-containing food additives in the Chinese diet, this study conducted a dietary exposure assessment of Al in the general population based on the national surveillance data of Al content in foods and national food consumption data. It was found that the mean dietary exposure of the whole Chinese population to Al from Al-containing food additives was 1.795 mg kg‒1 bw week‒1, not exceeding the PTWI, while high dietary exposures (e.g., 97.5th percentile) to Al were 7.660 and 2.103-2.903 mg kg‒1 bw week‒1 for children, respectively, both exceeding the PTWI. It was found that the dietary exposure to Al for 32.5% of the total Chinese population and 42.6% of children aged 4-6 years exceeded the PTWI. Wheat flour and wheat-based products are the main source of dietary A l exposure (85% of the total intake); and puffed foods are the major source of Al intake for children. These findings suggested that consumption of Al-containing food additives could be a health concern for consumers with high food consumption (97.5th percentile) and children under the age of 14 years.


[The internal consistency and content validity of the Spanish version of the Asthma Autonomy Questionnaire].
The Asthma Autonomy Questionnaire (AAQ) was designed to evaluate asthmatics' desire to learn about their disease and to make decisions. The AAQ consists of 26 items distributed in two scales: Preferences in the Search for Information (PSI, 8 items) and Preferences in Decision Making (PDM, 6 general items and 12 related to 3 scenarios depicting asthma in stable phase, during mild exacerbation and during severe exacerbation). The aim of this study was to analyze the internal consistency (Cronbach's-coefficient) and content validity (factorial analysis of principal components) of the AAQ. After translation and back translation, the Spanish version of the AAQ was administered to 115 adult asthmatics of both sexes and differing levels of severity. The alpha coefficients for the two scales and 3 scenarios ranged from 0.42 (PSI) to 0.73 (stable phase scenario); only for the stable-phase scenario were values high or statistically acceptable. Factorial analysis reproduced the content of the scales only approximately, with some items proving to relate to factors that were different from the scale they originally belonged to. These results indicate that, in its current formulation, the AAQ presents important measurement problems and revision is advisable.


Morphometry of the pelvic ring in definition of biomechanical factors influencing the type of pelvic fracture.
The aim of the study was to supplement data on pelvic morphology and structural geometry. Using these data, a mathematical and biomechanical model was constructed. The research was divided into two parts. The first part comprised radiogrammetric analysis of pelvic morphology and geometry based on 60 AP x-rays of male and female pelvises. The spatial definition of the pelvis was given by three transverse and one sagittal diameter. Transverse diameters were measured at the level of iliac wings, at the narrowest supraacetabular portion and on the line passing through the center of both femoral heads. The fourth diameter was the height of the pelvis. Geometric properties and structure of pelvic bones and position of muscles in relation to bone elements of the pelvis were analyzed in the second part. Knowing geometric dimensions of the pelvis and the body weight, it is possible to calculate the magnitude of gravitational forces acting upon certain pelvic portions. This biomechanical model serves for simulation of operative methods of fixation and allows search for the optimal solution, which is stable enough to withstand all the forces acting upon fragments of a fractured pelvic ring.


Decamethylytterbocene complexes of bipyridines and diazabutadienes: multiconfigurational ground states and open-shell singlet formation.
Partial ytterbium f-orbital occupancy (i.e., intermediate valence) and open-shell singlet formation are established for a variety of bipyridine and diazabutadiene adducts with decamethylytterbocene, (C(5)Me(5))(2)Yb, abbreviated as Cp*(2)Yb. Data used to support this claim include ytterbium valence measurements using Yb L(III)-edge X-ray absorption near-edge structure spectroscopy, magnetic susceptibility, and complete active space self-consistent field (CASSCF) multiconfigurational calculations, as well as structural measurements compared to density functional theory calculations. The CASSCF calculations indicate that the intermediate valence is the result of a multiconfigurational ground-state wave function that has both an open-shell singlet f(13)(pi*)(1), where pi* is the lowest unoccupied molecular orbital of the bipyridine or diazabutadiene ligands, and a closed-shell singlet f(14) component. A number of other competing theories for the unusual magnetism in these materials are ruled out by the lack of temperature dependence of the measured intermediate valence. These results have implications for understanding chemical bonding not only in organolanthanide complexes but also for f-element chemistry in general, as well as understanding magnetic interactions in nanoparticles and devices.


Implementing Lumberjacks and Black Swans Into Model-Based Tools to Support Human-Automation Interaction.
The objectives were to (a) implement theoretical perspectives regarding human-automation interaction (HAI) into model-based tools to assist designers in developing systems that support effective performance and (b) conduct validations to assess the ability of the models to predict operator performance. Two key concepts in HAI, the lumberjack analogy and black swan events, have been studied extensively. The lumberjack analogy describes the effects of imperfect automation on operator performance. In routine operations, an increased degree of automation supports performance, but in failure conditions, increased automation results in more significantly impaired performance. Black swans are the rare and unexpected failures of imperfect automation. The lumberjack analogy and black swan concepts have been implemented into three model-based tools that predict operator performance in different systems. These tools include a flight management system, a remotely controlled robotic arm, and an environmental process control system. Each modeling effort included a corresponding validation. In one validation, the software tool was used to compare three flight management system designs, which were ranked in the same order as predicted by subject matter experts. The second validation compared model-predicted operator complacency with empirical performance in the same conditions. The third validation compared model-predicted and empirically determined time to detect and repair faults in four automation conditions. The three model-based tools offer useful ways to predict operator performance in complex systems. The three tools offer ways to predict the effects of different automation designs on operator performance.


Targeting cytokines secreted by CD4+ CD25high CD127low regulatory T cells inhibits ovarian cancer progression.
Epithelial ovarian cancer (EOC) is one of the major malignant cancers with high rates of early metastasis in which regulatory T cells (Tregs) play an important role. Tregs suppress immune responses and promote the development of tumours in patients with EOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4+ CD25high CD127low Tregs in patients with EOC than in patients with benign ovarian tumours and healthy donors. The immune inhibitory effect of Tregs functions by maintaining high levels of immunosuppressive cytokines in EOC. The high levels of Tregs and related cytokines (TGF-β1 or IL-10) were associated with lymphatic metastasis and FIGO stages of patients with EOC. Expression of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-2 in EOC cell lines were significantly regulated in the coculture experiment with CD4+ CD25high CD127low Tregs sorted from EOC patients. Levels of MMP-2 and TIMP-2 conversely changed after blocking IL-10R and TGF-β1R in EOC cells. The invasion ability of EOC cells was also significantly downregulated in this process. The metastasis of EOC cells was correlated with the levels of TGF-β1 or IL-10. These findings suggested that immunosuppressive cytokines secreted by CD4+ Tregs could be a novel target for inhibiting EOC progression.


[Results of radioiodine therapy in 47 patients with distant metastases of differentiated thyroid carcinoma].
In the last ten years, 47 patients with distant metastases of differentiated thyroid carcinoma have been treated with 131I following total thyroidectomy. Post-therapy whole body 131I scans revealed detectable uptake in the metastatic lesions in 23 (62%) of 37 patients with lung metastases, 10 (67%) of 15 patients with bone metastases five (71%) of seven patients with mediastinal metastases, and neither of two patients with brain metastases. The concentration of 131I in the metastases was significantly correlated with serum T3 and T4 concentrations, and inversely correlated with serum TSH concentrations. Most of the patients with a strong positive scan were euthyroid, suggesting that thyroid hormones produced by the tumor compensated for hypothyroidism following total thyroidectomy. There was no significant relationship between serum thyroglobulin concentration during T4 replacement therapy and 131I uptake or the efficacy of therapy. Twenty patients with lung (54%), five with bone (33%), two with mediastinal (29%), and none with brain metastases showed tumor regression after treatment. Significantly increased 131I uptake in lung metastases, better therapeutic results and better prognosis were demonstrated in young patients. In conclusion, age, 131I whole body scanning and serum thyroid hormone concentrations are considered to be useful in predicting the efficacy of 131I treatment for distant metastases, especially in the lung.


Dexamethasone suppression test and selection of antidepressant medications.
Endogenous depressives with abnormal dexamethasone suppression tests (DSTs) respond better to somatic antidepressant treatments than those with normal DSTs. Whether the DST also aids in the selection of specific antidepressants has not been determined. A pilot report suggested that patients with abnormal DSTs might be noradrenaline-deficient and respond preferentially to imipramine or desipramine, whereas those with normal DSTs might be serotonin-deficient and respond best to amitriptyline or clomipramine. Attempting to replicate this observation, we studied 26 patients diagnosed with Research Diagnostic Criteria as major depressive disorder, endogenous subtype, and with DSM-III as having melancholia. All were drug-free during baseline evaluation. All had abnormal DST results, with post-dexamethasone plasma cortisol levels exceeding 5 microgram/dl. We treated subjects with either imipramine or amitriptyline and compared clinical response with weekly Hamilton Depression Rating Scales, completed by raters blind to both DST results and the research question. Thereapeutic plasma levels were documented. We found no significant differences in treatment response between the subgroups. Twenty of the 26 subjects did well. The imipramine-treatment group failed to have either earlier response or better final outcome. These data fail to replicate suggestions that DST results assist in the selection of either imipramine or amitriptyline.


Nasopharyngeal flora in the first three years of life in normal and otitis-prone children.
Nasopharyngeal carriage of the three major middle ear pathogens (Streptococcus pneumoniae, nontypeable Hemophilus influenzae, and Moraxella catarrhalis) was evaluated prospectively in a group of 110 children followed up for the first 3 years of life. The findings suggested that nasopharyngeal carriage of middle ear pathogens increases significantly during respiratory illness among the general population of young children; however, otitis-prone children demonstrated a tendency to carry nontypeable H influenzae at an unusually high rate even during health. This propensity to carry nontypeable H influenzae might explain why nontypeable H influenzae is a major cause of recurrent or chronic otitis media.


Osteogenesis imperfecta murine: interaction between type I collagen homotrimers.
Types I, II, and III collagens are believed to have evolved from the same homotrimer ancestor and they have substantial sequence homology, but type I molecules are alpha1(I)(2)alpha2(I) heterotrimers, unlike homotrimeric types II and III. It is believed that the alpha2(I) chain first appeared in lower vertebrates and that it plays a particularly important role in bone formation. For instance, spontaneous mutations resulting in non- functional alpha2 chains and formation of type I homotrimers cause severe bone pathology (osteogenesis imperfecta) in humans and in animals. However, the exact role of the alpha2 chain is not known. Here, we report measurements of intermolecular forces between collagen helices in native and reconstituted fibers composed of type I homotrimers, heterotrimers and their mix. For comparison, we report forces between type II homotrimers in reconstituted fibers. In agreement with previous studies, we find that the absence of the alpha2 chain reduces temperature-favored attraction between collagen helices, either because of the difference in amino acid sequence of the alpha1 and alpha2 chains or because of more extensive post-translational modification of homotrimers. We find that forces between helices in fibers from type I (as well as type II) homotrimers are not sensitive to pH between pH 6 and 7.5, in contrast to type I heterotrimers. Apparently, the effect of pH is related to extra histidine residues present on alpha2 chains but not on alpha1 chains. Finally, our measurements indicate that the alpha2 chain is responsible for binding some soluble compound(s), possibly glycosaminoglycans, whose displacement results, e.g., in the loss of tendon crystallinity. The ability of the alpha2 chain to bind non-collagen matrix components may be particularly important for bone matrix formation and mineralization.


Creating pathology models from MRI data: a comparison of virtual 3D modelling and rapid prototyping techniques.
This paper discusses a pilot study in collaboration between the Centre for Anatomy and Human Identification and the Pathology Department at Ninewells Hospital, Dundee. Anonymised patient MRI data depicting renal cancer was used to create a virtual 3D model and two rapid prototype models of the kidneys and surrounding anatomy. A questionnaire was conducted to collect feedback from tutors and students in order to evaluate the models and determine user preference. It was found that the majority preferred the physical models to the virtual model.


Regulation of cell proliferation, apoptosis, and transcription factor activities during the promotion of liver carcinogenesis by polychlorinated biphenyls.
Polychlorinated biphenyls (PCBs) are environmental pollutants that are complete carcinogens and tumor promoters in the liver. The mechanisms of their promoting activities are not clear, but one possible mechanism is the induction of oxidative stress. In the present study we evaluated the ability of two PCB congeners to activate the oxidative stress-responsive transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), as well as hepatocyte cell proliferation and apoptosis, which are influenced by activation of these transcription factors, in rat liver. Two transcription factors not activated by oxidative stress, signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5), were also examined. All the animals in this study received a single dose of diethylnitrosamine (150 mg/kg) followed by four biweekly injections of 3,3',4,4'-tetrachlorobiphenyl (PCB-77) or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) (100 or 300 micromol/kg), or both PCBs (100 micromol/kg each). Ten days after the last PCB injection, all animals were euthanized; 3 days before euthanasia all animals were implanted with Alzet osmotic pumps containing 5-bromo-2'-deoxyuridine (BrdU). The number of placental glutathione S-transferase (PGST)-positive foci were increased in rats administered PCBs, with the highest increase seen in rats administered PCB-77. The number of foci in rats administered both PCBs was intermediate between the numbers seen with either PCB-77 or PCB-153, indicating that a synergistic effect did not occur. There was a significant increase in NF-kappaB and AP-1 binding activities in hepatic nuclear extracts from rats receiving the high dose of PCB-77 or PCB-153 and in rats receiving both PCBs. In contrast, the DNA binding activities of STAT3 and STAT5 were decreased in rats administered PCBs. Cell proliferation in both focal and nonfocal hepatocytes was increased by PCB-77 but was not affected by PCB-153. Apoptotic indexes, as quantified by the TUNEL method, were increased in both focal and nonfocal hepatocytes by PCB-77 but were decreased in focal hepatocytes by PCB-153. This study shows that both PCBs alone or in combination can increase the DNA binding activities of NF-kappaB and AP-1, whereas the DNA binding activities of STAT3 and STAT5 are decreased. The induction of altered hepatic foci appears to be related to compensatory cell proliferation in PCB-77-treated rats, whereas the inhibition of apoptosis appears to be important in PCB-153-treated rats.


Case Report: A case of uterine leiomyosarcoma metastasized to the vena cava, excised with the aid of preoperative CT three-dimensional imaging.
Leiomyosarcoma of the uterus (ULMS) is a rare malignant tumor originating from embryonic mesenchymal cells. ULMS tends to metastasize to the lungs, lymph nodes, liver, and bone. Computed tomography three-dimensional (CT 3D) imaging is an advanced diagnostic technique that can track the vessels and their relationships with tumors and reveal the invasion of vessels, including small vessels, around tumors in any slice. Here, we describe a case in which ULMS extended to the retrohepatic inferior vena cava. To date, no report has described resection of metastatic ULMS of the vena cava through supplemental CT 3D imaging. Our patient presented with right lumbar abdominal pain as the main symptom. After using CT 3D reconstruction to accurately assess the relationship between the tumor and the surrounding organs and blood vessels before the operation, the operation was successfully completed through multidisciplinary surgical collaboration.


Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.
Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G→A (p.G305R), and a synonymous substitution, c.1011C→T (p.G337G), were also detected in two sporadic PKD cases. This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.


Dose-dependency of intra-articular morphine analgesia.
We have examined if the analgesic effects of intra-articular morphine are dose-dependent in patients undergoing elective arthroscopic knee surgery. At the end of surgery, patients were allocated randomly to one of four groups to receive intra-articular saline (n = 22), or morphine 1 mg (n = 24), 2 mg (n = 21) or 4 mg (n = 19). After operation, patients remained in hospital overnight and pain intensity was assessed using a visual analogue scale at 1, 2, 3, 6, 9, 12, 18 and 24 h after intra-articular injection. Patients requesting additional analgesia received a loading dose of piritramide 0.1 mg kg-1 i.v. and were connected to a PCA device using the same drug. Increasing doses of intra-articular morphine were associated with greater analgesic effects and less supplementary analgesic requirements.


Associations of COVID-19 lockdown with gestational length and preterm birth in China.
The effects of COVID-19 lockdown measures on maternal and fetal health remain unclear. We examined the associations of COVID-19 lockdown with gestational length and preterm birth (PTB) in a Chinese population. We obtained medical records of 595,396 singleton live infants born between 2015 and 2020 in 5 cities in Guangdong Province, South China. The exposed group (N = 101,900) included women who experienced the COVID-19 Level I lockdown (1/23-2/24/2020) during pregnancy, while the unexposed group (N = 493,496) included women who were pregnant during the same calendar months in 2015-2019. Cumulative exposure was calculated based on days exposed to different levels of emergency responses with different weighting. Generalized linear regression models were applied to estimate the associations of lockdown exposure with gestational length and risk of PTB (< 37 weeks). The exposed group had a shorter mean gestational length than the unexposed group (38.66 vs 38.74 weeks: adjusted β = - 0.06 week [95%CI, - 0.07, - 0.05 week]). The exposed group also had a higher risk of PTB (5.7% vs 5.3%; adjusted OR = 1.08 [95%CI, 1.05, 1.11]). These associations seemed to be stronger when exposure occurred before or during the 23rd gestational week (GW) than during or after the 24th GW. Similarly, higher cumulative lockdown exposure was associated with a shorter gestational length and a higher risk of PTB. The COVID-19 lockdown measures were associated with a slightly shorter gestational length and a moderately higher risk of PTB. Early and middle pregnancy periods may be a more susceptible exposure window.


To know or not to know: influence of explicit advance knowledge of occlusion on interceptive actions.
This study examined how explicit advance knowledge might influence adaptive behavior to visual occlusions. Catching performance and kinematics of good ball catchers were compared between no, early and late occlusion trials. Discrete visual occlusions of 400 ms, occurring early or late in the ball's approach trajectory, were randomly interspersed between no occlusion trials. In one condition, the presence and type of occlusion were announced a priori (expected), whereas in another condition no such information was provided (unexpected). Expectation of occlusion resulted in an adapted limb transport and increased grasping time, whereas in the unexpected condition a higher peak of wrist velocity was evident for all occlusion conditions. The observed different adaptations cannot be explained by trial-by-trial adaptations alone and instead provide evidence for the influence of explicit advance knowledge in the motor response of interceptive actions.


San-Huang-Xie-Xin-Tang protects cardiomyocytes against hypoxia/reoxygenation injury via inhibition of oxidative stress-induced apoptosis.
Oxidative stress has been widely implicated in the pathogenesis of hypoxia/reoxygenation (H/R) injury. San-Huang-Xie-Xin-Tang (SHXT), a widely used traditional Chinese medication, has been shown to possess antioxidant effects. Here, we investigated whether SHXT and its main component baicalin can attenuate oxidative stress induced by H/R injury. H9c2 rat ventricular cells were exposed to SHXT or baicalin followed by hypoxia for 24 h and/or reoxygenation for 8 h. Pretreatment with SHXT and baicalin both significantly prevented cell death and production of reactive oxygen species induced by hypoxia or H/R in H9c2 cardiomyoctes. In addition, SHXT and baicalin also inhibited hypoxia- or H/R-induced apoptosis, with associated decreased Bax protein, increased Bcl-2 protein, and decreased caspase-3 activity. Furthermore, we found that hypoxia and H/R decreased endothelial nitric oxide synthase (eNOS) expression and nitrite production, and these effects were counteracted by SHXT and baicalein. Finally, SHXT inhibited H/R-induced activation of p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation in H9c2 rat ventricular cells. The present study demonstrates for the first time that SHXT can protect cardiomyocytes from H/R injury via inhibition of oxidative stress-induced apoptosis. These cardioprotective effects are possibly mediated through eNOS enhancement and p38 MAPK and JNK-dependent signaling pathways.


Mental health in the Medicare Part D drug benefit: a new regulatory model?
The Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 represents the most significant expansion of Medicare benefits since the program's inception and has important implications for mental health. Medicare will become a major payer for psychotropic medications through the new prescription drug benefit. The structure of the drug benefit's delivery system creates incentives for plans to underprovide medications, like psychotropic drugs, that are used persistently and are associated with high expected costs. Regulators have put policies in place to counteract these incentives. This paper examines these strategies' likely success and suggests additional approaches to be considered.


An unusual form of crystal-forming chronic interstitial nephritis following long-term exposure to tosufloxacin tosilate.
Fluoroquinolones are known to cause acute renal failure because of interstitial nephritis with or without epithelioid granulomas. We report the first case of slowly progressive renal failure caused by crystal-forming chronic interstitial nephritis with non-Langerhans' cell histiocytosis after long-term exposure to a fluoroquinolone, tosufloxacin tosilate. Lesions consisted of spindle- to cuboidal-shaped histiocytes with minimal collagenous matrix and low-level lymphocyte infiltration replacing normal tubulointerstitial structure of the kidney. Histiocytes were positive for CD68, but negative for S-100, suggesting they were derived from macrophages. There were numerous rhomboid- to needle-shaped crystal deposits in the cytoplasm of histiocytes, which showed bright birefringence under polarized light. No immunoglobulin deposits were seen in the kidney, and no evidence of paraproteinemia/lymphoproliferative diseases was identified in this patient. Despite a negative drug lymphocyte-stimulating test result using tosufloxacin tosilate, withdrawal of the drug and treatment with steroids gradually improved renal function. In this report, we describe the clinical course and histopathologic findings of this patient and discuss the possible pathogenesis.


Ultrafast dynamics of the azobenzene-coumarin complex: investigation of cooling dynamics measured by an integrated molecular thermometer.
The energy dissipation mechanism from photoexcited azobenzene (Az) was studied by femtosecond time-resolved UV absorption spectroscopy using 7-amino-4-trifluoromethylcoumarin (ATC) as a probe. The distance between the probe molecule and Az was fixed by covalently linking them together through a rigid proline spacer. Picosecond dynamics in THF solutions were studied upon excitation into the S1 state by a 100 fs laser pulse at 480 nm. Transient absorption spectra obtained for Az-Pro-ATC combined the S1 state absorption and vibrationally excited ground-state absorption of ATC. Correction of the transient spectrum of Az-Pro-ATC for the S1 absorption provided the time-resolved absorption spectrum of the ATC hot band. Three major components were observed in the transient kinetics of Az-Pro-ATC vibrational cooling. It is proposed that in ca. 0.25 ps after the excitation, the S1 state of azobenzene decays to form an initial vibrationally excited nonthermalized ground state of Az-Pro-ATC that involves vibrational modes of both azobenzene and coumarin. This hot ground state decays in ca. 0.32 ps to the next, vibrationally equilibrated, transient state by redistributing the energy within the molecule. Subsequently, the latter state cools by transferring its energy to the closest solvent molecules in ca. 5 ps; then, the energy diffuses to the bulk solvent in 13 ps.


Chronic Renal Failure and Cardiovascular Disease: A Comprehensive Appraisal.
Coronary artery disease is highly prevalent in patients with chronic kidney disease. The concomitant renal disease often poses a major challenge in decision making as symptoms, cardiac biomarkers and noninvasive studies for evaluation of myocardial ischemia have different sensitivity and specificity thresholds in this specific population. Moreover, the effectiveness and safety of intervention and medical treatment in those patients is of great doubt as most clinical studies exclude patients with advance CKD. In the present paper, we discuss and review the literature in the diagnosis, treatment and prevention of CAD in the acute and chronic setting, in patients with CKD.


The ringlike structure of macular pigment in age-related maculopathy: results from the Muenster Aging and Retina Study (MARS).
The role of macular pigment (MP) in age-related maculopathy (ARM) is still not clearly understood. Recent studies have reported on variations in the spatial distribution of MP optical density (MPOD) including a secondary peak ("ring") in the slope of the MPOD profile. The authors investigated in a cross-sectional manner the presence of ringlike structures, their determinants, and their relationship with ARM. In all, 369 participants of the Muenster Aging and Retina Study were examined using dual-wavelength analysis of autofluorescence images. ARM was graded using digital fundus photographs according to the International Classification System. A ringlike structure was observed in 73 (19.8%) study participants. The MP maximum of the ring was located on average at 0.85° and the minimum at 0.48° from the center of the fovea. Their concordance between pairs of eyes was highly significant. MPOD measured at eccentricities of 0°, 0.25°, and 0.5° from the fovea was significantly lower in eyes with ringlike structure, whereas it was significantly higher at 1.0° and 2.0° than that in eyes without the ring. Ringlike structures were significantly more common in females and never smokers and were found significantly less often in eyes with ARM than in healthy eyes, even after adjustment for influential factors (adjusted odds ratio, 0.347; 95% confidence interval, 0.196-0.617). Ringlike structures in the MP spatial profile are fairly common, show a high degree of bilaterality, and appeared inversely related with ARM.


Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: Evidence for "polygenic epistasis".
The majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors. We applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection. Unlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast.


Deficiency in DNA repair in mouse lymphoma strain L5178Y-S.
The production and repair of radiation-induced DNA damage were measured by filter elution in strains of mouse lymphoma L5178Y cells differing in their sensitivity to ionizing radiation. The induction of radiation-induced damage, as measured by filter elution at pH 12.1, 9.6, and 7.2, was similar in the resistant strain LY-R and the sensitive strain LY-S. The repair of single-strand breaks and alkali-labile sites, as measured by filter elution at pH 12.1 at various times after irradiation, was somewhat slower in strain LY-S than in strain LY-R, although after a 20-min repair period the extent of repair was equal in the two strains. However, when filter elution was performed at either pH 9.6 or pH 7.2, the repair of x-radiation-induced damage was much less extensive in strain LY-S than in strain LY-R. We have assumed that the extent of filter elution at pH 9.6 is a measure of the occurrence of frank double-strand breaks as well as closely opposing single-strand breaks and pH 9.6-labile sites (and combinations thereof), and that the extent of elution at pH 7.2 is a measure of the occurrence of frank double-strand breaks alone. If these assumptions are correct, the results suggest that the sensitivity of strain LY-S to the cytotoxic effects of ionizing radiation is caused by a deficiency in the ability of this strain to repair frank double-strand breaks and pH 9.6-labile lesions. The repair of pH 9.6-labile lesions was temperature sensitive in strain LY-S, as previously found for cellular recovery processes in this strain. Two independent radiation-resistant variants of strain LY-S, isolated after protracted exposure of LY-S cells to low-dose-rate radiation, showed a deficiency in the repair of pH 9.6-labile lesions similar to that observed in strain LY-S. However, the repair of frank double-strand breaks was more extensive in the radiation-resistant variants than in strain LY-S and was similar in extent to that occurring in strain LY-R after a 60-min postirradiation incubation. The results suggest that there is a difference in the nature of DNA damage measured by filter elution at pH 9.6 vs. pH 7.2 and that a deficiency in the repair of pH 9.6-labile lesions does not contribute to cell lethality in the case of the radiation-resistant variants. The radiation resistance of these variants in comparison to strain LY-S may be due at least in part to recovery of the ability to rejoin frank DNA double-strand breaks.


Myocardial angiogenesis and coronary perfusion in left ventricular pressure-overload hypertrophy in the young lamb. Evidence for inhibition with chronic protamine administration.
In contrast to young growing animals, pressure-overload hypertrophy in adults is frequently associated with diminished myocardial capillary density and maximal coronary flow per gram. To determine the role of angiogenesis in maintaining perfusion capacity in the hypertrophying heart, the angiogenesis inhibitor protamine sulfate was administered to young lambs during the development of left ventricular (LV) pressure-overload hypertrophy. Baseline and maximum (adenosine) myocardial perfusion was measured in four groups of chronically instrumented 10-week-old lambs subjected to 1) ascending aortic bands since the age of 4 weeks (LVH group, n = 10), 2) sham operation at the age of 4 weeks (SHAM group, n = 8), 3) aortic bands and twice daily injections of protamine since the age of 4 weeks (LVH + P group, n = 9), 4) sham operation and injection of protamine (SHAM + P group, n = 8). Capillary density was measured postmortem. Peak LV pressure and the LV/body weight ratio were similarly increased in LVH and LVH + P compared with sham-operated lambs (p less than 0.001). In LVH lambs, LV capillary number increased by 32% compared with sham-operated lambs (p less than 0.05), and capillary density, coronary flow reserve, and minimal coronary resistance remained normal. In contrast, LVH + P lambs had no significant increase over SHAM lambs in LV capillaries and total maximum coronary flow. The LVH + P lambs had lower LV subendomyocardial capillary density and higher minimal coronary resistance per gram (p less than 0.05 versus LVH lambs). Right ventricular capillary density and minimal resistance were similar in all groups. These findings support the hypotheses that myocardial angiogenesis with pressure-overload hypertrophy is important in maintaining maximal LV coronary flow in the young and that impairment of angiogenesis results in diminished coronary flow capacity.


Time to reflect.
In an attempt to introduce creative ways of reflecting, art projects were included in group personal tutor sessions for student midwives. One was a reflective timeline drawn annually, documenting the student's own journey through a year. The intention was that this informal and interactive activity may help the students to relax and enjoy the reflective process, and also have some fun. Due to the high pressured risk management orientated nature of contemporary midwifery this was to be a welcome contrast to many of the traditional taught classes within the course. The student's evaluation of the activity exceeded all expectations in terms of demonstrating their learning from the experience and that sharing had helped them bond as a group thus supporting and understanding each other better. This exercise fostered a culture of self awareness, relationship building, caring and support for colleagues, all crucial aspects of woman centred midwifery practice.


Wegener's granulomatosis. Typical symptoms in an atypical patient.
Wegener's granulomatosis classically involves the respiratory tract and kidneys, and the disorder may be confused with any of a number of diseases having similar symptoms. Although most common in middle-aged whites, Wegener's granulomatosis may occur in atypical patients, as in the case described here. Accurate diagnosis depends on lung biopsy, and prompt treatment prevents permanent damage and significant sequelae.


What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease?
The smaller airways (<2 mm in diameter) offer little resistance in normal lungs but become the major site of obstruction in chronic obstructive pulmonary disease (COPD). We examined bronchiolar remodeling in COPD by combining quantitative histology, micro-computed tomography (CT), and gene expression studies. Volumes of bronchiolar tissue, total collagen, collagen-1, and collagen-3 were measured in lung tissue from 52 patients with different levels of COPD severity. Micro-CT was used to measure the number and lumen area of terminal bronchioles in four lungs removed before lung transplantation and in four donor lungs that served as controls. Laser capture microdissection provided 136 paired samples of bronchiolar and surrounding lung tissue from 63 patients and the gene expression of a cluster of tissue repair genes was compared. This study shows that total bronchiolar tissue decreased with progression of COPD and was associated with a reduction in total collagen and relative increase in collagen-3 over collagen-1. The micro-CT studies showed a 10-fold reduction in terminal bronchiolar number and a 100-fold reduction in lumen area. Interestingly, most genes associated with tissue accumulation during repair decreased their expression in both airways and in the surrounding lung as FEV(1) declined, but eight genes previously associated with COPD increased expression in the surrounding lung tissue. Our study shows that small airway remodeling is associated with narrowing and obliteration of the terminal bronchioles that begins before emphysematous destruction in COPD and in relation to differential expression of tissue repair genes in the airways and surrounding lung.


Pregabalin: preliminary experience in intractable childhood epilepsy.
Pregabalin is a new antiepileptic drug that acts at presynaptic calcium channels, modulating neurotransmitter release. We report on treating consecutive children with severe drug-resistant epilepsy in a prospective, open-label, add-on trial. Nineteen children (63% male) aged 4-15 years (mean, 9.7; S.D., 2.9) were included. Most (74%) had daily seizures that failed multiple drugs (mean, 5). Epilepsy was symptomatic in 58%, and 74% exhibited associated cognitive deficits. Seizures were mixed in nine (47%), and four (21%) manifested Lennox-Gastaut syndrome. Pregabalin was maintained at 150-300 mg/day. On pregabalin, one (6%) child became seizure-free, and seven (37%) had >50% seizure reduction. The percentage of children with daily seizures was reduced from 74% before pregabalin to 37% afterward (P < 0.002). Side effects were evident in six (32%) with somnolence, weight gain, dizziness, or behavioral change. The drug was withdrawn in five (26%) children for lack of efficacy, and in two (11%) for worsening of myoclonic epilepsy. We conclude that pregabalin is a useful addition in the treatment of refractory childhood epilepsy. The drug should be used with caution in myoclonic epilepsy. Controlled studies are needed to establish long-term efficacy and tolerability.


Hydrogel Layers on the Surface of Polyester-Based Materials for Improvement of Their Biointeractions and Controlled Release of Proteins.
The modification of bioresorbable polyester surfaces in order to alter their biointeractions presents an important problem in biomedical polymer science. In this study, the covalent modification of the surface of poly(lactic acid)-based (PLA-based) films with poly(acryl amide) and sodium alginate hydrogels was performed to change the non-specific polyester interaction with proteins and cells, as well as to make possible the covalent attachment of low-molecular weight ligands and to control protein release. The effect of such modification on the film surface properties was studied. Parameters such as swelling, water contact angle, surface area, and binding capacity of low-molecular weight substances were evaluated and compared. The comparative study of adsorption of model protein (BSA) on the surface of non-modified and modified films was investigated and the protein release was evaluated. Cell viability on the surface of hydrogel-coated films was also tested. The developed approach could be applied for the modification of PLA-based scaffolds for tissue engineering and will be further studied for molecular-imprinting of biomolecules on the surface of polyester-based materials for control of biointeractions.