Complete nucleotide sequence and deduced polypeptide sequence of a nonmuscle myosin heavy chain gene from Acanthamoeba: evidence of a hinge in the rodlike tail.
We have completely sequenced a gene encoding the heavy chain of myosin II, a nonmuscle myosin from the soil ameba Acanthamoeba castellanii. The gene spans 6 kb, is split by three small introns, and encodes a 1,509-residue heavy chain polypeptide. The positions of the three introns are largely conserved relative to characterized vertebrate and invertebrate muscle myosin genes. The deduced myosin II globular head amino acid sequence shows a high degree of similarity with the globular head sequences of the rat embryonic skeletal muscle and nematode unc 54 muscle myosins. By contrast, there is no unique way to align the deduced myosin II rod amino acid sequence with the rod sequence of these muscle myosins. Nevertheless, the periodicities of hydrophobic and charged residues in the myosin II rod sequence, which dictate the coiled-coil structure of the rod and its associations within the myosin filament, are very similar to those of the muscle myosins. We conclude that this ameba nonmuscle myosin shares with the muscle myosins of vertebrates and invertebrates an ancestral heavy chain gene. The low level of direct sequence similarity between the rod sequences of myosin II and muscle myosins probably reflects a general tolerance for residue changes in the rod domain (as long as the periodicities of hydrophobic and charged residues are largely maintained), the relative evolutionary "ages" of these myosins, and specific differences between the filament properties of myosin II and muscle myosins. Finally, sequence analysis and electron microscopy reveal the presence within the myosin II rodlike tail of a well-defined hinge region where sharp bending can occur. We speculate that this hinge may play a key role in mediating the effect of heavy chain phosphorylation on enzymatic activity.


MIB1/Ki-67 labelling index can classify grade 2 breast cancer into two clinically distinct subgroups.
Histological grade is recognized as one of the strongest prognostic factors in operable breast cancer (BC). Although grade 1 and grade 3 tumours are biologically and clinically distinct, grade 2 tumours bear considerable difficulty in outcome prediction and planning therapies. Several attempts such as genomic grade index have been performed to subclassify grade 2 into two subgroups with clinical relevance. Here, we present evidence that the routinely evaluable immunohistochemical MIB1/Ki67 labelling index (MIB-LI) can classify grade 2 tumours into two clinically distinct subgroups. In this study, growth fractions of 1,550 primary operable invasive breast carcinomas were immunohistochemically assayed on full-face tissue sections using the MIB1 clone of Ki-67. Growth fractions were assessed as number of MIB1 positive nuclei in 1,000 tumour nuclei at high-power magnification and expressed as MIB1-LI. Using a 10% cut-point of MIB1-LI, grade 2 BCs were classified into low (49.8%) and high (50.2%) proliferative subgroups. Univariate and multivariate survival analysis revealed statistically significant differences between these subgroups regarding patients' BC specific survival (P < 0.001), and metastasis free survival (P < 0.001) which was independent of the well-established prognostic factors (HR = 2.944, 95% CI = 1.634-5.303, P < 0.001). In conclusion, our results further demonstrate that grade 2 BCs may represent at least two biological or behaviourally different entities. Assay of growth fraction in BC using MIB1/Ki67 immunohistochemistry is a robust cost-effective diagnostic tool that subdivides grade 2 tumours into low and high risk populations providing additional prognostic information in planning therapies and outcome prediction.


Evaluation of the Predictive Value of CHA2DS2-VASc Score for In-Stent Restenosis.
The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke, vascular disease, age 65-74 years, female gender) score is used to estimate thromboembolic risk in atrial fibrillation (AF). Its usefulness in predicting in-stent restenosis (ISR) is unknown. We evaluated the predictive value of the CHA2DS2-VASc score in AF-free patients who have undergone stent implantation. A total of 1350 patients who underwent coronary angiography and successful bare-metal stent implantation were analyzed. The CHA2DS2-VASc score was calculated before percutaneous coronary intervention, and the association between the score and ISR was investigated. Patients (n = 700; mean age: 61.4 [8.7] years, 63% men) were divided in 2 subgroups according to the presence of ISR; 265 of 700 patients had ISR. Mean CHA2DS2-VASc score was significantly higher in the ISR (+) group than the ISR (-) group (3.7 [1.8] vs 2.1 [1.4], P < .001). According to multivariate logistic regression analysis, diabetes, hyperlipidemia, smoking, stent length, and CHA2DS2-VASc score were independent predictors of ISR. In conclusion, the CHA2DS2-VASc score may be useful as a new and simple tool to predict ISR.


Differential role of MyD88 and TRIF signaling in myeloid cells in the pathogenesis of autoimmune diabetes.
Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic beta cells. While the role of adaptive immunity has been extensively studied, the role of innate immune responses and particularly of Toll- like Receptor (TLR) signaling in T1D remains poorly understood. Here we show that myeloid cell-specific MyD88 deficiency considerably protected mice from the development of streptozotocin (STZ)-induced diabetes. The protective effect of MyD88 deficiency correlated with increased expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in pancreatic lymph nodes from STZ-treated mice and in bone marrow-derived dendritic cells (BMDC) stimulated with apoptotic cells. Mice with myeloid cell specific TIR-domain-containing adapter-inducing interferon-β (TRIF) knockout showed a trend towards accelerated onset of STZ-induced diabetes, while TRIF deficiency resulted in reduced IDO expression in vivo and in vitro. Moreover, myeloid cell specific MyD88 deficiency delayed the onset of diabetes in Non-Obese Diabetic (NOD) mice, whereas TRIF deficiency had no effect. Taken together, these results identify MyD88 signaling in myeloid cells as a critical pathogenic factor in autoimmune diabetes, which is antagonized by TRIF-dependent responses. This differential function of MyD88 and TRIF depends at least in part on their opposite effects in regulating IDO expression in phagocytes exposed to apoptotic cells.


Inflation-Adjusted Trends in Medicare Reimbursement for Common Dermatologic Procedures, 2007-2021.
Medicare enrollment, dermatologist utilization of Medicare, and dermatologic procedural volume have all increased over time. Despite this, there are limited studies evaluating changes in Medicare reimbursement within dermatology. To identify trends in Medicare reimbursement for 46 common dermatologic procedures from 2007 to 2021. In this cross-sectional study, reimbursement data were obtained from the Centers for Medicare & Medicaid Services Physician Fee Schedule for commonly used dermatologic Current Procedural Terminology (CPT) codes from 2007 to 2021. The CPT codes in several major dermatologic categories were analyzed, including skin biopsy, shave removal, benign/premalignant/malignant destruction, benign/malignant excision, Mohs micrographic surgery, simple/intermediate/complex repair, flap, graft, and laser/phototherapy. All procedure prices were adjusted for inflation to January 2021 dollar value. The primary outcomes were percentage changes and cumulative annual growth rates of pricing for each dermatologic procedure. From 2007 to 2021, there was a mean decrease in dermatologic procedure reimbursement of -4.8% after adjusting for inflation. Mean inflation-adjusted changes in reimbursements during this time period significantly varied by procedure type, including skin biopsy (+30.3%), shave removal (+24.5%), benign/premalignant/malignant destruction (-7.5%), Mohs micrographic surgery (-14.4%), benign/malignant excision (-3.9%), simple/intermediate/complex repair (-9.9%), flap repair (-14.1%), graft repair (-12.0%), and laser/phototherapy (-6.6%; P < .001). Changes in reimbursement did not vary by anatomical risk categories. The findings of this cross-sectional analysis suggest that changes in Medicare reimbursement can have several downstream effects, including concomitant private insurance changes and decreased patient access. Future adjustments in reimbursement should balance high-value care with sustainable pricing to optimize patient access.


Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation.
Src homology 3 domain (SH3)-containing proline-rich protein kinase (SPRK)/mixed-lineage kinase (MLK)-3 is a serine/threonine kinase that upon overexpression in mammalian cells activates the c-Jun NH(2)-terminal kinase pathway. The mechanisms by which SPRK activity is regulated are not well understood. The small Rho family GTPases, Rac and Cdc42, have been shown to bind and modulate the activities of signaling proteins, including SPRK, which contain Cdc42/Rac interactive binding motifs. Coexpression of SPRK and activated Cdc42 increases SPRKs activity. SPRKs Cdc42/Rac interactive binding-like motif contains six of the eight consensus residues. Using a site-directed mutagenesis approach, we show that SPRK contains a functional Cdc42/Rac interactive binding motif that is required for SPRKs association with and activation by Cdc42. However, experiments using a SPRK variant that lacks the COOH-terminal zipper region/basic stretch suggest that this region may also contribute to Cdc42 binding. Unlike the PAK family of protein kinases, we find that the activation of SPRK by Cdc42 cannot be recapitulated in an in vitro system using purified, recombinant proteins. Comparative phosphopeptide mapping demonstrates that coexpression of activated Cdc42 with SPRK alters the in vivo serine/threonine phosphorylation pattern of SPRK suggesting that the mechanism by which Cdc42 increases SPRKs catalytic activity involves a change in the in vivo phosphorylation of SPRK. This is, to the best of our knowledge, the first demonstrated example of a Cdc42-mediated change in the in vivo phosphorylation of a protein kinase. These studies suggest an additional component or cellular environment is required for SPRK activation by Cdc42.


Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency.
The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy. Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement. GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement. The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.


Nontraumatic hemoabdomen and pancytopenia secondary to myelolipoma in a cat.
(1) To report an unusual etiology for nontraumatic hemoabdomen in cats, and (2) to describe onset and recovery from severe, unexpected pancytopenia seen after surgical removal of a large intra-abdominal myelolipoma. A 14-year-old neutered male domestic shorthair cat was presented for emergent treatment of suspected nontraumatic hemoabdomen. A hyperechoic mass, with ultrasonographic echogenicity similar to fat, was found in the right cranial abdomen and believed to be associated with the mesentery. Cytological examination of abdominal fluid identified marked extramedullary hematopoiesis within the hemorrhagic effusion. Exploratory laparotomy identified a hepatic mass, which was resected, and revealed to be a hepatic myelolipoma on histopathological examination. The patient's initial recovery was uneventful. However, continued hyporexia resulted in readmission 4 days postoperatively, at which time the patient was found to have a profound, tri-lineage pancytopenia, and cytological evidence indicative of bone marrow recovery. The pancytopenia resolved with continued medical management and supportive care. Ruptured myelolipoma is not a commonly considered differential for nontraumatic hemoabdomen in cats. Furthermore, severe pancytopenia is unexpected following surgical resection of a myelolipoma. This case provides a unique clinical presentation of both nontraumatic hemoabdomen and bone marrow recovery.


Intranasal nerve growth factor administration improves neurological outcome after GBS meningitis.
Nerve growth factor (NGF) is a neurotrophin that promotes neural recovery and plasticity after experimental brain injury, supporting neuronal growth, differentiation, and survival of brain cells. Only a few studies reported NGF administration in pediatric patients with impaired brain functions after traumatic injuries, ischemic or infectious diseases, such as meningitis. We described the beneficial therapeutic effects of human-recombinant nerve growth factor (hr-NGF) treatment in an infant with persistent unresponsive wakefulness syndrome (UWS), due to late-onset group B Streptococcus meningitis. The infant received five monthly cycles of intranasal hr-NGF (0.1 mg/kg, 3 times daily for 7 consecutive days) through a mucosal atomizer device (MAD). NGF administration improved functional [positron emission tomography/computed tomography (PET/CT), single-photon emission/computed tomography (SPECT/CT), and magnetic resonance imaging (MRI)] assessments, electrophysiological [Electroencephalogram (EEG)] studies, as well as main cognitive processes and clinical and neurological functions. After hr-NGF treatment, significant improvements in facial mimicry, attention, motor reactions, oral motility, and feeding capacity were observed. She also recovered some hypothalamic functions and her cough reflex was restored. No side effects were reported during and after the treatment. For the first time ever, hr-NGF has been successfully utilized in an infant with UWS and severe neurologic outcome due to a bacterial meningitis. Although further studies are needed for better understanding the neuroprotective role of this neurotrophin, intranasal hr-NGF administration appears to be a promising and save rescuing strategy treatment in infants with severe neurological impairment after brain damage.


Pain intensity and abdominal muscle activation during walking in patients with low back pain: The STROBE study.
Nonspecific low back pain (LBP) is a common musculoskeletal problem that is intensified during physical activity. Patients with LBP have been reported to change their abdominal muscle activity during walking; however, the effects of pain intensity, disability level, and fear-avoidance belief on this relationship have not been evaluated. Thus, we compared abdominal muscle activity in patients with LBP and asymptomatic controls, and assessed the impact of pain intensity, disability level, and fear-avoidance belief.Thirty patients with LBP divided into groups reporting low (LLBP) and high-pain intensity low back pain (HLBP), and 15 participants without LBP were recruited. LBP patients' self-reported pain intensity, disability, and fear-avoidance belief were recorded. To examine abdominal muscle activity (rectus abdominis [RA], internal [IO], and external oblique [EO] muscles) during walking, all subjects walked at a self-selected speed. Abdominal muscle activity (RA, IO, and EO) was compared among groups (LLBP, HLBP, and controls) in different phases of walking (double support vs swing). Relationships between abdominal muscle activity and clinical measures (pain intensity, disability, fear-avoidance belief) were analyzed using partial correlation analysis.Right IO muscle activity during walking was significantly decreased in LLBP and HLBP compared with controls in certain walking phase. Partial correlation coefficients showed significant correlations between fear-avoidance belief and right EO activity (r = .377, P < .05) and between disability index and left IO activity (r = .377, P < .05) in patients with LBP. No significant difference was found in abdominal muscle activity in walking between patients with LLBP and HLBP (P > .05).This study demonstrated decreased IO muscle activity during certain walking phases in LLBP and HLBP compared with asymptomatic participants. Although altered IO muscle activity during walking was observed in patients with LBP, no changes were found with other abdominal muscles (EO, RA). Thus, these results provide useful information about abdominal muscle activity during walking in patients with LBP.


[Hypophosphatemia and refeeding syndrome: a severe and underdiagnosed adverse effect].
A 68-year-old woman was hospitalised because of generalised weakness and development of confusional state, related to severe hyponatremia, probably due to an eating disorder with malnutrition. During the first days of hospitalisation the patient eats surprising large amounts of food. The worsening of the confusional state in spite of normalisation of natremia, and the progressive development of anemia and thrombocytopenia, leads to the discovery of a new onset severe hypophosphatemia. The rapid fall in plasma levels of phosphorus, magnesium and potassium are the main futures of the refeeding syndrome. Its clinical manifestations are neurological, muscular, haematological and renal. The development of this syndrome is associated with a high mortality. The refeeding syndrome is seen when carbohydrates are introduced after a period of malnutrition. Identification of patients at risk for the refeeding syndrome (anorexia nervosa, chronic alcoholism, chronic malnutrition, elderly patients, oncology patients), the introduction of cautious progressive nutrition and the careful monitoring of vital signs, electrolytes levels and fluid balance, allows to prevent morbidity and mortality of this syndrome.


Managing the farmscape for connectivity increases conservation value for tropical bird species with different forest-dependencies.
Land clearing for agricultural use is a primary driver of biodiversity loss and fragmentation of natural ecosystems. Restoring natural habitat connectivity by retaining quality habitats and increasing on-farm tree cover contributes to species' mobility and persistence in agricultural landscapes. Nonetheless, remarkably few studies have quantified the impacts of on-farm practices for species' mobility measured as functional connectivity within the context of farm and broader spatial levels of landscape organization. We tested how adding and removing trees in different configurations on a farm comprised of coffee plantations and cattle pastures can help evaluate species' mobility at the farmscape level (an area comprising the farm plus a 1.5 km buffer area). We coupled bird capture data and scenario modeling to assess species mobility of five neotropical bird species with distinct life history characteristics representing a gradient of forest dependency. We used seven years of mist-netting data to estimate species habitat affinity and to predict species mobility using the Circuitscape model across a 4371 ha farmscape in Costa Rica. Circuitscape allowed us to estimate changes in movement probability and relative changes in resistance to movement that species experience during dispersal (measured as resistance distance and passage area through which species can move) under four farmscape management scenarios. The four land-use scenarios included: (a) the 2011 farmscape land-use composition and configuration, b) converting all existing live fences to post-and-wire fence lines in the farm c) converting simplified coffee agroforests to multistrata coffee agroforests in the farm, and d) placing multistrata live fences around the perimeter of every parcel and roads on the farm. Model results suggest that existing multistrata live fences maintain the sporadic movement of all five species irrespective of forest dependence. Likewise, adding multistrata live fences around individual fields presents a more efficient strategy for increasing species mobility than multistrata coffee agroforestry systems in the assessed farmscape, by doubling the passage areas available to all species, although it created labyrinths with "dead-ends" for two species. While retaining large habitat patches remains important for conservation, managing on-farm connectivity complements these efforts by increasing movement probability and reducing dispersal resistance for forest-dependent bird species.


High-molecular-mass complexes formed in vivo contain smHSPs and HSP70 and display chaperone-like activity.
Stress can have profound effects on the cell. The elicitation of the stress response in the cell is often accompanied by the synthesis of high-molecular-mass complexes, sometimes termed heat shock granules (HSGs). The presence of the complexes has been shown to be important for the survival of cells subjected to stress. We purified these complexes from heat-stressed BY-2 tobacco cells. HSG complexes formed in vivo contain predominantly smHSPs, HSP40 and HSP70 and display chaperone-like activity. Tubulins as well as other proteins may be part of the complex or its substrate. The proteins, except smHSPs and to some extent HSP70, were hypersensitive to proteolysis, suggesting that they were partially denatured and not an integral part of the HSG complexes. When citrate synthase was used as the substrate, in vivo generated HSG complexes exhibited strong nucleotide-dependent in vitro chaperone activity. Measurable ATP-mediated hydrolytic activity was detected. Isolated HSG complexes are stable until ATP is added, which leads to rapid dissociation of the complex into subunits. It is proposed that smHSPs form the core of the complex in association with ATP-dependent HSP70 and HSP40 cochaperones. Implications of these findings are discussed.


Delayed Post-hypoxic Leukoencephalopathy: A Case Series and Review of the Literature.
Delayed post-hypoxic leukoencephalopathy (DPHL) is a unique clinical entity that presents with cognitive impairment days to weeks after an episode of acute hypoxic brain injury. Frequently hypoxia is unrecognized as a mechanism for clinical decline and extensive workup ensues. We present two cases of DPHL highlighting the neuroimaging findings. In both patients, a cerebral hypoxic event was followed by a recovery phase with subsequent delayed clinical decline. Patient 1 suffered hypoxia from drug-induced respiratory depression and lack of post-operative positive airway pressure (PAP) support. Her neurological exam on follow-up revealed progressive cognitive decline. Magnetic resonance imaging (MRI) brain showed bilateral white matter changes involving the centrum semiovale. Patient 2 developed a generalized tonic-clonic seizure during an endobronchial biopsy procedure and was found to have multiple air emboli on computed tomography (CT) head scan. She was initially in a drug-induced coma for her seizures. Electroencephalography (EEG) on day 14 of admission showed changes consistent with diffuse encephalopathy. MRI brain showed bilateral white matter changes particularly at the watershed zones and in the centrum semiovale. DPHL is a rare and under-recognized clinical entity that requires clinical suspicion and detailed evaluation for diagnosis. Neuroimaging studies can provide prognostic information regarding the extent of neurological injury.


Development and validation of a cardiac findings checklist for use with simulator-based assessments of cardiac physical examination competence.
Objective outcome measures for use with simulator-based assessments of cardiac physical examination competence are lacking. The current study describes the development and validation of an approach to scoring performance using a cardiac findings checklist. A cardiac findings checklist was developed and implemented for use with a simulator-based assessment of cardiac physical examination competence at a Canadian national specialty examination in internal medicine. Candidate performance as measured using the checklist was compared with global ratings of clinical performance on the cardiac patient simulator and with overall examination performance. Interrater reliability for scoring the checklist ranged from 0.95 for scoring correct findings to 0.72 for scoring incorrect findings. A summary checklist score had a Pearson correlation of 0.60 with overall candidate performance on the simulator-based station. Use of a cardiac findings checklist provides one objective measure of cardiac physical examination competence that may be used with simulator-based assessments.


[Cytoplasmic estrogen and progesterone receptors in primary cervical carcinoma--relation between clinical aspects and histopathology].
The measurement of cytoplasmic estrogen and progesterone receptors (ERc and PRc) as markers of specific hormone in the human breast and endometrial cancer leads to the application of receptor levels as a means in clinical management. Comprehensive investigations have not been completed in invasive cervical cancer. From 1977 to 1981, 39 cases of primary cervical carcinoma were assayed as to the presence or absence of ERc and PRc by the saturation point dextran-coated charcoal method. The level of ERc and PRc of various clinical stages, histological types, histological grades, menstrual status, age and survival was compared each other. Positive and negative receptor groups were proposed using more than or equal to 5 fmol/mg cytosol protein for ERc ane more than or equal to 10 fmol/mg cytosol protein for PRc as discrimination points. Survival of the measured patients was computed by the product-limit analysis according to Kaplan-Meier. A statistical difference between the PRc (+) and PRc (-) group in survival was noted by the Mantel-Cox test (P = 0.049). There was a longer survival in the PRc (+) patients. As to premenopausal or menopausal status, a statistical difference between the PRc (+) and PRc (-) group in survival was only observed in the premenopausal patients. The demonstration of the relationship between the PRc level and survival in cervical carcinoma would certainly be clinical significant to identify the high-risk patients for failure as treated by routine radiotherapy or surgery.


Fibrinogen Manchester. Detection of a heterozygous phenotype in the intraplatelet pool.
Family members heterozygous for the congenitally abnormal fibrinogen designated fibrinogen Manchester, A alpha 16Arg----His, have previously been shown by h.p.l.c. and amino acid analysis to release a variant fibrinopeptide, [His16]fibrinopeptide A, from plasma fibrinogen after the addition of thrombin. The present study was designed to determine if the same abnormal phenotype was also present in the intraplatelet fibrinogen pool. Fresh platelets were washed in buffers containing EDTA until it could be shown that all washable plasma fibrinogen was removed. Normal platelets were then lysed by freezing and thawing to release their intracellular proteins, which were then treated with thrombin. The fibrinopeptides, cleaved from the intraplatelet fibrinogen, could be detected by an optimized h.p.l.c. technique. Quantification of the intraplatelet fibrinogen gave a result (means +/- S.D., n = 5) of 110 +/- 30 and 90 +/- 30 micrograms/10(9) platelets, when determined by h.p.l.c. quantification of fibrinopeptide B content and fibrinogen fragment E radioimmunoassay respectively. Examination of fibrinopeptides released from the platelet fibrinogen from the family with fibrinogen Manchester with the same techniques showed elution peaks in the same positions as both [His16]fibrinopeptide A and normal fibrinopeptide A. The identity of these peaks was further substantiated by analysis of the h.p.l.c. peaks by using specific radioimmunoassay to fibrinopeptide A. Our results therefore demonstrate that platelet fibrinogen expresses the heterozygous A alpha 16His phenotype. This supports the view that the A alpha chains of platelet and plasma fibrinogen are produced from a single genetic locus.


Complex dynamic development of poliovirus membranous replication complexes.
Replication of all positive-strand RNA viruses is intimately associated with membranes. Here we utilize electron tomography and other methods to investigate the remodeling of membranes in poliovirus-infected cells. We found that the viral replication structures previously described as "vesicles" are in fact convoluted, branching chambers with complex and dynamic morphology. They are likely to originate from cis-Golgi membranes and are represented during the early stages of infection by single-walled connecting and branching tubular compartments. These early viral organelles gradually transform into double-membrane structures by extension of membranous walls and/or collapsing of the luminal cavity of the single-membrane structures. As the double-membrane regions develop, they enclose cytoplasmic material. At this stage, a continuous membranous structure may have double- and single-walled membrane morphology at adjacent cross-sections. In the late stages of the replication cycle, the structures are represented mostly by double-membrane vesicles. Viral replication proteins, double-stranded RNA species, and actively replicating RNA are associated with both double- and single-membrane structures. However, the exponential phase of viral RNA synthesis occurs when single-membrane formations are predominant in the cell. It has been shown previously that replication complexes of some other positive-strand RNA viruses form on membrane invaginations, which result from negative membrane curvature. Our data show that the remodeling of cellular membranes in poliovirus-infected cells produces structures with positive curvature of membranes. Thus, it is likely that there is a fundamental divergence in the requirements for the supporting cellular membrane-shaping machinery among different groups of positive-strand RNA viruses.


Viral eradication restores normal iron status in chronic hepatitis C patients with abnormal iron studies.
Abnormal serum iron studies are seen in a third or more of patients with chronic hepatitis C infection (HCV), where they have been linked to accelerated fibrosis progression and increased risk of hepatocellular carcinoma and sometimes lead to concern for coexisting hereditary hemochromatosis. The aim of this study was to assess the effect of HCV eradication in patients with abnormal serum iron studies prior to treatment with direct-acting antiviral agents (DAAs). HCV-infected subjects with iron studies obtained before and after successful treatment with DAAs were identified (n=27). All had one or more abnormal iron test before treatment. Following HCV eradication, serum iron, transferrin-iron saturation and ferritin levels decreased significantly (pre- versus post-treatment, p<0.01 for each). Serum iron and/or transferrin-iron saturations normalized in 16/19 subjects and raised ferritin levels returned to the normal range in 14/18 subjects, including several with pretreatment transferrin-iron saturation >90% and/or serum ferritin >1000ng/mL. Elimination of HCV infection was associated with a significant reduction in post-treatment ferritin levels even among subjects whose ferritin levels were within normal limits at baseline. Risk factors for other conditions associated with abnormal iron status were present in the few cases in which iron studies failed to normalize following DAA treatment. Eradication of HCV infection restores normal iron status in most patients with abnormal iron tests, including those whose baseline parameters are suggestive of hemochromatosis.


Comorbidity Management in Black Women Diagnosed with Breast Cancer: the Role of Primary Care in Shared Care.
Black women are more likely to have comorbidity at breast cancer diagnosis compared with White women, which may account for half of the Black-White survivor disparity. Comprehensive disease management requires a coordinated team of healthcare professionals including primary care practitioners, but few studies have examined shared care in the management of comorbidities during cancer care, especially among racial/ethnic minorities. To examine whether the type of medical team composition is associated with optimal clinical care management of comorbidities. We used the Women's Circle of Health Follow-up Study, a population-based cohort of Black women diagnosed with breast cancer. The likelihood of receiving optimal comorbidity management after breast cancer diagnosis was compared by type of medical team composition (shared care versus cancer specialists only) using binomial regression. Black women with a co-diagnosis of diabetes and/or hypertension at breast cancer diagnosis between 2012 and 2016 (N = 274). Outcome-optimal clinical care management of diabetes (i.e., A1C test, LDL-C test, and medical attention for nephropathy) and hypertension (i.e., lipid screening and prescription for hypertension medication). Main predictor-shared care, whether the patient received care from both a cancer specialist and a primary care provider and/or a medical specialist within the 12 months following a breast cancer diagnosis. Primary care providers were the main providers involved in managing comorbidities and 90% of patients received shared care during breast cancer care. Only 54% had optimal comorbidity management. Patients with shared care were five times (aRR: 4.62; 95% CI: 1.66, 12.84) more likely to have optimal comorbidity management compared with patients who only saw cancer specialists. Suboptimal management of comorbidities during breast cancer care exists for Black women. However, our findings suggest that shared care is more beneficial at achieving optimal clinical care management for diabetes and hypertension than cancer specialists alone.


Platelet PlA2 polymorphism enhances risk of neurocognitive decline after cardiopulmonary bypass. Multicenter Study of Perioperative Ischemia (McSPI) Research Group.
Neurocognitive decline, often produced by atherosclerotic plaque embolization, remains a frequent complication of cardiopulmonary bypass. Plaque fragments may initiate local thrombosis, which, in turn, aggravates the embolic insult. Prothrombotic genetic factors may exacerbate this process. We investigated whether the PlA2 polymorphism of platelet GPIIIa, a prothrombotic risk factor in other cardiovascular settings, is associated with early neurocognitive decline after cardiopulmonary bypass. Neurocognitive changes were evaluated by the Mini-Mental State Examination administered preoperatively and on postoperative day 4 and the PlA genotype determined in 70 patients undergoing cardiopulmonary bypass. Forty-nine patients were PlA1/A1, and 21 were PlA1/A2 or PlA2/A2. Fifty-two patients (74%) demonstrated post-cardiopulmonary bypass neurocognitive decline, of which 34 were PlA1/A1 and 18 were PlA1/A2 or PlA2/A2 Multivariate analysis revealed that the PlA2 genotype and baseline Mini-Mental State Examination were significantly associated with greater neurocognitive decline (decreased Mini-Mental State Examination scores, p = 0.036 and 0.024, respectively). This study demonstrates a link between the PlA2 allele of platelet GPIIIa and more severe neurocognitive decline after cardiopulmonary bypass. Although the mechanism is unknown, it could represent exacerbation of platelet-dependent thrombotic processes associated with plaque embolism.


Lavender Products Associated With Premature Thelarche and Prepubertal Gynecomastia: Case Reports and Endocrine-Disrupting Chemical Activities.
Previous case reports associated prepubertal gynecomastia with lavender-containing fragrances, but there appear to be no reports of premature thelarche. To add to a case series about lavender-fragranced product use and breast growth in children and to measure endocrine-disrupting chemical activity of essential oil components. Patients experiencing premature thelarche or prepubertal gynecomastia with continuous exposure to lavender-fragranced products were evaluated in the pediatric endocrinology departments of two institutions. Mechanistic in vitro experiments using eight components of lavender and other essential oils were performed at National Institute of Environmental Health Sciences. Case reports and in vitro estrogen and androgen receptor gene expression activities in human cell lines with essential oils. Three prepubertal girls and one boy with clinical evidence of estrogenic action and a history of continuous exposure to lavender-containing fragrances were studied. Breast growth dissipated in all patients with discontinuation of the fragranced products. Some of the components tested elicited estrogenic and antiandrogenic properties of varying degrees. We report cases of premature thelarche that resolved upon cessation of lavender-containing fragrance exposure commonly used in Hispanic communities. The precise developmental basis for such conditions could be multifactorial. In vitro demonstration of estrogenic and antiandrogenic properties of essential oil components suggests essential oils in these cases could be considered a possible source and supports a possible link with idiopathic prepubertal breast development. Whether the level of lavender oil estrogenic potency is sufficient to cause these effects is unknown.


Lead in ammunition: a persistent threat to health and conservation.
Many scavenging bird populations have experienced abrupt declines across the globe, and intensive recovery activities have been necessary to sustain several species, including the critically endangered California condor (Gymnogyps californianus). Exposure to lead from lead-based ammunition is widespread in condors and lead toxicosis presents an immediate threat to condor recovery, accounting for the highest proportion of adult mortality. Lead contamination of carcasses across the landscape remains a serious threat to the health and sustainability of scavenging birds, and here we summarize recent evidence for exposure to lead-based ammunition and health implications across many species. California condors and other scavenging species are sensitive indicators of the occurrence of lead contaminated carcasses in the environment. Transdisciplinary science-based approaches have been critical to managing lead exposure in California condors and paving the way for use of non-lead ammunition in California. Similar transdisciplinary approaches are now needed to translate the science informing on this issue and establish education and outreach efforts that focus on concerns brought forth by key stakeholders.


Photocatalyzed Diastereoselective Isomerization of Cinnamyl Chlorides to Cyclopropanes.
Endergonic isomerizations are thermodynamically unfavored processes that are difficult to realize under thermal conditions. We report a photocatalytic and diastereoselective isomerization of acyclic cinnamyl chlorides to strained cyclopropanes. Quantum mechanical calculations (uM06-2X and DLPNO), including TD-DFT calculations, and experimental studies provide evidence for the energy transfer from an iridium photocatalyst to the allylic chloride substrate followed by C-Cl homolytic cleavage. Subsequent Cl• radical migration forms a localized triplet 1,3-diradical intermediate that, after intersystem crossing, undergoes ring-closing to form the desired product. The mild reaction conditions are compatible with a broad range of functional groups to generate chlorocyclopropanes in high yields and diastereoselectivities. A more efficient process is developed by addition of a catalytic amount of a nickel complex, and we propose a novel role for this cocatalyst to recycle an allyl chloride byproduct generated in the course of the reaction. The reaction is also shown to be stereoconvergent, as an E/Z mixture of cinnamyl chlorides furnish the anti-chlorocyclopropane product in high diastereoselectivity. We anticipate that the use of a visible light activated photocatalyst to transform substrates in combination with a transition metal catalyst to recycle byproducts back into the catalytic cycle will provide unique opportunities for the discovery of new reactivity.


The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence.
The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in 'lipotoxic danger signals' such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, T cell progenitors and maintenance of T cell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates T cell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the re-establishment of a diverse T cell repertoire in middle-aged or elderly patients undergoing HSCT.


[Dynamics of the immunodepressive and antitumor activity of adriamycin].
It was revealed in experiments on mice that the immunodepressive activity of adriamycin depends exponentially on the dose of the preparation and is marked both before and after the antigen stimulation. The degree of immunodepression, the kinetics of formation and attenuation of the immune response depend on the dose of adriamycin. The preparation possesses antitumoral activity in relation to the plasmacytoma MOPC-315.


The genome sequence of Mycoplasma hyopneumoniae strain 232, the agent of swine mycoplasmosis.
We present the complete genome sequence of Mycoplasma hyopneumoniae, an important member of the porcine respiratory disease complex. The genome is composed of 892,758 bp and has an average G+C content of 28.6 mol%. There are 692 predicted protein coding sequences, the average protein size is 388 amino acids, and the mean coding density is 91%. Functions have been assigned to 304 (44%) of the predicted protein coding sequences, while 261 (38%) of the proteins are conserved hypothetical proteins and 127 (18%) are unique hypothetical proteins. There is a single 16S-23S rRNA operon, and there are 30 tRNA coding sequences. The cilium adhesin gene has six paralogs in the genome, only one of which contains the cilium binding site. The companion gene, P102, also has six paralogs. Gene families constitute 26.3% of the total coding sequences, and the largest family is the 34-member ABC transporter family. Protein secretion occurs through a truncated pathway consisting of SecA, SecY, SecD, PrsA, DnaK, Tig, and LepA. Some highly conserved eubacterial proteins, such as GroEL and GroES, are notably absent. The DnaK-DnaJ-GrpR complex is intact, providing the only control over protein folding. There are several proteases that might serve as virulence factors, and there are 53 coding sequences with prokaryotic lipoprotein lipid attachment sites. Unlike other mycoplasmas, M. hyopneumoniae contains few genes with tandem repeat sequences that could be involved in phase switching or antigenic variation. Thus, it is not clear how M. hyopneumoniae evades the immune response and establishes a chronic infection.


Prognostic Significance of Tumor-Infiltrating Lymphocytes and the Tertiary Lymphoid Structures in HER2-Positive Breast Cancer Treated With Adjuvant Trastuzumab.
Tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The tertiary lymphoid structure (TLS) is related to the influx of TILs, and expression of major histocompatibility complex (MHC) I in tumor cells is necessary for the effective action of TILs. We retrospectively evaluated the relationship of TILs and TLS and the expression of MHC I in 447 HER2-positive breast cancers treated with chemotherapy and 1 year of trastuzumab. TILs were more abundant in hormone receptor (HR)-/HER2+ tumors than in HR+/HER2+ tumors. HR-/HER2+ breast cancers with abundant TILs showed a higher histologic grade, the absence of lymphovascular invasion, the presence of peritumoral lymphocytic infiltration, moderate to abundant TLSs in adjacent tissue, and stronger HLA-ABC and HLA-A expression. Abundant TILs and the absence of lymphovascular invasion were found to be good, independent prognostic factors for disease-free survival in patients with HR-/HER2+ breast cancer. The level of TILs was not associated with the patients' prognosis in HR+ tumors. Abundant TILs are an independent prognostic factor in HR-/HER2+ breast cancers. Evaluation of TILs in HR-/HER2+ breast cancers may provide valuable information regarding the prognosis of patients treated using adjuvant chemotherapy and trastuzumab.


A task-based support architecture for developing point-of-care clinical decision support systems for the emergency department.
The purpose of this study was to create a task-based support architecture for developing clinical decision support systems (CDSSs) that assist physicians in making decisions at the point-of-care in the emergency department (ED). The backbone of the proposed architecture was established by a task-based emergency workflow model for a patient-physician encounter. The architecture was designed according to an agent-oriented paradigm. Specifically, we used the O-MaSE (Organization-based Multi-agent System Engineering) method that allows for iterative translation of functional requirements into architectural components (e.g., agents). The agent-oriented paradigm was extended with ontology-driven design to implement ontological models representing knowledge required by specific agents to operate. The task-based architecture allows for the creation of a CDSS that is aligned with the task-based emergency workflow model. It facilitates decoupling of executable components (agents) from embedded domain knowledge (ontological models), thus supporting their interoperability, sharing, and reuse. The generic architecture was implemented as a pilot system, MET3-AE--a CDSS to help with the management of pediatric asthma exacerbation in the ED. The system was evaluated in a hospital ED. The architecture allows for the creation of a CDSS that integrates support for all tasks from the task-based emergency workflow model, and interacts with hospital information systems. Proposed architecture also allows for reusing and sharing system components and knowledge across disease-specific CDSSs.


Mechanical ventilation weaning and extubation after spinal cord injury: a Western Trauma Association multicenter study.
Respiratory failure after acute spinal cord injury (SCI) is well recognized, but data defining which patients need long-term ventilator support and criteria for weaning and extubation are lacking. We hypothesized that many patients with SCI, even those with cervical SCI, can be successfully managed without long-term mechanical ventilation and its associated morbidity. Under the auspices of the Western Trauma Association Multi-Center Trials Group, a retrospective study of patients with SCI at 14 major trauma centers was conducted. Comprehensive injury, demographic, and outcome data on patients with acute SCI were compiled. The primary outcome variable was the need for mechanical ventilation at discharge. Secondary outcomes included the use of tracheostomy and development of acute lung injury and ventilator-associated pneumonia. A total of 360 patients had SCI requiring mechanical ventilation. Sixteen patients were excluded for death within the first 2 days of hospitalization. Of the 344 patients included, 222 (64.5%) had cervical SCI. Notably, 62.6% of the patients with cervical SCI were ventilator free by discharge. One hundred forty-nine patients (43.3%) underwent tracheostomy, and 53.7% of them were successfully weaned from the ventilator, compared with an 85.6% success rate among those with no tracheostomy (p < 0.05). Patients who underwent tracheostomy had significantly higher rates of ventilator-associated pneumonia (61.1% vs. 20.5%, p < 0.05) and acute lung injury (12.8% vs. 3.6%, p < 0.05) and fewer ventilator-free days (1 vs. 24 p < 0.05). When controlled for injury severity, thoracic injury, and respiratory comorbidities, tracheostomy after cervical SCI was an independent predictor of ventilator dependence with an associated 14-fold higher likelihood of prolonged mechanical ventilation (odds ratio, 14.1; 95% confidence interval, 2.78-71.67; p < 0.05). While many patients with SCI require short-term mechanical ventilation, the majority can be successfully weaned before discharge. In patients with SCI, tracheostomy is associated with major morbidity, and its use, especially among patients with cervical SCI, deserves further study. Prognostic study, level III.


Using simulation to study difficult clinical issues: prenatal counseling at the threshold of viability across American and Dutch cultures.
Prenatal counseling at the threshold of viability is a challenging yet critically important activity, and care guidelines differ across cultures. Studying how this task is performed in the actual clinical environment is extremely difficult. In this pilot study, we used simulation as a methodology with 2 aims as follows: first, to explore the use of simulation incorporating a standardized pregnant patient as an investigative methodology and, second, to determine similarities and differences in content and style of prenatal counseling between American and Dutch neonatologists. We compared counseling practice between 11 American and 11 Dutch neonatologists, using a simulation-based investigative methodology. All subjects performed prenatal counseling with a simulated pregnant patient carrying a fetus at the limits of viability. The following elements of scenario design were standardized across all scenarios: layout of the physical environment, details of the maternal and fetal histories, questions and responses of the standardized pregnant patient, and the time allowed for consultation. American subjects typically presented several treatment options without bias, whereas Dutch subjects were more likely to explicitly advise a specific course of treatment (emphasis on partial life support). American subjects offered comfort care more frequently than the Dutch subjects and also discussed options for maximal life support more often than their Dutch colleagues. Simulation is a useful research methodology for studying activities difficult to assess in the actual clinical environment such as prenatal counseling at the limits of viability. Dutch subjects were more directive in their approach than their American counterparts, offering fewer options for care and advocating for less invasive interventions. American subjects were more likely to offer a wider range of therapeutic options without providing a recommendation for any specific option.


Adenoviral infections in pediatric liver transplant recipients.
Over a 5 1/2-year period, 22 of 262 children receiving liver transplants developed adenoviral infections. Five had adenoviral hepatitis in the allograft, caused by serotype 5. All five were treated for rejection, either just before or at the time of infection. Liver biopsy specimens had characteristic histological appearance, and diagnosis of adenoviral infection was confirmed with monoclonal antiadenoviral antibodies, electron microscopy, and by culture of liver tissue. In the remaining 17 patients, adenovirus was isolated from urine, stool, throat secretions, and/or blood samples, but none had any detectable visceral infection. Serotypes 1 and 2 predominated, similar to children not receiving transplants during the same time period. Three of the patients with hepatitis are alive and well; two died of liver failure. Adenoviral hepatitis did not recur in the second allograft of a patient who underwent retransplantation for combined rejection and adenoviral hepatitis, and appears, therefore, not to be a contraindication to retransplantation when liver failure ensues.


The effect of granulocyte colony stimulating factor on genotoxicity in allogeneic peripheral blood stem cell transplantation donors: a prospective case-control study.
Every year, thousands of donors are exposed to granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in hematopoietic stem cell transplantations (HSCT). Previous studies about the genotoxicity of G-CSF were inconclusive. In this study, the genotoxic effects of G-CSF in peripheral blood stem cell (PBSC) donors were evaluated prospectively by using three different validated and reliable methods for the first time in the literature to the best of our knowledge. Donors of PBSC transplantation (n=36), who received G-CSF were evaluated for genotoxicity by micronucleus test (MNT), nuclear division index (NDI), and comet assay (CA). Genotoxic effects are expected to cause an increase in MNT and CA values and decrease in NDI. Blood samples were collected at three timepoints (TP): before starting G-CSF (TP1), after G-CSF for five days (TP2), and one month after the last dose (TP3). Sixteen controls were included for baseline comparison of genotoxicity tests. CD34 cell counts and hemograms were also analyzed. MNT and CA parameters; comet and tail length, tail DNA%, and tail moment, showed no change in time whereas another CA parameter, Olive`s tail moment (OTM) was increased significantly at TP3 compared to both baseline and TP2 (p=0.002 and p=0.017, respectively). Nuclear division index decreased significantly at TP2 (p < 0.001), then increased above baseline at TP3 (p=0.004). Baseline comparison with controls showed higher MN frequency in donors without statistical significance (p=0.059). Whereas, CA results were significantly higher in controls. CD34 cell count showed moderate positive correlation with white blood cell count at TP2 (Pearson R=0.495, p=0.004). Our results showed the genotoxic effect of G-CSF in healthy donors, in two of the three tests performed, short-term effect in NDI, and long-lasting effect in OTM. So, this study provides novel information for the debate about the genotoxicity of G-CSF and supports the need for further studies with a larger sample size and longer follow-up.


Directionality of the lizard ear.
Lizards have highly sensitive ears, but most lizard heads are small (1-2 cm in diameter) compared to the wavelengths of sound of frequencies to which they are most sensitive (1-4 kHz, wavelengths 34-8.5 cm). Therefore, the main cues to sound direction that mammals use - binaural time and intensity cues due to arrival-time differences and sound shadowing by the head--will be very small in lizards. The present work shows that acoustical coupling of the two eardrums in lizards produces the largest directionality of any terrestrial vertebrate ear studied. Laser vibrometric studies of tympanic motion show pronounced directionality within a 1.8-2.4 kHz frequency band around the best frequency of hearing, caused by the interference of ipsi- and contralateral inputs. The results correspond qualitatively to the response of a simple middle ear model, assuming coupling of the tympana through a central cavity. Furthermore, observed directional responses are markedly asymmetrical, with a steep gradient of up to 50-fold (34 dB) response differences between ipsi- and contralateral frontal angles. Therefore, the directionality is easily exploitable by simple binaural subtraction in the brain. Lizard ears are the clearest vertebrate examples of directionality generated by tympanic coupling.


Identifying a neuroanatomical signature of schizophrenia, reproducible across sites and stages, using machine learning with structured sparsity.
Structural MRI (sMRI) increasingly offers insight into abnormalities inherent to schizophrenia. Previous machine learning applications suggest that individual classification is feasible and reliable and, however, is focused on the predictive performance of the clinical status in cross-sectional designs, which has limited biological perspectives. Moreover, most studies depend on relatively small cohorts or single recruiting site. Finally, no study controlled for disease stage or medication's effect. These elements cast doubt on previous findings' reproducibility. We propose a machine learning algorithm that provides an interpretable brain signature. Using large datasets collected from 4 sites (276 schizophrenia patients, 330 controls), we assessed cross-site prediction reproducibility and associated predictive signature. For the first time, we evaluated the predictive signature regarding medication and illness duration using an independent dataset of first-episode patients. Machine learning classifiers based on neuroanatomical features yield significant intersite prediction accuracies (72%) together with an excellent predictive signature stability. This signature provides a neural score significantly correlated with symptom severity and the extent of cognitive impairments. Moreover, this signature demonstrates its efficiency on first-episode psychosis patients (73% accuracy). These results highlight the existence of a common neuroanatomical signature for schizophrenia, shared by a majority of patients even from an early stage of the disorder.


Therapeutic Efficacy of Alpha-RIT Using a (213)Bi-Anti-hCD138 Antibody in a Mouse Model of Ovarian Peritoneal Carcinomatosis.
Ovarian peritoneal carcinomatosis is a pathology for which effective cures are currently lacking. New research protocols seek to eradicate residual micrometastases following cytoreductive surgery by using hyperthermic intraperitoneal chemotherapy (HIPEC) or radioimmunotherapy (RIT). This study aims to first develop alpha-RIT using an anti-CD138 mAb radiolabeled with an alpha-emitter, bismuth-213 ((213)Bi-B-B4) and HIPEC in a nude mouse model and second to compare and combine these techniques. A murine model of postoperative ovarian peritoneal carcinomatosis was established. A pilot group of six mice received an intraperitoneal injection of luciferase-tagged SHIN-3 cells and bioluminescence was measured every day. Cytoreductive surgery was performed at day 14 (n = 4) and 29 (n = 2). Because the residual bioluminescence signal measured after surgery was equivalent to that obtained 3 days after the graft, HIPEC or alpha-RIT treatments were applied 3 days after the graft. Ten mice were treated by HIPEC with cisplatine (37.5 mg/mL), 11 with 7.4 MBq of (213)Bi-B-B4, seven with 11.1 MBq of (213)Bi-B-B4, and 10 mice were treated with the combined therapy (HIPEC + 7.4 MBq of (213)Bi-B-B4). Eleven mice received no treatment. Bioluminescence imaging and survival were assessed. Alpha-RIT 7.4 MBq and 11.1 MBq significantly improved survival (p = 0.0303 and p = 0.0070, respectively), whereas HIPEC and HIPEC + alpha-RIT treatments did not significantly ameliorate survival as compared to the control group. Survival was significantly increased by alpha-RIT treatment in mice with peritoneal carcinomatosis of ovarian origin; however, HIPEC alone or in combination with alpha-RIT had no significant effect.


[Immune activation and inflammation in chronic heart failure].
This survey shows that among chronic heart failure (CHF) and its characteristic inflammation observed mutual activation. Given the role of inflammation in the pathophysiology of heart failure, it is to study how the combination drug treatment of CHF, its variants influence on markers of inflammation. It is expedient to determine not only the level of cytokines, but also acute phase proteins (haptoglobin, seroglikoidy C3-complement, transferrin), reflecting inflammation and necrosis in the connective tissue, as well as IgA, IgG, IgM and protein spectrum. The importance of the study of haptoglobin due to its involvement in the metabolism of hemoglobin and transferrin--the exchange of iron.


Efficacy of interventions to improve psychological adjustment for parents of infants with or at risk of neurodevelopmental disability: A systematic review.
Supportive and targeted interventions for families are required to optimize parental adjustment and the parent-infant relationship in line with earlier diagnosis of neurodevelopmental risk for infants. The purpose of this systematic review was to determine the efficacy of interventions in improving psychological adjustment and well-being for parents who have an infant diagnosed with or at risk of neurodevelopmental disability. The Cochrane Review Group search strategy was followed with search of The Cochrane Central Register of Controlled Trials, PubMed, CINAHL, PsycINFO, and Embase between July and December 2017. Methodological quality of included articles was assessed using the Physiotherapy Evidence Database (PEDro) Scale by two independent reviewers. Twelve studies met the inclusion criteria. A small number of high-quality trials demonstrated moderate to large effectiveness of reducing adverse parent psychological symptoms of trauma and stress. Significant improvements in depression and anxiety symptoms emerged at longer-term (6 months to 8 years) follow-up postinterventions. There is promising support for the effectiveness of some interventions to reduce maladaptive psychological symptoms in parents with infants diagnosed at risk of neurodevelopmental disability. Further quality RCTs of psychological interventions addressing broader neurodevelopmental risk conditions for infants are required.


The Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene contributes to the interindividual variation in serum C-peptide response during an oral glucose tolerance test: evidence from studies of 231 glucose-tolerant first degree relatives of type 2 diabetic probands.
The third form of maturity-onset diabetes of the young is caused by mutations in the hepatocyte nuclear factor-1alpha gene. Recently, we demonstrated an association between a prevalent polymorphism at codon 98, Ala/Val98, of this gene and a 20% decreased insulin release during an oral glucose tolerance test (OGTT) in middle-aged glucose-tolerant Danish Caucasian subjects. The major objective of the present study was to replicate this finding among glucose-tolerant first degree relatives of type 2 diabetic patients of the same ethnic origin. All participants, 231 glucose-tolerant offspring of 62 type 2 diabetic probands, underwent an OGTT with measurements of plasma glucose, serum insulin, and serum C peptide during the test. Thirty-three heterozygous carriers of the Ala/Val variant were identified, whereas no subjects had the variant in its homozygous form. Ala/Val carriers had a 20% reduction in serum C peptide at 30 min during the OGTT (1225+/-636 vs. 1507+/-624 pmol/L; P=0.02) compared to wild-type carriers. No significant differences in serum insulin levels during the OGTT were observed between carriers of the variant and Ala/Ala homozygotes. In conclusion, among Danish glucose-tolerant first degree relatives of type 2 diabetic patients the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene is associated with a decreased serum C-peptide secretion during an OGTT. This finding confirms our previously reported observation of the functional importance of the variant to insulin secretion during an OGTT among middle-aged healthy subjects.


Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa.
Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.


Signalling pathways activated by ultraviolet radiation: role in ocular and cutaneous health.
The eye and the skin are protected by a multi-layered epithelial barrier that provides the first line of defence against invading pathogens and environmental stresses such as damaging solar ultraviolet radiation. Extensive epidemiological findings supported by compelling experimental evidence in culture and animal models suggest that ultraviolet radiation is the most important environmental carcinogen leading to the development of a variety of benign and malignant ocular and cutaneous conditions. Epithelial cells have evolved several key defence mechanisms to prevent ultraviolet radiation-induced DNA mutations from stably entering the genome and ultraviolet radiation-damaged cells from establishing themselves in an otherwise normal microenvironment. Firstly, through the process excision repair, cells have the ability to correct carcinogen-induced DNA damage. Secondly, severely damaged cells are eliminated from healthy tissues by molecular programs that trigger cell death. These processes are activated through complex intracellular signalling circuits that ensure that organs such as the eyes and skin are maintained in a disease-free state. Finally, abnormal cells can be recognized, targeted and destroyed by surveillance from the immune system, however this is complicated further by the immunosuppressive effects of ultraviolet radiation that promote tumour growth. This review will discuss in greater detail some of the processes and pathways that are activated in response to ultraviolet radiation and their effect on ocular and cutaneous health.


miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.
Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both, in sterile and non-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.


Alendronate/vitamin D3 70 mg/2800 IU with and without additional 2800 IU vitamin D3 for osteoporosis: results from the 24-week extension of a 15-week randomized, controlled trial.
Although vitamin D supplementation is a fundamental part of osteoporosis treatment, many patients do not regularly take adequate amounts. A once-weekly (OW) alendronate (ALN) preparation that includes 2800 IU of vitamin D3 in a single combination tablet (ALN+D2800) is available for treating patients and ensuring intake of vitamin D that is consistent with existing guidelines. This randomized, double-blind study extension was conducted to evaluate the safety and tolerability of ALN+D2800 and ALN+D2800 plus an additional 2800 IU vitamin D3 single tablet supplement (ALN+D5600) administered for 24 weeks in men and postmenopausal women with osteoporosis previously treated OW for 15 weeks with either ALN or ALN+D2800. The primary endpoint was the proportion of participants who developed hypercalciuria (defined as a 24-hour urine calcium >300 mg in women or >350 mg in men and an increase of >25% versus randomization baseline) at week 39. The key secondary endpoint was the proportion of participants with vitamin D insufficiency (serum 25(OH)D <15 ng/mL [37.4 nmol/L]) at the end of the study. Hypercalciuria incidence (4.2% [ALN+D5600] vs. 2.8% [ALN+D2800]), did not differ between groups (p = 0.354). No participants developed hypercalcemia. Among the participants with vitamin D insufficiency at the week 0 baseline, the prevalence of insufficiency at the end of the study was reduced by 92% in the ALN+D5600 group and by 86% in the ALN+D2800 group. The incidences of clinical adverse experiences, including drug-related adverse experiences, were similar in both groups. In subjects previously treated with ALN+D2800 for 15 weeks, the addition of 2800 IU D3 for 24 weeks did not produce hypercalcemia nor increase the risk of hypercalciuria.


Clinical analysis of Enterobacter bacteremia in pediatric patients: a 10-year study.
Enterobacter species has emerged as an important pathogen of nosocomial bacteremia. The purpose of this study is to review the clinical characteristics of bacteremia in pediatric patients. We reviewed retrospectively the medical records of patients (under the age of 18 years) having Enterobacter bacteremia who were treated at Taipei the Veterans General Hospital from January 2001 to June 2011. In total, 853 positive blood cultures were obtained from 620 patients during the study period. Among them, 96 episodes of Enterobacter bacteremia were found in 83 patients, accounting for 11.3% of all bacteremia. Eighty-two cases (98.8%) were nosocomial infections. Most of the cases were neonates (62 cases, 74.7%) and premature infants (51 cases, 61.5%). The common sources of bacteremia were the respiratory tract (53.0%), followed by intravascular catheter (10.8%), multiple sources (10.8%), and the gastrointestinal tract (8.4%). The overall case fatality rate was 18.1%, with the highest rate being reported among premature infants. The factors responsible for the deaths were leukocytosis and a higher median number of underlying diseases. Based on the findings of the present study, it can be concluded that Enterobacter species are probably an important pathogen of nosocomial bacteremia in premature neonates. The number of underlying diseases should be considered a major factor influencing the prognosis.


Evaluation of the accuracy of electronic apex locators, cone-beam computed tomography, and radiovisiography in primary teeth: An in vitro study.
Electronic apex locators (EALs), cone-beam computed tomography (CBCT), and radiovisiography (RVG) claim to determine of working length (WL) in primary molar teeth. To evaluate the accuracy of WL determination by using three EALs, RVG, and CBCT imaging in extracted human primary molar teeth with/without root resorption. Twenty extracted primary molar teeth with resorption and 20 extracted primary molar teeth without resorption were used. After measuring actual lengths (AL) (Group 1), the electronic WL measurements were performed by using three different EALs [COXO C Smart-1 Pro (Group 2), iPex (Group 3), and Apex ID (Group 4)]. Two different image sets were obtained as follows: CBCT imaging (Group 5) and RVG (Group 6). AL measurements performed with an endodontic measuring ruler and compared with the EAL, CBCT, and RVG image measurements. For all groups, there were no significant differences between the teeth with resorption and without. There were no significant differences in measuring methods from AL and between the methods used (p > .05). When electronic and radiographic method were compared in different frequency ranges, there was no statistically significant difference (p > .05). This study showed that EALs, CBCT, and RVG have high accuracy in primary molar teeth both with resorption and without root resorption and can be used for determining WL.


The activity of an ancient atypical protein kinase is stimulated by ADP-ribose in vitro.
The piD261/Bud32 protein kinases are universal amongst the members of the Eucarya and Archaea. Despite the fact that phylogenetic analyses indicate that the piD261/Bud32 protein kinases descend directly from the primordial ancestor of the "eukaryotic" protein kinase superfamily, our knowledge of their physiological role is relatively fragmentary and largely limited to two eucaryal representatives: piD261/Bud32 from yeast and the p53-related protein kinase from humans. A deduced archaeal homolog, SsoPK5, is encoded by open reading frame sso0433 from the acidothermophile Sulfolobus solfataricus. Recombinantly-expressed SsoPK5 exhibited protein kinase activity, with a noticeable preference for phosphorylating proteins of acidic character and for Mn(2+) as cofactor. The protein kinase also can phosphorylate itself on serine and threonine residues. The activity of rSsoPK5 was increased several-fold upon preincubation with either millimolar concentrations of 5'-AMP or submicromolar concentrations of ADP-ribose. Other mono- and di-nucleotides were ineffective. While activation was enhanced by the presence of ATP, no autophosphorylation of the protein kinase could be detected prior to addition of exogenous substrate proteins. We therefore suggest that ADP-ribose acts by evoking a conformational transition in the enzyme. Activation by ADP-ribose represents a potential regulatory link between chromatin remodeling and the activity of SsoPK5.


Mixing ecology and epidemiology.
Mixing matrices can be used to describe subgroup interactions in mathematical models which have heterogeneity in population structure. A discussion is presented of two different approaches to the formulation of such mixing matrices. The relation between the two different methods is discussed, using examples based upon models of the transmission dynamics of HIV. There follows a discussion of the application of the mixing matrix approach to other areas in population biology, and a complementary overview of recent advances in theoretical ecology that may have applications in theoretical epidemiology.


Advanced glycation end products stimulate gene expression of fibroblast growth factor 23.
Osteoblasts produce fibroblast growth factor 23 (FGF23), a hormone inhibiting renal phosphate reabsorption and the formation of biologically active vitamin D, calcitriol. FGF23-deficient mice age rapidly and develop age-associated diseases at least in part due to massive calcification. Elevated FGF23 serum levels are detected in patients suffering from acute and chronic renal, cardiovascular, inflammatory, and metabolic diseases. Advanced glycation end products (AGEs) are sugar-modified proteins, nucleic acid, and lipids which contribute to these disorders. Here, we studied the significance of AGEs for the generation of FGF23. As AGE sources, bread crust extract (BCE) and ribose-modified bovine serum albumin (r-BSA) were used. UMR106 osteoblast-like cells were exposed to BCE and r-BSA, and Fgf23 transcripts were determined by qRT-PCR. UMR106 cells express the receptor for AGEs, RAGE. BCE and r-BSA were powerful stimulators of Fgf23 transcription. NFκB inhibitor wogonin and store-operated calcium entry (SOCE) antagonist 2-APB attenuated the r-BSA and BCE effects on FGF23 synthesis. Sources of AGEs induce the transcription of Fgf23 in UMR cells. At least in part, the effect is mediated through up-regulation of NFκB and subsequent SOCE. AGE-induced FGF23 production may contribute to increased FGF23 serum levels observed in chronic disease.


Profound reduction in sedation and analgesic requirements using extended dexmedetomidine infusions in a patient with an open abdomen.
We present a 20-year-old previously healthy male who suffered a gunshot wound to the abdomen and underwent multiple surgeries because of abdominal abscess and fistula formation. Pain control was difficult to achieve despite high-dose opioid therapy. Post-traumatic stress disorder was a confounding factor in treating this patient's pain. Ten months after the original injury, the patient returned to the operating room for an exploratory laparotomy with restoration of bowel continuity and abdominal wall closure. The patient presented to the intensive care unit after a 12-hour operation with an open abdomen and the requirement of mechanical ventilation, sedation, and analgesia. Sedation and analgesia were difficult to achieve and maintain with combinations of extremely high doses of midazolam, lorazepam, propofol, and fentanyl (motor assessment activity scale [MAAS] scores of 5), but profoundly achievable with dexmedetomidine. Dexmedetomidine also improved the patient's mental stability, which resulted in improved patient care through compliance with physicians, nurses, and physical therapists.


Risk factors for developing upper limb cellulitis after breast cancer treatment.
Cellulitis is one of the most important troubling complications of breast cancer treatment. Therefore, elucidating the risk factors for cellulitis in patients that have undergone breast cancer treatment is crucial. This is a retrospective medical record study among 523 patients who had received breast cancer treatment and were referred to the Lymphedema Clinic. Data on age, height, weight, BMI (body mass index), education level, arm dominance, history of previous surgery, axillary lymph node dissection, radiotherapy, and chemotherapy were noted. The time between operation and onset of lymphedema, duration of lymphedema, history of cellulitis, and number of cellulitis attacks were recorded. Circumference measurements were taken at four points on the upper limb. Univariate analysis showed that longer duration of lymphedema, larger circumference of the unaffected arm and larger circumference of the arm with lymphedema were associated with higher risk of cellulitis (p=0.008, p=0.007, p< 0.001, respectively). The incidence of cellulitis was higher in patients with lymphedema than patients who had no lymphedema (p< 0.001). Moreover, the frequency of cellulitis was higher in patients with lower education level (p=0.015). It was deter-mined that patients with cellulitis needed more compression garments (p< 0.001) and multi-layered bandage therapy (p< 0.001) than those without. Regression analysis revealed that presence of lymphedema (p=0.036), duration of lymphedema (p=0.048), radiotherapy (p=0.01) and educational level (0.019) are significantly associated with developing upper extremity cellulitis. It is important to consider these risk factors for the prevention and management of cellulitis in patients who undergo treatment for breast cancer. Early detection and treatment of lymphedema also remains essential for these patients.


The acquisition of full fluoroquinolone resistance in Salmonella Typhi by accumulation of point mutations in the topoisomerase targets.
To determine the contribution to fluoroquinolone resistance of point mutations in the gyrA and parC genes of Salmonella Typhi. Point mutations that result in Ser-83-->Phe, Ser-83-->Tyr and Asp-87-->Asn amino acid substitutions in GyrA and Glu-84-->Lys in ParC were introduced into a quinolone-susceptible, attenuated strain of Salmonella Typhi using suicide vector technology. This is the first time that this approach has been used in Salmonella and abrogates the need for selection with quinolone antibacterials in the investigation of resistance mutations. A panel of mutants was created using this methodology and tested for quinolone resistance. The ParC substitution alone made no difference to quinolone susceptibility. Any single GyrA substitution resulted in resistance to nalidixic acid (MIC >or= 512 mg/L) and increased by up to 23-fold the MIC of the fluoroquinolones ofloxacin (MIC <or= 2 mg/L) ciprofloxacin (MIC <or= 1 mg/L) and gatifloxacin (MIC <or= 0.38 mg/L). Among the double substitution mutants, those with a substitution in ParC were less prone to killing with ciprofloxacin. The triple substitution mutants (Ser-83-->Phe or Tyr and Asp-87-->Asn in GyrA with Glu-84-->Lys in ParC) showed high levels of resistance to all the fluoroquinolones tested (MICs: gatifloxacin, 3-4 mg/L; ofloxacin, 32 mg/L; ciprofloxacin, 32-64 mg/L). In Salmonella Typhi the fluoroquinolones tested act on GyrA and, at higher concentrations, on ParC. The point mutations conferred reduced susceptibility to ofloxacin and ciprofloxacin, and also reduced susceptibility to gatifloxacin. Three mutations conferred resistance to ofloxacin (32 mg/L), ciprofloxacin (32 mg/L) and to the more active fluoroquinolone gatifloxacin (MIC >or= 3 mg/L). These results predict that the use of ofloxacin or ciprofloxacin will select for resistance to gatifloxacin in nature.


Novel Micro-Phenotyping Approach to Chemical Genetic Screening for Increased Plant Tolerance to Abiotic Stress.
Studying the effects of small molecules on root system development in the context of a large-scale chemical genetic screen has previously been a technical challenge. The recent development of novel seedling growth devices ("Phytostrips"), used in combination with standard 96-well microtiter plates, has made it possible to perform detailed studies of changes in root morphology and root system architecture following the application of a library of chemical compounds. Phytostrips were originally designed to allow automated robotic capture of images of roots and shoots of the model species Arabidopsis thaliana, but can also be used for manual screens that are more laborious but do not require the investment in expensive robotics.Here we describe a protocol for the use of Phytostrips to perform chemical genetic screens that rely on clearly observable changes in root morphology or root system architecture. As an example, we describe the use of polyethylene glycol to impose an abiotic stress related to reduced water potential and the application of a chemical screen for small molecules that are able to rescue Arabidopsis root development from the disruptive effect of the polyethylene glycol treatment. The protocol we describe provides a template for the application of a multiplicity of other screens for compounds that can antagonize the effects of a range of abiotic stresses on root development.


The evaluation of a virtual education system based on the DeLone and McLean model: A path analysis.
Background: The Internet has dramatically influenced the introduction of virtual education. Virtual education is a term that involves online education and e-learning. This study was conducted to evaluate a virtual education system based on the DeLone and McLean model. Methods: This descriptive analytical study was conducted using the census method on all the students of the Nursing and Midwifery Department of Alborz University of Medical Sciences who had taken at least one online course in 2016-2017. Data were collected using a researcher-made questionnaire based on the DeLone and McLean model in six domains and then analyzed in SPSS-16 and LISREL-8.8 using the path analysis. Results: The goodness of fit indices (GFI) of the model represent the desirability and good fit of the model, and the rational nature of the adjusted relationships between the variables based on a conceptual model (GFI = 0.98; RMSEA = 0.014).The results showed that system quality has the greatest impact on the net benefits of the system through both direct and indirect paths (β=0.52), service quality through the indirect path (β=0.03) and user satisfaction through the direct path (β=0.73). Conclusions: According to the results, system quality has the greatest overall impact on the net benefits of the system, both directly and indirectly by affecting user satisfaction and the intention to use. System quality should therefore be further emphasized, to use these systems more efficiently.


Does more education cause lower BMI, or do lower-BMI individuals become more educated? Evidence from the National Longitudinal Survey of Youth 1979.
More educated adults have lower average body mass index (BMI). This may be due to selection, if adolescents with lower BMI attain higher levels of education, or it may be due to causation, if higher educational attainment reduces BMI gain in adulthood. We test for selection and causation in the National Longitudinal Survey of Youth 1979, which has followed a representative US cohort from age 14-22 in 1979 through age 47-55 in 2012. Using ordinal logistic regression, we test the selection hypothesis that overweight and obese adolescents were less likely to earn high school diplomas and bachelor's degrees. Then, controlling for selection with individual fixed effects, we estimate the causal effect of degree completion on BMI and obesity status. Among 18-year-old women, but not among men, being overweight or obese predicts lower odds of attaining higher levels of education. At age 47-48, higher education is associated with lower BMI, but 70-90% of the association is due to selection. Net of selection, a bachelor's degree predicts less than a 1 kg reduction in body weight, and a high school credential does not reduce BMI.


CeO2-modified Au@SBA-15 nanocatalysts for liquid-phase selective oxidation of benzyl alcohol.
Tuning the interfacial perimeter and structure is crucial to understanding the origin of catalytic performance. This paper describes the design, characterization, and application of CeO2 modified Au@SBA-15 (Au-CeO2@SBA-15) catalysts in selective oxidation of benzyl alcohol. The reaction results showed that Au-CeO2@SBA-15 catalysts exhibited higher catalytic activity compared with Au@SBA-15 and Au/CeO2 catalysts under identical conditions along with the high selectivity towards benzaldehyde (>99%). The turnover frequency of benzyl alcohol over the Au-100CeO2@SBA-15 catalyst is about nine-fold and four-fold higher than those of Au@SBA-15 and Au/CeO2 catalysts, respectively. The supported catalysts were characterized by N2 adsorption-desorption, inductively coupled plasma optical emission spectroscopy, X-ray diffraction, transmission electron microscopy, high-angle annular dark-field scanning transmission electron microscopy, scanning transmission electron microscopy-energy dispersive spectrometry, and X-ray photoelectron spectroscopy. It was found that the Au and small CeO2 nanoparticles (∼5 nm) were homogeneously mixed in the channels of SBA-15, which led to an increase in the interfacial area between Au and CeO2 and consequently a better catalytic performance of Au-CeO2@SBA-15 catalysts for the selective oxidation of benzyl alcohol to benzaldehyde compared with that of Au/CeO2. The prevention of agglomeration and leaching of Au nanoparticles by restricting them inside the mesopores of SBA-15 was conducive to the stable existence of large quantities of Au-CeO2 interface, which leads to high stability of the Au-CeO2@SBA-15 catalyst.


Early Invasive Versus Ischemia-Guided Strategy in Non-ST-Segment Elevation Acute Coronary Syndrome With Chronic Obstructive Pulmonary Disease: A National Inpatient Sample Analysis.
Chronic obstructive pulmonary disease (COPD) is a risk factor for non-ST-segment elevation-acute coronary syndromes (NSTE-ACS). Whether early invasive strategy (EIS) or ischemia-guided strategy (IGS) confers better outcomes in NSTE-ACS with COPD is largely unknown. Nationwide Inpatient Sample database of the United States was queried from 2010 to 2015 to identify NSTE-ACS with and without COPD. Early invasive strategy was defined as coronary angiogram with or without revascularization on admission day 0 or 1, whereas IGS included patients who did not receive EIS. Standardized morbidity ratio weight was used to calculate the adjusted odds ratio. A total of 228 175 NSTE-ACS admissions with COPD were identified of which 34.0% received EIS. In-hospital mortality was lower with EIS in patients with COPD (3.1% vs 5.5%, adjusted odds ratio 0.57, 95% confidence interval 0.50-0.63) compared to IGS, but the magnitude of mortality reduction observed in EIS in patients with COPD was less compared to non-COPD patients (P interaction = .02). Length of stay was shorter (4.2 vs 4.7 days, P < .0001) but the cost was higher (US$23 804 vs US$18 533, P < .0001) in EIS in COPD. Early invasive strategy resulted in lower in-hospital mortality and marginally shorter length of stay but higher hospitalization cost in NSTE-ACS with COPD.


Quality of ethnicity data within Scottish health records and implications of misclassification for ethnic inequalities in severe COVID-19: a national linked data study.
We compared the quality of ethnicity coding within the Public Health Scotland Ethnicity Look-up (PHS-EL) dataset, and other National Health Service datasets, with the 2011 Scottish Census. Measures of quality included the level of missingness and misclassification. We examined the impact of misclassification using Cox proportional hazards to compare the risk of severe coronavirus disease (COVID-19) (hospitalization & death) by ethnic group. Misclassification within PHS-EL was higher for all minority ethnic groups [12.5 to 69.1%] compared with the White Scottish majority [5.1%] and highest in the White Gypsy/Traveller group [69.1%]. Missingness in PHS-EL was highest among the White Other British group [39%] and lowest among the Pakistani group [17%]. PHS-EL data often underestimated severe COVID-19 risk compared with Census data. e.g. in the White Gypsy/Traveller group the Hazard Ratio (HR) was 1.68 [95% Confidence Intervals (CI): 1.03, 2.74] compared with the White Scottish majority using Census ethnicity data and 0.73 [95% CI: 0.10, 5.15] using PHS-EL data; and HR was 2.03 [95% CI: 1.20, 3.44] in the Census for the Bangladeshi group versus 1.45 [95% CI: 0.75, 2.78] in PHS-EL. Poor quality ethnicity coding in health records can bias estimates, thereby threatening monitoring and understanding ethnic inequalities in health.


Validation of dynamic 3-dimensional whole heart magnetic resonance myocardial perfusion imaging against fractional flow reserve for the detection of significant coronary artery disease.
The goal of this study was to determine the diagnostic accuracy of dynamic 3-dimensional (3D) whole heart myocardial perfusion cardiovascular magnetic resonance (CMR) against invasively determined fractional flow reserve (FFR) and to establish the correlation between myocardium at risk defined by using the invasive Duke Jeopardy Score (DJS) and noninvasive 3D whole heart myocardial perfusion CMR. 3D whole heart myocardial perfusion CMR overcomes the limited spatial coverage of conventional two-dimensional perfusion CMR methods and allows estimation of the extent of ischemia. The method has shown good diagnostic accuracy for the detection of coronary artery disease (CAD) as defined by using quantitative coronary angiography. However, quantitative coronary angiography does not provide a functional assessment of CAD as available from pressure wire-derived FFR. In the catheter laboratory, the DJS can complement FFR to estimate the myocardium at risk. Fifty-three patients referred for angiography underwent rest and adenosine stress 3D whole heart myocardial perfusion CMR at 3-T. Perfusion was scored visually on a patient and coronary territory basis, and ischemic burden was calculated by quantitative segmentation of the volume of hypoenhancement. FFR was measured in vessels with ≥50% severity stenosis and an FFR <0.75 considered as hemodynamically significant. The DJS was calculated from the coronary angiograms to quantify the myocardium at risk. FFR was measured in 64 of 159 coronary vessels, and 39 had an FFR <0.75. Sensitivity, specificity, and diagnostic accuracy of CMR for the detection of significant CAD were 91%, 90%, and 91%, on a patient basis and 79%, 92%, and 88%, respectively, by coronary territory. There was a strong correlation between the DJS and ischemic burden on CMR (p < 0.0001; Pearson's r = 0.82). 3D whole heart myocardial perfusion CMR accurately detects functionally significant CAD as defined by using FFR and provides an assessment of ischemic burden in agreement with the invasive DJS. The accurate detection of significant CAD combined with an estimation of ischemic burden by using 3D myocardial perfusion CMR holds promise for noninvasive guidance of therapy and risk stratification of patients with CAD.


Activity Based Anorexia as an Animal Model for Anorexia Nervosa-A Systematic Review.
Anorexia nervosa (AN) is a severe eating disorder affecting around 1 per 100 persons. However, the knowledge about its underlying pathophysiology is limited. To address the need for a better understanding of AN, an animal model was established early on in the late 1960's: the activity-based anorexia (ABA) model in which rats have access to a running wheel combined with restricted food access leading to self-starving/body weight loss and hyperactivity. Both symptoms, separately or combined, can also be found in patients with AN. The aim of this systematic review was to compile the current knowledge about this animal model as well as to address gaps in knowledge. Using the data bases of PubMed, Embase and Web of science 102 publications were identified meeting the search criteria. Here, we show that the ABA model mimics core features of human AN and has been characterized with regards to brain alterations, hormonal changes as well as adaptations of the immune system. Moreover, pharmacological interventions in ABA animals and new developments, such as a chronic adaptation of the ABA model, will be highlighted. The chronic model might be well suited to display AN characteristics but should be further characterized. Lastly, limitations of the model will be discussed.


Interatomic Coulombic Decay: The Mechanism for Rapid Deexcitation of Hollow Atoms.
The impact of a highly charged ion onto a solid gives rise to charge exchange between the ion and target atoms, so that a slow ion gets neutralized in the vicinity of the surface. Using highly charged Ar and Xe ions and the surface-only material graphene as a target, we show that the neutralization and deexcitation of the ions proceeds on a sub-10 fs time scale. We further demonstrate that a multiple Interatomic Coulombic Decay (ICD) model can describe the observed ultrafast deexcitation. Other deexcitation mechanisms involving nonradiative decay and quasimolecular orbital formation during the impact are not important, as follows from the comparison of our experimental data with the results of first-principles calculations. Our method also enables the estimation of ICD rates directly.


The Distribution of &mgr; and delta Opioid Binding Sites Belonging to a Single Cervical Dorsal Root in the Superficial Dorsal Horn of the Rat Spinal Cord: A Quantitative Autoradiographic Study.
Numerous studies have demonstrated a dense concentration of opioid receptors in the superficial layers (laminae I - II) of the spinal cord. These receptors are located both pre- and postsynaptically at this level. The purpose of this study was to assess the distribution of opioid receptors belonging to a single (C7) dorsal root. Thus, quantitative autoradiography of &mgr; ([3H]Tyr-d-Ala-Gly-NMe-Phe-Gly-ol; [3H]DAMGO) and delta ([3H]Tyr-d-Thr-Gly-Phe-Leu-Thr; [3H]DTLET) opioid binding sites was performed for several experimental groups: control rats with intact dorsal roots and lesioned rats with a unilateral dorsal rhizotomy of (a) the C7 root alone, (b) the three successive roots rostral and caudal to the spared C7 root, and (c) the seven roots C4 - Th2. By subtracting results of the 'C7 cut' group from the 'intact' group or by subtracting results of the C4 - Th2 cut group from the C7 spaced group, it was possible to measure the distribution of &mgr; and delta opioid binding sites belonging to the C7 root. The combination of these two methods of calculation allowed us to demonstrate a significant distribution over two segments rostral and one segment caudal to the segment of entry. For [3H]DAMGO, the distribution was 10% (P < 0.05) in the C5, 27%, (P < 0.001) in the C6, 38% (P < 0.001) in the C7 and 14% (P < 0.05) in the C8 segment. For [3H]DTLET, the distribution was 11% (P=0.05) in the C5, 27%, (P < 0.01) in the C6, 37% (P < 0.001) in the C7 and 18% (P < 0.05) in the C8 segment. It is also noted that rostral distributions spread more densely and further than the caudal ones.